Beneficial effect of nitric oxide synthase inhibitor on hepatotoxicity induced by allyl alcohol

The effect of aminoguanidine (a selective inhibitor of inducible nitric oxide synthase) on allyl alcohol-induced liver injury was assessed by the measurement of serum ALT and AST activities and histopathological examination. When aminoguanidine (50-300 mg/kg, i.p.) was administered to mice 30 min before a toxic dose of allyl alcohol (75 microL/kg, i.p.), significant changes related to liver injury were observed. In the presence of aminoguanidine the level of ALT and AST enzymes were significantly decreased. All symptoms of liver necrosis produced by allyl alcohol toxicity almost completely disappeared when animals were pretreated with aminoguanidine at 300 mg/kg. Depletion of hepatic glutathione as a consequence of allyl alcohol metabolism was minimal in mice pretreated with aminoguanidine at 300 mg/kg. It was found that the inhibition of toxicity was not due to alteration in allyl alcohol metabolism since aminoguanidine did not effect alcohol dehydrogenase activity both in vivo and in vitro.     

Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling

Lysophosphatidic acid (LPA) is a bioactive lipid with activity in the nervous system mediated by G-protein-coupled receptors. Here, we examined the role of LPA signaling in the development of neuropathic pain by pharmacological and genetic approaches, including the use of mice lacking the LPA(1) receptor. Wild-type animals with nerve injury develop behavioral allodynia and hyperalgesia paralleled by demyelination in the dorsal root and increased expression of both the protein kinase C gamma-isoform within the spinal cord dorsal horn and the alpha(2)delta(1) calcium channel subunit in dorsal root ganglia. Intrathecal injection of LPA induced behavioral, morphological and biochemical changes similar to those observed after nerve ligation. In contrast, mice lacking a single LPA receptor (LPA(1), also known as EDG2) that activates the Rho-Rho kinase pathway do not develop signs of neuropathic pain after peripheral nerve injury. Inhibitors of Rho and Rho kinase also prevented these signs of neuropathic pain. These results imply that receptor-mediated LPA signaling is crucial in the initiation of neuropathic pain.     

Performance of Fast Routing Algorithms in Large Optical Switches Built on the Vertical Stacking of Banyan Structures

Vertical stacking of multiple optical banyan networks is a novel scheme for building banyan-based nonblocking optical switches. The resulting network, namely vertically stacked optical banyan (VSOB) network, preserves the properties of small depth and absolutely loss uniformity but loses the nice self-routing capability of banyan networks. To guarantee a high switching speed, routing in VSOB network needs special attentions so that paths can be established as fast as possible. The best known global routing algorithm for an N×N nonblocking VSOB network has the time complexity of O(NlogN), which will introduce an unacceptable long delay in path establishment for a large size optical switch. In this paper, we propose two fast routing algorithms for the VSOB network based on the idea of inputs grouping. The two algorithms, namely plane fixed routing (PFR) algorithm and partially random routing (PRR) algorithm, have the time complexities of O(logN) and O( ) respectively, and FR algorithm can actually turn a VSOB network into a self-routing one. Extensive simulation based on a network simulator indicates that for large VSOB networks our new algorithms can achieve a reasonably low blocking probability while guarantee a very high switching speed.     

Effect of sigmaS on sigmaE-directed cell lysis in Escherichia coli early stationary phase

The sigmaE regulon has been shown to perform a novel function that causes dead-cell lysis specific to the early stationary phase in addition to its well-known role in the extracytoplasmic stress response in Escherichia coli. Here, the effect of sigmaS as a general stress-responsive sigma factor on sigmaE-directed cell lysis was investigated. The lysis phenomena were observed in both rpoS mutant and parental strains constitutively expressing active sigmaE, but the former lysis occurred at a relatively early stage compared to the latter. Based on these results and experiments with hydrogen peroxide, we propose that some stresses generate living but non-culturable cells, which are subject to sigmaE-directed cell lysis.     

A major functional difference between the mouse and human ARF tumor suppressor proteins

Suppression of tumorigenesis is considerably more stringent in the human than in the much shorter lived mouse species, and the reasons for this difference are poorly understood. We investigated functional differences in the control of the ARF (alternative reading frame) protein that acts upstream of p53 and is encoded along with p16(INK4a) at a major tumor suppressor locus in both the human and mouse genomes. The mouse and human ARF proteins are substantially divergent at their carboxyl termini. We have shown that the mouse ARF protein (p19ARF) interacts with Pex19p in the cell cytoplasm leading to its nuclear exclusion and repression of its p53 activation function. The human ARF protein (p14ARF) is substantially smaller than its mouse counterpart and is not subject to this functional inactivation by Pex19p. In an identical cellular background, ribozymes directed against Pex19p enhanced p19ARF- but not p14ARF-activated p53 function. This is the first demonstration of a functional difference between the mouse and human ARF proteins. In view of the major role of ARF in tumor suppression, this distinction may contribute to the different levels of tumor proneness of these species.     

Expression of three mitochondrial solute carriers, citrin, aralar1 and ornithine transporter, in relation to urea cycle in mice

The present report describes the expression profiles of different tissues and developmental changes of mouse aspartate/glutamate carrier (AGC) genes, Slc25a13 and Slc25a12, and an ornithine transporter gene, Ornt1, in relation to urea cycle enzyme genes, carbamoylphosphate synthetase I (CPS) and argininosuccinate synthetase (ASS). Slc25a13 encodes citrin, recently found to be deficient in adult-onset type II citrullinemia and to function as AGC together with its isoform and product of Slc25a12, aralar1. Citrin was broadly distributed, but mainly in the liver, kidney and heart. Aralar1 was expressed in diaphragm, skeletal muscle, heart, brain and kidney, but not in the liver. These distribution profiles are different from the restricted of Ornt1, ASS and CPS. Citrin, ASS, CPS and Ornt1 showed similar patterns of developmental changes in the liver and small intestine, where they play a role in urea and arginine synthesis. Dietary, hormonal and physical manipulations caused varied changes of CPS, ASS and Ornt1 in the liver, but the change of citrin was not so marked as that of the others. Analysis using RT-PCR and restriction enzyme digestion revealed that the ornithine transporter most expressed is Ornt1, although Ornt2 is detectable at a minute level. All these results suggest that citrin as AGC plays a role in urea synthesis as well as many fundamental metabolic pathways in the liver, and shares metabolic functions with aralar1 in other tissues, and that Ornt1 is an important component in urea synthesis in the liver and in arginine synthesis in the small intestine during the neonatal period.     

Nicotinamide and structurally related compounds show halting activity against zoospores of the phytopathogenic fungus Aphanomyces cochlioides

In a survey of plant secondary metabolites regulating the behavior of phytopathogenic Aphanomyces cochlioides zoospores, we found that leaf extracts of Amaranthus gangeticus and cotyledon extracts of pea (Pisum sativum) remarkably halted the motility of zoospores. Bioassay-directed fractionation of A. gangeticus and pea constituents revealed that the halting activity was dependent on a single chemical factor (halting factor). The active principle was identified as nicotinamide (1) by comparing its biological activity and spectroscopic properties with those of the authentic compound. Nicotinamide (1) showed potent halting activity toward the zoospores of A. cochlioides and A. euteiches, but it exhibited very less activity against other Oomycetes, Pythium aphanidermatum and Phytophthora infestans zoospores. Interestingly, the zoospores halted by nicotinamide (1) encysted within 10-15 min and then the resulting cystospores regenerated zoospores instead of germination. Nicotinamide (1) and related compounds were subjected to the halting activity bioassay to elucidate the structure-activity relationships. These bioassays revealed that part structures of (A) the aromatic ring containing at least one nitrogen atom, (B) carbonyl-like group adjacent to the aromatic ring and (C) hydrogen atoms on the amide group are responsible for the strong activity. So far, this is the first report of halting activity of nicotinamide (1) against fungal zoospores.     

Liposome encapsulated tumor-associated antigens elicited humoral and cellular immune responses in mice bearing tumor

Chemically induced tumors in mice provide a system to investigate tumor-associated antigens (TAA). The cell surface glycoprotein antigens on such tumor cells have been identified as suitable targets for immune attack. The induction of immune responses against (TAA) in N-nitrosodiethylamine (DEN) exposed mice has been examined. In order to present antigens to the immune system, the liposome was used as vehicle to deliver the TAA. Liposomal-TAA formulation, elicited both humoral and the cellular immune responses, when administered intramuscularly in DEN-exposed mice. Presence of circulatory antibodies against TAA and the induction of cellular responses in immunized mice were monitored using ELISA and in vitro cell proliferation assay of lymphocytes respectively. Specificity of antibody against TAA in immune sera was analysed using immunoblotting technique. Based on these results, it is proposed that the liposome encapsulated TAA may successfully be used to induce humoral and cellular immune responses against tumor.