Psychological Stress and Cancer: New Evidence of An Increasingly Strong Link.

To date stress, a highly complex process that disrupts homeostasis and involves environmental and psychosocial factors, is considered as one of the most crucial factor that affects our daily life, especially urban dweller's life. Clinical and experimental studies widely support the notion that adrenergic stimulation due to chronic stress affects inflammation and metabolism. In this work, supported by several recent scientific evidences, we show how stress plays a positive role in cancer initiation, progression and cancer metastasis, a negative role for anti-tumor immune function and therapy response. Understanding the intricacies of this interaction could provide an additional help on how act in cancer prevention and therapy.

Reaction of nitric oxide at the beta-carbon of enamines. A new method of preparing compounds containing the diazeniumdiolate functional group.

The reaction of nitric oxide (NO) with enamines has been investigated. Unlike previously reported reactions of NO as a free radical with alkenes, the electrophilic addition of NO to the beta-carbon of enamines results in the formation of compounds containing the diazeniumdiolate functional group (-[N(O)NO](-)). This reaction between NO and enamines has been shown to be quite general and a variety of enamine-derived diazeniumdiolates have been isolated and characterized. While enamines derived from aldehydes and ketones whose structures allow for sequential multiple electrophilic additions tended to undergo overreaction leading to unstable products, it has been shown that this complication may be overcome by suitable choice of reaction solvent. The products obtained may exist as zwitterionic iminium salts or as neutral species depending upon the structure of the parent enamine. The diazeniumdiolate derived from 1-(N-morpholino)cyclohexene is unique among the new compounds in that it spontaneously releases NO upon dissolution in buffered aqueous solution at pH 7.4 and 37 degrees C. While the total quantity of NO released by this material (ca. 7% of the theoretical 2 moles) is apparently limited by a competing reaction in which it hydrolyzes to an alpha-diazeniumdiolated carbonyl compound and the parent amine, this feature may prove to be of great value in the development of multiaction pharmaceuticals based upon this new type of NO-releasing compound. Reports of enzymatic (oxidative) release of NO from previously known carbon-bound diazeniumdiolates also suggest that analogues of these compounds may be useful as pharmaceutical agents. This new method of introducing the relatively rarely studied diazeniumdiolate functional group into organic compounds should lead to further research into its chemical and biological properties.

Conversion of a polysaccharide to nitric oxide-releasing form. Dual-mechanism anticoagulant activity of diazeniumdiolated heparin.

We describe heparin/diazeniumdiolate conjugates that generate nitric oxide (NO) at physiological pH. Like the heparin from which they were prepared, they inhibit thrombin-induced blood coagulation. Unlike heparin, they can also inhibit and reverse ADP-induced platelet aggregation (as expected for an NO-releasing agent), suggesting potential utility as dual-action antithrombotics.

Esterase-sensitive nitric oxide donors of the diazeniumdiolate family: in vitro antileukemic activity.

We have designed a novel prodrug class that is stable in neutral aqueous media but releases bioactive nitric oxide (NO) on metabolism by esterase. Diazeniumdiolates of structure R(2)N-N(O)=N-OR', in which R' = Na, were reacted with BrCH(2)OAc to convert the spontaneously NO-releasing salts 1a (R(2)N = diethylamino) and 1b (R(2)N = pyrrolidino) to prodrugs 2a (AcOM-DEA/NO) and 2b (AcOM-PYRRO/NO), respectively, where R' = CH(2)OAc. In contrast to anions 1a and 1b (half-lives in pH 7.4 phosphate at 37 degrees C of 2 min and 3 s, respectively), 2a and 2b showed only minimal decomposition after 16 h under these conditions. Very rapid hydrolysis occurred in the presence of porcine liver esterase, however, with free anion 1a being observed as an intermediate in the esterase-induced generation of NO from 2a. The potential utility of this prodrug class is illustrated with a comparison of 1 and 2 as antiproliferative agents in NO-sensitive human leukemia cell lines HL-60 and U937. While the 72-h IC(50)'s for 1a and 1b (which generate NO throughout the medium) in HL-60 cell cultures were >600 microM, those of 2a and 2b were 8.3 and 6.4 microM, respectively. This result is consistent with our hypothesis that 2 is selectively hydrolyzed to 1 and thence to NO intracellularly. For U937 cells, the 72-h IC(50) for both 2a and 2b was 53 microM. By contrast, relatively high antiproliferative IC(50)'s (>100 microM in U937 cells) were observed for analogues in which R' = CH(2)CH(2)SC(O)Me, from which acetyl and 2-mercaptoethyl groups must be successively cleaved to free the NO-releasing diazeniumdiolate function. Within 24 h at initial concentrations of 50 microM, 2a and 2b induced apoptosis in 50% and 57% of the HL-60 cells, respectively (35% and 40% of the U937 cells, respectively). The data reveal significant in vitro antileukemic activity on the part of these novel compounds. Moreover, their substantial ease-of-handling advantages over the anionic diazeniumdiolates from which they are derived suggest their use as convenient agents for probing the biological roles of NO.

Nitric oxide-releasing polymers containing the [N(O)NO]- group.

Ions of structure X[N(O)NO]- display broad-spectrum pharmacological activity that correlates with the rate and extent of their spontaneous, first-order decomposition to nitric oxide when dissolved. We report incorporation of this functional group into polymeric matrices that can be used for altering the time course of nitric oxide release and/or targeting it to tissues with which the polymers are in physical contact. Structural types prepared include those in which the [N(O)NO]- group is attached to heteroatoms in low molecular weight species that are noncovalently distributed throughout the polymeric matrix, in groupings pendant to the polymer backbone, and in the polymer backbone itself. They range in physical form from films that can be coated onto other surfaces to microspheres, gels, powders, and moldable resins. Chemiluminescence measurements confirm that polymers to which the [N(O)NO]- group is attached can serve as localized sources of nitric oxide, with one prototype providing sustained NO release for 5 weeks in pH 7.4 buffer at 37 degrees C. The latter composition, a cross-linked poly-(ethylenimine) that had been exposed to NO, inhibited the in vitro proliferation of rat aorta smooth muscle cells when added as a powder to the culture medium and showed potent antiplatelet activity when coated on a normally thrombogenic vascular graft situated in an arteriovenous shunt in a baboon's circulatory system. The results suggest that polymers containing the [N(O)NO]- functional group may hold considerable promise for a variety of biomedical applications in which local delivery of NO is desired.

[The HLA system and insulin-dependent diabetes mellitus. A review and personal studies]. / Sistema HLA e diabete insulina-dipendente. Rassegna e indagini personali.

Present knowledge regarding the HLA system and the association between HLA antigens and insulin-dependent type 1 diabetes mellitus (IDDM) is reviewed. The heterogeneity of diabetes, immunogenetically speaking, is emphasized. Results are reported for HLA typing in 18 cases of known IDDM recently diagnosed and observed at the Karen Bruni Diabetes Center in approximately one year (1981-82). The frequency of HLA antigens B7, B8 (in linkage disequilibrium with DR3), B15 (in linkage disequilibrium with DR4) and B18 was examined in comparison with a Piemontese control group. The X2 method was used for calculating the relative risk and statistic importance of the intensity of association. IDDM susceptibility in association with HLA-B18 was confirmed and resulted significantly higher in our cases in respect to controls. Correlations without, however, reliable importance, have also been found between HLA-B8 and B15. IDDM protection by HLA-B7 was not confirmed. Diabetes began during the winter, from October to February, in 10 out of 18 cases, and some were positively related to a previous respiratory viral infection. Previous virus infection was found in three B7-positive cases. The more frequent arousal of diabetic symptoms during the winter in subjects positive for HLA-B8 and B18 was confirmed in 7 out of 8 cases. This work demonstrates the current practicability of HLA typing of recently diagnosed insulin-dependent diabetic in a Diabetes Center. This element helps to a more correct classification--on a subclinical basis--of initial cases of type 1 and 2 diabetes and can be used for possible problems during the course of insulin therapy.