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Biomedical subjects

Z Zídek

Publications and source records attributed to Z Zídek.

At least 37 records · Page 2Linked to original sources
PubMed1995

Interferon-gamma/tumour necrosis factor-alpha synergism as a mechanism for enhanced nitric oxide production following in vivo administration of muramyl dipeptide (MDP) to mice.

The aim of the present study was to investigate the role of muramyl dipeptide (MDP) in triggering host non-specific defence mechanisms, namely its influence upon the L-arginine-dependent biotransformation pathways leading to formation of nitric oxide (NO). MDP was applied subcutaneously to mice as one or three daily injections, 300 micrograms MDP each. Production of NO by peritoneal macrophages from these animals or the capability of their splenocytes to render virgin macrophages for enhanced NO production was assayed. It has been found that macrophages from MDP-treated animals produce considerably enhanced amounts of NO and that the splenocytes secrete soluble factors providing all the signals required for induction of NO biosynthesis. Introduction of anti-IFN-gamma or anti-TNF-alpha antibodies into these splenocyte supernatants resulted in complete suppression of inducible NO production by macrophages.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1995

Lack of causal relationship between inducibility/severity of adjuvant arthritis in the rat and disease associated changes in production of nitric oxide by macrophages.

OBJECTIVE: To investigate the formation of nitric oxide (NO) by peritoneal macrophages in three inbred strains of rats differing both in their susceptibility to the induction of adjuvant arthritis (AA) and in the severity of the disease. METHODS: AA was induced by intraplantar injection of Mycobacterium tuberculosis (M.tb) in paraffin oil. Isolated peritoneal macrophages were cultured for 24 hours and supernatants were assayed for nitrite using Griess reagent. RESULTS: All rats of the LEW and BN strains became diseased, but the F344 strain included both responders and non-responders. No significant interstrain differences were observed in the generation of NO by macrophages from control animals. Nitrite concentrations were remarkably enhanced in all M.tb treated animals, regardless of the absence or presence of AA, and did not parallel its severity. Altered production of NO by macrophages from adjuvant treated rats was normalised in vitro in the presence of lipopolysaccharide. CONCLUSIONS: Our findings suggest that the activity of constitutive or inducible NO synthase in peritoneal macrophages cannot be regarded as a determinant of genetically controlled disease inducibility and severity. Secretion of latent forms of certain NO downregulatory factors during development of AA may be implicated.

Animals↗
PubMed1995

[Differences in the behavior of organic lesions, immunologic and metabolic parameters in 2 inbred strains of rats].

Two inbred rat strains were obtained by selective breeding and inbreeding: IR (isoprenaline resistant) and IS (isoprenaline sensitive). In addition to known differences between the two strains (1) other differences were found. As compared to IS strain, IR rats were more aggressive and showed more comfort behaviour in open field test. IR rats developed larger stress-induced gastric lesions but smaller heart lesions. They had larger spleen and thymus and more severe arthritis after Freund adjuvans administration. The two strains might be useful in studying the effects of drugs on various pathological processes. Their hybrids are being used to study interrelations between different genetic factors.

Animals↗
PubMed1994

Immune-related edemagenic activity of glutamines and glutamic acid, components of immunomodulatory agents.

A number of compounds, in their structure similar to the immunomodulatory agent adamantylamide-L-alanyl-D-isoglutamine (AdDP), a desmuramyl analog of muramyl dipeptide (MDP), were compared with respect to their in vivo immunobiological activity. The agents were represented by adamantylamide-peptides or -amino acids differing principally in the nature of glutaminyl moieties. They were all able to induce inflammatory reaction which was prevented by anti-T-cell (TH) mAb, silica, indomethacin and dexamethasone. Responsible for this effect proved to be glutaminyl moieties (glutamine, isoglutamine, or glutamic acid), irrespective of their stereospecificity. Unlike the immunomodulatory molecule of AdDP, neither of the compounds and amino acids were able to stimulate production of antibodies in immunized animals, however.

Adjuvants, Immunologic↗
PubMed1994

Immunomodulatory properties of 9-(2-phosphonomethoxyethyl)-adenine (PMEA).

PMEA was found to influence the immune system of the mouse and rat in vivo in different ways. PMEA administered after injection of parental splenocytes to F1 recipients reduced the development of local graft-versus-host reaction (GVHR). However, PMEA treatment of donors of splenocytes had no influence on GVHR. Modifications in the immune system triggered by PMEA were confirmed in the rat model by evaluation of subsets of white blood cells isolated from peripheral blood by a set of monoclonal antibodies. Enhanced formation of nitric oxide (NO) was found in both unconditioned and LPS-stimulated macrophage cultures on day 14 of the drug treatment of rats.

Adenine↗
PubMed1993

Some cellular and pathophysiological correlates of the inflammatory effects of a synthetic immunomodulatory agent, muramyl dipeptide (MDP).

Acute, fully reversible paw edema was produced in mice after systemic administration of muramyl dipeptide (MDP, i.e. N-acetylmuramyl-L-alanyl-D-isoglutamine). Its stereoisomer N-acetylmuramyl-D-alanyl-D-isoglutamine (MDP-D,D) was much less effective. The swelling of paws occurred very soon (1 h) after MDP injection, reached the maximum severity at an interval of 6 h and declined afterwards. While no substantial quantitative differences were found in the sensitivity of the various inbred strains of mice to edemagenic activity of MDP, athymic nude mice were completely resistant to the induction of edema. Formation of edema was blocked by silica, indomethacin (partially also by nordihydroguaiaretic acid), monoclonal antibodies against T-cells and their TH-subpopulation. It is suggested that the MDP-induced edema is a macrophage- and T-cell-dependent, prostaglandin- (and partially leukotriene)-mediated acute reaction associated with increased vascular permeability. Possible engagement of immune/inflammatory cytokines like IL-1 has been discussed. The data support the view that this type of edema is a consequence of changes in the activity of important cellular components of the immune system.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1993

T-cell-dependent immunobiological activity of a desmuramyl analog of muramyl dipeptide, adamantylamide dipeptide (AdDP), and D-isoglutamine.

The present experiments demonstrate that, similar to immunomodulatory muramyl dipeptide, its desmuramyl analog adamantylamide dipeptide is able to induce mild and fully reversible paw edema in mice. This effect is an immune-related phenomenon depending on the activation of T-cell/macrophage interactions and on production of prostaglandins. Possible involvement of certain immunoregulatory/inflammatory cytokines (e.g. IL-1, IL-2) has been suggested. The most probable intrinsic moiety of the adamantylamide dipeptide molecule responsible for triggering the edema formation is obviously D-isoglutamine.

Adjuvants, Immunologic↗
PubMed1992

Differences in proinflammatory activity of several immunomodulatory derivatives of muramyl dipeptide (MDP) with special reference to the mechanism of the MDP effects.

Immunomodulatory agents, muramyl dipeptide (MDP) and several of its analogues, i.e. adamantylamide dipeptide, murametide, murabutide and their glucosaminylated derivatives, were tested for edemagenic activity in rats. Given systemically in aqueous solutions, only MDP and glucosaminylated MDP, at the dose of 3 mg/kg (s.c. or p.o.), were found to produce edematous swelling of the paws. Local (intra-pad) application of MDP was more effective than the systemic one. Supernatants of macrophages, in vitro cultured in presence of MDP, caused the swelling as well. The edema was of a transient nature. After reaching the maximum severity (about 6 h after injection of MDP solution or 1 h after macrophage supernatants), it was subsiding and disappeared completely within approximately 6 days after cessation of the treatment. It was found that this type of rat paw edema is probably a prostaglandin-dependent consequence of macrophage activation. Hypotheses on the involvement of immunoregulatory cytokines, and possible chemical structure-inflammatory activity relationships have been suggested.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1986

The influence of immune status on the in vitro sensitivity of serotoninergic receptors in the rat stomach strip.

Serotoninergic contractions of the rat stomach strip were evoked and EC50 determined. In preparations from control animals MDP, 50 mumol/l, decreased EC50 or sensitized the preparation. In the strips from animals where adjuvant arthritis was induced, higher sensitivity to 5-HT was observed and the sensitizing effect of MDP was retained. In the strips from animals pretreated with cyclophosphamide or in the terminal stage of tumor growth lower sensitivity to 5-HT, which could be further decreased by MDP, were noticed. These opposite effects in serotoninergic reactions were tentatively linked with the modulation of the immune status in vivo.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

Edemagenic activity of aqueous form of muramyl dipeptide (MDP) in rats.

Repeated systemic administration of MDP in saline has been found to produce dose-dependent edema of paws in rats. Two to three daily doses are sufficient to induce significant increase of the paw volume. The edema is spontaneously well reversible. Its formation may substantially be reduced by indomethacin or prednisone, suggesting thus an involvement of prostaglandins. Body-weight loss and impaired walking of animals were also observed. Severity of all the effects was found to be markedly dependent on the strain of rats used.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

Anti-inflammatory effects of muramyl dipeptide in experimental models of acute inflammation.

Synthetic muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP), has been tested for activity against acute inflammation. In all models employed (Bayol + Arlacel paw oedema in rats, carrageenan pleurisy in rats, and carrageenan of dextran paw oedema in mice), MDP given in admixture with the phlogistic agents significantly lowered the resulting inflammatory reaction by about 30-40%. 0.1-0.2 mg of MDP per animal was applied. The mechanism of anti-inflammatory activity of this substance remains unknown.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

Hepatic mixed-function oxidase system and microsomal lipid peroxidation in rats treated with a synthetic immunomodulator, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP).

Effects of synthetic muramyl dipeptide (MDP) on activity of liver microsomal mixed-function oxidase system and on the susceptibility of liver microsomes to lipid peroxidation, were tested in rats at intervals of 1 or 24 hours after single i.p. injection of MDP (1 mg per animal). No significant changes were found in levels of cytochrome P-450 and b5, microsomal heme, or in activities of aniline hydroxylase, ethylmorphine demethylase, glucuronide transferase or cytosol glutathione-S-transferase. However, significantly less (about 45%) TBA-reactive material accumulated in microsomal samples at the 1 h-interval after the MDP administration. The same inhibitory effect of MDP on lipid peroxidation was shown in vitro (in 1 mM concentration) after incubation of microsomes with the NADPH/ADP/Fe system.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1983

Opposite effects of the synthetic immunomodulator, muramyl dipeptide, on rejection of mouse skin allografts.

The influence of muramyl dipeptide (N-acetylmuramyl-L-alanyl-D-isoglutamine) on the rejection of mouse skin allografts was investigated. While the 0.1-mg dose administered on days 7, 6, 5 prior to transplantation caused significant prolongation of the graft survival, the 0.5-mg dose administered on days 3, 2, 1 prior to transplantation resulted in remarkable augmentation of the graft rejection. The present results support the view that muramyl dipeptide can induce both stimulatory and suppressive immune mechanisms, depending on the treatment regimen.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1983

Biotransformation of drugs in rats treated with a synthetic muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP).

Natural immunoadjuvant mixtures like BCG and FCA are known to produce gross alterations of drug-metabolizing systems in the rat. Since it has been shown that the smallest structure of various bacterial peptidoglycans, possessing adjuvant activity, is muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP), the possibility has been tested whether this substance is involved in production of the observed metabolic changes. Synthetic compound was applied subcutaneously for the period of 21 days, and the in vitro activity of 7-ethoxycoumarin-O-de-ethylase, aminopyrine-N-demethylase, together with the microsomal content of cytochrome P-450 and b5, and the in vivo acetylation of sulphadimidine, were investigated. No effect of MDP on any of these tests was noted in both the Lewis arthritic strain and the AVN disease-free strain. It is suggested that MDP is metabolically inactive and that the defects in metabolism of drugs, following bacterial-adjuvant treatment, are likely to be due to some additional cell-wall components, other than peptidoglycans. Furthermore, our data support the view of no relationship between the development of metabolic changes and the established arthritic lesions in rats.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1982

Arthritogenic activity of a synthetic immunoadjuvant, muramyl dipeptide.

A synthetic muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine, dissolved in saline only and applied subcutaneously to rats of the Lewis inbred strain, produced arthritis, clinically manifest by hind feet paresis but without apparent paw swelling in most cases. Histologically, the disease was characterized by edema and hyperemia of connective tissues, joint synovias, and tendon sheaths, with massive accumulation of inflammatory cell infiltrates composed mainly of lymphoplasmocytes and partly of neutrophil leukocytes. Fibrin exudation and fibrinoid necrosis in connective tissues were observed in the most severe cases. Synovial layers of the talocrural joint, especially on their villi, exhibited marked swelling or cell desquamation of the inner zone. Clinical symptoms of the disease disappeared spontaneously within 5 days after cessation of the treatment; also, histological examinations showed that the effects were reversible. Our results prove that (i) muramyl dipeptide is the principal substance involved in the production of arthritis, (ii) there is no necessity for the presence of additional mycobacterial cell wall components, and (iii) the involvement of the oil moiety is not requisite for the production of arthritis.

Acetylmuramyl-Alanyl-Isoglutamine↗