How the chemical features of molecules may have addressed the settlement of metabolic steps

Introduction: While the evolutionary adaptation of enzymes to their own substrates is a well assessed and rationalized field, how molecules have been originally selected in order to initiate and assemble convenient metabolic pathways is a fascinating, but still debated argument. Objectives: Aim of the present study is to give a rationale for the preferential selection of specific molecules to generate metabolic pathways. Methods: The comparison of structural features of molecules, through an inductive methodological approach, offer a reading key to cautiously propose a determining factor for their metabolic recruitment. Results: Starting with some commonplaces occurring in the structural representation of relevant carbohydrates, such as glucose, fructose and ribose, arguments are presented in associating stable structural determinants of these molecules and their peculiar occurrence in metabolic pathways. Conclusions: Among other possible factors, the reliability of the structural asset of a molecule may be relevant or its selection among structurally and, a priori, functionally similar molecules

Thiol oxidase ability of copper ion is specifically retained upon chelation by aldose reductase

Bovine lens aldose reductase is susceptible to a copper-mediated oxidation, leading to the generation of a disulfide bridge with the concomitant incorporation of two equivalents of the metal and inactivation of the enzyme. The metal complexed by the protein remains redox active, being able to catalyse the oxidation of different physiological thiol compounds. The thiol oxidase activity displayed by the enzymatic form carrying one equivalent of copper ion (Cu1-AR) has been characterized. The efficacy of Cu1-AR in catalysing thiol oxidation is essentially comparable to the free copper in terms of both thiol concentration and pH effect. On the contrary, the two catalysts are differently affected by temperature. The specificity of the AR-bound copper towards thiols is highlighted with Cu1-AR being completely ineffective in promoting the oxidation of both low-density lipoprotein and ascorbic acid

Ipocorticosurrenalismo secondario: come valutare il compenso? Differenze con la forma primaria?

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Terapia sostitutiva corticosteroidea alla luce delle nuove proposte farmacologiche (Plenadren

SommarioLa terapia sostitutiva corticosteroidea è indispensabile per la sopravvivenza dei pazienti con insufficienza surrenalica. Per oltre cinquant'anni sono stati impiegati steroidi a breve emivita e solo negli ultimi vent'anni sono state proposte nuove formulazioni derivate dall'idrocortisone, nate con l'obiettivo di migliorare gli effetti delle terapie convenzionali. In particolare, è stata prodotta una formulazione di idrocortisone a rilascio modificato in due fasi (DR-HC, Plenadren®). In questa rassegna si descriveranno le caratteristiche e gli effetti di tale formulazione

Apparent cooperativity and apparent hyperbolic behavior of enzyme mixtures acting on the same substrate

It is well known that a negative cooperative behavior displayed by a monomeric enzyme may be associated with the simultaneous presence of two enzymes acting on the same substrate. In this paper, emphasis is given to the effect exerted by a rapid equilibrium between the enzyme forms in leading to a hyperbolic behavior, thus masking the presence of multiple enzyme forms

Cysteinyl-glycine in the control of glutathione homeostasis in bovine lenses

PURPOSE: To define a possible metabolic and/or signaling role for Cys-Gly in glutathione homeostasis in bovine eye lenses. METHODS: Bovine lenses were cultured up to 24 h in a medium containing 0.5 mM reduced glutathione (GSH) under different conditions. The intracellular and the extracellular contents of thiol compounds were evaluated using a free zone capillary electrophoresis method. RESULTS: Culture of lenses in the presence of GSH and the gamma-glutamyl transferase inhibitor serine-borate demonstrated a 1.5 fold increase in the level of extra-lenticular glutathione with respect to the initial value. Cys-Gly exogenously added impaired the extra-lenticular accumulation of glutathione. Both cysteine and gamma-Glu-Cys were ineffective in reducing extra-lenticular glutathione accumulation. In all conditions no differences in reduced and total intra-lenticular glutathione levels were observed. CONCLUSIONS: The impairment of Cys-Gly generation correlated with inhibition of gamma-glutamyl transferase by serine/borate, resulting in high extra-lenticular concentration of glutathione effluxed from the bovine lens. The possibility that Cys-Gly may intervene either in the replenishment processes for cysteine in the GSH biosynthetic step or in the function of the efflux GSH-transporters is considered

Resolution of tongue lesions caused by Leishmania infantum in a dog treated with the association miltefosine-allopurinol

Canine leishmaniosis is a severe systemic disease caused by the kinetoplastid protozoan Leishmania infantum, an obligatory intracellular parasite of mammalian macrophages, transmitted by the bite of phlebotomine sandflies. The infection in dogs might occur without any clinical signs or might be characterised by chronic viscerocutaneous signs, such as lymphadenopathy, skin lesions, splenomegaly, onychogryphosis, and renal as well as ocular damage due to immunocomplex deposition. In atypical cases the parasites can be found in the striated musculature, the central nervous system, the endocrine glands or gonads, with or without functional damage. Leishmania infection might seldom induce oral lesions, particularly on the tongue. The authors describe the clinical case of a four-year old mongrel dog with tongue lesions caused by L. infantum. The dog was presented due to diarrhoea, lack of appetite and hypersalivation. Examination of the oral cavity revealed the presence of multiple red, nodular lesions on the dorsal and lateral surfaces of the tongue. Definite diagnosis of an infection with L. infantum was obtained by an indirect immunofluorescence antibody test (IFAT) and by the cytological identification of the parasite in nodular, lingual lesions and bone marrow aspirates. The dog was treated with a combination of miltefosine (Milteforan®, Virbac), 2 mg/kg orally once a day for four weeks and allopurinol (Ziloric®, GlaxoSmithKline), 10 mg/kg orally twice a day for six months. At the end of the treatment, the animal showed full remission of clinical signs. The authors outline the atypical manifestations in the oral cavity in combination with a L. infantum infection and discuss the therapeutic potential of the combination treatment of miltefosine and allopurinol in canine leishmaniosis

Edible vegetables as a source of aldose reductase differential inhibitors

The hyperactivity of aldose reductase (AR) on glucose in diabetic conditions or on glutathionyl-hydroxynonenal in oxidative stress conditions, the source of cell damage and inflammation, appear to be balanced by the detoxifying action exerted by the enzyme. This detoxification acts on cytotoxic hydrophobic aldehydes deriving from membrane peroxidative processes. This may contribute to the failure in drug development for humans to favorably intervene in diabetic complications and inflammation, despite the specificity and high efficiency of several available aldose reductase inhibitors. This paper presents additional features to a previously proposed approach, on inhibiting the enzyme through molecules able to preferentially inhibit the enzyme depending on the substrate the enzyme is working on. These differential inhibitors (ARDIs) should act on glucose reduction catalyzed by AR without little or no effect on the reduction of alkenals or alkanals. The reasons why AR may be an eligible enzyme for differential inhibition are considered. These mainly refer to the evidence that, although AR is an unspecific enzyme that recognizes different substrates such as aldoses and hydrophobic aldehydes, it nevertheless displays a certain degree of specificity among substrates of the same class. After screening on edible vegetables, indications of the presence of molecules potentially acting as ARDIs are reported

Modulation of aldose reductase activity by aldose hemiacetals

Glucose is considered as one of the main sources of cell damage related to aldose reductase (AR) action in hyperglycemic conditions and a worldwide effort is posed in searching for specific inhibitors of the enzyme. This AR substrate has often been reported as generating non-hyperbolic kinetics, mimicking a negative cooperative behavior. This feature was explained by the simultaneous action of two enzyme forms acting on the same substrate

The use of dimethylsulfoxide as a solvent in enzyme inhibition studies: the case of aldose reductase

Aldose reductase (AR) is an enzyme devoted to cell detoxification and at the same time is strongly involved in the aetiology of secondary diabetic complications and the amplification of inflammatory phenomena. AR is subjected to intense inhibition studies and dimethyl sulfoxide (DMSO) is often present in the assay mixture to keep the inhibitors in solution. DMSO was revealed to act as a weak but well detectable AR differential inhibitor, acting as a competitive inhibitor of the L-idose reduction, as a mixed type of non-competitive inhibitor of HNE reduction and being inactive towards 3-glutathionyl-4-hydroxynonanal transformation. A kinetic model of DMSO action with respect to differently acting inhibitors was analysed. Three AR inhibitors, namely the flavonoids neohesperidin dihydrochalcone, rutin and phloretin, were used to evaluate the effects of DMSO on the inhibition studies on the reduction of L-idose and HNE