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http://hdl.handle.net/2003/25619

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J. G. Hengstler
Leibniz Research Centre for Working Environment and Human Factors
Ardeystr. 67
D-44139 Dortmund
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L. S. Weilemann, Mainz, Germany
I. Ishibashi, Tokyo, Japan
P. Micke, Uppsala, Sweden
J. Timmer, Freiburg, Germany
A. Winterpacht, Erlangen, Germany
B. C. Behera, Pune, India

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One pot synthesis of pyrrolidines type 3,7-diazabicyclo [3.3.0] octane and biological activity
(2008-12-05T12:49:38Z) Amornraksa, Kitti; Prachayasittikul, Virapong; Worachartcheewan, Apilak
Pyrrolidines type 2,4-disubstituted (alkyl, aryl or heteroaryl)-6,8-dioxo-3,7-diazabicyclo [3.3.0] octanes (8a-d) were successfully synthesized by an efficient one pot 1,3-dipolar cycloaddition of azomethine ylides (in situ generated from the reaction of aromatic aldehydes and methyl ester of alpha-amino acids) with dipolarophile (N-phenylmaleimide). The reaction of compounds 8a-d with hydrazine in ethanol at room temperature took place under nucleophilic substitution which furnished 5-amino-4,6-dioxo-octahydropyrrolo [3,4-b] pyrrole-3-carboxylic acid phenylamides (12a-d). Structures of the products were confirmed by IR and 1H NMR. The compounds (8b and 12a) were evaluated for antimicrobial (agar dilution method) and antioxidative (DPPH; 2,2-diphenyl-1-picrylhydrazyl and SOD; superoxide dismutase assays) activities. The results showed that at concentrations of 4-256 µg/mL, the tested compounds exhibited non-significant antimicrobial growth, whereas the 12a at 200 µg/mL began to exert some antioxidative activity.
Enhanced interleukin-10 signaling with 14-member macrolides in lipopolysaccharide-stimulated macrophages
(2008-10-21T12:42:53Z) Abe, Shuichi; Inoue, Sumito; Ishikawa, Tomomi; Kubota, Isao; Shibata, Yoko; Takabatake, Noriaki; Yamauchi, Keiko
Immunomodulatory effects of 14-member macrolides, namely erythromycin (EM) and clarithromycin (CAM), have been reported in chronic respiratory infectious diseases. It has been suggested that 14-member macrolides have immunomodulatory effects on various lung cells such as alveolar macrophages. Interleukin (IL)-10 is an immunomodulatory cytokine that performs an irreplaceable role in negatively regulating inflammation, primarily via a mechanism that selectively blocks the expression of pro-inflammatory genes. It activates sig-nal transducer and activator of transcription (STAT)-3, and subsequently induces the suppres-sor of cytokine signaling-3 (SOCS-3), resulting in the resolution of inflammatory response in macrophages. However, it has been still unclear whether 14-member macrolides exert immu-nomodulatory effects via IL-10 signaling pathway. We aimed to evaluate whether 14-member macrolides affect the IL-10 signaling pathway. The RAW264.7 macrophage cell line was pre-treated with EM or CAM, and stimulated with lipopolysaccharide (LPS). The levels of IL-10, IL-10 receptor, phosphorylated (p) STAT-3, and SOCS-3 were determined by RT-PCR, ELISA and immunoblotting. We observed increased levels of IL-10, p-STAT-3 and SOCS-3 in the treated cells. In addition, while the levels of tumor necrosis factor-α 6 h after LPS stimulation was equal between vehicle-treated and CAM-treated macrophage cells, those of CAM-treated cells were repressed 36 h following LPS stimulation, compared with those of the control cells. Therefore, the 14-member macrolides may initiate an early resolution of inflammation, in part, via the enhancement of the IL-10/STAT-3/SOCS-3 pathway.
Mitochondrial DNA might be influenced in calprotectin-induced cell death
(2008-10-21T12:27:12Z) Marashi, Sayed-Amir; Rezaei-Tavirani, Mostafa; Shokrgozar, Mohammad Ali; Zali, Hakimeh
It is generally believed that calprotectin acts via exclusion of extracellular zinc, and/or binding of calprotectin to a cell membrane receptor, and consequently, activation of a signaling pathway for apoptosis. Recently, we suggested that calprotectin may have an “internal target” within cells. Here, using target theory, we provided evidence that this internal target is DNA. Trypan blue (TB) and dimythylthiazol diphenyl tetrazolium bromide (MTT) assays were used to estimate survival of calprotectin-treated cells. TB assay relies on the viability of cell membrane, while MTT assay relies on the functionality of mitochondria. We demonstrated that MTT-based survival values fit to the “single-hit, single-target” model, while TB-based survival values are best matched to the “single-hit, multi-target” model with N=2. Assumption of DNA as the target of calprotectin is fully consistent with the models, since each mitochondrion contains one chromosome and each “cell” is diploid and contains two chromosome sets. To the best of our knowledge this is the first report that suggests mitochondrial DNA is affected during calprotectin-induced cell death. Furthermore, our results explain why toxicity measures (like LD50), when estimated based on TB assay, are sometimes significantly greater than toxicity measures based on MTT assay.
Nonrandom gene distribution on human chromosomes
(2008-07-17T13:59:53Z) Mohsenzadeh, Sasan; Rafiee, Laleh; Saadat, Mostafa
Human chromosomes are heterogeneous in structure and function. This is the reason for specific banding patterns produced by various chromosome staining techniques. The human genome is a mosaic of isochors and can be partitioned into five families, L1, L2, H1, H2 and H3, characterized by increasing GC level and gene concentrations. In this study we investigated the chromosome distribution of 22845 genes mapped at whole chromosomes reported in the Human Genome Data Base as of January 2007. Pearson correlation coefficient analysis showed that there is significant correlation between the number of mapped genes and percent of G-dark bands (r=-0.608, p=0.002). Also the correlation between the ratio (observed versus expected genes) and percent of G-dark bands was significant (r=-0.506, p=0.012). There was a significant difference between observed number of mapped genes and expected number of mapped genes on human chromosomes (?2=4842.7, df=23, p<0.00001). Taken together, these findings indicating the gene density in G-light bands is higher than that of the G-dark bands.
Protective effect of L-ornithine-L-aspartate and silymarin on chemically induced kidney toxicity and thyroid dysfunction in mice
(2008-05-20) Jatwa, Rameshwar; Kar, Anand
The present study was designed to reveal the hitherto unknown efficacy of two commonly used hepatoprotective drugs, L-ornithine-L-aspartate (lornit) and silymarin in the regulation of kidney toxicity and thyroid dysfunction in mice. Renal and hepatic lipid peroxidation (LPO) was induced by the administration of carbon tetrachloride (CCl4) for 2 weeks (2.0 gm/kg twice a week). In two separate groups, along with CCl4 animals were also treated with either lornit (200 mg/kg) or silymarin (100 mg/kg) every day for the same duration. Other than hepatic and renal LPO, alterations in the concentrations of serum triiodothyronine (T3), thyroxine (T4), glucose and insulin and in hepatic type-1 iodothyronine 5’monodeiodinase (5’DI) activity were considered as major parameters. Simultaneously activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphahatase (ALP) and hepatic and renal superoxide dismutase (SOD), catalase (CAT) and reduced glutathione content (GSH) were also studied. Lornit or silymarin administration reversed almost all the toxic effects exhibited by CCl4 including enhanced tissue LPO, serum ALT, AST and ALP activities and the concentrations of insulin and glucose. Both test drugs also significantly increased hepatic 5’DI activity, cellular antioxidants such as SOD, CAT and GSH and serum levels of both the thyroid hormones.
Effect of some natural antioxidants on aflatoxin B1-induced hepatic toxicity
(2008-05-08) Kheir Eldin, Adel A.; Motawi, Tarek M. K.; Sadik, Nermin A. H.
Aflatoxins are potent hepatotoxic and hepatocarcinogenic agents. This hepatotoxicity is thought to be mediated by their ability to generate reactive oxygen species and cause peroxidative damage. In the present investigation we assessed the ability of some natural antioxidants namely, vitamin E and Se, ß-carotene, silymarin and coenzyme Q10 on aflatoxin B1 (AFB1)-induced hepatotoxicity in a rat model. Alanine and aspartate aminotransferases and alkaline phosphatase (ALP) were found to be significantly increased in the serum of AFB1 administered (250 µg/kg body weight/day for 2 weeks) rats, suggesting hepatic damage. There was a marked increase in the lipid peroxide levels and a concomitant decrease in the hepatic reduced glutathione (GSH) and serum protein thiol (PrSHs) along with a nearly twofold increase in hepatic glutathione-S-transferase (GST) activity. The significant increase in GST may be attributed to its being a phase ?? enzyme that predominately participates in the detoxification of the ultimate electrophilic metabolite AFB1-8, 9 epoxide. On the other hand, no significant change was detected in the activities of glutathione peroxidase (GPx), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G-6-PDH), cytochrome creductase and levels of DNA and RNA in the hepatic tissue of AFB1 administered rats. Results also revealed that cotreatment with studied antioxidants offered substantial hepatoprotective effects in the AFB1 administered rats. Moreover, results revealed that vitamin E and selenium combination and ß-carotene are more efficient than coenzyme Q10 and silymarin in modulating the liver antioxidant enzymatic system.
Inheritance involved in the pathogenesis of idiopathic scoliosis
(2008-04-22) Fan, Xing; Li, Ming; Shangguan, Lei
Idiopathic scoliosis is a common cause of spinal deformity in children and adolescents. Although the incidence of the scoliosis is up to 2 %-3 % of the world’s population, the pathogenesis is still obscure. Recent evidences show that the disease has a hereditary basis. Clinical manifestations as well as family studies reveal the familial tendency of idiopathic scoliosis, and support that the heredity is an important cause of this disease. Many related genes, such as SNTGI and CHD7, are believed to play a role in the development of idiopathic scoliosis but the underlying mechanism is still not clear. This review focus on the mode of inheritance of idiopathic scoliosis and some related molecules.
Citric acid strongly inhibits visceral pain response in mice
(2008-04-17) Abdel-Salam, Omar M. E.; Baiuomy, Ayman R.
Citric acid introduced into the stomach of mice at increasing concentrations of 0.1, 1 or 10 % (4.8 µM-0.48 mM; 95 µmol/kg-9.5 mmol/kg, 0.5 ml) caused dose-dependent inhibition of abdominal constrictions induced 1 h later by i. p. acetic acid injection by -51 % to -69.5 %. When administered at 10 % (0.48 mM, 0.5 ml) 15 min before nociceptive challenge, citric acid inhibited the nociceptive response by 96.8 %. Inhibition of the acetic acid-induced abdominal constrictions was also observed when lower doses of citric acid were introduced into the stomach (0.2 ml of 0.1-1 %; 38.1 µmol/kg-0.38 mmol/kg). The effect was evident as early as 5 min after administration of citric acid into the stomach and with the maximal effect being at 15-30 min after dosing. Lidocaine given orally 5 min prior to citric acid (1 %, 48 µM; 0.38 mmol/kg, 0.2 ml) prevented antinociception by citric acid, but lidocaine given 15 min before oral introduction of citric acid enhanced the citric acid-induced inhibition of the nociceptive response to acetic acid. The antinociceptive effect of orally administered citric acid (1 %, 48 µM; 0.38 mmol/kg, 0.2 ml) was increased by pre-treatment with propranolol (4 mg/kg, s. c.), yohimbine (4 mg/kg, s. c.), guanethidine (32 mg/kg, s. c.), but reduced after treatment with atropine (3 mg/kg, s. c.), which itself increased the nociceptive behavior. Similar inhibition of the acetic acid-induced nociceptive behavior was also observed when sodium citrate (pH 7.21) or 0.1 N HCl (pH 3) or 1 % sucrose solution (0.2 ml) was intragastrically given. It is suggested that citric acid might act to stimulate sensory afferents and that transmission of nociceptive information centrally leads to the activation of descending antinociceptive mechanism to a noxious stimulus.
Erythropoietin stimulates hepatocyte regeneration after liver resection
(2008-03-31) Bauer, Alexander; Donaubauer, Bernd; Faber, Sonya C.; Hauss, Johann P.; Hengstler, Jan G.; Hogrebe, Esther; Jelkmann, Wolfgang; Pietsch, Uta-Carolin; Schön, Michael R.; Tannapfel, Andrea; Thiery, Joachim
The increased relevance of liver surgery and transplantation as a therapeutic modality over the last two decades mandates the development of novel strategies to improve liver regeneration. Here we studied whether erythropoietin (EPO) improves liver regeneration after hepatectomy in pigs. Eighteen female pigs underwent laparoscopic left lateral liver resection and were allocated randomly into three groups. No EPO was administered to the control group (group 1, n=6). Group 2 (n=6) received EPO topically to the liver resection surface in a fibrin sealant. Group 3 (n=6) received EPO topically and systemically. Pigs were sacrificed 14 days after hepatectomy. The fraction of proliferating hepatocytes was determined by ki-67 immunostaining. Liver volume was determined by the principle of Archimedes, Liver weight and volume were significantly increased in group 3 (1249 ± 223 g, 1073 ± 190 ml) compared to group 2 (1027 ± 167 g, 894 ± 105 ml) and group 1 (923 ± 186 g, 813 ± 165 ml). Ki-67 immunostaining of liver tissue close to the resection surface demonstrated a significantly increased percentage of proliferating hepatocytes in group 3 (4.3 ± 1.96 %) and in group 2 (3.5% ± 0.98 %) as compared to group 1 (1.15 ± 1.2 %) 14 days after hepatectomy. Our results indicate for the first time that EPO supports liver regeneration after hepatectomy.
4-Hydroxy-2-nonenal induces endothelial cell injury via PKCdelta and biphasic JNK activation
(2008-03-10) Goya, Sho; Hirata, Haruhiko; Hoshino, Shigenori; Inoue, Koji; Kashiwa, Yozo; Kawase, Ichiro; Kijima, Takashi; Kumagai, Toru; Mayumi, Masahiko; Osaki, Tadashi; Suzuki, Mayumi; Tachibana, Isao; Takeda, Yoshito; Takimoto, Takayuki; Yano, Yukihiro; Yoshida, Yoshida
4-Hydroxy-2-nonenal (4-HNE), a major product generated during oxidative stress, exhibits cytotoxic effects; however, the mechanisms of 4-HNE-induced endothelial cell injury are not well defined. To explore this issue, we examined how 4-HNE damages human umbilical vein endothelial cells (HUVECs) and found that 4-HNE induced biphasic activation of c-Jun N-terminal kinase (JNK). Both pre- and post-treatment of HUVECs with SP600125, a specific JNK inhibitor, significantly suppressed the cytotoxic effects of 4-HNE. Inhibition of protein kinase Cd (PKCd), which was also phosphorylated by 4-HNE, reduced endothelial cell injury as well as late-phase JNK phosphorylation elicited by 4-HNE. Inversely, pre-treatment of HUVECs with SP600125 suppressed PKCd activation. Taken together, these results support the concept that 4-HNE induces vascular endothelial cell injury by the interaction between biphasic JNK activation and the PKCd pathway.
Antimicrobial and antioxidative activities of 1-adamantylthio derivatives of 3-substituted pyridines
(2008-03-10) Isarankura-Na-Ayudhya, Chartchalerm; Prachayasittikul, Supaluk; Prachayasittikul, Virapong; Ruchirawat, Somsak; Suksrichavalit, Thummaruk
Diverse biological activities of sulfur containing pyridines were reported. To investigate for new lead compounds, thus, 1-adamantylthiopyridines bearing 3-substituents (OEt, OAc, NAc2, Br and OH) were prepared and evaluated for antimicrobial and antioxidative activities. The antimicrobial assay against 27 strains of microorganisms was performed using agar dilution method. The results show that all the tested 2-(1-adamantylthio)-3-ethoxypyridine (4a), 2-(1-adamantylthio)-3-acetoxypyridine (4b), N-acetyl-2-(1-adamantylthio)-3-acetamidopyridine (4c), 2-(1-adamantylthio)-3-bromopyridine (4d), 2-(1-adamantylthio)-5-hydroxypyridine (5) and 3-(1-adamantylthio)-5-bromopyridine (6) exhibit antigrowth activity on Streptococci at 30 µg/mL. Particularly, the thiopyridines 4c, 5 and 6 are the most active compounds, displaying complete inhibition against ß-hemolytic Streptococcus group A at 30 µg/mL. These pyridyl sulfides 4a-d, 5 and 6 represent a new group of antimicrobial agents. Antioxidative activity was analyzed using the DPPH assay. The sulfides 4a-d, 5 and 6 show only a weak antioxidative activity. In contrast the 2-(1-adamantylthio)-3-bromopyridine (4d) shows the highest radical scavenging activity.
Reactions of N-acetylcysteine adducts of aromatic (di)isocyanates with functional groups of organic molecules
(2008-02-21) Frank, Petra; Mormann, Werner; Schupp, Thomas; Seel, Klaus
Glutathione thiocarbamate conjugates of isocyanates play a key role in transport and final reactions of isocyanates in the human body by transcarbamoylation. N-acetylcysteine is the simplest model for thiocarbamate reactions. Therefore, transcarbamoylation of Nacetylcysteine adducts of p-tolylisocyanate (pTI-AcCys) and 4,4’-diisocyanatodiphenyl- methane (MDI(AcCys)2) with N-acetylcysteine methyl ester (thiolysis), morpholine (aminolysis), methoxyethanol (alcoholysis), and water (hydrolysis) has been studied in aqueous phosphate buffer solution and in dimethylacetamide (DMAc). Expected reaction products have been synthesised as reference compounds for HPLC-analysis. Concentrations of adducts and of reaction products were monitored by HPLC. Reaction rates and activation energies were determined for pTI in both media, reactions of MDI(AcCys)2 were run at one temperature only. Formation of insoluble reaction products and side reactions due to hydrolysis prevented in depth kinetic analysis of the reactions. Two regimes of reaction rate were observed in aqueous buffer, clear second order kinetics resulted in DMAc. In aqueous buffer (pH 7.4) a reactivity thiolysis > aminolysis > hydrolysis was found, while in DMAc aminolysis was faster than thiolysis. This can be explained by formation of thiolate at pH 7.4, which is not possible in anhydrous DMAc. Reactions of (MDI(AcCys)2) are by a factor of 2 to 4 faster than those of pTI-AcCys. p-Toluidine (pTA) was found in the aqueous system due to hydrolysis, while no 4,4’-methylene dianiline (MDA) could be detected. Under physiological conditions hydrolysis should compete with thiolysis under homogeneous conditions while ureas and carbamates should be much more stable against hydrolysis. No free isocyanate groups could be detected in any of the reactions. In conclusion the isocyanate moiety in thiocarbamates is readily transferred to sulfhydryl- and amino groups but not to aliphatic hydroxy groups. Under physiological conditions hydrolysis competes with these transcarbamoylation reactions. Formation of free isocyanate groups in analytical quantities was shown to be highly unlikely.
Adrenaline inhibited cell proliferation and regulated expression of TGF-beta1 and bFGF in cultured human hypertrophic scar fibroblasts via alpha-receptor
(2008-01-08) Song, Lan; Tian, Ying; Xu, Zhao-Jun; Zhang, Cai-Ping
Adrenaline has been shown to modulate proliferation of mouse fibroblasts, adventitial fibroblasts and synovial B (fibroblasts-like) cells. However, little is known about the response of cultured human hypertrophic scar fibroblasts to adrenaline. In this study, we investigated cell proliferation and involved mechanisms in hypertrophic scar fibroblasts in response to adrenaline. Population doubling time (PDT) assay and MTT assay were performed to determine the cell proliferation and cell viability, respectively. The expression of bFGF and TGF- ß1 was measured by reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme linked immunosorbent assay (ELISA). The results showed that adrenaline inhibited proliferation of normal and hypertrophic scar fibroblasts in a dose-dependent manner. Moreover, adrenaline up-regulated the expression of bFGF and down-regulated the expression of TGF- ß1 in normal and hypertrophic scar fibroblasts. Interestingly incubation with the a receptor antagonist regitine indicated that adrenaline mediated inhibition of cell proliferation and regulation of TGF-ß1 and bFGF in cultured normal and hypertrophic scar fibroblasts were mediated by the a receptor. These studies suggest that adrenaline inhibits proliferation and alters the expression of TGF-ß1 and bFGF in human hypertrophic scar fibroblast involving an a receptor mediated pathway.

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