Retinol dehydrogenase (RDH12) protects photoreceptors from light-induced degeneration in mice

RDH12 has been suggested to be one of the retinol dehydrogenases (RDH) involved in the vitamin A recycling system (visual cycle) in the eye. Loss of function mutations in the RDH12 gene were recently reported to be associated with autosomal recessive childhood-onset severe retinal dystrophy. Here we show that RDH12 localizes to the photoreceptor inner segments and that deletion of this gene in mice slows the kinetics of all-trans-retinal reduction, delaying dark adaptation. However, accelerated 11-cis-retinal production and increased susceptibility to light-induced photoreceptor apoptosis were also observed in Rdh12(-/-) mice, suggesting that RDH12 plays a unique, nonredundant role in the photoreceptor inner segments to regulate the flow of retinoids in the eye. Thus, severe visual impairments of individuals with null mutations in RDH12 may likely be caused by light damage(1).     

Expression of insulin-like growth factor-I (IGF-I) in alveolar macrophages and lymphocytes obtained by bronchoalveolar lavage (BAL) in interstitial lung diseases (ILD). Assessment of IGF-I as a potential local mitogen and antiapoptotic cytokine

Little is known about IGF-I expression in the alveolar lymphocytes (AL), and about local role of IGF-I in physiological conditions and in interstitial lung diseases. Bronchoalveolar lavage was carried out in patients with silicosis, asbestosis, idiopathic pulmonary fibrosis (IPF) and sarcoidosis, as well as in control subjects (n = 13, 9, 12, 56, 15, resp). Alveolar macrophages (AM) and lymphocytes (AL) were studied for (1) IGF-I, BCL-2, Fas and Fas Ligand expression and (2) cell cycle (incl. sub-G1 peak of late apoptosis) with propidium iodide (PI). Flow cytometry (FC) and immunocytochemistry were used. AL early apoptosis was detected by Annexin V FITC/PI staining. IGF-I was present in AL of all tested groups. The number of IGF-I positive AL was significantly higher in IPF (52 +/- 6.7%) and in later (II and III) stages of sarcoidosis (39 +/- 7.8 vs 16 +/- 4.0% in controls, p < 0.05). Increased BCL-2 expression in AL was detected in IPF and sarcoidosis. In all tested groups, AL were almost exclusively Fas+ T cells. Generally, a low number of AL entered apoptosis; no significant differences were found between patient groups, except decreased apoptosis rate in sarcoidosis (0.60 +/- 0.17 vs 1.15 +/- 0.33% in controls, p < 0.05). Proportion of AL positive for IGF-I was significantly correlated with parameters reflecting AL and AM cell proliferation and BCL-2 expression (e.g. AL IGF-I+ vs AM in S phase of cell cycle: r(S) = +0.50, p = 0.001), but not with apoptosis. The results show that human alveolar lymphocytes express IGF-I in normal conditions, as well as in ILD. The proportion of IGF-I+ lymphocytes was significantly increased in IPF and at later stages of sarcoidosis. In our material there was no evidence for profibrogenic or antiapoptotic activity of IGF-I. We suggest that IGF-I originating from AL may be locally active as a mitogen for alveolar macrophages and lymphocytes in ILD.     

Protective effects of melatonin and indole-3-propionic acid against lipid peroxidation, caused by potassium bromate in the rat kidney

Potassium bromate (KBrO(3)) is classified as a carcinogenic agent. KBrO(3) induces tumors and pro-oxidative effects in kidneys. Melatonin is a well known antioxidant and free radical scavenger. Indole-3-propionic acid (IPA), an indole substance, also reveals antioxidative properties. Recently, some antioxidative effects of propylthiouracil (PTU)-an antithyroid drug-have been found. The aim of the study was to compare protective effects of melatonin, IPA, and PTU against lipid peroxidation in the kidneys and blood serum and, additionally, in the livers and the lungs, collected from rats, pretreated with KBrO(3). Male Wistar rats were administered KBrO(3) (110 mg/kg b.w., i.p., on the 10th day of the experiment) and/or melatonin, or IPA (0.0645 mmol/kg b.w., i.p., twice daily, for 10 days), or PTU (0.025% solution in drinking water, for 10 days). The level of lipid peroxidation products-malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA)-was measured spectrophotometrically in thyroid homogenates. KBrO(3), when injected to rats, significantly increased lipid peroxidation in the kidney homogenates and blood serum, but not in the liver and the lung homogenates. Co-treatment with either melatonin or with IPA, but not with PTU, decreased KBrO(3)-induced oxidative damage to lipids in the rat kidneys and serum. In conclusion, melatonin and IPA, which prevent KBrO(3)-induced lipid peroxidation in rat kidneys, may be of great value as protective agents under conditions of exposure to KBrO(3).     

Covalent binding of the natural antimicrobial peptide indolicidin to DNA abasic sites

Indolicidin is a host defense tridecapeptide that inhibits the catalytic activity of HIV-1 integrase in vitro. Here we have elucidated its mechanism of integrase inhibition. Using crosslinking and mass spectrometric footprinting approaches, we found that indolicidin interferes with formation of the catalytic integrase-DNA complex by directly binding DNA. Further characterization revealed that the peptide forms covalent links with abasic sites. Indolicidin crosslinks single- or double-stranded DNAs and various positions of the viral cDNA with comparable efficiency. Using truncated and chemically modified peptides, we show that abasic site crosslinking is independent of the PWWP motif but involves the indolicidin unique lysine residue and the N- and C- terminal NH₂ groups. Because indolicidin can also inhibit topoisomerase I, we believe that multiple actions at the level of DNA might be a common property of antimicrobial peptides.     

PDB-UF: database of predicted enzymatic functions for unannotated protein structures from structural genomics

Background  

The number of protein structures from structural genomics centers dramatically increases in the Protein Data Bank (PDB). Many of these structures are functionally unannotated because they have no sequence similarity to proteins of known function. However, it is possible to successfully infer function using only structural similarity.     

Serum pancreatic lipase [EC 3.1.1.3] activity, serum lipid profile and peripheral blood dendritic cell populations in normolipidemic males with psoriasis

The purpose of the study was to explore serum pancreatic lipase activity and the serum lipid profile in relation to peripheral blood dendritic cell subsets and disease severity in males with psoriasis.

Material and methods

The study population consisted of 22 normolipidemic males with psoriasis and 12 aged-matched and body mass index (BMI)-matched healthy males. The percentages of peripheral blood dendritic cell (DC) subsets were evaluated using appropriate monoclonal antibodies and flow cytometry. The serum pancreatic lipase activity and the lipid profile were determined using standard enzymatic and colorimetric techniques.

Results

Pancreatic lipase activity was increased (p = 0.56421), high-density lipoprotein (HDL)-cholesterol concentration (p = 0.00584) was significantly decreased, triglyceride (p = 0.00766) and VLDL-cholesterol (p = 0.00765) levels were significantly increased in serum of psoriatic patients compared to controls. The serum pancreatic lipase activity showed significant correlation with serum triglyceride (r = 0.42; p = 0.04721) and serum VLDL-cholesterol levels (r = 0.42; p = 0.04721) in psoriatic individuals. In psoriatic patients the percentage of myeloid DCs was increased (p = 0.54932), the percentage of lymphoid DCs was decreased (p = 0.14210) and myeloid DC/lymphoid DC ratio was significantly increased (p = 0.03569) compared to healthy individuals.

Conclusion

The direct cause of the abnormal lipid profile in psoriasis and its relationship with the immune system disturbances remains unclear. The reciprocal relationship between serum pancreatic activity and serum triglyceride level appears to confirm the hypothesis about abnormal lipid metabolism in psoriasis.     

Targeting of solid tumors and blood malignancies by antibody-based therapies — EGFR-pathway as an example

A well-coordinated interaction between extracellular signals and intracellular response forms the basis of life within multicellular organisms, with growth factors playing a crucial role in these interactions. Discoveries in recent years have shown that components of the Epidermal Growth Factor (EGF) signaling system have frequently been used by cancer cells to autonomously provide survival and proliferation signals. The main focus of this review is the ErbB epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases including ErbB1/EGFR, ErbB2/HER2/neu, ErbB3/HER3, and ErbB4/HER4 as therapeutic targets. Since the ErbB receptor family regulates cell proliferation through the Ras-mitogen-activated protein kinase (RAS/MAPK) pathway, and cell survival and transformation through the phosphatidylinositol 3-kinase (PI3K/AKT) pathway, pharmacological targeting of these pathways is also discussed. We will also address the clinical studies that have been conducted to evaluate antibody-based therapies mostly on solid tumors and hematologic malignancies.     

Synthesis of imidazoline and imidazo[2,1-c][1,2,4]triazole aryl derivatives containing the methylthio group as possible antibacterial agents

1-Arylimidazolidine-2-thiones (1a-g) were synthesized by the condensation reaction of N-arylethylenediamines with carbon disulfide in xylene medium. Their further alkylation with methyl iodide led to the formation of some biologically active 1-aryl-2-methylthio-imidazolines (2a-g). The 7-(4-methylphenyl)-3-methylthio-5H-6,7-dihydroimidazo[2,1-c][1,2,4]triazole (4b) was obtained by the alkylation of the respective 7-(4-methylphenyl)-2,5,6,7-tetrahydroimidazo[2,1-c][1,2,4]triazol-3(H)-thione (3b) with methyl iodide. Antimicrobial activities of 1-aryl-2-methylthio-imidazolines (2a-g) and the 7-(4-methylphenyl)-3- methylthio-5H-6,7-dihydroimidazo[2,1-c][1,2,4]triazole (4b) are presented. All tested compounds showed MIC in the range of 11.0-89.2 microM. Compounds 2a,e were found to be equipotent to chloramphenicol in vitro, whereas 2a,c,e-g and 4b showed superior activity (MIC) to ampicillin.