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Biomedical subjects

B Silvestrini

Publications and source records attributed to B Silvestrini.

At least 19 recordsLinked to original sources
PubMed1992

Abnormal glycosylation of hemopexin in arthritic rats can be blocked by bindarit.

Induction of arthritis in rats with Freund's complete adjuvant was accompanied by a distinctive alteration of concanavalin A (Con-A) reactivity in their serum proteins in which the concentrations of selected Con-A reactive proteins were significantly higher when compared to healthy rats. To assess if the observed increase in Con-A reactivity of specific serum proteins reflects an increase in carbohydrate moieties in these proteins in addition to an increase in their protein concentrations, a heme binding serum glycoprotein, hemopexin, also an acute phase reactant, was selected as a marker protein. Hemopexin was purified to apparent homogeneity from pools of serum samples derived from rats with yeast induced inflammation, a monospecific polyclonal antibody was prepared and was used for immunoblot analysis. It was noted that the concentration of hemopexin increased in rats with adjuvant induced arthritis; however, its concentration fell to normal levels after administration with a newly synthesized drug, bindarit, (2-[(1-benzyl-indazol-3-yl)methoxy]-2-methyl propionic acid, C19H20N2O3. Hemopexin was micropurified individually from healthy rats, adjuvant induced arthritic rats, and adjuvant arthritic rats treated with bindarit, cleaved with a Glu-C endopeptidase, Staphylococcus aureus protease V8, and the resultant peptide fragments resolved by SDS-PAGE and examined by silver staining, Coomassie blue staining, and lectin blots using Con-A. It was subsequently noted that hemopexin isolated from adjuvant induced arthritic rats showed a significant increase in Con-A reactivity in selected peptide fragments and that such an increase in glycosylation could be reversed to a pattern similar to healthy rats following treatment with bindarit.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute-Phase Reaction↗
PubMed1992

Identification of multiple biological factors in rabbit serum that modulate dopamine-mediated aortic constriction.

A bioassay was established using freshly prepared rabbit aortic strip to monitor the effects of various biological factors contained in rabbit serum that modulate vasoconstriction. Serotonin was shown to be a major vasoconstriction modulator in rabbit serum. A rapid procedure is described for its isolation from rabbit serum by sequential gel filtration chromatography and reversed-phase HPLC using C4, C18, and C2/C18 columns with an overall cumulative yield of about 20%. It was also noted that rabbit serum contains multiple biological factors that modulate dopamine-mediated aortic contraction other than serotonin. A potent vasoconstriction inhibitor was identified in rabbit serum which appears to be a novel regulator that mediates its effect via both alpha-adrenergic and serotonin receptors.

Animals↗
PubMed1992

A new protein antidenaturant agent, bindarit, reduces secondary phase of adjuvant arthritis in rats.

Bindarit (or 2-[(1-benzyl-indazol-3-yl)methoxy]-2-methyl propionic acid) reduces heat induced denaturation of bovine and rat serum albumin in vitro (EC50 = 8.5 and 65 micrograms/ml, respectively) and inhibits heat induced serum albumin denaturation after in vivo (12.5-25-50 mg/kg po) administration in rats. To assess the relationship between protein denaturation and the development of chronic inflammatory diseases, the drug (0.5 or 0.12% medicated diet) was studied in comparison with indomethacin (1 mg/kg po daily) in rats injected with complete Freund's adjuvant. Bindarit appeared different from aspirin-like drugs, antiinflammatory steroids and immunosuppressants because it does not reduce primary inflammation of arthritic rats and was shown to be completely inactive on cyclo and lipooxygenase activity in vitro and on immune reactions of mice in vivo. Nevertheless, the drug strongly reduced the development of the secondary phase of adjuvant induced arthritis. The most significant effect of bindarit in this phase was a strong inhibition of serum albumin denaturation in arthritic rats. Assessment of both electrophoretic and quantitative changes suggests that the reduction of albumin during inflammation is due, at least in part, to a denaturation of native albumin, which loses its electrophoretic mobility. The involvement of protein denaturation in the production of new antigenic determinants, their pathogenic relevance in the development of adjuvant arthritis and the possibility that protein stabilization by bindarit could be the mechanism of action of the drug are discussed.

Animals↗
PubMed1991

Facilitating effect of amphetamine on the response of rabbit aortic strips to adrenaline, dopamine and serotonin.

Amphetamine increased the response of rabbit aortic strips to adrenaline, dopamine and serotonin at consistently lower doses than those exerting a direct contracting effect. The amphetamine-facilitated contraction had the same shape as that produced by biogenic amines alone, whereas the contraction produced by amphetamine alone was more delayed and flatter. Serotonin and dopamine facilitated each other, but less markedly and with a narrower interval between facilitating and contracting doses than amphetamine. Pargyline exerted no facilitating effect on biogenic amines. Phentolamine and prazosin inhibited the direct response to adrenaline, dopamine and amphetamine, and the amphetamine-facilitated response to adrenaline and dopamine; they were inactive against serotonin alone and combined with a facilitating dose of amphetamine or dopamine. Cyproheptadine inhibited the direct response to serotonin and amphetamine, and the amphetamine-facilitated response to serotonin; it was inactive against dopamine and adrenaline both alone and combined with a facilitating dose of amphetamine or serotonin.

Amphetamine↗
PubMed1991

Pretreatment with bendazac attenuates retinal damage induced by intense light in rats.

Bendazac is a drug which protects proteins from denaturation induced by different agents. It is also effective in protecting rabbits from X-ray-induced cataract. This study deals with the effects of bendazac on the intense light-induced retinal damage in rats. Four groups of animals received orally 0, 50, 100 or 200 mg/kg of bendazac L-lysine salt three times a day for 3 days and once the fourth day, before 1 h exposure to intense-green filtered light. Fourteen days after housing in a dark room, the rats were sacrificed and the retinae were examined by light microscopy. Retinal damage was graded according to a score severity from 0 to 5. The mean score for control animals was 2.23, whereas a dose-related and statistically significant reduction of retinal damage was detected in bendazac treated rats, i.e. 1.72, 1.54 and 1.40. A protective activity in the distribution of the severity score, i.e. a higher incidence of no damaged retinae and a lower frequency in the most severely affected ones, was also observed in treated versus control rats. These results suggest a potential therapeutic value of bendazac in the treatment of those conditions, such as retinitis pigmentosa and senile macular degeneration, in which the light exposure plays a role as a co-factor.

Animals↗
PubMed1991

Alpha 2-macroglobulin is not an acute-phase protein in the rat testis.

Earlier studies from this laboratory have shown that Sertoli cells actively synthesize and secrete a nonspecific protease inhibitor in vitro; N-terminal sequence analysis, subunit structural analysis, and other biological studies revealed that this protein is the homolog of serum alpha 2-macroglobulin. We have now quantified the relative distribution of alpha 2-macroglobulin in the reproductive compartments and their comparison with nonreproductive organs. In serum and all nonreproductive tissues examined, the concentration of alpha 2-macroglobulin progressively decreased with advancing age. However, in both the testis and epididymis, the levels of this protein increased with the age of the animals. Serum alpha 2-macroglobulin levels were consistently higher than those in any other tissues until 60 days when the concentrations of this protein were the highest in the epididymis. The distribution of alpha 2-macroglobulin in various nonreproductive tissues from female rats was similar to that observed for male rats in that its levels tended to decrease with age. However, uterine levels of alpha 2-macroglobulin increased progressively with advancing age, whereas ovarian levels of alpha 2-macroglobulin remained relatively stable with an increase in animal age. As serum alpha 2-macroglobulin is an acute-phase protein in the rat, the response of this protein in the testis to induced inflammation was examined. The concentration of alpha 2-macroglobulin in serum rose about 150-fold after injection of fermented yeast. By contrast, the levels of this protein in rete testis fluid, which is derived exclusively from seminiferous fluid, did not change in response to inflammation. These results suggest that there might be distinctive mechanisms that regulate this protein in the systemic circulation vs. the microenvironment behind the blood-testis barrier in the seminiferous epithelium.

Acute-Phase Proteins↗
PubMed1991

Lonidamine: an overview.

The attention of pharmaco-therapeutic research is shifting from the cell duplication mechanisms to the oncogene expressions and cofactors that are the actual cause of cancer. This trend corresponds to the appearance of a second generation of anticancer agents that are typically represented by tamoxifen and lonidamine. The first is a hormonal agent with endocrine effect that was developed making use of a rationale and methods already available, although in a different context. The second, an energolytic agent, is a more complicated case. It was discovered when neither a solid knowledge of cancer energy systems nor the related pharmacological methods were available. Both had to be developed along with a basic research in which lonidamine was at the same time target and tool. In this way, the indication was obtained that cancer activates a specialized energy system in the repair phase following exposure to hyperthermia, alkylating agents, and radiations. This system confers cancer cells an advantage over the normal ones, but is vulnerable and appears to be lonidamine's target. The presently available data show that lonidamine, when used in appropriate conditions with respect to its mode of action, increases the disease-free interval and survival in some types of tumours.

Antineoplastic Agents↗
PubMed1990

Sertoli cell synthesizes and secretes a protease inhibitor, alpha 2-macroglobulin.

The mechanism by which the seminiferous epithelium limits the damaging effects of proteases that are released from degenerating late spermatids does not depend upon protease inhibitors in the systemic circulation since these proteins are excluded from the seminiferous tubule by the blood-testis barrier. The purpose of this study was to identify the major protease inhibitor of the testis and determine its cellular origin. Sertoli cells, the major epithelial component of the seminiferous epithelium, release a protease inhibitor, testicular alpha 2-macroglobulin, in vitro. Immunoprecipitation using [35S]methionine and a monospecific polyclonal antibody prepared against purified testicular alpha 2-macroglobulin establishes that this protein is actively synthesized and secreted by Sertoli cells. Measurements of immunoreactive protease inhibitors in tubular and rete testis fluids collected by micropuncture suggest that alpha 2-macroglobulin rather than alpha 1-antitrypsin is the major protease inhibitor in the seminiferous tubules in vivo. The ability of alpha 2-macroglobulin to inactivate proteases and growth factors such as TGF-beta by a common mechanism suggests that this protein may have a dual function in the testis.

Amino Acid Sequence↗
PubMed1990

Development of an enzyme-linked immunosorbent assay with a monoclonal antibody prepared against alpha 1-antitrypsin for diagnostic screening of inflammatory disorders.

A monoclonal antibody, designated A2a18b8, of IgG1 class prepared against human alpha 1-antitrypsin, cross-reacts with alpha 1-antitrypsin in the serum of rat and baboon, but not with alpha 1-antitrypsin in serum of rabbit, pig, hamster, guinea pig, dog, or turtle. We used A2a18b8 in an enzyme-linked immunosorbent assay (ELISA) developed for human alpha 1-antitrypsin. Preliminary ELISA screening of 247 serum samples from patients with various inflammatory disorders indicated that the concentration of a specific epitope(s) on alpha 1-antitrypsin recognized by this monoclonal antibody was increased significantly in patients with active systemic lupus erythematosus, mixed connective tissue disease, and rheumatoid arthritis, but not in patients with sclerodermic disorders or Sjögren's syndrome. Evidently, A2a18b8 has diagnostic value in that it selectively recognizes a specific epitope(s) on alpha 1-antitrypsin that is (are) apparently exposed during selective inflammatory disorders.

Animals↗
PubMed1990

The paradoxical stress response: a possible common basis for depression and other conditions.

This paper assumes that there are two types of stress-related pathology, the orthodox and the paradoxical, both depending on a positive feedback mechanism controlling the stress-related sympathetic discharge. The paradoxical stress response is speculated to be the common basis for a group of conditions, including depression, panic attacks, obesity, sexual deviations, alcoholism, and drug addiction. Evidence is provided that trazodone inhibits the stress-related sympathetic discharge. This would provide a rationale for its use not only in depression, but also in other conditions depending on an exaggeration of the orthodox or paradoxical stress response.

Animals↗
PubMed1989

Trazodone: from the mental pain to the "dys-stress" hypothesis of depression.

Trazodone was developed according to the mental pain hypothesis, which was postulated from studying patients and which proposes that depression is associated with a decreased pain threshold. Trazodone is devoid of the typical aminergic properties of tricyclics and monoamine oxidase inhibitors. Its preeminent effects are increased pain threshold and alpha-adrenergic blockade. The "dys-stress" hypothesis maintains the concept of the decreased pain threshold in depression, but attributes it to a pathology of the stress response. Whereas physiologically this response produces various effects, including analgesia and alertness that improve the mental and physical performance, in some individuals it is impaired. Abnormalities of the stress response are proposed to be a predisposing or pathogenetic factor for depression and other conditions. According to the "dys-stress" hypothesis, the alpha-adrenergic blockade produced by trazodone and its congeners would also be implicated in its antidepressant activity, as well as its side effects and preferential uses in depressive states associated with adrenergic hyperactivity.

Adrenergic alpha-Antagonists↗
PubMed1989

Changes in concanavalin A-reactive proteins in inflammatory disorders.

Quantitative changes of concanavalin A (Con A)-reactive proteins in serum samples obtained from rats with induced inflammation and from patients with inflammatory and autoimmune diseases were examined by use of lectin blots. Treatment of rats with a single dose of fermented yeast to induce inflammation caused an extensive increase in Con A-reactivity. These changes were time dependent and were similar in both sexes of the animals. When we examined serum samples obtained from patients with various inflammatory disorders for their Con A-reactive proteins as compared with normal donors, we noted that the Con A-reactivity increased in patients with rheumatoid arthritis and systemic lupus erythematosus. Among all the glycoproteins examined by lectin blots with use of Con A, a set of five proteins was selected for detailed analysis by densitometric scanning. These included alpha 2-macroglobulin, P-150, P-95, P-40, and P-35, of Mr 180,000, 150,000, 95,000, 40,000, and 35,000, respectively, by sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions. Densitometric scanning analysis of the lectin blots revealed that the Con A-reactivity of these proteins increased during inflammation. Because alpha 2-macroglobulin is not an acute-phase protein in humans, an increase in Con A staining of this protein suggested that altered glycation is associated with autoimmune diseases. Thus, study of changes in Con A-reactive proteins in human sera may facilitate our understanding of the etiology and pathophysiology of autoimmune diseases.

Animals↗
PubMed1989

Photosensitized haemolysis of human erythrocytes is reduced by bendazac.

Bendazac is a drug previously reported to prevent protein denaturation produced by various agents, including free radicals. Results of these experiments show that bendazac also prevents the photosensitized haemolysis of intact red blood cells which is related to damage of membrane proteins and/or lipids induced by reactive species originating from oxygen. Based on results of a previous study, it is proposed that the antioxidant activity of bendazac is due to interaction with protein molecules rather than free radicals. The protective activity of bendazac against photo-oxidative damage might have therapeutic implications in conditions such as cataract and haemolytic anaemias.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Effect of lonidamine on human malignant gliomas: biochemical studies.

Lonidamine (LND) has been shown to inhibit tumor aerobic glycolysis. Its effect was evaluated on several human astrocytomas at different degrees of malignancy; a correlation was found between LDN effect on lactate production and tumor malignancy: in grade I and II astrocytomas LND stimulates lactate production, while in grade III, IV and glioblastoma multiforme lactate production is inhibited. In an attempt to explain this different behaviour, hexokinase content and compartmentation was evaluated in astrocytomas from fresh operatory specimens and from cultured cells as well, observing a significative correlation between malignancy, hexokinase activity, percent of mitochondrially-bound hexokinase and LND effect. The results justify from a biochemical point of view the role of LND as a 'non-conventional' agent in multimodality combined treatment for malignant gliomas.

Astrocytoma↗
PubMed1988

Beyond the limits of typical antidepressants.

Trazodone and tricyclics share similar activity towards the core symptoms of depression, whereas their effects on neurohumoral transmission tend to be opposite. This once again casts doubt upon the theories on depression postulated from the study of monoamine oxidase inhibitors and tricyclics. The effects of trazodone and tricyclics on the autonomic nervous system are also different, reflecting, respectively, the alpha-adrenergic blocking activity of the former and the muscarinic-anticholinergic and alpha-adrenergic stimulating properties of the latter. It is stressed that the autonomic changes that accompany depression to some extent overlap those produced by tricyclics, whereas they are generally relieved by trazodone. This drug, therefore, extends the previous limitations of antidepressant treatment.

Amines↗
PubMed1988

Modulation of adriamycin uptake by lonidamine in Ehrlich ascites tumor cells.

The effect of Lonidamine, 1-(2,4 dichlorobenzyl)-1-H-indazol-3-carboxylic acid, on the uptake of Adriamycin by Ehrlich ascites tumor cells has been investigated. The uptake of Adriamycin is greatly stimulated by Lonidamine and the increase depends on the energy sources of the cell. In the presence of glucose the intracellular drug content is remarkably lower than that in its absence. This difference lies in the mechanism by which Lonidamine enhances the uptake of Adriamycin. The Adriamycin efflux is via an active transport process and, in the presence of glucose, both aerobic glycolysis and oxidative phosphorylation contribute to ATP synthesis. Although Lonidamine inhibits both these pathways, there is still sufficient ATP to extrude a certain amount of Adriamycin. The elevated intracellular concentration of Adriamycin depends not only on the Lonidamine-inhibited outward transport but also on higher membrane permeability which allows a low concentration of Adriamycin (18 microM) to interfere also with the oxidative metabolism of Ehrlich ascites tumor cells.

Animals↗