Biomedical subjects

Michał Zimecki

Publications and source records attributed to Michał Zimecki.

At least 19 recordsLinked to original sources

PubMed2006

The immunoregulatory effects of edeine analogues in mice.

The edeines analogs were tested in several in vitro and in vivo assays using the mouse model, with edeine B (peptide W1) and cyclosporine A as reference compounds. The peptides displayed moderate, stimulatory effects on concanavalin A-induced (ConA-induced) splenocyte proliferation, whereas their effects on pokeweed mitogen-induced (PWM-induced) splenocyte proliferation were inhibitory. The peptides inhibited lipopolysacharide-induced (LPS-induced) tumor necrosis factor alpha production but had little effect on interleukin 6 production. In the model of the humoral immune response in vitro to sheep red blood cells, peptide 1 was distinctly stimulatory in the investigated concentrations (1-100 microg/ml), whereas peptides 3 and 4 only stimulated the number of antibody-forming cells at the highest concentration (100 microg/ml). In the model of the delayed type hypersensitivity in vivo to ovalbumin, the peptides were moderately suppressive (3 being the most active). The reference peptide W1 stimulated ConA-induced cell proliferation at 1-10 microg/ml but was inhibitory at 100 microg/ml. It also inhibited PWM-induced cell proliferation in a dose-dependent manner. This peptide had no effect on the humoral immune response in vitro or on cytokine production, but inhibited DTH reaction in vivo. The relationship between structure and activity, and a possible mode of action of the peptides, is discussed in this paper.

Animals↗

PubMed2006

Lactoferrin ameliorates symptoms of experimental encephalomyelitis in Lewis rats.

Lactoferrin (LF) is a multifunctional protein present in secretory fluids of mammals and circulating neutrophils. Beside anti-inflammatory properties, LF was found to inhibit some autoimmune disorders. In this investigation we studied effects of oral administration of LF on experimental autoimmune encephalomyelitis (EAE) in Lewis rats. LF was given in drinking water as 0.25% solution beginning the day of elicitation of EAE or with a seven-day delay. The effects of LF were evaluated by the following criteria: clinical score, lymph node cell number, serum cytokine levels and histopathological changes. We found that LF treatment led to a significant acceleration of the recovery process, particularly on days 16-18 following elicitation of EAE. The delayed administration of LF was less effective in reducing the score of EAE. In addition, cell number of the inguinal lymph nodes of untreated EAE rats, almost 3 times higher as compared with control, naïve rats, was normalized by LF treatment. Furthermore, LF decreased elevated serum concentrations of tumor necrosis factor alpha and transforming growth factor beta. The histological analysis of the spinal cord revealed reduction in the number and size of inflammatory foci in LF-treated rats. In summary, treatment of EAE Lewis rats with LF reduced the clinical symptoms and accelerated the recovery of animals.

Animals↗

PubMed2006

Effects of bacteriophages on free radical production and phagocytic functions.

Reactive oxygen species (ROS) play a major role in mediating antibacterial functions of phagocytic cells. However, excessive ROS production may cause oxidative stress and tissue damage. Uncompensated ROS release has been implicated in a variety of disorders. Novel means of controlling elevated ROS production are urgently needed. We showed that homologous but not the heterologous phages inhibited, in a dose dependent manner, the degree of chemiluminescence in phagocytes induced by Escherichia coli. Treatment of the cells with the phages alone resulted in a small increase in ROS production. Homologous phages also facilitated phagocytosis when preincubated with bacteria. On the other hand, both homologous and heterologous phages inhibited phagocytosis following preincubation with phagocytic cells. The treatment of infected and uninfected mice with phages did not significantly alter the rate of phagocytosis by blood granulocytes and monocytes. In conclusion, we showed that bacteriophages can decrease ROS production by phagocytes. Although in some in vitro experimental models the phages tended to diminish phagocytosis, this phenomenon may be of little significance in clinical situations, since the process of eliminating bacteria in phage-treated patients is predominantly accomplished by both phages and phagocytes.

Animals↗

PubMed2006

The lunar cycle: effects on human and animal behavior and physiology.

Human and animal physiology are subject to seasonal, lunar, and circadian rhythms. Although the seasonal and circadian rhythms have been fairly well described, little is known about the effects of the lunar cycle on the behavior and physiology of humans and animals. The lunar cycle has an impact on human reproduction, in particular fertility, menstruation, and birth rate. Melatonin levels appear to correlate with the menstrual cycle. Admittance to hospitals and emergency units because of various causes (cardiovascular and acute coronary events, variceal hemorrhage, diarrhea, urinary retention) correlated with moon phases. In addition, other events associated with human behavior, such as traffic accidents, crimes, and suicides, appeared to be influenced by the lunar cycle. However, a number of reports find no correlation between the lunar cycle and human reproduction and admittance to clinics and emergency units. Animal studies revealed that the lunar cycle may affect hormonal changes early in phylogenesis (insects). In fish the lunar clock influences reproduction and involves the hypothalamus-pituitary-gonadal axis. In birds, the daily variations in melatonin and corticosterone disappear during full-moon days. The lunar cycle also exerts effects on laboratory rats with regard to taste sensitivity and the ultrastructure of pineal gland cells. Cyclic variations related to the moon's phases in the magnitude of the humoral immune response of mice to polivinylpyrrolidone and sheep erythrocytes were also described. It is suggested that melatonin and endogenous steroids may mediate the described cyclic alterations of physiological processes. The release of neurohormones may be triggered by the electromagnetic radiation and/or the gravitational pull of the moon. Although the exact mechanism of the moon's influence on humans and animals awaits further exploration, knowledge of this kind of biorhythm may be helpful in police surveillance, medical practice, and investigations involving laboratory animals.

Animals↗

PubMed2005

New amides of 5-acylamino-3-methyl-4-isothiazolecarboxylic acid and their immunotropic activity.

Several new amides 4 of 5-substituted 3-methyl-4-isothiazolecarboxylic acid were obtained. These compounds have acetylamino or benzoylamino groups in position 5 of the isothiazole ring. In position 4, the carboxylic group was transformed in the amides using amino-acid esters. Activities of the obtained derivatives were checked in the humoral immune response and delayed type hypersensitivity reaction to sheep red blood cells (SRBCs) in vivo.

Amides↗

PubMed2005

[Therapeutic properties of proteins and peptides from colostrum and milk].

Colostrum and milk are rich in proteins and peptides which play a crucial role in innate immunity when transferred to the offspring and may accelerate maturation of the immune system in neonates. The immunotropic properties of these proteins prompted investigators research their potential application in prevention and therapy. Lactoferrin (LF) exhibits antibacterial, antifungal, antiviral, antiparasitice, and antitumoral activities. It is protective with regard to intestinal epithelium, promotes bone growth, and accelerates the recovery of immune system function in immunocompromised animals. LF was tried in the treatment of hepatitis C infection and the intestinal form of graft-versus-host disease (GvHD). A proline-rich polypeptide (PRP) demonstrated a variety of immunotropic functions, including the promotion of T-cell maturation and inhibition of autoimmune disorders. PRP, in the form of chewable tablets (Colostrinin) was recently found to improve or stabilize the health status of Alzheimer's disease patients. Casein and casein-derived peptides showed protective activities in enamel demineralization and as caries-preventing agents. The protein hydrolyzates were also protective in diabetic animals, reduced tumor growth, had antihypertensive activity and diminished colicky symptoms in infants. Glycomacropeptide (GMP), a peptide derived from kappa-casein, exhibited various antibacterial and antithrombotic activities. Alpha-lactalbumin (LA) demonstrated antiviral, antitumoral and anti-stress properties. LA-enriched diets were anxiolytic, lowered blood pressure in rats, prevented diarrhea, and led to a better weight gain in malnourished children. HAMLET, a complex of LA and oleic acid, was effective in patients with cutaneous papillomas. Lysozyme found application in infant formulas, the treatment of periodentitis, and the prevention of tooth decay. Milk enriched in lysozyme was used in feeding premature infants suffering from concomitant diseases. Interesting, antibacterial properties were exhibited by lactoperoxidase. Both lysozyme and lactoperoxidase required cooperative action with LF in combating bacteria. In conclusion, preparations derived from milk and colostrum are effective, easily bioaccessible, and safe, finding wide application in prevention and therapy for newborns and adults.

Adult↗

PubMed2005

[The role of lactoferrin in the proper development of newborns].

Colostrum and milk contain, in addition to nutritional constituents, also proteins crucial for the normal development of the offspring. Lactoferrin (LF) belongs to the family of iron-binding proteins and exhibits a wide spectrum of antimicrobial and immunotropic properties. LF is particularly resistant to proteolytic degradation in alimentary tract, in contrast to other milk proteins, e.g. casein. In any case, LF-derived peptides also possess potent antibacterial activities. LF is absorbed from the intestine by means of specific receptors located on brush border cells. Administered orally, LF stimulates both local and systemic immune response. LF plays a role in the absorption of nutrients. The protein can deliver such metal ions as iron, manganese, and zinc and facilitate the absorption of sugars. LF stimulates the proliferation of gut endothelial cells and the growth of gut-associated lymphatic follicles. This property suggests the possibility of applying LF in premature infants and patients with damaged intestinal mucus. LF controls the proper composition of the gut microflora. It suppresses the growth of pathogenic bacteria while promoting the multiplication of nonpathogenic Lactobacillus and Bifidobacterium. Newborns fed an artificial diet develop harmful microflora (Enterococcus, Enterobacter, Bacteroides, Escherichia). The non-pathogenic microflora ensures low pH, produces some vitamins, increases the activity of NK cells, T lymphocytes, and macrophages, promotes the production of protective immunoglobulins, and lowers the risk of allergies. In studies on mice, LF was found to be protective in bacteremia and endotoxemia. The protein stimulates the activity of reticulo-endothelial system cells and elicits myelopoiesis, thus increasing the killing and clearance of bacteria. In the model of experimental endotoxemia, LF inhibits the activity of pro-inflammatory cytokines, nitric oxide, and reactive forms of oxygen. LF can also promote the differentiation of T and B cells from their immature precursors and increases the activity of NK and LAK cells. It also protects against the toxicity of reactive oxygen radicals. This property may be particularly relevant when baby food, based on modified cow's milk, contains mineral iron, which may be a source of harmful free radicals. In summary, it is obvious that natural human milk has the best value for newborns. Supplementation of artificial baby food with LF seems essential to improve the protective and immunoenhancing property of this kind of diet. It is clear that cow's milk is not appropriate for human newborns. Cow's milk contains 50 times less LF, only traces of lysozyme, and lower concentrations of other whey proteins and immunologically relevant immunoglobulins. Therefore commercially available baby foods (United States, Japan) are supplemented with LF.

Adjuvants, Immunologic↗

PubMed2005

The synthesis, physicochemical properties and immunological activity of 5-amino-3-methylisoxazolo[5,4-d]4-pyrimidinone derivatives.

A series of 5-amino-3-methylisoxazole[5,4-d]4-pyrimidinone derivatives were obtained by reacting substituted 5-amino-3-methylisoxazol-4-carboxylic acid hydrazide with ethyl ortho-formate. The compounds were tested using the models of in vivo cellular and humoral immune response in mice and pokeweed mitogen-induced (PWM-induced) polyclonal antibody production in a culture of human peripheral blood mononuclear cells (PBMC). The compounds exhibited differential inhibitory activities in the described models, depending on the character and location of the substituted groups. We suggest that the compounds affect the early stages of the immune response.

Animals↗

PubMed2004

Lethality in LPS-induced endotoxemia in C3H/HeCr mice is associated with prevalence of proinflammatory cytokines: lack of protective action of lactoferrin.

C3H/HeCr mice are more susceptible to infection compared with other strains. Lactoferrin (LF), a protein involved in innate defense, was shown to protect mice against lethal endotoxemia. In this investigation we attempt to explain the cause of increased susceptibility of C3H/HeCr mice to LPS and lack of protective LF action in these mice. We found that C3H/HeCr mice produced up to 5-fold more serum TNFalpha and 66% higher IFNgamma levels in response to i.v. LPS injection than the control, CBA strain. 24 h pretreatment of C3H/HeCr mice with LF did not cause inhibition of the LPS-induced TNFalpha serum levels, whereas in CBA mice LF significantly decreased TNFalpha level. IL-6 serum levels, in turn, were lowered in C3H/HeCr mice but elevated in CBA mice. That differential regulation of cytokine production by LF in C3H/HeCr mice paralleled a decreased survival after lethal LPS injection - 10% vs. 60% in control, PBS treated mice. In addition, determination of colony forming units (CFU) in livers and spleens after administration of 10(8) Escherichia coli revealed that pretreatment of CBA mice with LF caused a marked reduction of CFU in these organs, whereas in C3H/HeCr mice the changes were insignificant. These results indicate that the altered TNFalpha/IL-6 ratio in C3H/HeCr mice, as compared to control CBA mice, as well as the increased IFNgamma level, may be responsible for the increased susceptibility to endotoxemia in that substrain. We also suggest that an association exists between the LF protective effect against endotoxic sequelae and the insult-induced systemic immune response.

Animals↗

PubMed2004

Immunosuppressory activity of ubiquitin fragments containing retro-RGD sequence.

A peptide fragment corresponding to the ubiquitin(50-59) sequence (LEDGRTLSDY) (U50-59) possesses a very high immunosuppressory activity, comparable to that of cyclosporine, both in the cellular and humoral immune responses. We found that the pentapeptide DGRTL (U52-56) is the shortest, effective immunosuppressory fragment of ubiquitin, although its potency is weaker than that of U50-59. Replacement of each consecutive residue with alanine in U52-56 allowed identification of essential amino acids involved in the immunosuppression. We also evaluated the roles of its N- and C-terminal groups by their acetylation and/or amidation, respectively. The active sequence is located in the external loop of the molecule and therefore it may serve as an important functional epitope for intermolecular binding. Based on the crystal structure of ubiquitin molecule, we designed and synthesized the cyclic analogue with a restricted conformation, cyclo(Glt-Gln-Leu-Glu-Asp-Gly-Arg-Thr-Leu-Ser-Asp-Lys)-NH2 (Glt = glutaryl) by reacting the C-terminal Lys side chain with the glutarylated N-terminus. The peptide was designed to mimic the ubiquitin(48-59) loop, in order to obtain the ligand that may interact with hypothetical receptors of the loop. The cyclization product selectively but strongly suppresses the cellular immune response. The results indicate that the 48-59 loop may serve as an important functional epitope in the ubiquitin molecule for intermolecular binding.

Amino Acid Sequence↗

PubMed2004

[Effect of methotrexate on the immune response in selected experimental models].

Methotrexate (MTX) is one of the immunosuppressory compounds applied in the prophylaxis and treatment of several diseases, including: rheumatoid arthritis, systemic lupus erythematosus, psoriasis, graft-versus-host disease and, in combination with other drugs, neoplastic diseases. Studies in humans and in animal model, of clinical disease, have demonstrated that MTX diminishes the clinical symptoms of various immunological disorders. MTX, an antagonist of folic acid synthesis, causes apoptosis in activated cells, primarily in the G1 and S phases of the cell cycle. One of its actions, is inhibition of the synthesis or activity of several proinflammatory cytokines. At high doses, MTX is cytotoxic to hemopoietic cells; low doses, however, promote hemopoiesis. MTX also induces the differentiation of monocytic tumor cells, which may explain, in part, its therapeutic effects in the treatment of some disorders. The compound suppresses both cellular and humoral immune response and mitogen-induced lymphocyte proliferation. These effects are dose- and time-dependent. The strongest suppressory activity is exerted when MTX is applied 24 or 48 hours after immunization or mitogen stimulation. Administration of MTX in unfavorable conditions such as stress or other diseases, diminishes its tolerance and increases its toxicity. Side-effects of MTX may be ameliorated by application of pharmacological synthetic agents and plant extracts. In summary, MTX has been an effective agent in suppressing immunological disorders (for 50 years) and is still finding many applications.

Animals↗

PubMed2004

[The effect of psychic stress on the immune response].

Linkage between the central nervous system and the immune system is obvious and is accomplished through the hypothalamus-pituitary-adrenal (HPA) and sympathetic-adrenal medullary (SAM) axes. This review focuses on the effects of psychic stress in animals and humans on immune system function. The effects of stress depend on its duration, type, and intensity. Generally, mild stress enhances the immune response. The effects of stress also depend on the animal's behavioral profile, genetic background and preexposure to stressful conditions. Prenatal stress modifies the immune response of the offspring. Stress also modifies autoimmune reactions in animals and humans. Knowledge of the mediators and their receptors involved in the functioning of the HPA and SAM axes allows pharmacological intervention to alleviate the harmful effects of stress on the immune system. Our studies revealed a benefit of oral lactoferrin application in reversing stress-induced changes in the humoral and cellular immune response in mice.

Administration, Oral↗

PubMed2004

Normalization of peripheral blood cell composition by lactoferrin in cyclophosphamide-treated mice.

BACKGROUND: Cyclophosphamide (CP) is used in the treatment of autoimmune disorders and leukemia. The compound induces severe leuko- and neutropenia. Lactoferrin (LF) is a protein which plays a role in the innate immunity. In this study we evaluated the usefulness of LF in reversing CP-induced lympho- and neutropenia in mice. MATERIAL/METHODS: CBA mice were treated with CP (350 mg/kg body weight, intraperitoneally) and given LF as a 0.5% addition to drinking water. Alternatively, LF was administered orally (seven doses, 1 mg each) on alternate days following CP injection. Control groups received CP or LF only. Blood samples were taken before treatment and on days 4, 8, 15 and 22 following CP injection to determine leukocytosis and cell types in blood smears. RESULTS: Mice treated with CP showed severe leukopenia, strong eosinophilia (day 4), and an altered lymphocyte/neutrophil ratio (days 8-22). Treatment of mice with LF for 21 days partially normalized the cell composition in CP-treated mice (increased percentage of lymphocytes and decreased eosinophil content). The content of leukocytes increased upon LF treatment on days 4, 8, 15 and 22 (by 36.8, 39.5, 72 and 70.7%, respectively). More importantly, LF partly normalized the neutrophil and lymphocyte composition on day 22 (neutrophils: 29.2% in control mice, 50.6% in CP-treated, and 39.16% in CP/LF-treated; lymphocytes: 66.18% in control mice, 35% in CP-treated and 48.8% in CP/LF-treated). Administration of LF alone did not change the cell numbers or composition. CONCLUSIONS: LF given orally to CP-immunocompromised mice accelerates reconstitution of lymphopoiesis and myleopoiesis.

Animals↗

PubMed2004

Threonine at position 6 is not essential for the immunosuppressive activity of HLA-DQ(beta164-172)-hexapeptide.

It has been previously found that the nonapeptide fragment of human leukocyte antigen (HLA)-DQ molecule, located in the beta chain 164-172 with the Thr-Pro-Gln-Arg-Gly-Asp-Val-Tyr-Thr sequence, suppresses the immune response. The hexapeptide: Arg-Gly-Asp-Val-Tyr-Thr was the shortest fragment of HLA-DQ showing both cellular and humoral immunosuppressive activity, while the analog deprived of the last amino acid (Arg-Gly-Asp-Val-Tyr) showed very weak stimulatory activity with respect to the humoral immune response. This suggested that the threonine residue in the hexapeptide plays an essential role in immunosuppression. In this study, the role of the side chain of threonine residue was scrutinized in a series of synthetic analogs in which the Thr residue was substituted by various amino acids, amides and methyl ester. The synthesized peptides were evaluated for their immunosuppressive activity. Our results indicate that the substitutions did not significantly affect the immunomodulatory properties, revealing that the threonine side chain is not critical for the immunosuppressive potency of the peptides. Interestingly, a simple analogue, pentapeptide amide H-Arg-Gly-Asp-Val-Tyr-NH2 possessed high immunosuppressive potency, comparable to that of cyclosporine.

Biological Assay↗

PubMed2004

Dimerization of the immunosuppressive peptide fragment of HLA-DR molecule enhances its potency.

Our previous studies revealed that the nonapeptide fragment of HLA-DR molecule, located in the beta chain 164-172 with the VPRSGEVYT sequence, suppresses the immune responses. The sequence is located on the exposed molecule loop, therefore it may be involved in the interactions with other proteins. We suggested that the loop may serve as a functional epitope on the HLA class II surface for intermolecular binding, and that possible mechanism of biological action of the synthesized peptides is associated with interfering of adhesion of HLA class II molecules to their coreceptors. It has been postulated that oligomerization of the coreceptors is required for stable binding to class II HLA. Based on the crystal dimeric structure of HLA-DR molecules, we designed, and synthesized molecules able to induce the putative coreceptors dimerization. The synthesized series of compounds consisted of two VPRSGEVYT sequences linked through their C-termini by spacers of different length: (VPRSGEVYTGn)2K-NH2 ( n = 4-6). The results demonstrate that the dimerization of the nonapeptide fragment of HLA-DR results in enhanced immunosuppressory properties.

Amino Acid Sequence↗

PubMed2004

New analogue of cyclolinopeptide B modified by amphiphilic residue of alpha-hydroxymethylmethionine.

In order to evaluate the role and influence of the methionine residue on the biological activity of cyclolinopeptide B, an analogue with methionine residue in position 7 replaced by the amphiphilic (S)-alpha-hydroxymethylmethionine residue was synthesized. This peptide exhibits high immunosuppressive activity in the cellular, and to a lesser degree in the humoral immune response, comparable to that of CsA. In addition, the peptide was devoid of toxicity, even at high doses.

Animals↗

PubMed2004

Search for new lead structures for low-molecular-weight immune response modifiers.

In this report we describe different types of 5-amino-3-methylisoxazolo-4-carboxylic acid amides and 5-amino-3-methylisoxazolo-4-ureilenes and their immunological activities. The immunoregulatory activities were tested in the humoral and cellular immune response in mice. The compounds exhibited both immunostimulatory and immunosuppressory activities.

Amides↗

PubMed2004

Structure and immunological activity of disubstituted thiosemicarbazide isoxazole derivative.

As a part of the research program on isoxazole compounds of immunological activity, we synthesized a new derivative possessing thiosemicarbazide group between 5-amino-3-methylisoxazole-4-carbonyl and phenyl substituent. In the present study, we examined the effect of compound RM2 on the spontaneous proliferative response of splenocytes and mitogen-induced splenocyte proliferation. Synthesis and biological effect is reported.

Adjuvants, Immunologic↗