Complete Regression of Recurrent Advanced Hepatocellular Carcinoma After Liver Transplantation in Response to Sorafenib Treatment: A Case Report.

Liver transplantation is a potentially curative treatment for hepatocellular carcinoma. However, patients with recurrent hepatocellular carcinoma after liver transplantation have few treatment options and local treatment may not be feasible. Sorafenib, an orally active multikinase inhibitor approved for the treatment of advanced hepatocellular carcinoma, significantly improves progression-free and overall survival. However, only a few studies have evaluated the efficacy of sorafenib in patients with recurrent hepatocellular carcinoma following liver transplantation. Here, we report a case of a patient with recurrent advanced hepatocellular carcinoma after living donor liver transplantation who achieved complete remission in response to sorafenib treatment. The patient has survived for more than 4 years post-transplantation.

Combination drug therapy using edaravone and Daio-Orengedoku-to after transient focal ischemia in rats.

In this study, we investigated the effect of Daio-Orengedoku-to (DOT) on ischemic brain damage in a rat model of focal ischemia-reperfusion and attempted to identify synergistic effects for the combination of edaravone and DOT against ischemic insult. Ischemia was induced by intraluminal occlusion of the right middle cerebral artery for 2 h and reperfusion followed for 22 h. To determine the neuroprotective effect of DOT, it was administered orally just before reperfusion and then 2 h after reperfusion. To examine the effects of combination therapy on survival, rats were divided into groups treated with edaravone, DOT, and edaravone and DOT. Microglial activation, neutrophil infiltration and brain-derived neurotrophic factor (BDNF) expression were examined in surviving animals. Infarct volume was significantly reduced by DOT (100, 200 and 400 mg/kg; P < 0.05), and edaravone plus DOT markedly improved the survival rate after transient ischemia (P = 0.0133). Microglial activation was reduced by edaravone and DOT and their combination (P < 0.05), and neutrophil infiltration was lowered in these groups (P < 0.05). BDNF-positive cells were increased in the combination edaravone and DOT group (P < 0.05). It appears that the neuroprotective mechanisms of combined therapy involve inhibition of microglial activation, reduction of invading neutrophils and enhancement of BDNF expression.

Synthesis and phosphodiesterase inhibitory activity of new sildenafil analogues containing a carboxylic acid group in the 5'-sulfonamide moiety of a phenyl ring.

New sildenafil analogues possessing a carboxylic acid group in the 5'-sulfonamide of the phenyl ring, 9a-l, were prepared from the readily available starting compounds 6a-b and cyclic amines 3-5 in a three-step sequence. In the enzyme assays, it has been shown that all the target compounds 9a-l proved to be more potent in inhibiting phosphodiesterase type 5 (PDE5) than sildenafil by 4-38-fold. The effects on the IC(50) values were investigated by varying the alkoxy group (R) of the phenyl ring, the sulfonamide type (X), and the length of the methylene chain linking the carboxylic acid, and the results were discussed in detail. From this study, we have clearly demonstrated that introduction of a carboxylic acid group to the 5'-sulfonamide moiety of the phenyl ring greatly enhanced PDE5 inhibitory activity, probably by mimicking the phosphate group of cGMP. The piperidinyl propionic acid derivative 9i, which showed the highest PDE5 inhibitory activity and comparable to better selectivity over PDE isozymes in comparison with sildenafil, has been selected for more detailed biological investigations.

A curcuminoid and sesquiterpenes as inhibitors of macrophage TNF-alpha release from Curcuma zedoaria.

Tumor necrosis factor-alpha (TNF-alpha) is one of the major mediators produced in activated macrophages which contribute to the circulatory failure associated with septic shock. In the course of screening marketed oriental anti-inflammatory herbal drugs for TNF-alpha antagonistic activity, a crude methanolic extract of the rhizomes of Curcuma zedoaria exhibited significant activity. The activity-guided fractionation and repetitive chromatographic procedures with the EtOAc-soluble fraction resulted in the isolation of three active compounds. They were identified as 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (1), procurcumenol (2) and epiprocurcumenol (3) by spectral data analysis. They inhibited the production of TNF-alpha by lipopolysaccharide (LPS)-activated macrophages from the results of bioassay (IC(50) values of 1 and 2 are 12.3 and 310.5 microM, respectively) and Western blot assay. These results imply that the traditional use of C. zedoaria rhizome as anti-inflammatory drug may be explained at least in part, by the inhibition of TNF-alpha production.

Synthesis and phosphodiesterase 5 inhibitory activity of novel phenyl ring modified sildenafil analogues.

New sildenafil analogues containing an ether ring fused into the phenyl moiety, 6a--d and 7a--d, were efficiently synthesized from the readily available starting materials, 1a--d and 2, in five steps. Ab initio calculations indicated that introduction of a cyclic ether to the phenyl group might enhance the co-planarity of the molecule. The torsional angles were calculated to be 2--3 degrees for the 5-membered cyclic ether derivatives, 6a, 6c, 7a, and 7c, and 12--16 degrees for the 6-membered ones, 6b, 6d, 7b, and 7d. On the other hand, sildenafil showed the least co-planarity with the torsional angle of 23 degrees compared with the target compounds, 6a--d and 7a--d. In the enzyme assay, however, the in vitro PDE 5 inhibitory activity was found out to be inversely related to the degree of co-planarity. In other words, the least planar sildenafil showed the highest activity, and the most planar 5-membered cyclic ether derivatives were least active by 100--200-fold compared with sildenafil. Our study clearly demonstrated that the open chain 2'-alkoxy group of the phenyl ring, although less effective for inducing the co-planarity, seemed to act as a much better lipophilic requirement than the cyclic alkoxy moiety.

A new guaiane type sesquiterpene from Torilis japonica.

A new guaiane type sesquiterpene was isolated from the fruit of Torilis japonica (Umbelliferae). Based on NMR, IR and mass spectroscopy its structure was confirmed as deangeloyloxy torilin, 1beta, 7alpha, 10alphaH-11-acetoxy-guaia-4-en-3-one (1). This is the first report showing that this compound can be isolated from Torilis japonica.

Polyacetylenes from angelica gigas and their inhibitory activity on nitric oxide synthesis in activated macrophages.

In activated macrophages the inducible form of nitric oxide synthase (i-NOS) generates high amounts of the toxic mediator, nitric oxide (NO) which contributes to the circulatory failure associated with septic shock. Two polyacetylenes were isolated from the medicinal plant Angelica gigas and their structures were elucidated as octadeca-1,9-dien-4,6-diyn-3,8,18-triol (1) and 18-acetoxy-octadeca-1,9-dien-4,6-diyn-3,8-diol (2) by spectroscopic method. These polyacetylenes and their peracetate, 3, 8, 18-triacetoxy-octadeca-1, 9-dien-4, 6-diyn (3) inhibited the production of NO in LPS-activated RAW 264.7 cells by suppressing the i-NOS enzyme expression. These new inhibitors of i-NOS expression may have potential in the treatment of endotoxemia and inflammation accompanied by the overproduction of NO.

Inhibitors of nitric oxide synthesis and TNF-alpha expression from Magnolia obovata in activated macrophages.

Nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha) are the major mediators produced in activated macrophages which contribute to the circulatory failure associated with septic shock. An activity-guided fractionation of an MeOH extract of stem bark of Magnolia obovata afforded two inhibitors of NO production in lipopolysaccharides (LPS)-activated macrophages by the suppression of i-NOS expression. Their structures were elucidated by spectroscopic methods to be magnolol and honokiol with IC50 values of 16.8 and 6.4 microM, respectively. They also inhibited the production of TNF-alpha in LPS-activated macrophages. Thus, these compounds may be possible candidates for the development of new drugs to treat endotoxemia accompanied by the overproduction of NO and TNF-alpha.

Neuroprotective effect of green tea extract in experimental ischemia-reperfusion brain injury.

Eicosanoids accumulation and formation of oxygen free radicals have been implicated in the pathogenesis of ischemia/reperfusion brain injury. In the present study, we examined whether green tea extract protects against ischemia/reperfusion-induced brain injury by minimizing eicosanoid accumulation and oxygen radical-induced oxidative damage in the brain. Green tea extract (0.5%) was orally administered to Wistar rats for 3 weeks before induction of ischemia. Ischemia was induced by the occlusion of middle cerebral arteries for 60 min and reperfusion was achieved for 24 h. Infarction volume in the ipsilateral hemisphere of ischemia/reperfusion animals was 114 +/- 16 mm(3) in the 0.5% green tea pretreated animals compared to 180 +/- 54 mm(3) in left hemisphere of nontreated animals. Green tea extract (0.5%) also reduced ischemia/reperfusion-induced eicosanoid concentration: Leukotriene C(4) (from 245 +/- 51 to186 +/- 22), prostoglandin E(2) (from 306 +/- 71 to 212 +/- 43) and thromboxane A(2) (327 +/- 69 to 251 +/- 87 ng/mg protein). Ischemia/reperfusion-induced increases of hydrogen peroxide level (from 688 +/- 76 to 501 +/- 99 nmole/mg protein), lipid peroxidation products (from 1010 +/- 110 to 820 +/- 70 nmole/mg protein) and 8-oxodG formation (from 1.3 +/- 0.3 to 0.8 +/- 0.2 ng/microg DNA, x10(-2)) were also reduced. Moreover, 0.5% green tea extract also reduced the apoptotic cell number (from 44 +/- 11 to 29 +/- 1 in the striatum, and from 72 +/- 11 to 42 +/- 5 apoptotic cells/high power field in the cortex region). Green tea extract pretreatment also promoted recovery from the ischemia/reperfusion-induced inhibition of active avoidance. The present study shows that the minimizing effect of green tea extract on the eicosanoid accumulation and oxidative damage in addition to the reduction of neuronal cell death could eventually result in protective effect on the ischemia/reperfusion-induced brain injury and behavior deficit.

A new bisabolene epoxide from Tussilago farfara, and inhibition of nitric oxide synthesis in LPS-activated macrophages.

A new bisabolene epoxide was isolated from the flower buds of Tussilago farfara, and the structure was determined by spectroscopic methods to be 1alpha,5alpha-bisacetoxy-8-angeloyloxy-3beta, 4beta-epoxy-bisabola-7(14),10-dien-2-one (1). Compound 1 showed inhibition of nitric oxide synthesis in lipopolysaccharide-activated macrophages.

Nucleotide sequence analysis of the 3'-terminal region of two Korean isolates of lily symptomless Carlavirus and expression of the coat protein in E. coli.

The 3'-terminal regions of the genomic RNAs of two Korean isolates of the lily symptomless Carlavirus (LSV), LSV-Ko and LSV-KII, were cloned and their nucleotide sequences were determined. The nucleotide sequence analysis and protein analysis by the Western blot revealed that E. coli expressed a 32-kDa protein that is the viral coat protein (CP) for the LSV. The two Korean strains share 98.4% and 98.3% sequence identities at the nucleotide and amino acid levels, respectively. The CP gene of LSV-Ko showed 99.1% and 87.0% nucleotide sequence identities, and 99.0% and 96.6% amino acid sequence identities with those of the Netherlands and the Japanese LSV strains, respectively. A pairwise amino acid sequence comparison revealed a sequence similarity of 29.6% to 69.8% between LSV-Ko and other species of the carlavirus. The 16 kDa protein of LSV-Ko shares 17.6% to 42.7% amino acid similarity with those of 8 other the carlaviruses, and they are variable in the N-terminal region. The Cys repeated zinc finger nucleic acid binding domain was found in the 16 kDa protein for all of the LSV strains. Sequence comparisons of the 7 kDa protein of LSV in the strain level showed significant identities from 100.0% to 98.4%. LSV-Ko shares 21.9% to 42.2% amino acid similarity with those of 8 other carlaviruses, 4 members of the potexviruses, and a closterovirus. LSV is closely related to blueberry scorch virus (BISV) based upon the phylogenetic tree analyses of the three proteins, indicating LSV to be a quite distinct member of the genus Carlavirus.

A sesquiterpene, dehydrocostus lactone, inhibits the expression of inducible nitric oxide synthase and TNF-alpha in LPS-activated macrophages.

Nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha) are the major mediators produced in activated macrophages which contribute to the circulatory failure associated with septic shock. A sesquiterpene lactone compound (dehydrocostus lactone) isolated from the medicinal plant, Saussurea lappa, inhibited the production of NO in lipopolysaccharide (LPS)-activated RAW 264.7 cells by suppressing inducible nitric oxide synthase enzyme expression. This compound also decreased the TNF-alpha level in LPS-activated systems in vitro and in vivo. Thus, dehydrocostus lactone may be a possible candidate for the development of new drugs to treat endotoxemia accompanied by the overproduction of NO and TNF-alpha.

Yomogin, an inhibitor of nitric oxide production in LPS-activated macrophages.

In activated macrophages the inducible form of nitric oxide synthase (i-NOS) generates high amounts of toxic mediator, nitric oxide (NO) which contributes to the circulatory failure associated with septic shock. A sesquiterpene lactone compound (yomogin) isolated from medicinal plant Artemisia princeps Pampan inhibited the production of NO in LPS-activated RAW 264.7 cells by suppressing i-NOS enzyme expression. Thus, yomogin may be a useful candidate for the development of new drugs to treat endotoxemia and inflammation accompanied by the overproduction of NO.

Supercritical carbon dioxide extraction of podophyllotoxin from Dysosma pleiantha roots.

Supercritical fluid extraction (SFE) was utilized to extract podophyllotoxin from the roots of Dysosma pleiantha. The extraction was carried out in the temperature range of 40-80 degrees C and the pressure range of 13.6-34.0 MPa with supercritical carbon dioxide. However, podophyllotoxin was not sufficiently extracted by pure supercritical carbon dioxide. Methanol was used as modifier to enhance the extraction yield of podophyllotoxin. As a result, SFE produced a higher recovery of podophyllotoxin than conventional 95% ethanol extraction.

Selective effect of chronic lead ingestion on tyrosine hydroxylase activity in brain regions of rats.

Alterations of tyrosine hydroxylase activity in various regions of brain from rats postnatally exposed to lead were tested. Three groups of animals were prepared; (1) Rats exposed to lead at a low dose (0.05% lead acetate, PbAc); (2) Rats exposed to lead at a high dose (0.2% PbAc); (3) Age-matched normal control rats. At 2, 4, 6, and 8 weeks of age, weight of brain and body, and concentrations of lead in whole brain of animals in each group were measured. Activities of tyrosine hydroxylase and Na(+)-K+ ATPase were also measured at the same ages in 4 brain regions of each animal. Body weight gain was decreased after 6 weeks of age in rats exposed to lead at a high dose. Concentrations of lead in whole brain were increased from 0.37 to 0.83 (ng/mg wet tissue) in these animals. Exposure of rats to lead generally increased tyrosine hydroxylase activity and decreased Na(+)-K+ ATPase activity. However, changes of tyrosine hydroxylase activity were detected without concomitant changes of Na(+)-K+ ATPase activity in pons-medulla at 2 weeks of age and telencephalon at 6 weeks of age in rats exposed to lead at a low dose, and in midbrain at 4 and 6 weeks of age in rats exposed to lead at a high dose. These data imply that catecholaminergic nervous system in the brain regions described above could be selectively affected by lead.