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PubMed2005

The peptide molecular links between the central nervous and the immune systems.

The central nervous system (CNS) and the immune system were for many years considered as two autonomous systems. Now, the reciprocal connections between them are generally recognized and very well documented. The links are realized mainly by various immuno- and neuropeptides. In the review the influence of the following immunopeptides on CNS is presented: tuftsin, thymulin, thymopoietin and thymopentin, thymosins, and thymic humoral factor. On the other side, the activity in the immune system of such neuropeptides as substance P, neurotensin, some neurokinins, enkephalins, and endorphins is discussed.

Animals↗
PubMed1994

Chemotherapy of experimental filariasis: enhancement of activity profile of ivermectin with immunomodulators.

The effect of certain immunopotentiators (Freund's complete adjuvant, picroliv, tuftsin and CDRI Compound 86/448) was evaluated on exertion of antifilarial activity of ivermectin at different dose levels in cotton rats experimentally infected with Litomosoides carinii. Ivermectin alone (up to 250 micrograms/kg p.o. x 5 days) caused sterilization of most of the surviving female parasites, but had no lethal effect on adult worms. In combination with immunomodulators, ivermectin brought about significant lethal effect on adult parasites even at a dose of 1 microgram/kg x 5 days. Nevertheless, in animals receiving FCA alone, sterility was caused in > 50% of female parasites. Other immunomodulators used alone had a suppressive effect on microfilaraemia only. Immunomodulators alone or in combination with ivermectin also caused enhanced filaria-specific antibody response.

Adjuvants, Immunologic↗
PubMed1985

Introduction of the dansyl group into histidine and tyrosine residues in peptides and proteins.

Two dansyl derivatives: 1-(5-dimethylaminonaphthalene) sulfonyl (4-amino)-benzyl amine and 1-(5-dimethylaminonaphthalene) sulfonyl beta(4-aminophenyl) ethylamine, have been recently synthesized. Reaction of these compounds with nitrous acid lead to the corresponding dansyl-bearing diazonium salts. The latter derivatives can couple, under mild basic conditions, to the imidazole moiety of histidine, the phenolic ring of tyrosine and to the epsilon-amino function of lysine. The applicability of the two reagents was tested in the modification of several peptides, including [D-Phe6]LHRH, [D-Gln6]LHRH, Leu-enkephalin and Tyr-tuftsin, and proteins such as calmodulin, bovine serum albumin and nerve growth factor.

Chemical Phenomena↗
PubMed1985

Peptides and histamine release from rat peritoneal mast cells.

Various vasoactive peptides were compared for their histamine releasing effects on rat mast cells. Neurotensin, substance P (SP), and kallidin were the most active natural peptides, followed by bradykinin; neurokinin A and B, bombesin, angiotensin and tuftsin were practically inactive. Several kinins and tachykinin-related peptides were tested in an attempt to characterize the receptors mediating histamine liberation. The order of potency of the kinins was the following: kallidin greater than [Tyr(Me)8]bradykinin = bradykinin greater than [desArg10]kallidin greater than desArg9-bradykinin, the same as that found in smooth muscle possessing receptors of the B2 type. Tachykinin-related peptides were potent stimulants and followed the order: [D-Tryp7,9,10]SP-(1-11) greater than [D-Pro2,D-Tryp7,9,10]SP-(1-11) greater than SP-(1-11) greater than SP-(1-9) greater than [D-Pro4,D-Tryp7,9,Leu11]SP-(4-11) greater than SP-(1-7) greater than SP-(4-11) greater than neurokinin A = neurokinin B, indicating that: (a) undecapeptide antagonists of SP behave as superagonists; (b) both N- and C-terminal portions of SP-(1-11) are essential for activity; and (c) receptors for the tachykinins mediating histamine release appear to be of the SP-P type.

Animals↗
PubMed1986

Characterization and cAMP inhibition of a lysyl-(N-epsilon-5'-phospho) adenosyl phosphoamidase in Dictyostelium discoideum.

A lysyl-(N-epsilon-5'-phospho) adenosyl phosphoamidase activity has been identified in Dictyostelium discoideum. Conjugates, formed by coupling AMP via a phosphoamide bond to the epsilon amino group of lysine in avidin and tuftsin, served as substrate. Lysyl-N-epsilon-5'-phosphoadenosine and adenosine phosphoramidate (AMPNH) were substrates as well. The phosphoamidase liberated AMP from all four compounds but did not degrade cAMP. Approximately 90% of the phosphoamidase activity was inhibited competitively by 100 microM cAMP with an apparent Ki of 35 microM for all substrates.

Chromatography, High Pressure Liquid↗
PubMed1984

Are the proposed substance P receptor sub-types, substance P receptors?

Recently, a number of laboratories have postulated the existence of receptor sub-types for substance P. This review is intended to represent a critical appraisal of these reports. In the majority of cases, the evidence for the existence of receptor sub-types has been obtained from observed potency differences of agonists. The problems with this approach are discussed. In addition, information obtained through substance P antagonists, binding studies and investigations of second messenger systems is presented and discussed in relation to the above receptor subdivisions. It is concluded that the present results are consistent with the existence of three receptor sub-types; however, it is suggested that substance P is the natural agonist for only one of these receptors, and that substance K and tuftsin may be the transmitters for the other two receptor sub-types.

Amino Acid Sequence↗
PubMed1986

Synthetic immunostimulants (excluding sulfur-containing compounds).

Many different approaches have been used, over the last 15 years, for the design of potential immunostimulating drugs: Fractionation of crude natural substances (of eukaryotic or prokaryotic origin) already known to enhance immune functions, followed by chemical characterization and, in many cases, full synthesis of the active moiety: examples are provided by thymic hormones and the muramyldipeptide (MDP); Chemical modification of natural substances of known chemical structure in order to potentiate or change their biological activities or reduce their toxicity: murabutide, lipophilic MDP derivatives, lipopeptides (such as pimelautide), tuftsin analogs; Chemical synthesis (often without preconceived ideas about structure-activity relationship) of a great variety of molecules which are then screened in vitro and in vivo for immunopharmacological activity. The chemical structures and the biological profiles (in terms of possible primary cellular targets and mechanisms of immunostimulating activities) of representatives of class (b) and class (c) immunostimulants are reviewed in this paper.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1987

Natural and synthetic peptides (other than neuropeptides) endowed with immunomodulating activities.

A large number of peptides, in most cases of low or relatively low molecular weight, exert immunomodulating activities, i.e., they interact in vitro with various cell populations of the immune system and, in vivo, enhance or depress, according to the case, cell-mediated and humoral immune functions. Immunomodulating peptides include glycopeptides from the bacterial cell wall, natural acyloligopeptide ciclosporin, peptidic hormones from the thytide cyclosporine, peptidic hormones from the thymus, peptidic fragments of immunoglobulins and other plasma proteins, as well as peptides isolated from food proteins. An amazing diversity of structure exists among the various immunomodulating peptides. The molecular mechanisms of interaction between these peptides and the cells of the immune system remain, in most cases, to be elucidated. Possibilities of therapeutic applications exist for many of these immunomodulating peptides: one of them (ciclosporin) is widely used as an immunosuppressive drug, several others (glycopeptides, lipopeptides, tuftsin, thymic peptides) are under clinical investigation as immunostimulating and/or immunorestoring agents.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1983

Sequential hydrolysis of proline-containing peptides with immobilized aminopeptidases.

Proline-containing polypeptides are shown to be sequentially degraded by two aminopeptidases. Clostridial aminopeptidase (EC 3.4.11-) cleaves off any N-terminal amino acid residue including proline from polypeptide chains, but does not cleave the N-terminal secondary peptide bonds involving a prolyl nitrogen. Aminopeptidase P (EC 3.4.11.9) cleaves exclusively such secondary bonds. The two enzymes were immobilized by coupling them covalently to porous amino glass beads. Highly stable preparations were obtained with unchanged pH optimum and thermal stability. The applicability of clostridial aminopeptidase to sequence determination was demonstrated by the time-dependent hydrolysis of enkephalin and Substance P octapeptide. Sequential hydrolysis with the two immobilized enzymes was demonstrated with the proline-containing (Pro-Gly-Pro)10, [Asn1, Val5]angiotensin II, bradykinin, Substance P and tuftsin. Absence of endopeptidase activities was demonstrated by resistance of cytochrome c to hydrolysis and by the ordered release of amino acids during the sequential degradation by immobilized clostridial aminopeptidase and aminopeptidase P.

Amino Acid Sequence↗
PubMed1980

Induction of histamine secretion by polycations.

Poly(arginine), poly(lysine) and poly(ornithine) induce histamine secretion from human basophil leukocytes in the concentration range 1--100 nmol/l. Histamine secretion induced by poly(arginine) requires extracellular calcium at 0.1--1 mmol/l. Strontium (1--10 mmol/l) will substitute for calcium. Lanthanum (30--90 nmol/l) inhibits histamine release induced by poly(arginine). Histamine secretion induced by poly(arginine) is inhibited by 1--30 mumol/l N-ethyl-maleimide, 0.3--3 mmol/l 2-deoxy-D-glucose, 0.3--3 mmol/l dibutyryl cyclic AMP, 0.3--3 mmol/l, adenosine 3'5'-cyclicphosphorothioate. The action of poly(arginine) is inhibited by pretreatment of basophils at 47 degrees C or with neuraminidase. 10 microgram/ml heparin inhibits the response to poly(arginine). Histamine releasing potency of the polymer amino acids is dependent on chain length of the peptide. Succinylated poly(lysine) is inactive. Monomer amino acids do not release histamine and do not inhibit the action of the polymers. Histones and protamine do not release histamine, nor do the peptides eledoisin and tuftsin. Putrescine, cadaverine, spermine and spermidine do not release histamine. Poly(glutamic acid), poly(aspartic acid) and poly(tyrosine) are also inactive. The IgE-mediated release of histamine appears to be independent of that mediated by poly(arginine).

Amino Acids↗
PubMed1994

Actions of selected proteins, peptides and amino acid derivatives on mouse embryonic development in vitro.

1. The actions of various compounds with antiproliferative and/or immunomodulatory activities including the ribosome-inactivating protein gelonin, the tetrapeptide tuftsin, the opioid peptide leucine-enkephalin, the antireproductive tripeptide Thr-Ser-Lys, the melatonin analog 6-methoxy-2-benzoxazolinone, and the amino acid derivatives 5-hydroxytryptamine and oxalysine on mouse embryonic development and organogenesis in vitro were investigated. 2. The various compounds were tested up to a concentration of 300 micrograms/ml. It was found that only 6-methoxy-2-benzoxazolinone, a derivative of tryptophan, produced an increase in the number of abnormal embryos and reductions in the final somite numbers and axial lengths of embryos. 3. 6-Methoxy-2-benzoxazolinone treatment also resulted in an increased incidence of abnormal morphogenesis of various organ primordia, including abnormal yolk sac circulation, twisting of body axis, absence of forelimb bud and opening of cranial neural tube.

Amino Acid Sequence↗
PubMed1991

Bestatin, an aminopeptidase inhibitor with a multi-pharmacological function.

Bestatin, the dipeptide N-((2S, 3R)-3-amino-2-hydroxy-4-phenyl butanyl) L-leucine is a leucine aminopeptidase and aminopeptidase-B inhibitor. It exerts a direct stimulating effect on lymphocytes (and monocytes) via its fixation on cell surface leucine-aminopeptidase, and an indirect effect on monocytes (and lymphocytes) via aminopeptidase B inhibition of tuftsin catabolism. Thus it is an immuno-modifier as shown by the Japanese and also our groups: a) immuno-modifier, especially stimulator, in normal young mice; b) immunorestorator and spontaneous tumor preventive agent in aged mice; c) immunorestorator in the elderly and in cancer patients and HIV infected subjects. It stimulates granulocytopoiesis and thrombocytopoiesis in vitro, and can restore them in vivo in myelo-hypoplastic man. The anti-aminopeptidase action of Bestatin also protects enkephalins against their catabolism, which encouraged us, with good preliminary results, to study its analgesic action and search for a preventive effect on "desaddicted" toxicomaniac relapses.

Aminopeptidases↗
PubMed1989

Immunomodulators and feeding regulation: a humoral link between the immune and nervous systems.

Cells of the nervous and immune systems have specific receptors for humoral substances that originate in both systems. These elements establish a bidirectional information exchange network between the nervous and immune systems. In particular, neuroregulators (neurotransmitters and neuromodulators) can modulate specific immune system function(s) and immunoregulators (immunomodulators) can modulate specific nervous system function(s). Modulation of immune functions by neuroregulators has been receiving considerable attention; however, modulation of nervous system functions by immunomodulators has been little studied. The presence of immunomodulators in the brain and cerebrospinal fluid may represent local synthesis by astrocytes, microglia, endothelial cells, intrinsic macrophages and blood-derived lymphocytes which cross the blood-brain barrier, or the concentration of substances derived from the peripheral blood. Acute and chronic inflammatory processes, malignancy, and immunological reactions stimulate the synthesis and release of immunomodulators in various cell systems. These immunomodulators have pivotal roles in the coordination of the host defense mechanisms and repair and induce a series of endocrine, metabolic, and neurologic responses. This paper focuses on the effects of immunomodulators (interleukins, tumor necrosis factor, tuftsin, platelet activating factor, and others) on the central nervous system (CNS), in particular, on feeding regulation. It is proposed that an immunomodulatory system regulates food intake by a direct action in the CNS through a specific neuro-immuno interaction. This regulatory system may be operative during acute and chronic disease.

Animals↗
PubMed1991

Immunoregulators in the nervous system.

The nervous system, through the production of neuroregulators (neurotransmitters, neuromodulators and neuropeptides) can regulate specific immune system functions, while the immune system, through the production of immunoregulators (immunomodulators and immunopeptides) can regulate specific nervous system functions. This indicates a reciprocal communication between the nervous and immune systems. The presence of immunoregulators in the brain and cerebrospinal fluid is the result of local synthesis--by intrinsic and blood-derived macrophages, activated T-lymphocytes that cross the blood-brain barrier, endothelial cells of the cerebrovasculature, microglia, astrocytes, and neuronal components--and/or uptake from the peripheral blood through the blood-brain barrier (in specific cases) and circumventricular organs. Acute and chronic pathological processes (infection, inflammation, immunological reactions, malignancy, necrosis) stimulate the synthesis and release of immunoregulators in various cell systems. These immunoregulators have pivotal roles in the coordination of the host defense mechanisms and repair, and induce a series of immunological, endocrinological, metabolical and neurological responses. This review summarizes studies concerning immunoregulators--such as interleukins, tumor necrosis factor, interferons, transforming growth factors, thymic peptides, tuftsin, platelet activating factor, neuro-immunoregulators--in the nervous system. It also describes the monitoring of immunoregulators by the central nervous system (CNS) as part of the regulatory factors that induce neurological manifestations (e.g., fever, somnolence, appetite suppression, neuroendocrine alterations) frequently accompanying acute and chronic pathological processes.

Adjuvants, Immunologic↗
PubMed2000

The detection and quantitation of inflammation in the central nervous system during experimental allergic encephalomyelitis using the radiopharmaceutical 99mTc-RP128.

RP128 is a novel agent which readily chelates 99mTc to form a radiopharmaceutical which binds in vivo to the tuftsin receptor located specifically on neutrophils and monocyte-macrophages, therefore removing the need for in vitro cell labelling prior to intravenous administration. We have assessed the ability of 99mTc-RP128 to detect central nervous system (CNS) inflammation in experimental allergic encephalomyelitis (EAE), an animal model of the human disease multiple sclerosis. The radiopharmaceutical was recorded at significantly increased levels in all EAE diseased CNS tissues, compared to normal and control samples, at 0.5, 1 and 3 h post-injection using a dual radioisotope technique to correct for non-extravasated tracer (P<0.05). Moreover, extravascular accumulation of the agent could be clearly demonstrated in inflammatory tissues with minimal loss of sensitivity when the secondary isotopic correction for blood volume was omitted. In addition, 99mTc-RP128 successfully monitored glucocorticoid suppression of inflammation (P<0.05), recording a typical dose-response to increasing steroid concentration. Clearly, 99mTc-RP128 can quantitatively detect CNS inflammation and assess responses to therapy indicating potential value as an imaging agent both clinically and as a research aid. Furthermore, the rapid in vivo labelling by 99mTc-RP128 of specific inflammatory cells combined with the ability to monitor the progress of anti-inflammatory therapeutics may recommend the agent for use in a variety of inflammatory conditions.

Animals↗
PubMed1996

Will killing the last HIV1 particle cure AIDS patients? II: Second Part. Decrease of viral load and of T-suppressor cells, and increase of the cytotoxic cells, without effect on CD4, after the use of 10 virostatics applied in 3 or 4 drug combinations of different sequences. The time for CD4 immunotherapy?

We reported in the first part of this editorial and in an article AIDS therapy with five HIV1 virostatics applied in two then three, or initially three, or initially four agent combinations, given in 3 week sequences differing from each other due to drug rotation, the contrast between: a) the decrease of viral load, possible below the detectable level, b) the absence of effect on the helper CD4+, the CD8+ C57- cytotoxics and the CD8+ C57+ suppressor cells. We proposed a thesis according to which the HIV1-AIDS complex might have another pathogenic component other than HIV1, ie, a microchimerism graft-versus host reaction (GvH) or an autologous GvH-like reaction. Shifting from five to 10 virostatics owing to the availability of lamivudine or 3TC, stavudine or d4T and three HIV1 protease inhibitors, saquinavir, ritonavir and indinavir, applied according to the same modality, we have enhanced the reduction of viral load, and significantly decreased the CD8+ C57+ suppressor cell counts, and increased those of the CD8+ C57- cytotoxic cells. This result which indirectly shows the role of HIV1 in the increase of suppressor CD8+ cells, hence in the late loss of immune memory and of opportunistic infections, reinforces the thesis of a role, in AIDS pathogenesis, of a latent GvH reaction activated by HIV1 primo-infection, and its evolution from the hyperplastic phase to the hypoplastic one, which, inducing severe immune suppression, is responsible for HIV1 active infection relapse after the so-called latent phase. Hence the proposition we make, of an indication of CD4 modulation with non specific immunotherapy by bestatin, of which we showed the effect in another population of HIV1-AIDS complex patients. Its effect can be potentiated by tuftsin. When the suppressor cell number goes up over that of the cytotoxic one after the HIV1 active infection relapse, interferon gamma could be added, which, by amplifying the CD28 pathway on CD8+ cytotoxics, while suppressor cells lack CD28, which might reestablish a ratio of suppressor over cytotoxic cells nearer to normal. It remains that the role of the five secondarily included agents in the decrease of suppressor cells will only be attributed with certainty and entirely to their virostatic effect, if it is shown that none of them exerts a selective anti-suppressor cell action.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Combinations of four virostatics applied in rotational sequences induce an exponential VL regression curve, the first part of which is rapidly decreasing to a PCR-undetectable level, while the last part is insensitive to the model. Indications for virostatic and immunotherapeutic reinforcements?

Between 1992 and 1995, we have had five virostatics available: zidovudine (AZT), didanosine (ddI), zalcitabine (ddC) (as retrotranscriptase nucleosidic antagonists, RTNA), acriflavine (ACF), and hydroxy-methyl-ellipticine (HEL), as respectively a DNA synthesis and structure antagonist, and a topoisomerase II inhibitor. Between 1995 and now, we have had ten virostatics the same, plus lamivudine (3TC), stavudine (d4T) as RTNA, and indinavir (IDV), ritonavir (RTV) and saquinavir (SQV) as protease inhibitors. We first conducted a phase I-like study concerning the ratios of the drug numbers in combinations over the numbers available. The optimal model for the study was that of four virostatics selected out of the ten. The four virostatic combinations were applied in short (3 week) sequences, differing each others by drug rotation. The patients were, before treatment, nine at the phase of AIDS, one at the A3 stage. They presented a very rapid decrease of viral load (VL) which became undetectable at PCR, being first below 200 RNA copies/mL, then below 20. We call this condition 'minimum residual disease' as HIV1 persistence is revealed by virus rebounds, reversible, and probably induced by cofactors. The frequency of the latter selection is due to the very frequent (each 3 weeks) VL evaluations. The last part of the VL exponential curve which the minimum residual disease represents, is almost horizontal and quasi insensitive to the powerful virostatic model described above, though no resistance has appeared at the combination or sequence levels. Thus we propose to add phases of: a) reinforcements by virostatics, adding two more ones to the four of the model; and b) treatment complement by active immunotherapy phases: the most adapted immunomodulator is the combination of the peptidic cytokine, tuftsine, and of its antipeptidase, bestatine If they are not available, another interleukine, able to help restoring the AIDS disturbed immunologic system, interleukin 2, could be tried, as it has induced beneficial effects at very small doses by subcutaneous injections.

Anti-HIV Agents↗
PubMed2002

Azo cyclization: peptide cyclization via azo bridge formation.

A novel method for peptide cyclization in solution: the azo cyclization is presented herein. Ring closure by forming an azo bridge was achieved in situ by connecting the corresponding side chains of para amino phenylalanine (Pap) residues to those of tyrosine or histidine residues present in the corresponding linear precursors. The reaction was performed using an initial diazotization step in acidic media followed by intramolecular azo cyclization in a mild basic media. This new method of cyclization is facile, applicable to various sequences and results in a high yield of pure products and hence is suggested as an additional method for peptide cyclization. Here we report the successful utilization of this method for the synthesis of 10 new cyclic azo peptides, derived from RGD, GnRH, Tuftsin, VIP and SV40 NLS.

Amino Acid Sequence↗