Cyclo(His-Pro) up-regulates heme oxygenase 1 via activation of Nrf2-ARE signalling

Paraquat (1,1'-dimethyl-4,4'-bipyridinium), a widely used non-selective herbicide, is a redox cycling agent with adverse effects on dopamine systems. Epidemiological data have shown that exposure to paraquat is one of the several risk factors for Parkinson's disease. We have already shown that cyclo(His-Pro), an endogenous cyclic dipeptide produced by the cleavage of the thyrotropin releasing hormone, has a cytoprotective effect through a mechanism involving Nrf2 activation that decreases production of reactive oxygen species and increases glutathione synthesis. Using primary neuronal cultures and PC12 cells as targets of paraquat neurotoxicity, we addressed whether and how cyclo(His-Pro) causes cellular protective response against paraquat-mediated cell death. We found that cyclo(His-Pro) attenuated reactive oxygen species production, and prevented glutathione depletion by up-regulating Nrf2 gene expression, triggering its nuclear accumulation and activating the expression of heme oxygenase1. These protective effects were abolished by RNA interference-mediated Nrf2 knock down whereas were unaffected by RNA interference-mediated Keap1 knock down. Inhibition of heme oxygenase activity decreased cyclo(His-Pro)-induced neuroprotection. These results suggest that cyclo(His-Pro), acting as a selective activator of the brain modulable Nrf2 pathway, may be a promising candidate as neuroprotective agent that act through induction of phase II genes.     

The report of an Italian family with heterozygous protein C deficiency

A heterozygote protein C deficit was found in 4 members of the same family. The propositus is a 40 year old male with a clear thrombotic tendency. This included repeated thrombophlebitis of the right leg, and one episode of pulmonary embolism. Arterial thrombosis was not noted. The anticoagulant therapy undertaken by the patient appears to be of some benefit in the sense that no recurrence of thrombotic manifestations occurred. One brother and two nephews of the propositus, even though asymptomatic showed reduced levels of Protein C both as activity and antigen. The parallel reduction of Protein C activity and antigen points towards a "true" deficit of Protein C. The normal, although reduced, pattern in the crossed immunoelectrophoresis supplies further confirmation to this interpretation.     

The nitrite reductase gene of Pseudomonas aeruginosa: Effect of growth conditions on the expression and construction of a mutant by gene disruption

Abstract The expression of nitrite reductase has been tested in a wild-type strain of Pseudomonas aeruginosa (Pao1) as a function of nitrate concentration under anaerobic and aerobic conditions. Very low levels of basal expression are shown under non-denitrifying conditions (i.e. absence of nitrate, in both aerobic and anaerobic conditions); anaerobiosis is not required for high levels of enzyme production in the presence of nitrate. A Pseudomonas aeruginosa strain, mutated in the nitrite reductase gene, has been obtained by gene replacement. This mutant, the first of this species described up to now, is unable to grow under anaerobic conditions in the presence of nitrate. The anaerobic growth can be restored by complementation with the wild-type gene.     

Evidence against the presence of "inhibitors" in coumarin treated patients.

Coumarin drugs or vitamin K absence cause a decrease of factor II, VII, IX and X activities and the appearance of pre-factors into the circulation. Such pre-factors have been postulated to inhibit thrombin conversion. The current of research on the alleged activity of such "inhibitors" is taken into consideration. Thrombotest discrepancy, mixing experiments etc.) speak against the inhibitor theory. So far the only sure demonstration of the presence of coumarin induced pre-factors has been obtained by immunological means. However, this does not say anything about their biological activity. These pre-factors could well be "inert" as far as clotting is concerned. Until new, unequivocal data on the subject will be available, any method or technique claiming to be able to detect or monitor the "inhibitory" effect should be accepted with extreme caution. Too many unjustified views have been put forward in recent years.     

Ovipositional deterrents in Dacus oleae

The deterrent substances diverting D. oleae females from ovipositing on already attacked olives are contained, at least partly, in the juice which trickles from the oviposition wounds. Surprisingly, the water fraction of the olive juice had limited deterrent activity. The principal deterrent stimuli are present in the oil fraction. Acetophenone and benzaldehyde are likely to be involved.Some liposoluble volatile substances can be deterrent to the females as vapours. The deterrent power of olives containing D. oleae larvae is probably linked to these substances.Most deterrent hydro-soluble substances had two contiguous hydroxyls, characterized by a comparative acidity and located in the ortho position in diphenols and somewhat analogously in glycolic acid.Amongst orthodiphenols, Pyrocatechol-the simplest compound-was the most active substance.

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Résumé Les jus d'olive qui sourt des blessures dues à la ponte, contient des substances inhibitrices qui empêchent les attaques ultérieures de la mouche de l'olivier.Une telle activité était attribuée à des substances hydrosolubles et, en particuliet, au dihydroxyphenil ethanol.On a testé l'activité inhibitrice des fractions huileuse et acqueuse obtenues par centrifugation de la pulpe des olives, rendue homogène.De facon inattendue, la fraction huileuse s'estavérée posséder une activité inhibitrice environ 20 fois supérieure à celle de la fraction acqueuse.Les différences d'activités inhibitrices d'huile d'olives mûres ou non, ou d'huiles commerciales, permet de penser que l'activité inhibitrice principale est liée à des substances liposolubles présentes dans l'huile.En outre, on a constaté que la pulpe d'olives, broyée, présente une action inhibitrice en l'absence de contact direct avec les femelles. Des substances inhibitrices volatiles sont aussi présentes dans l'huile.Des inhibiteurs volatiles qui se libèrent des tissus lacérés par les larves, peuvent expliquer l'activité inhibitrice des olives attaquées durant la période de développement des larves. Les substances inhibitrices dont la femelle couvre la surface cireuse des fruits, sont, en effet, facilement éliminées par la pluie.Parmi les substances liposolubles dont on connaît la présence dans l'huile, l'aceto-phénone et le benzaldehyde, possèdent un pouvoir inhibiteur prononcé.Les substances hydrolsolubles jouent un rôle mineur dans l'ensemble des stimuli inhibiteurs. Le pouvoir inhibiteur relatif est lié à deux hydroxyles contigus à une fonction acide présente en position ortho dans les diphénols, ceci par analogie avec l'acide glycolique qui possède un hydroxyle en caractérisé par une certaine acidité.Le plus actif orthodiphénol s'est avéré être la pyrocatéchine. Aussi une part des inhibiteurs liposolubles sont des substances liées au biochimisme des phénols.

     

Behaviour of antithrombin III abnormalities in the crossed immunoelectrophoresis system

Antithrombin III (AT III) abnormalities can be characterized by means of crossed immunoelectrophoresis. In the past, it was thought that the abnormalities could be demonstrated only if heparin is present in the system. Now some conditions (AT III Trento, for example) are known to show an abnormal pattern only in the absence of heparin. This indicates that some of the changes are heparin-independent. Furthermore, it could be demonstrated that in some cases the abnormality is present only in serum (AT III Vicenza, for example). Therefore, the test should be carried out as a screening procedure both in plasma and serum and in the presence or absence of heparin in every case of suspected AT III abnormality.     

Platelet adhesiveness and aggregation in combined factor V and factor VIII deficiency and in combined factor VII and factor VIII deficiency.

Platelet aggregation and adhesiveness were studied in 3 patients with combined factor V and factor VIII deficiency and in 3 patients with combined factor VII and factor VIII deficiency. The first three patients belonged to three different kindreds whereas the second group belonged to the same kindred. Serotonin C14 uptake and release was also found to be normal in these patients. These studies indicate that platelet function is normal in combined defects of factor VIII. These findings were in agreement with the presence of a normal bleeding time and a normal factor VIII antigen level in all these patients.     

Uniparental isodisomy of chromosome 2 causing MRPL44-related multisystem mitochondrial disease

Mutations in nuclear-encoded protein subunits of the mitochondrial ribosome are an increasingly recognised cause of oxidative phosphorylation system (OXPHOS) disorders. Among them, mutations in the MRPL44 gene, encoding a structural protein of the large subunit of the mitochondrial ribosome, have been identified in four patients with OXPHOS defects and early-onset hypertrophic cardiomyopathy with or without additional clinical features. A 23-year-old individual with cardiac and skeletal myopathy, neurological involvement, and combined deficiency of OXPHOS complexes in skeletal muscle was clinically and genetically investigated. Analysis of whole-exome sequencing data revealed a homozygous mutation in MRPL44 (c.467 T?>?G), which was not present in the biological father, and a region of homozygosity involving most of chromosome 2, raising the possibility of uniparental disomy. Short-tandem repeat and genome-wide SNP microarray analyses of the family trio confirmed complete maternal uniparental isodisomy of chromosome 2. Mitochondrial ribosome assembly and mitochondrial translation were assessed in patient derived-fibroblasts. These studies confirmed that c.467 T?>?G affects the stability or assembly of the large subunit of the mitochondrial ribosome, leading to impaired mitochondrial protein synthesis and decreased levels of multiple OXPHOS components. This study provides evidence of complete maternal uniparental isodisomy of chromosome 2 in a patient with MRPL44-related disease, and confirms that MRLP44 mutations cause a mitochondrial translation defect that may present as a multisystem disorder with neurological involvement.