Hepatoprotective phenylpropanoids from Scrophularia buergeriana roots against CCl(4)-induced toxicity: action mechanism and structure-activity relationship

Phenylpropanoids isolated from the roots of Scrophularia buergeriana MIQ. (Scrophulariaceae) protected primary cultures of rat hepatocytes from toxicity induced by carbon tetrachloride (CCl(4) ). In this report, we show that two of these phenylpropanoids, 4-O-E- p-methoxycinnamoyl-alpha-L-rhamnopyranoside ester ( 1) and p-methoxycinnamic acid ( 3) have significant hepatoprotective activity; another phenylpropanoid used for comparison, isoferulic acid ( 11), was equally active. To determine the mechanism(s) by which these three phenylpropanoids exerted their hepatoprotective activity, we measured activities of enzymes involved in the glutathione (GSH) redox system and assayed the level of hepatic mitochondrial GSH. The GSH levels in primary cultures of rat hepatocytes were significantly reduced with CCl(4) insult, but were significantly preserved by the treatment with these three phenylpropanoids. The activities of glutathione disulfide reductase and glutathione-S-transferase which normally decrease in CCl(4) -injured rat hepatocytes were significantly preserved by the treatment with these three phenylpropanoids. In addition, in CCl(4) -injured rat hepatocytes, the increased formation of malondialdehyde, a byproduct of lipid peroxidation, was reduced by the treatment with these phenylpropanoids. We determined the essential structural moiety within these three phenylpropanoids needed to exert hepatoprotective activity. The alpha,beta-unsaturated ester moiety seemed to be essential for exerting hepatoprotective activity.     

ACE gene polymorphism and disease progression of IgA nephropathy in Asians in Singapore

The deletion polymorphism of the angiotensin-converting enzyme (ACE) gene has been considered as a risk factor for IgA nephropathy and for its progression to end-stage renal failure. However, results from various studies are conflicting. We had genotyped the ACE gene in 100 patients with IgA nephropathy, 32 of whom were in end-stage renal failure and in 90 normal adult subjects. All DD cases were subjected to confirmation with a second PCR, performed with the insert-specific forward primer. Similar genotype frequencies were obtained for the 90 normal control subjects (II: 47%, ID: 44%, DD: 9%); for the 68 patients not in end-stage renal failure (ESRF) (II: 47%, ID: 46%, DD: 7%) and for the 32 patients with ESRF (II: 53%, ID: 38%, DD: 9%). The genotype frequencies in all 3 series are in Hardy-Weinberg equilibrium. These results suggest that ACE gene polymorphism is not a risk factor for IgA nephropathy and is not a predictor for its progression. Definitive proof of association between ACE gene polymorphism and progression in IgA nephropathy will require a prospective study, controlled for important risk factors, with adequate patient numbers and facility for confirming DD genotypes.     

Age-related changes in the distribution of nitrotyrosine in the cerebral cortex and hippocampus of rats

A wealth of indirect evidence implicates oxidative damage of cellular constituents in aging, as well as in the pathogenesis of the neurodegenerative diseases of later years. In the present study, we have determined age-related changes in the distribution of 3-nitrotyrosine (3-NT) in the cerebral cortex and hippocampus of rats. In adult rats, no 3-NT-immunoreactive cells were found in the cerebral cortex and hippocampus, whereas 3-NT immunoreactivity was significantly increased in aged rats. Some pyramidal cells of CA3 area and granule cells of the dentate gyrus highly expressed 3-NT in aged rats. Many interneurons located within stratum pyramidale and stratum oriens of CA1 were strongly immunoreactive for 3-NT. Our first demonstrations of increased 3-NT in the cerebral cortex and hippocampus during aging implicate these areas as sites for functionally significant oxidative damage. The mechanisms underlying the increased immunoreactivity for 3-NT, and the functional implications of this increase, require elucidation.     

Immunohistochemical study on the distribution of nitrotyrosine and neuronal nitric oxide synthase in aged rat cerebellum

In the present study, we examined age-related changes in 3-nitrotyrosine (NT) and neuronal nitric oxide synthase (nNOS) in rat cerebellum using immunohistochemistry. No immunoreactivity for NT was found in any layers of adult cerebellar cortex. In aged cerebellar cortex, the most prominent labeling of NT was found in the Purkinje cell layers and molecular layers. In aged cerebellar nuclei, NT immunoreactivity was observed in the surrounding neuropil. In aged rat cerebellum, nNOS immunoreactivity was significantly decreased in the molecular layer, while it was slightly increased in the granular layer. Image analysis showed no significant age-related changes in nNOS immunoreactivity in the cerebellar nuclei. In summary, this report has demonstrated that NT increases with age in the cerebellum, and suggests that NO production by the neuronal form of NOS may not be the rate limiting step in NT formation in the aged brain. Further work is needed to examine the mechanisms underlying the increased immunoreactivity for NT, and the functional implications of this increase.     

Preoperative radiotherapy for soft tissue sarcoma: The Peter MacCallum Cancer Centre experience

AIM: Radiotherapy has been shown to improve local control in combination with limb-sparing or conservative surgery in the management of localised soft tissue sarcoma. Our centre's treatment protocol is to offer preoperative external beam radiotherapy (50.4Gy in 28 fractions) followed by surgery four to six weeks later. The aim of this study is to review the treatment outcome and toxicity of patients treated with this protocol. METHODS: Consecutive patients with localised extremity or truncal soft tissue sarcoma who presented between January 1996 and December 2000 and treated with preoperative radiotherapy followed by limb-sparing surgery were reviewed. Patients with recurrent disease or metastatic disease at diagnosis and patients below the age of 16years were excluded. Local and distant recurrence, overall survival and treatment toxicity were analyzed. RESULTS: Sixty-seven cases were identified (41 males and 26 females). The median age was 52years (range 17 to 82). The majority (79%) had tumours located in the lower limb. The most common histological diagnoses were malignant fibrous histiocytoma and liposarcoma. The median follow-up was 4.1years (range 0.6 to 6.9). There were six local recurrences, two of which were successfully salvaged. Twenty patients developed distant metastases. The estimated 5-year actuarial local recurrence free, distant recurrence free and overall survival were 93%, 68% and 73% respectively. Acute radiotherapy toxicity and wound complications were acceptable and late toxicity was uncommon. CONCLUSION: Preoperative radiotherapy followed by surgery provides effective local control in the management of soft tissue sarcoma.