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1.
Biomedicines ; 11(4)2023 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-37189633

RESUMEN

In this article, we review the benefits of applying bovine colostrum (BC) and lactoferrin (LF) in animal models and clinical trials that include corticosteroid application and psychic stress, treatment with non-steroid anti-inflammatory drugs (NSAIDs) and antibiotics. A majority of the reported investigations were performed with native bovine or recombinant human LF, applied alone or in combination with probiotics, as nutraceutics and diet supplements. Apart from reducing adverse side effects of the applied therapeutics, BC and LF augmented their efficacy and improved the wellness of patients. In conclusion, LF and complete native colostrum, preferably administered with probiotic bacteria, are highly recommended for inclusion in therapeutic protocols in NSAIDs and corticosteroid anti-inflammatory, as well as antibiotic, therapies. These colostrum-based products can also be of value for individuals subjected to prolonged psychophysical stress (mediated by endogenous corticosteroids), especially at high ambient temperatures (soldiers and emergency services), as well as physically active people and training athletes. They are also recommended for patients during recovery from trauma and surgery, which are always associated with severe psychophysical stress.

2.
Int Immunopharmacol ; 118: 109995, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-36963263

RESUMEN

The in vitro immunotropic actions of a calf thymus extract - thymus factor X (TFX®) preparation were investigated. The preparation did not lower the viability of the A549 epithelial cell line and mouse bone marrow cells in the investigated concentration range. TFX® exhibited a co-stimulatory action of concanavalin A (Con A)-induced mouse thymocyte proliferation and partially restored the mitogen-induced proliferation capability of mouse thymocytes exposed to hydrocortisone (HC). The preparation also inhibited Herpes virus-1 (HSV-1) replication in A549 cells when preincubated with the virus and when added to the infected cells. In addition, it weakly inhibited lipopolysaccharide (LPS)-induced TNF α, IL-1ß and IL-6 by the THP-1 monocyte cell line. The determination of mitogen activated protein kinase (MAPK) expression in Jurkat T cells revealed strong increases in ERK-2 kinase and p38α subunits. In WEHI 231 immature B cells, TFX® elevated p38α, and had a particularly strong elevating effect on p38γ. In HL-60 myeloblastic cells, the expression of p38α, ß and γ was not detectable, almost blocked for p38δ and JNK, but accompanied by an increase in ERK-1. In turn, the effects of TFX® in J744E macrophages resulted in a strong increase in p38γ expression, moderate elevations of ERK and a drop in p38δ. Significant increases in MAPK expression were also found in cells from the lymphoid organs. In the bone marrow cell population, p38α, ß and γ, in thymocytes p38α, γ and δ, and in splenocytes p38ß and γ, subunit expression was elevated. We conclude that the changes in MAPK expression may be attributed to cell maturation and differentiation, and explain the beneficial therapeutic effects of TFX®.


Asunto(s)
Proteínas Quinasas Activadas por Mitógenos , Extractos del Timo , Animales , Ratones , Proteína Quinasa 13 Activada por Mitógenos , Timocitos , Proteínas Quinasas p38 Activadas por Mitógenos
3.
Biomedicines ; 11(1)2023 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-36672622

RESUMEN

In this article, we review the benefits of application of colostrum and colostrum-derived proteins in animal models and clinical trials that include chemotherapy with antimetabolic drugs, radiotherapy and surgical interventions. A majority of the reported investigations was performed with bovine colostrum (BC) and native bovine or recombinant human lactoferrin (LF), applied alone, in nutraceutics or in combination with probiotics. Apart from reducing side effects of the applied therapeutics, radiation and surgical procedures, BC and LF augmented their efficacy and improved the wellness of patients. In conclusion, colostrum and colostrum proteins, preferably administered with probiotic bacteria, are highly recommended for inclusion to therapeutic protocols in cancer chemo- and radiotherapy as well as during the surgical treatment of cancer patients.

4.
Biometals ; 36(3): 617-627, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36136256

RESUMEN

Lactoferrin (LTF) is a natural iron-binding protein with a potential for clinical utility in many human immune disorders, including cancer. A fusion of LTF with the Fc domain of IgG2 (FcLTF) was designed with inherent properties of an extended the half-life in circulation. Furthermore, the effects of LTF and FcLTF were assessed for influence on the activity of natural killer (NK) cells isolated from human peripheral blood, on the NK-92 cell line, and on human monocytes. The NK cytotoxic activity induced by LTF and FcLTF was determined against the human leukemia K562 cell line, and also for monocytes, by measuring TNFα and granzyme B production, and in an assay for Jurkat cell viability. Selected gene expression in NK-92 cells and monocytes, induced by LTF and FcLTF, was performed by Real Time PCR. No significant difference was observed in NK-92 cytotoxicity stimulated by LTF and FcLTF. The effects on NK cells isolated from the human peripheral blood were varied, possibly due to the immunoregulatory nature of LTF sensing the immune status of donors. Furthermore, only the FcLTF group strongly stimulated production of TNFα and granzyme B in isolated monocytes. In addition, only supernatants from the monocyte cultures treated with FcLTF decreased the viability of Jurkat cells. The ability of FcLTF to induce TNFα in monocytes was strongly inhibited by anti-CD32 and moderately inhibited by anti-CD14 antibody. Lastly, it was demonstrated that FcLTF, strongly induced expression of PI3K, with subsequent activation of AKT/mTOR signaling pathway. Overall, it was demonstrated that this novel fusion molecule may be a perferred choice for clinical utility than the wild type LTF.


Asunto(s)
Antineoplásicos , Lactoferrina , Humanos , Lactoferrina/farmacología , Lactoferrina/metabolismo , Granzimas/genética , Granzimas/metabolismo , Granzimas/farmacología , Factor de Necrosis Tumoral alfa , Antineoplásicos/farmacología , Monocitos , Inmunoglobulina G/farmacología , Inmunoglobulina G/metabolismo
5.
Int J Mol Sci ; 23(13)2022 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-35806175

RESUMEN

Short peptides have great potential as safe and effective anticancer drug leads. Herein, the influence of short cyclic peptides containing the Pro-Pro-Phe-Phe sequence on patient-derived melanoma cells was investigated. Cyclic peptides such as cyclo(Leu-Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe-), called CLA, and cyclo(Pro-homoPro-ß3homoPhe-Phe-), called P11, exert the cytotoxic and the cytostatic effects in melanoma cells, respectively. CLA was the most active peptide as it reduced the viability of melanoma cells to 50% of control at about 10 µM, whereas P11 at about 40 µM after 48 h incubation. Interestingly, a linear derivative of P11 did not induce any effect in melanoma cells confirming previous studies showing that cyclic peptides exert better biological activity compared to their linear counterparts. According to in silico predictions, cyclic tetrapeptides show a better pharmacokinetic and toxic profile to humans than CLA. Notably, the spatial structure of those peptides containing synthetic amino acids has not been explored yet. In the Cambridge Structural Database, there is only one such cyclic tetrapeptide, cyclo((R)-ß2homoPhe-D-Pro-Lys-Phe-), while in the Protein Data Bank-none. Therefore, we report the first crystal structure of cyclo(Pro-Pro-ß3homoPhe-Phe-), denoted as 4B8M, a close analog of P11, which is crucial for drug discovery. Comparative molecular and supramolecular analysis of both structures was performed. The DFT findings revealed that 4B8M is well interpreted in the water solution. The results of complex Hirshfeld surface investigations on the cooperativity of interatomic contacts in terms of electrostatic and energetic features are provided. In short, the enrichment ratio revealed O…H/H…O and C…H/H…C as privileged intercontacts in the crystals in relation to basic and large supramolecular H-bonding synthon patterns. Furthermore, the ability of self-assemble 4B8M leading to a nanotubular structure is also discussed.


Asunto(s)
Melanoma , Péptidos Cíclicos , Dipéptidos , Humanos , Melanoma/tratamiento farmacológico , Péptidos , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología
6.
Molecules ; 27(11)2022 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-35684487

RESUMEN

The core of Cyclolinopeptide A (CLA, cyclo(LIILVPPFF)), responsible for its high immunosuppressive activity, contains a Pro-Pro-Phe-Phe sequence. A newly synthesized cyclic tetrapeptide, cyclo(Pro-Pro-ß3-HoPhe-Phe) (denoted as 4B8M) bearing the active sequence of CLA, was recently shown to exhibit a wide array of anti-inflammatory properties in mouse models. In this investigation, we demonstrate that the peptide significantly inhibits the replication of human adenovirus C serotype 5 (HAdV-5) and Herpes simplex virus type-1 (HSV-1) in epithelial lung cell line A-549, applying Cidofovir and Acyclovir as reference drugs. Based on a previously established mechanism of its action, we propose that the peptide may inhibit virus replication by the induction of PGE2 acting via EP2/EP4 receptors in epithelial cells. In summary, we reveal a new, antiviral property of this anti-inflammatory peptide.


Asunto(s)
Herpesvirus Humano 1 , Animales , Antivirales/farmacología , Dipéptidos , Inmunosupresores/farmacología , Ratones , Péptidos , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología
7.
Front Chem ; 9: 784003, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34869231

RESUMEN

During inflammation neutrophils become activated and segregate neutrophil serine proteases (NSPs) to the surrounding environment in order to support a natural immune defense. However, an excess of proteolytic activity of NSPs can cause many complications, such as cardiovascular diseases and chronic inflammatory disorders, which will be elucidated on a biochemical and immunological level. The application of selective serine protease inhibitors is the logical consequence in the management of the indicated comorbidities and will be summarized in this briefing.

8.
Biomedicines ; 9(12)2021 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-34944756

RESUMEN

Women's intimate health depends on several factors, such as age, diet, coexisting metabolic disorders, hormonal equilibrium, sexual activity, drug intake, contraception, surgery, and personal hygiene. These factors may affect the homeostasis of the internal environment of the genital tract: the vulva, vagina and cervix. This equilibrium is dependent on strict and complex mutual interactions between epithelial cells, immunocompetent cells and microorganisms residing in this environment. The microbiota of the genital tract in healthy women is dominated by several species of symbiotic bacteria of the Lactobacillus genus. The bacteria inhibit the growth of pathogenic microorganisms and inflammatory processes by virtue of direct and multidirectional antimicrobial action and, indirectly, by the modulation of immune system activity. For the homeostasis of the genital tract ecosystem, antimicrobial and anti-inflammatory peptides, as well as proteins secreted by mucus cells into the cervicovaginal fluid, have a fundamental significance. Of these, a multifunctional protein known as lactoferrin (LF) is one of the most important since it bridges innate and acquired immunity. Among its numerous properties, particular attention should be paid to prebiotic activity, i.e., exerting a beneficial action on symbiotic microbiota of the gastrointestinal and genital tract. Such activity of LF is associated with the inhibition of bacterial and fungal infections in the genital tract and their consequences, such as endometritis, pelvic inflammation, urinary tract infections, miscarriage, premature delivery, and infection of the fetus and newborns. The aim of this article is to review the results of laboratory as well as clinical trials, confirming the prebiotic action of LF on the microbiota of the lower genital tract.

10.
Biomedicines ; 9(8)2021 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-34440102

RESUMEN

Pregnancy is a physiological state that demands higher level of nutrients, including vitamins and minerals, for the growth and maintenance of the fetus. Iron deficiency is a part of most common diet deficiencies in pregnancy and has high clinical significance leading to the development of syderopenic anemia and its consequences for mother and child, such as higher risk of perinatal death, susceptibility to infection, intra-uteral growth inhibition, prematurity and low birth weight. Hence, iron supplementation is recommended for pregnant women; however dietary intake of iron from most commercially available formulas is often insufficient due to iron-poor bioavailability, or have undesired side-effects in the gastrointestinal tract, resulting in a discouraging and distrustful attitude to such treatment. The results of numerous studies indicate that diet supplementation with lactoferrin (LTF), an iron-binding protein, may be advantageous in prophylaxis and treatment of iron deficiency anemia. LTF, administered orally, normalizes iron homeostasis, not only by facilitating iron absorption, but also by inhibiting inflammatory processes responsible for anemia of chronic diseases, characterized by a functional iron deficit for physiological processes. LTF also protects against infections and inflammatory complications, caused by diagnostic surgical interventions in pregnant women. Beneficial, multidirectional actions of LTF during pregnancy encompass, in addition, inhibition of oxidative stress, normalization of intestine and genital tract microbiota and carbohydrate-lipid metabolism, protection of intestine barrier function, promotion of wound healing, as well as hypotensive, analgesic and antistress actions. Bovine lactoferrin (BLTF) is readily available on the nutritional market and generally recognized as safe (GRAS) for use in human diet.

11.
Ann Clin Lab Sci ; 51(3): 359-367, 2021 May.
Artículo en Inglés | MEDLINE | ID: mdl-34162566

RESUMEN

OBJECTIVE: The aim of this investigation was to evaluate the property of bovine lactoferrin (LF) in the generation of delayed type hypersensitivity (DTH) as an oral adjuvant during immunization with ovalbumin (OVA) and BCG. METHODS: LF admixed with OVA or BCG was used for immunization of CBA or C57BL/6 mice when given via oral or subcutaneous routes. Elicited DTH response was measured post immunization. Inhibition studies using mannose or galactose were accomplished by gavage prior to oral administration of antigens. LF was also examined for effects on BCG uptake by bone marrow derived macrophages (BMM). RESULTS: LF at doses of 1.0 mg and 10.0 mg, admixed with OVA (10.0 mg), significantly enhanced the antigen-specific DTH reaction. The stimulatory effects of LF were inhibited by the oral pretreatment of mice with 50.0 mg of mannose but not galactose. LF also enhanced the DTH reaction to orally administered BCG. LF enhanced uptake of BCG by BMM in a dose-dependent manner. CONCLUSION: LF was able to augment development of DTH when orally administered with OVA or BCG antigens. Inhibition studies suggest the involvement of the receptor with an affinity to mannose in mediation of the adjuvant effect. LF augmentation of the DTH response was partially effective when given in advance of oral delivery of the antigen; this effect could also be saturated by mannose. BCG studies provide preliminary evidence for LF in the potential augmentation of oral vaccination to prevent mycobacterial infection. In vitro experiments provide evidence that LF plays a role in modulation of antigen presenting cell activation.


Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Antígenos/administración & dosificación , Hipersensibilidad Tardía/patología , Lactoferrina/administración & dosificación , Macrófagos/inmunología , Mycobacterium bovis/inmunología , Ovalbúmina/administración & dosificación , Administración Oral , Animales , Antígenos/inmunología , Hipersensibilidad Tardía/etiología , Lactoferrina/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ovalbúmina/inmunología
12.
Pharmaceuticals (Basel) ; 14(5)2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-34063515

RESUMEN

Previous studies demonstrated strong anti-inflammatory properties of isoxazolo[5,4-e]-1,2,4-triazepine (RM33) in vivo. The aim of this investigation was to describe synthesis, determine physicochemical characteristics, evaluate biological activities in murine and human in vitro models, as well as to propose mechanism of action of the compound. The compound was devoid of cell toxicity up to 100 µg/mL against a reference A549 cell line. Likewise, RM33 did not induce apoptosis in these cells. The compound stimulated concanavalin A (ConA)-induced splenocyte proliferation but did not change the secondary humoral immune response in vitro to sheep erythrocytes. Nevertheless, a low suppressive effect was registered on lipopolysaccharide (LPS)-induced splenocyte proliferation and a stronger one on tumor necrosis factor alpha (TNFα) production by rat peritoneal cells. The analysis of signaling pathways elicited by RM33 in nonstimulated resident cells and cell lines revealed changes associated with cell activation. Most importantly, we demonstrated that RM33 enhanced production of cyclooxygenase 2 in LPS-stimulated splenocytes. Based on the previous and herein presented results, we conclude that RM33 is an efficient, nontoxic immune suppressor with prevailing anti-inflammatory action. Additionally, structural studies were carried out with the use of appropriate spectral techniques in order to unequivocally confirm the structure of the RM33 molecule. Unambiguous assignment of NMR chemical shifts of carbon atoms of RM33 was conducted thanks to full detailed analysis of 1H, 13C NMR spectra and their two-dimensional (2D) variants. Comparison between theoretically predicted chemical shifts and experimental ones was also carried out. Additionally, N-deuterated isotopologue of RM33 was synthesized to eliminate potentially disturbing frequencies (such as NH, NH2 deformation vibrations) in the carbonyl region of the IR (infrared) spectrum to confirm the presence of the carbonyl group.

13.
Molecules ; 26(9)2021 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-33925288

RESUMEN

The consequences of manipulations in structure and amino acid composition of native cyclolinopeptide A (CLA) from linen seeds, and its linear precursor on their biological activities and mechanisms of action, are reviewed. The modifications included truncation of the peptide chain, replacement of amino acid residues with proteinogenic or non-proteinogenic ones, modifications of peptide bond, and others. The studies revealed changes in the immunosuppressive potency of these analogs investigated in a number of in vitro and in vivo experimental models, predominantly in rodents, as well as differences in their postulated mechanism of action. The modified peptides were compared with cyclosporine A and parent CLA. Some of the synthesized and investigated peptides show potential therapeutic usefulness.


Asunto(s)
Secuencia de Aminoácidos/genética , Péptidos Cíclicos/genética , Péptidos/genética , Relación Estructura-Actividad , Animales , Ropa de Cama y Ropa Blanca , Inmunosupresores/química , Inmunosupresores/farmacología , Modelos Animales , Péptidos/química , Péptidos/farmacología , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Semillas/química
14.
Int Immunopharmacol ; 95: 107571, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33765614

RESUMEN

The COVID-19 pandemic is a serious global health threat caused by severe acute respiratory syndrome of coronavirus 2 (SARS-CoV-2). Symptoms of COVID-19 are highly variable with common hyperactivity of immune responses known as a "cytokine storm". In fact, this massive release of inflammatory cytokines into in the pulmonary alveolar structure is a main cause of mortality during COVID-19 infection. Current management of COVID-19 is supportive and there is no common clinical protocol applied to suppress this pathological state. Lactoferrin (LF), an iron binding protein, is a first line defense protein that is present in neutrophils and excretory fluids of all mammals, and is well recognized for its role in maturation and regulation of immune system function. Also, due to its ability to sequester free iron, LF is known to protect against insult-induced oxidative stress and subsequent "cytokine storm" that results in dramatic necrosis within the affected tissue. Review of the literature strongly suggests utility of LF to silence the "cytokine storm", giving credence to both prophylactic and therapeutic approaches towards combating COVID-19 infection.


Asunto(s)
COVID-19/terapia , Síndrome de Liberación de Citoquinas/terapia , Lactoferrina/inmunología , Lactoferrina/uso terapéutico , Animales , COVID-19/complicaciones , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/inmunología , Citocinas/metabolismo , Microbioma Gastrointestinal/inmunología , Humanos , Pulmón/inmunología , Pulmón/patología , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/terapia
15.
Pharmaceutics ; 12(11)2020 Oct 28.
Artículo en Inglés | MEDLINE | ID: mdl-33126725

RESUMEN

A cyclic tetrapeptide Pro-Pro-Pheß3ho-Phe (4B8M) was tested for immunosuppressive activity and potential therapeutic utility in several in vitro and in vivo mouse and human models. The tetrapeptide was less toxic for mouse splenocytes in comparison to cyclosporine A (CsA) and a parent cyclolinopeptide (CLA). The tetrapeptide demonstrated potent anti-inflammatory properties in antigen-specific skin inflammatory reactions to oxazolone and toluene diisocyanate as well to nonspecific irritants such as salicylic acid. It also inhibited inflammatory processes in an air pouch induced by carrageenan. In addition, 4B8M proved effective in amelioration of animal models corresponding to human diseases, such as nonspecific colon inflammation induced by dextran sulfate and allergic pleurisy induced by ovalbumin (OVA) in sensitized mice. The tetrapeptide lowered expression of EP1 and EP3 but not EP2 and EP4 prostaglandin E2 (PGE2) receptors on lipopolysaccharide-stimulated Jurkat T cells and ICAM-1 expression on human peripheral blood mononuclear cells (PBMC). Its anti-inflammatory property in the carrageenan reaction was blocked by EP3 and EP4 antagonists. In addition, 4B8M induced an intracellular level of PGE2 in a human KERTr keratinocyte cell line. In conclusion, 4B8M is a low toxic and effective inhibitor of inflammatory disorders with potential therapeutic use, affecting the metabolism of prostanoid family molecules.

16.
Molecules ; 25(15)2020 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-32759841

RESUMEN

The synthesis of a series of novel 7-aminooxazolo[5,4-d]pyrimidines 5, transformations during their synthesis and their physicochemical characteristics have been described. Complete detailed spectral analysis of the intermediates 2-4, the N'-cyanooxazolylacetamidine by-products 7 and final compounds 5 has been carried out using MS, IR, 1D and 2D NMR spectroscopy. Theoretical research was carried out to explain the privileged formation of 7-aminooxazolo[5,4-d]pyrimidines in relation to the possibility of their isomer formation and the related thermodynamic aspects. Additionally, the single-crystal X-ray diffraction analysis for 5h was reported. Ten 7-aminooxazolo[5,4-d]pyrimidines 5 (SCM1-10) were biologically tested in vitro to preliminarily evaluate their immunological, antiviral and anticancer activity. Compounds SCM5 and SCM9 showed the best immunoregulatory profile. The compounds displayed low-toxicity and strongly inhibited phytohemagglutinin A-induced proliferation of human peripheral blood lymphocytes and lipopolysaccharide-induced proliferation of mouse splenocytes. Compound SCM9 caused also a moderate suppression of tumor necrosis factor α (TNF-α) production in a human whole blood culture. Of note, the compounds also inhibited the growth of selected tumor cell lines and inhibited replication of human herpes virus type-1 (HHV-1) virus in A-549 cell line. Molecular investigations showed that the compounds exerted differential changes in expression of signaling proteins in Jurkat and WEHI-231 cell lines. The activity of SCM5 is likely associated with elicitation of cell signaling pathways leading to cell apoptosis. The compounds may be of interest in terms of therapeutic utility as inhibitors of autoimmune disorders, virus replication and antitumor agents.


Asunto(s)
Técnicas de Química Sintética , Oxazoles/síntesis química , Oxazoles/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Células Sanguíneas/efectos de los fármacos , Células Sanguíneas/metabolismo , Fenómenos Químicos , Humanos , Enlace de Hidrógeno , Linfocitos/inmunología , Linfocitos/metabolismo , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Oxazoles/química , Pirimidinas/química , Transducción de Señal , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa
17.
Peptides ; 132: 170365, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32622694

RESUMEN

The synthesis of new analogues of cyclolinopeptide A (CLA) and their linear precursors modified with (R)- and (S)-4-methylpseudoproline in the Pro3-Pro4 fragment are presented. The peptides were tested in comparison with cyclosporine A (CsA) in concanavalin A (Con A) and pokeweed mitogen (PWM)-induced mouse splenocyte proliferation and in secondary humoral immune response in vitro to sheep erythrocytes (SRBC). Their effects on expression of selected signaling molecules in the Jurkat T cell line were also determined. In addition, the structural features of the peptides, applying nuclear magnetic resonance and circular dichroism, were analyzed. The results showed that only peptides 7 and 8 modified with (R)-4-methylpseudoproline residue (c(Leu1-Val2-(R)-(αMe)Ser(ΨPro)3-Pro4-Phe5-Phe6-Leu7-Ile8-Ile9) and c(Leu1-Val2-Pro3-(R)-(αMe)Ser(ΨPro)4-Phe5-Phe6-Leu7-Ile8-Ile9), respectively) strongly suppressed mitogen-induced splenocyte proliferation and the humoral immune response, with peptide 8 being more potent. Likewise, peptide 8 more strongly elevated expression of Fas, a proapoptotic signaling molecule in Jurkat cells. We postulate that the increased biological activity of peptide 8, compared to the parent molecule and other studied peptides, resulted from its more flexible structure, found on the basis of both CD and NMR studies. CD and NMR spectra showed that replacement of Pro3 by (R)-(αMe)Ser(¬Pro) caused much greater conformational changes than the same replacement of the Pro4 residue. Such a modification could lead to increased conformational freedom of peptide 8, resulting in a greater ability to adopt a more compact structure, better suited to its putative receptor. In conclusion, peptide 8 is a potent immune suppressor which may find application in controlling immune disorders.


Asunto(s)
Enfermedades del Sistema Inmune/tratamiento farmacológico , Inmunosupresores/química , Inmunosupresores/farmacología , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Prolina/análogos & derivados , Tiazoles/química , Tiazoles/farmacología , Secuencia de Aminoácidos , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Dicroismo Circular/métodos , Femenino , Humanos , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/metabolismo , Inmunosupresores/síntesis química , Linfocitos/citología , Linfocitos/efectos de los fármacos , Espectroscopía de Resonancia Magnética/métodos , Masculino , Ratones , Ratones Endogámicos CBA , Péptidos Cíclicos/síntesis química , Prolina/síntesis química , Prolina/química , Prolina/farmacología , Ovinos , Bazo/citología , Bazo/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/síntesis química
18.
Immunol Lett ; 220: 21-31, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31954800

RESUMEN

Yolkin is a product of proteolytic degradation of vitellogenin, a protein contained in eggs' yolk, with already described procognitive properties. Here, we investigated effects of yolkin on the humoral and cellular immune response in mice, phenotype of cells from lymphoid organs and function of innate immunity cells. In vitro studies included effects of yolkin on mitogen-induced thymocyte proliferation, percentage of CD19 cells in bone marrow cells culture, expression of signaling molecules in Jurkat cells, interleukin 2 receptor (IL-2R) subunits in WEHI 231 cells and susceptibility of these cells to anti-Ig-induced cell death. The results showed that repeatable i.p. injections of yolkin stimulated the humoral immune response to sheep red blood cells (SRBC) irrespective of the time of the treatment. On the other hand, yolkin inhibited contact sensitivity to oxazolone. Treatment of mice with yolkin diminished the percentage of double positive cells and increasing the content of single positive CD4+ and CD8+ cells in the thymus. At the same time an increase of percentage of CD19 + B cells in the spleen and mesenteric lymph nodes was observed. In addition, the protein, given i.p., diminished ex vivo ability to synthesize nitric oxide by resident, peritoneal macrophages, stimulated with lipopolisaccharide (LPS). In vitro studies showed that yolkin increased CD19+ cell content in bone marrow cell population. The protein also enhanced proliferation of thymocytes to concanavalin A and stimulated expression of MAP kinases in Jurkat cells. In WEHI 231 B cell line yolkin caused a loss of IL-2R gamma chain expression, correlated with an increased resistance of these cells to proapoptotic action of anti-Ig antibodies. In conclusion, this is a first demonstration of immunotropic properties of yolkin in in vitro and in vivo tests. The results provide evidence for induction of maturation and stimulatory signals in immature T and B cells by the protein, suggesting its potential role in the development of an embryo's immune system.


Asunto(s)
Inmunidad Celular/efectos de los fármacos , Inmunidad Humoral/efectos de los fármacos , Vitelogeninas/inmunología , Vitelogeninas/farmacología , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Femenino , Humanos , Células Jurkat , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Ovinos , Bazo/inmunología , Timocitos/efectos de los fármacos , Timocitos/inmunología , Timo/inmunología
19.
Histol Histopathol ; 35(7): 691-699, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31833559

RESUMEN

Phenothiazines represent a class of compounds of potential therapeutic utility. In this report we evaluated therapeutic value of an azaphenothiazine derivative, 6-acetylaminobutyl-9-chloroquino[3,2-b]benzo[1,4]thiazine (QBT), given intragastrically, in the model of dextran sodium sulfate-induced colitis in C57BL/6 mice using 5-aminosalicylic acid (5-ASA) as a reference drug. Colitis symptoms such as body weight loss, diarrhea and hematochezia (blood in stool) were observed and registered and disease activity index (DAI) was calculated. In addition, weight and cell numbers in the lymphatic organs and histological parameters of the colon wall were analyzed. The effects of QBT on viability of colon epithelial cell lines were also determined. We showed that weight and cell number of draining mesenteric lymph nodes were lower in mice treated with QBT in comparison to their control counterparts. The number of thymocytes, drastically reduced in control mice, was elevated in mice treated with the compounds with a significant effect of 5-ASA. In addition, an abnormal composition of blood cell types was partially corrected in these groups. Histological analysis of the colon revealed that the pathological changes were partially normalized by QBT and even to a higher degree by 5-ASA. In conclusion we demonstrated a therapeutic efficacy of the compound in amelioration of local and systemic pathological changes associated with chemically-induced colitis in mice. A possible mechanism of action of the compound is discussed.


Asunto(s)
Colitis Ulcerosa/patología , Colon/efectos de los fármacos , Inmunosupresores/farmacología , Fenotiazinas/farmacología , Animales , Modelos Animales de Enfermedad , Femenino , Células HCT116 , Humanos , Ratones , Ratones Endogámicos C57BL
20.
Immunol Lett ; 208: 1-7, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30825456

RESUMEN

Azaphenothiazines are predominantly immunosuppressive compounds. We evaluated the efficacy of an azaphenothiazine derivative, 6-chloroethylureidoethyldiquino[3,2-b;2',3'-e][1,4]thiazine (DQT) in prolongation of survival of skin allografts between BALB/c and C57Bl/6 mice. The mice were treated intraperitoneally (i.p.) with 100 µg of DQT on alternate days, on days 1-13 of the experiment (7 doses). The effect of DQT on a two-way mixed lymphocyte reaction (MLR) in the human model, as well as its effect on production of TNF α and IL-10 in a whole blood cell culture, stimulated by lipopolysaccharide (LPS), were evaluated. In addition, DQT effects were investigated regarding the proportion of T cell subsets in human peripheral blood lymphocytes (PBMC) by flow cytometry. Lastly, the effect of DQT on expression of signaling molecules involved in pro apoptotic pathways was determined by RT PCR. The results showed that DQT significantly extended skin graft survival. The compound also strongly suppressed two-way MLR in the human model at a concentration range of 2.5-5.0 µM. In addition, DQT inhibited LPS-inducible TNF α, but not IL-10 production. The compound preferentially caused a loss of the CD3-CD8+CD11b + PBMC cell subset, and transformed CD3+CD8+high into CD3+CD8+low cells. Lastly, we demonstrated significant increases in expression of caspases (in particular caspase 8) and of p53 in a culture of Jurkat T cells. We conclude that the immunosuppressive actions of the compound in allograft rejection may be predominantly associated with induction of cell apoptosis and inhibition of TNF α production. The apoptosis could be predominantly selective for the CD3-CD8+CD11b + cell phenotype.


Asunto(s)
Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/farmacología , Fenotiazinas/farmacología , Trasplante de Piel , Animales , Biomarcadores , Caspasa 8/metabolismo , Línea Celular , Femenino , Supervivencia de Injerto/inmunología , Humanos , Prueba de Cultivo Mixto de Linfocitos , Ratones , Modelos Animales , Transducción de Señal , Trasplante de Piel/efectos adversos , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Trasplante Homólogo , Proteína p53 Supresora de Tumor/metabolismo
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