Organ-Specific Toxicokinetics and Dose–Response of Arsenic in Tilapia <Emphasis Type="Italic">Oreochromis mossambicus</Emphasis>

We appraised organ-specific toxicokinetics and dose responses of arsenic burdens in tilapia Oreochromis mossambicus. We kinetically linked an Area-under-the-curve (AUC)–based acute toxicity model and a pharmacodynamic model to derive dose–response relationships between equilibrium organ-specific arsenic concentrations and mortality effects. The AUC-based acute toxicity model was also used to derive organ-specific internal effect concentration (IEC)–time-response relationships, which can also be applied to predict a time–mortality profile. We conducted a 7-day exposure experiment to obtain toxicokinetic parameters, whereas the AUC-based acute toxicity model was verified with LC₅₀(t) data obtained from a 7-day acute toxicity bioassay. Our results demonstrated that 96-hour LC₅₀ and incipient LC₅₀ for tilapia exposed to arsenic are 28.68 (95% confidence interval to 24.92 to 32.44) and 25.55 mg L^–1, respectively. Dose–response relationships followed the Hill equation, which could be expressed as organ-specific bioconcentration factors and incipient LC₅₀. Organ-specific dose-response relationships showed that muscle, gill, and liver have a relatively steep sigmoid dose-response profile in that IEC₅₀ were 26.6, 62.5, and 78.5 g g^–1 dry wt (dw), respectively. Organ-specific arsenic internal lethal burdens were the highest in the gill and the lowest in the muscle in waterborne-exposed tilapia. The IEC and target-organ concentrations derived in this study can be used in site-specific risk assessment.     

A prospective cohort study of nut consumption and the risk of gallstone disease in men

Gallstone disease is a major source of morbidity in Western countries. Nuts are rich in several compounds that may be protective against gallstones. The objective of the study was to examine the relation between nut consumption and gallstone disease in the Health Professionals Follow-up Study. The consumption of nuts was assessed starting in 1986 as part of a 131-item semiquantitative food frequency questionnaire. The main outcome measure was newly diagnosed symptomatic gallstones. During 457,305 person-years of follow-up, 1,833 participants reported gallstone disease. After adjustment for age and other known or suspected risk factors, men consuming 5 or more units of nuts per week (frequent consumption) had a significantly lower risk of gallstone disease (relative risk = 0.70, 95% confidence interval: 0.60, 0.86; p(trend) < 0.001) than did men who never ate or who ate less than 1 unit per month (rare consumption) (1 unit = 1 ounce (0.028 kg) of nuts). Further adjustment for fat consumption (saturated fat, trans-fat, polyunsaturated fat, and monounsaturated fat) did not materially alter the relation. In analyses examining consumption of peanuts and other nuts separately, both were significantly associated with a lower risk of gallstone disease in the age-adjusted and multivariate models. Our findings suggest that frequent nut consumption is associated with a reduced risk of gallstone disease in men.     

Diallyl trisulfide modulates cell viability and the antioxidation and detoxification systems of rat primary hepatocytes

This study investigated the effects of various concentrations of diallyl trisulfide (DATS) and incubation times on cell viability, glutathione (GSH) content, and GSH-related enzyme activity in rat primary hepatocytes. Isolated and cultured primary rat hepatocytes were used as an experimental model. Cells were treated with 0 (control), 0.025, 0.05, or 0.25 mmol/L DATS for 0, 4, 8, or 24 h. After 24 h of treatment, some cells were incubated in fresh medium without DATS for an additional 24 h (48-h incubations). Based on lactate dehydrogenase (LDH) leakage and morphological examination, hepatocytes treated with 0.025 mmol/L DATS did not differ from the control cells at 4, 8, 24, and 48 h of incubation. However, LDH leakage was higher than in the control cells (P < 0.05) when the hepatocytes were treated with 0.05 or 0.25 mmol/L DATS for 4 h or more. The intracellular GSH levels of hepatocytes treated with 0.025 or 0.05 mmol/L DATS were higher than those of the control cells (P < 0.05), whereas those treated with 0.25 mmol/L DATS did not differ. The activity of glutathione reductase (GRd) was higher than in the control cells at 24 h (P < 0.05) when the hepatocytes were treated with 0.025 mmol/L DATS. When the hepatocytes were treated with 0.025 mmol/L DATS, the activity of glutathione S-transferase (GST) was higher than in the control cells at 48 h (P < 0.05). In hepatocytes treated with 0.05 mmol/L DATS, the activity of GST and glutathione peroxidase (GPx) was higher than in the control cells (P < 0.05) at 24 and 48 h of incubation. The results indicate that 0.025 or 0.05 mmol/L DATS could enhance antioxidation and detoxification capabilities by increasing the intracellular GSH level and the activity of GPx, GRd, or GST in rat primary hepatocytes. However, 0.05 or 0.25 mmol/L DATS might adversely affect the viability of hepatocytes.     

The mortality risks of smokers in Taiwan: Part I: cause-specific mortality

BACKGROUND: Few studies of adverse health effects from smoking have been conducted in southeastern Asian populations which may exhibit racial, cultural, and smoking behavioral differences that could affect mortality patterns. This study aims to quantify cause-specific mortality risks among cigarette smokers in Taiwan. METHODS: The study population for this investigation was derived from two existing prospective study cohorts: a community-based cohort and a cohort composed of civil servants and teachers. Smoking data were obtained by face-to-face interview in the community cohort and by self-administered questionnaire in the civil servant/teacher cohort. The mortality risks of current smokers, adjusted for age, were compared to those of nonsmokers using Cox's proportional hazards model and dose-response relationships were examined by variables of smoking intensity and duration. RESULTS: Male smokers had significantly higher all-cause mortality than nonsmokers. Cigarette smoking was also significantly associated with increased risks of dying from cancer, cardiovascular disease, respiratory disease, chronic bronchitis, diabetes, peptic ulcer, liver cirrhosis, and kidney disease. In addition, smokers had an increase in risk of fatal injuries from motor vehicle accidents and nonmotor vehicle accidents, as well as cancers of the oral cavity nasopharynx, esophagus, stomach, rectum, liver, and lungs. Risks for women smokers were generally higher than those for men, although this is based on small numbers of smokers. In women, deaths from all causes, all cancers, and cancers of the cervix, liver, and lung, cardiovascular disease, and respiratory disease were also significantly increased. The mean age at death for smokers who died before age 65 from smoking-related diseases was 57.4 years, which represented a loss of 22 years of life expectancy. CONCLUSIONS: The pervasive and serious impact of cigarette smoking on the health of Taiwanese cannot be underestimated.     

A codon 31ser-arg polymorphism of the WAF-1/CIP-1/p21/tumour suppressor gene in Chinese primary open-angle glaucoma

PURPOSE: Glaucomatous neuropathy is a type of cell death by apoptosis. Apoptosis is a genetically controlled form of cell death, and one of its primary regulatory steps is the activation of the tumour suppressor protein p53, of which p21 is an effector protein. The association between p21 codon 31 polymorphism and primary open-angle glaucoma (POAG) patients was evaluated in this study. METHODS: The study included 58 POAG patients and a control group of 59 healthy volunteers. Polymerase chain reaction-based analysis was used to resolve the p21 codon 31 polymorphism. RESULTS: The genotype frequencies of p21 codon 31 polymorphism were statistically different (p < 0.05) between the two groups. The Arg allele of the p21 codon 31 polymorphism was more frequently found in POAG patients than in healthy individuals (odds ratio: 2.389, 95% confidence interval: 1.14-5.01). CONCLUSION: This study suggests that an association exists between the Arg allele of the p21 codon 31 polymorphism and POAG in the Chinese population.     

Development and evaluation of the essential oil from Magnolia fargesii for enhancing the transdermal absorption of theophylline and cianidanol

To improve the skin permeation of theophylline and cianidanol ((+)-catechin), the essential oil of Magnolia fargesii was evaluated using in-vitro and in-vivo permeation techniques. Oxygenated monoterpenes and sesquiterpenes are the major components of M. fargesii essential oil. The in-vitro permeation of theophylline and cianidanol was significantly enhanced after treatment with M. fargesii essential oil. The essential oil increased the in-vivo skin deposition of cianidanol but not theophylline. On the other hand, in-vivo microdialysis showed a higher subcutaneous theophylline amount after essential oil treatment. In-vitro cell viability and prostaglandin E(2) release by skin keratinocytes indicated that there was low or negligible cytotoxicity by M. fargesii essential oil. The in-vivo skin tolerance study determined by transepidermal water loss and colorimetry confirmed that no irritation of the skin was detected when using M. fargesii essential oil.     

C5a differentially stimulates the ERK1/2 and p38 MAPK phosphorylation through independent signaling pathways to induced chemotactic migration in RAW264.7 macrophages

We elucidate the roles of various protein kinases involved in complement 5a (C5a)-induced cell migration. Results showed that extracellular signal-regulated kinase1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK) and phosphatidylinositol 3-kinase (P13K) were necessary for C5a-induced migration, whereas protein kinase C and c-Jun N-terminal kinase (JNK) were nonessential. C5a-induced migration was also suppresses by phospholipase C (PLC) inhibitor U73122 and pertussis toxin (PTX). We found that C5a-induced, time-dependent (1) ERK1/2 phosphorylation was markedly diminished by PTX, U73122, P13K inhibitors wortmannin and LY294002 and ERK1/2 inhibitor PD98059; (2) Akt phosphorylation was also attenuated by the above inhibitors except PD98059; (3) p38 MAPK phosphorylation was only affected by PTX. Furthermore, C5a also stimulated PLCbeta(2) membrane translocation in a time-dependent manner that occurred early prior to Akt phosphorylation and could be abolished only by PTX and U73122. These results suggest that C5a, through the activation of PTX-sensitive G protein, to differentially stimulate ERK1/2 and p38 MAPK phosphorylation and evoke cell migration. That is, ERK1/2 but not p38 MAPK phosphorylation is down stream of P13K/Akt and modulated by PLC. Additionally, beta(2) isoform may be one of the participates in C5a signal and acts more upstream of P13K/Akt.     

Isolation of salicin derivatives from Homalium cochinchinensis and their antiviral activities

The chemical constituents of Homalium cochinchinensis were examined. From the root bark, in addition to the previously reported cochinolide and its beta-glucopyranoside, cochinchiside A (1) and tremulacinol (4) were isolated together with three known compounds [benzoic acid, tremulacin (2), and tremuloidin (3)]. From the leaves, cochinchiside B (5) was isolated as new compound. The structures of the new compounds (1, 4, 5) were determined by spectroscopic and/or chemical methods. Antiviral testing of compounds 2-5 against HSV-1 and HSV-2 showed that tremulacin (2) and cochinchiside B (5) were weakly active. Tremulacin (2) was also weakly active against HIV-1.     

A randomised phase II study of weekly paclitaxel or vinorelbine in combination with cisplatin against inoperable non-small-cell lung cancer previously untreated

Cyclooxygenase-2 (COX-2) expression is increased in breast cancer and surgery has been shown to increase the growth of metastatic tumours. We investigated the effect of selective COX-2 inhibition on the growth of metastases in either an experimental metastasis model or following excision of a murine primary breast tumour. 50,000 4T1 mammary carcinoma cells were injected into the mammary fat pad of female BALB/c mice. When the mean TD reached 8+/-0.4 mm, tumours were excised and the mice were randomised into two groups (n=12 per group) to receive daily intraperitoneal injections of the selective COX-2 inhibitor, SC-236 or drug vehicle for 14 days. Alternatively, experimental metastases were established by tail-vein injection of 50,000 4T1 cells. Mice received either the selective COX-2 inhibitor, SC-236 or drug vehicle for 14 days (n=12 per group). SC-236 treatment significantly reduced tumour burden, the number and size of spontaneous metastases following primary tumour excision. SC-236 treatment also reduced tumour burden, the number and size of experimental metastases. Immunohistochemical staining demonstrated that COX-2 inhibition reduced microvessel density and increased apoptosis within both spontaneous and experimental metastases. These data clearly demonstrate that the selective COX-2 inhibitor, SC-236, has potent antimetastatic activity against both spontaneous metastases arising following primary tumour excision and experimental metastases.