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-Met-enkephalin is a neuropeptide known to exert protective effects in various experimental models of autoimmune and inflammatory diseases. These effects are mediated through opioid receptors and can be abolished by the opioid receptor antagonist naltrexone. Investigation of peptide enantiomerism and the incorporation of d-amino acids are crucial for designing novel peptides with altered structural and biological properties compared with their native l-forms. Since no data are currently available on the properties or biological activity of the d-Met-enkephalin enantiomer, we evaluated its hepatoprotective potential in a mouse model of acetaminophen-induced hepatotoxicity. Male CBA mice were treated with d-Met-enkephalin, and hepatoprotection was assessed by measuring plasma alanine aminotransferase (ALT) and aspartate amino-transferase (AST) activities, along with histological liver necrosis scores. The peptide’s secondary structure and antisense peptide binding were analysed using circular dichroism and fluorescence spectroscopy, respectively. -Met-enkephalin demonstrated dose-dependent hepatoprotective effects within the range of 0.5–20 mg kg–1, with maximal protection observed at 5 mg kg , a dose comparable to that of the l-enantiomer (7.5 mg kg ). This preservation of biological activity may be attributed to the presence of the achiral amino acid glycine at positions 2 and 3, which maintains the functional conformation of the d-enantiomer. The role of opioid receptor involvement was further examined through direct receptor blockade using naltrexone and indirect inhibition with the antisense peptide IPPKY.

Muramyl dipeptide is the minimal structure of peptidoglycan with adjuvant properties. Replacement of the N -acetylmuramyl moiety and increase of lipophilicity are important approaches in the preparation of muramyl dipeptide analogues with improved pharmacological properties. Mannose receptors present on immunocompetent cells are pattern-recognition receptors and by mannose ligands binding they affect the immune system. Here we present the design, synthesis and biological evaluation of novel mannosylated desmuramyl peptide derivatives. Mannose was coupled to dipeptides containing a lipophilic adamantane on N- or C-terminus through a glycolyl or hydroxyisobutyryl linker. Adjuvant activities of synthesized compounds were investigated in the mouse model using ovalbumin as an antigen. Their activities were compared to the previously described mannosylated adamantane-containing desmuramyl peptide and peptidoglycan monomer. Tested compounds exhibited adjuvant activity and the strongest enhancement of IgG production was stimulated by compound 21 (Man-OCH 2 -ᴅ-(1-Ad)Gly-ʟ-Ala-ᴅ-isoGln).

Muramyl dipeptide (MDP) is the smallest peptidoglycan fragment able to trigger the immune response. Structural modification of MDP can lead to the preparation of analogs with improved immunostimulant properties, including desmuramyl peptides (DMPs). The aim of this work was to prepare the desmuramyl peptide (L-Ala-D-Glu)-containing adamantyl-triazole moiety and its mannosylated derivative in order to study their immunomodulatory activities in vivo. The adjuvant activity of the prepared compounds was evaluated in a murine model using ovalbumin as an antigen, and compared to the reference adjuvant ManAdDMP. The results showed that the introduction of the lipophilic adamantyl-triazole moiety at the C-terminus of L-Ala-D-Glu contributes to the immunostimulant activity of DMP, and that mannosylation of DMP modified with adamantyl-triazole causes the amplification of its immunostimulant activity.

The endemic Croatian species L., like other species from the genus , has been traditionally used in Croatia as an antibacterial agent and for the treatment of gastrointestinal and urogenital disorders. In several chromatographic steps, three flavonoids and three sesquiterpene lactones (STLs) were isolated and identified from the most active fractions of the ethanol extract. Two STLs, one for which we created the trivial name ragusinin, and hemistepsin A are here reported for the first time as constituents of the genus . All six compounds were screened for their effect on several tumor and one normal cell lines. Among them, ragusinin showed the best bioactivity and high specificity to affect tumor murine SCCVII, human HeLa and Caco-2 cell lines, but not the viability of normal V79 fibroblasts. Due to these characteristics the action of ragusinin was investigated in more detail. Since DNA is the primary target for many drugs with antibacterial and anticancer activity, we studied its interaction with ragusinin. Rather moderate binding affinity to DNA excluded it as the primary target of ragusinin. Due to the possibility of STL interaction with glutathione (GSH), the ubiquitous peptide that traps reactive compounds and other xenobiotics to prevent damage to vital proteins and nucleic acids, its role in deactivation of ragusinin was evaluated. Addition of the GSH precursor N-acetyl-cysteine potentiated the viability of HeLa cells, while the addition of GSH inhibitor L-buthionine sulfoximine decreased it. Moreover, pre-treatment of HeLa cells with the inhibitor of glutathione-S-transferase decreased their viability indicating the detoxifying role of GSH in ragusinin treated cells. Cell death, derived by an accumulation of cells in a G2 phase of the cell cylce, was shown to be independent of poly (ADP-ribose) polymerase and caspase-3 cleavage pointing toward an alternative cell death pathway.

Central and peripheral serotonin (5HT) have opposing functions in the regulation of energy homeostasis. Both increasing 5HT signaling in the brain and decreasing 5HT signaling in the periphery have been proposed as potential treatments for obesity. This study investigates the relationship between constitutionally high or low 5HT activity and systemic net energy balance. Two sublines of rats with high and low whole-body 5HT tone, obtained by selective breeding for platelet 5HT parameters, were examined for fat accumulation in different white adipose tissue (WAT) depots, glucose/insulin tolerance, blood metabolic parameters, and expression of various metabolic genes. High-5HT animals, unlike their low-5HT counterparts, developed widespread intra-abdominal obesity associated with glucose and insulin intolerance, which worsened with age. They also had elevated blood glucose and lipid parameters but showed no significant changes in circulating leptin, resistin, and adipsin levels. Surprisingly, adiponectin levels were increased in plasma but reduced in the WAT of high-5HT rats. A limited number of metabolic genes belonging to different functional classes showed differential expression in WAT of high-5HT compared to low-5HT rats. Overall, a constitutive increase in 5HT tone is associated with a positive energy balance acting through subtle dysregulation of a broad spectrum of metabolic pathways.

Muramyl dipeptide (N-acetylmuramyl-L-alanyl-D-isoglutamine, MDP) is the smallest peptidoglycan fragment able to trigger an immune response by activating the NOD2 receptor. Structural modification of MDP can lead to analogues with improved immunostimulating properties. The aim of this work was to prepare mannosylated desmuramyl peptides (ManDMP) containing lipophilic triazole substituents to study their immunomodulating activities in vivo. The adjuvant activity of the prepared compounds was evaluated in the mouse model using ovalbumin as an antigen and compared to the MDP and referent adjuvant ManDMPTAd. The obtained results confirm that the α-position of D-isoGln is the best position for the attachment of lipophilic substituents, especially adamantylethyl triazole. Compound 6c exhibited the strongest adjuvant activity, comparable to the MDP and better than referent ManDMPTAd.

Immunoglobulin G (IgG) N - glycosylation is crucial for its effector functions. It is a complex trait, and large sample sets are needed to discover multiple genetic factors that underlie it. While in humans such high-throughput studies of IgG N-glycans became usual, only one has been carried out in mice. Here we describe and validate a method for the relative quantification of IgG Fc-linked N - glycans in a subclass-specific manner using nano-reverse phase liquid chromatography coupled with mass-spectrometry (nanoRP-LC-MS) applied to murine IgG. High-throughput data processing is ensured by the LaCyTools software. We have shown that IgG isolation procedure is the main source of technical variation in the current protocol. The major glycoforms were quantified reliably with coefficients of variation below 6% for all the analytes with relative abundances above 5%. We have applied our method to a sample set of 3 inbred strains: BALB/c, C57BL/6 and C3H and observed differences in subclass-specific and strain - specific N - glycosylation of IgG, suggesting a significant genetic component in the regulation of Fc-linked IgG N - glycosylation.

Recent histopathological investigations in patients with hepatitis suggested possible involvement of Met-enkephalin and its receptors in the pathophysiology of hepatitis. Consequently, we evaluated the potential hepatoprotective effects of this endogenous opioid pentapeptide in the experimental model of acetaminophen induced hepatotoxicity in male CBA mice. Met-enkephalin exhibited strong hepatoprotective effects in a dose of 7.5 mg/kg, which corresponds to the protective dose reported for several different animal disease models. In this group plasma alanine aminotransferase and aspartate aminotransferase enzyme activities, as well as liver necrosis score were significantly reduced in comparison to control animals treated with physiological saline (p > 0.01). The specificity of the peptide hepatoprotection was investigated from the standpoint of the receptor and peptide blockade. It was concluded that Met-enkephalin effects on the liver were mediated via δ and ζ opioid receptors. Genotoxic testing of Met-enkephalin confirmed the safety of the peptide.

The mechanisms that lead to sex and age differences in biological responses to exposure to ionising radiation and related health risks have still not been investigated to a satisfactory extent. The significance of sex hormones in the aetiology of radiogenic cancer types requires a better understanding of the mechanisms involved, especially during organism development. The aim of this study was to show age and sex differences in genome damage between prepubertal and adult mice after single exposure to gamma radiation. Genome damage was measured 24 h, 48 h, and 72 h after exposure of 3-week and 12-week old BALB/CJ mice to 8 Gy of gamma radiation using an in vivo micronucleus assay. There was a significantly higher genome damage in prepubertal than in adult animals of both sexes for all sampling times. Irradiation caused a higher frequency of micronuclei in males of both age groups. Our study confirms sex differences in the susceptibility to effects of ionising radiation in mice and is the first to show that such a difference occurs already at prepubertal age.

The cytotoxic activity of phenylboroxine acid was evaluated in vitro on mouse mammary adenocarcinoma 4T1, mouse squamous cell carcinoma SCCVII, hamster lung fibroblast V79 and mouse dermal fibroblasts L929 cell lines. The cytotoxic effects were dose dependent for all tested tumour and non-tumour cell lines. Under in vivo conditions, three application routes of phenylboronic acid were studied: intra-peritoneal (i.p.), intra-tumour (i.t.) and per-oral. After tumour transplantation in syngeneic mice, phenylboronic acid was shown to slow the growth of both tumour cell lines (4T1 and SCCVII) compared with the control. The inhibitory effects were pronounced during the application of phenylboronic acid. For both tested tumour cell lines, the most prominent antitumour effect was obtained by intraperitoneal administration, followed significantly by oral administration.