The potential agents from food for preventing leukopenia induced by benzene: garlic preparations.

Leukopenia is the early clinical manifestation of benzene poisoning. The aim of our research was to evaluate the preventive effects of three kinds of garlic preparations on benzene induced leukopenia. The mouse model of Leukopenia was established with benzene orally. At the same time, mice were administrated with garlic homogenate (GH), garlic oil (GO) or diallyl trisulfide (DATS) as preventional measures. The counts of white blood cells (WBC), the organ indexes, pathological examinations, blood biochemical parameters, weight gains, and food intakes were evaluated to observe the protective effect and potential adverse events. The results demonstrated that the counts of WBC increased by 144.04%, 140.07%, and 148.34%, respectively, after intervention by GH (400 mg/kg), GO (60 mg/kg) and DATS (30 mg/kg), compared with that in the model group. The spleen and thymus indexes in the benzene model group were 44.99% and 54.04% lower than those in the blank control group, the number of spleen nodules reduced and the thymus atrophy, which were restored by three garlic preparations at different degree. The results suggested that the three preparations all could prevent the leukopenia and protect the organ injuries induced by benzene. However, the spleen index and weight gains revealed that GH and GO brought more adverse events than DATS.

DADS suppresses human esophageal xenograft tumors through RAF/MEK/ERK and mitochondria-dependent pathways.

Diallyl disulfide (DADS) is a natural organosulfur compound isolated from garlic. DADS has various biological properties, including anticancer, antiangiogenic, and antioxidant effects. However, the anticancer mechanisms of DADS in human esophageal carcinoma have not been elucidated, especially in vivo. In this study, MTT assay showed that DADS significantly reduced cell viability in human esophageal carcinoma ECA109 cells, but was relatively less toxic in normal liver cells. The pro-apoptotic effect of DADS on ECA109 cells was detected by Annexin V-FITC/propidium iodide (PI) staining. Flow cytometry analysis showed that DADS promoted apoptosis in a dose-dependent manner and the apoptosis rate could be decreased by caspase-3 inhibitor Ac-DEVD-CHO. Xenograft study in nude mice showed that DADS treatment inhibited the growth of ECA109 tumor in both 20 and 40 mg/kg DADS groups without obvious side effects. DADS inhibited ECA109 tumor proliferation by down-regulating proliferation cell nuclear antigen (PCNA). DADS induced apoptosis by activating a mitochondria-dependent pathway with the executor of caspase-3, increasing p53 level and Bax/Bcl-2 ratio, and downregulating the RAF/MEK/ERK pathway in ECA109 xenograft tumosr. Based on studies in cell culture and animal models, the findings here indicate that DADS is an effective and safe anti-cancer agent for esophageal carcinoma.

Efficacy and tolerability of diphenyl-dimethyl-dicarboxylate plus garlic oil in patients with chronic hepatitis.

OBJECTIVE: To investigate the hepatoprotective effect, safety and tolerability of oral preparation comprising dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylene dioxybiphenyl-2,2'-dicarboxylate (DDB) plus garlic oil (GO) in chronic hepatitis patients. METHODS: In this double-blind, placebo-controlled clinical trial conducted for 6 weeks with 1-week follow-up, a total of 88 patients with histologically confirmed chronic hepatitis and persistently elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were enrolled and randomly assigned to one of 4 treatment groups: placebo (Group A) and 3 escalating dose groups (2, 3, or 6 study drug capsules a day) (Groups B - D). Each study drug capsule contains 25 mg DDB plus 50 mg GO. Efficacy was assessed by monitoring changes in the circulating activities of ALT and AST as surrogate markers for liver injury. Safety and tolerability were assessed based on the evaluation of clinically adverse events and laboratory test results. RESULTS: Of 88 patients, 83 took at least one dose of study drug and 79 completed the study without any protocol violation. The majority of patients (81/83, 98%) had been infected with HBV. The proportions of patients whose ALT levels returned to normal ranges at Week 6, a primary outcome, were significantly different among 4 groups: 16% (3/19), 41% (9/22), 52% (11/21), and 88% (15/17) in Groups A, B, C, and D, respectively (p < 0.001). The proportions were significantly higher in Groups C (p = 0.022) and D (p < 0.001) but not in Group B compared to Group A. Interestingly, the proportion of Group D was higher than that of Group C (p = 0.034), suggesting a dose-response effect of DDB plus GO on the decrease of ALT levels. The mean ALT levels started to decrease from Week 1 in patients treated with DDB plus GO, whereas no decrease was seen in placebo group. The mean AST levels had a decreasing trend in all doses of DDB plus GO groups. Notably, patients treated with 6 capsules of DDB plus GO daily exhibited the statistically significant decrease in AST levels from Week 3. However, there was no difference in the proportions of patients with the AST decrease to normal ranges after 6-week therapy among 4 groups. The effects of DDB plus GO on decreases in ALT and AST levels lasted until 1 week after completion of treatment. Additionally, the ratios of ALT to AST gradually decreased in patients treated with DDB plus GO over time, suggesting higher degrees of reduction in ALT than in AST in those groups. No clinically meaningful adverse events and laboratory abnormalities were observed during the study period. CONCLUSIONS: The 6-week treatment of DDB plus GO lowered serum aminotransferase activities in patients with chronic hepatitis induced by HBV and/or HCV and was well tolerated. For the treatment of viral hepatitis patients, the optimal dose of this preparation was 3 to 6 capsules per day.

Dillapiole as antileishmanial agent: discovery, cytotoxic activity and preliminary SAR studies of dillapiole analogues.

In this paper, the isolation of dillapiole (1) from Piper aduncum was reported as well as the semi-synthesis of two phenylpropanoid derivatives [di-hydrodillapiole (2), isodillapiole (3)], via reduction and isomerization reactions. Also, the compounds' molecular properties (structural, electronic, hydrophobic, and steric) were calculated and investigated to establish some preliminary structure-activity relationships (SAR). Compounds were evaluated for in vitro antileishmanial activity and cytotoxic effects on fibroblast cells. Compound 1 presented inhibitory activity against Leishmania amazonensis (IC(50) = 69.3 µM) and Leishmania brasiliensis (IC(50) = 59.4 µM) and induced cytotoxic effects on fibroblast cells mainly in high concentrations. Compounds 2 (IC(50) = 99.9 µM for L. amazonensis and IC(50) = 90.5 µM for L. braziliensis) and 3 (IC(50) = 122.9 µM for L. amazonensis and IC(50) = 109.8 µM for L. brasiliensis) were less active than dillapiole (1). Regarding the molecular properties, the conformational arrangement of the side chain, electronic features, and the hydrophilic/hydrophobic balance seem to be relevant for explaining the antileishmanial activity of dillapiole and its analogues.

The composition of oil phase modulates venous irritation of lipid emulsion-loaded diallyl trisulfide.

INTRODUCTION: In this study, a nanoemulsion system (LE) was investigated for intravenous delivery of diallyl trisulfide (DT), which was a lipophilic and venous irritant drug for systemic therapy of bacterial and fungal infection. METHODS: Egg phospholipid was chosen as the only emulsifier, soybean oil, medium chain triglyceride (MCT), and olive oil were used as the oil phases, forming stable DT LEs (o/w) with small particle sizes. The venous irritation of DT LEs was evaluated by in vitro human umbilical cord endothelial cells (HUV-EC CRL 1730) tolerance model with the intracellular ATP and GTP concentrations as the indices. RESULTS: The intracellular ATP and GTP reduction changed with the incorporation of a variety of oils, which were strongly related with the free DT concentration of DT LEs. DISCUSSION: It was deduced that the free DT concentrations of LEs made of various oils depended on the particle sizes of the DT LEs. In conclusion, the oil phases modulated the free DT concentrations by forming DT LEs with different particle sizes, and optimization of the oil phase was an effective method to alleviate the venous irritation of DT LEs.

Reduced allergy rates in atopic eczema to contact allergens used in both skin products and foods: atopy and the 'hapten-atopy hypothesis'.

BACKGROUND: Food allergy is strongly associated with atopy. This retrospective study investigates whether atopic status affects responses to contact allergens also found in food. We compared incidences of atopic dermatitis/eczema (AD) in subjects who were patch-test positive (PT+) to diallyl disulfide from handling garlic and parabens used as a skin cream/ointment and food preservative with the incidence in those subjects who were PT+ to chemicals encountered at skin surfaces (lanolin and nickel). RESULTS: 36,658 patients with eczema/dermatitis were patch tested (1980-2006). 10,326 (28.2%) had AD. 13/83 (15.6%) PT+ subjects to diallyl disulfide/garlic had AD (AD/total population versus AD/diallyl disulfide PT+, P = 0.011). 54/239 parabens PT+ had AD (22.6%), while 181/608 lanolin PT+ had AD (29.8%) (P < 0.05). CONCLUSIONS: Contact allergy to haptens with oral and skin exposure is reduced in AD compared with non-AD, unlike food protein hypersensitivity. Lanolin frequency was not decreased. Possible explanations include (i) confounding factors, e.g. AD subjects handle garlic less than non-AD subjects, or (ii) AD patients tolerate haptens efficiently, secondary to their atopic status, or (iii) oral tolerance of haptens antagonizes tolerance of food proteins, contributing to development of atopy (hapten-atopy hypothesis). The recent upsurge of atopy took place when gut exposure to haptens in processed foods increased dramatically.

The soil ecotoxicology of 1,3-dichloropropene under commercial growing conditions.

Soil fumigants are used extensively in the protection of crops against parasitic nematodes and other soil borne pests. The active ingredient in Telone II soil fumigant is 1,3-Dichloropropene (1,3-D) which has a wide range of uses in Europe as a pre-plant nematocide. During the use of soil fumigants such as 1,3-D a range of non-target soil dwelling organisms has the potential to be exposed and impacted. We report here the results of a field study conducted in Italy to assess the impact of 1,3-D applications to soil-dwelling non-target organisms. This study was conducted under conditions of commercial tomato growing either without (untreated control) or with an application of 1,3-D at 224 kg a.i./hectare. Samples of arthropods and earthworms were taken before and up to 12 months after application to measure season long effects. A soil sample was taken at 4.5 months and a soil function test performed. By evaluating the effects of 1,3-D both in the Laboratory and under field conditions equivalent to commercial practices it was concluded that applications of 1,3-D would not adversely effect soil arthropods, but may have an effect on earthworms and soil microflora. These effects were, however, transient as full recovery was observed within six months of application for earthworms and 4.5 months for soil microflora. Consequently, the risk to non-target soil micro- and macro-organisms was considered acceptable according to current risk assessment guidelines within the European Union.

[Patterns of biochemical disorders under exposure to neurotoxic chemicals varying in nature].

The article covers results of examination of workers engaged into chemical production and contacting neurotoxic factors varying in nature. Findings are disorders of cholesterol metabolism in individuals engaged into vinylchloride and metallic mercury production, modified protein metabolism, activated lipid peroxidation and depressed antioxidant

Chemical carcinogenesis. A soil fumigant, 1,3-dichloropropene, as possible cause of hematologic malignancies.

Findings from three case reports suggest a causal relationship between exposure to a soil fumigant , 1,3- dichloropropene , and hematologic malignancy. Its chemical relationship to other carcinogens is noted. The purpose of this report is to record this evidence and alert physicians that prior exposure to this chemical of patients initially observed with neoplasms should be noted in the medical history.

Pharmacokinetics and pharmacodynamics of the monoamine oxidase B inhibitor mofegiline assessed during a phase I dose tolerance trial.

The safety, pharmacokinetics, and pharmacodynamics of single oral doses of up to 48 mg and daily (for 28 days) doses of up 24 mg mofegiline were investigated in healthy male volunteers. Plasma pharmacokinetics indicated rapid absorption and elimination: time to reach maximum concentration occurred at about 1 hour; half-life ranged from 1 to 3 hours. Maximal plasma concentration and area under the plasma concentration-time curve increased and oral clearance decreased disproportionately with dose. Mofegiline rapidly and markedly inhibited platelet monoamine oxidase B (MAOB) activity, which returned to baseline within 14 days. Urinary excretion of phenylethylamine increased proportionately with doses up to 24 mg. No changes in urinary elimination of catecholamines, blood pressure, heart rate, or ECG were observed. A classic maximum tolerated dose was not achieved in these studies. However, the 48 mg single dose and the 24 mg multiple daily dose far exceeded the dose (1 mg) that was associated with > 90% platelet MAOB inhibition.

Biomonitoring studies and susceptibility markers for acrolein congeners and allylic and benzyl compounds.

The importance of genotoxic acrolein congeners and allylic and benzyl compounds as industrial compounds, ubiquitous environmental pollutants, and naturally occurring substances necessitates the availability of adequate biomonitoring techniques. Endogenously formed acrolein congeners are considered to play an important role in carcinogenesis. Our studies have demonstrated that acrolein congeners react with DNA components and form adducts with the guanine moiety. We have identified and characterized cyclic 1,N2-deoxyguanosine adducts, cyclic 7,8-guanine adducts, linear 7-guanine adducts, 1,N2,7,8-bis-cyclic adducts, and 1,N2-cyclic, 7-linear bis adducts. Both the reactivity of the acroleins toward nucleosides and their mutagenicity in S. typhimurium TA100 decrease with increasing degree of alkyl substitution. Adducts are now available as reference substances for developing sensitive detection methods. Of the biomonitoring methods investigated for allylic and benzyl compounds, the detection of cysteine and histidine adducts isolated from hemoglobin seems to be the most sensitive. Gas chromatography with electron capture detection of heptafluorobutyric acid derivatives allows a detection limit in the femtomole range, HPLC-fluorescence detection of O-phthalic dialdehyde derivatives allows a limit in the picomole range, and detection of 9-fluorenylmethyl-chlorofomiate derivatives allows a limit in the femtomole range.

Mutagenicity of chloroolefins in the Salmonella/mammalian microsome test. III. Metabolic activation of the allylic chloropropenes allyl chloride, 1,3-dichloropropene, 2,3-dichloro-1-propene, 1,2,3-trichloropropene, 1,1,2,3-tetrachloro-2-propene and hexachloropropene by S9 mix via two different metabolic pathways.

In the presence of S9 mix all allylic chloropropenes tested exert considerable indirect mutagenic activity which is most pronounced for 1,2,3-trichloropropene. Lower as well as higher chlorinated derivatives are clearly less mutagenic. Longer than standard incubation time (120 min instead of 20 min) at 37 degrees C always leads to an increase in mutagenic activity. An increase in concentration of rat-liver homogenate fraction (S9) in the metabolising system (S9 mix) enhances mutagenicity only for 1,3-dichloropropene, 2,3-dichloro-1-propene and for the cis isomer of 1,1,2,3-tetrachloro-2-propene. According to the effects of the enzyme inhibitors SKF525 1,1,1-trichloropropene-2,3-oxide and cyanamide the allylic chloropropenes fall into 3 groups distinguished by their mode of metabolic activation by S9 mix: (a) allyl chloride and 1,3-dichloropropene are hydrolysed to the corresponding allylic alcohols which can be oxidised to the respective acroleins (hydrolytic-oxidative pathway); (b) 2,3-dichloro-1-propene, 1,1,2,3-tetrachloro-2-propene and hexachloropropene are epoxidised in the C=C double bond, giving rise to reactive epoxides (epoxidative pathway); (c) only 1,2,3-trichloropropene is obviously activated by both these alternative metabolic pathways. Structural parameters like chloro-substitution of the central C atom of the C=C-C sequence and substituent-induced polarisation of the C=C double bond as well as cis/trans isomerism might be responsible for different substrate properties for the enzymes involved in allylic chloropropene metabolism, thus determining different degrees of activation by either one or both pathways.

Inhibition of cyclooxygenase-2 by diallyl sulfides (DAS) in HEK 293T cells.

Cyclooxygenase (COX) is involved in modulating inflammatory response through the synthesis of prostaglandins. The inducible isoform of the enzyme, COX-2, is overexpressed in some malignant and premalignant lesions. Several preclinical and clinical studies have reported COX-2 inhibition as an effective strategy for chemoprevention. Nonsteroidal anitinflammatory drugs (NASIDs) such as celecoxib, are the most widely investigated COX-2 inhibitors. The oil-soluble diallyl sulfides (DAS) include monosulfides (DAMS), disulfides (DADS) and trisulfides (DATS). They were found to be effective against canine and human tumors, the mechanism of which remains unresolved. We attempted a comparative evaluation of the antiproliferative effect of DAS in HEK 293T cells. The cells were treated with increasing concentrations of DAMS, DADS and DATS. There were significant differences between the IC50 values of DAMS, DADS and DATS. RT-PCR was performed and the expression of COX-2 was compared with that of b actin. DATS inhibited COX-2 gene expression significantly stronger than DAMS and DADS. The data are suggestive of antineoplastic effect of DAS, mediated by controlling COX-2 expression.

Effects of allyl chloride on occupationally exposed subjects.

Effects of allyl chloride on occupationally exposed subjects were studied in two factories manufacturing sodium allyl sulfonate. Twenty-six subjects in factory A and 27 workers in factory B were exposed to allyl chloride at levels of 2.6-6 650 mg/m3 for 2.5 months--6 years and 0.2-25.13 mg/m3 for 1-4.5 years, respectively. Most subjects of factory A had weakness, paresthesia, and numbness in extremities with sensory impairment in the glove-stocking distribution, as well as reduced ankle reflexes. Electroneuromyography showed neurogenic abnormalities in 10 of the 19 subjects examined, the prevalence of neuropathy therefore being 52.6%. Similar symptoms of workers in factory B were clinically much milder, and there were few abnormal neurological signs--yet electromyographic findings indicating mild neuropathy were found in 13 of the 27 subjects. No significant abnormalities of other organs were noted. Possible etiologic factors other than exposure to allyl chloride were excluded. All the evidence obtained indicates that chronic exposure to allyl chloride mainly causes toxic polyneuropathy. The neurotoxicity of allyl chloride has also been confirmed by experimental neuropathological studies.

Environmental and drug factors in hepatic porphyria.

Numerous drugs and environmental chemicals are capable of influencing the clinical expression of human hepatic porphyria primarily by interfering with the orderly regulation of heme synthesis in the liver. Some agents trigger the disease in otherwise normal individuals whereas others exacerbate an underlying genetic abnormality leading to disease expression. In both instances careful avoidance of exposure to these drugs and chemicals can largely prevent the development of manifest disease. The mechanisms whereby these agents impair the normal regulation of hepatic heme synthesis have been carefully studied in recent years and have provided valuable new insights into this form of drug-induced hepatotoxicity.

Chronic inhalation toxicity and carcinogenicity studies of 3-chloro-2-methylpropene in BDF1 mice.

Chronic toxicity and carcinogenicity studies of 3-chloro-2-methylpropene (CMP), which has been widely used as an insecticide and chemical intermediate, were carried out in BDF1 mice. CMP was administered to mice in groups of 50 male and 50 female mice by the inhalation route 5 days per week for 104 weeks at doses of 0, 50, 100 or 200 ppm. Male and female mice in the CMP-exposed groups had decreased body weight but no noticeable clinical signs when compared with the control group. Dose-related increases in the incidences of gastric mucosal hyperplasia and squamous cell papilloma were observed in both sexes, and squamous cell carcinoma was observed in only one male mouse in the 100 ppm group. An increased incidence of Harderian gland adenoma in female mice was also recognized. In the nasal cavity, eosinophilic exudate associated with atrophy of olfactory epithelia, respiratory metaplasia of olfactory epithelia and olfactory gland, and eosinophilic changes in respiratory and olfactory epithelia were increased in both sexes.

Toxicology and hazard assessment of 1,3-dichloropropene (Telone II).

Potential adverse health effects from occupational exposure to 1,3-dichloro-propene (DCP) are reviewed and hazards assessed. Further toxicologic evaluations should be conducted using only high-purity material that is free from possibly confounding impurities and stabilizers. Safety considerations when handling the material are included.

Delirium due to intoxication from the novel synthetic tryptamine 5-MeO-DALT.

Synthetic tryptamines have gained popularity for their hallucinogenic properties, unscheduled status, and availability from "head shops" and through the internet. Here, we present a case of synthetic tryptamine-induced delirium secondary to 5-MeO-DALT ingestion in a previously healthy young male. 5-MeO-DALT led to the hospitalization of our patient after ingestion of a standard dose, presenting with extreme agitation, tachycardia, diaphoresis, and combativeness leading to physical restraint and intravenous sedation. A search of PubMed, Ovid, and Google Scholar for keywords of "5-MeO-DALT," "5-methoxy-N,N-diallyltryptamine," or "Lucy-N-Nate" found no case reports or clinical articles in the literature. Rapid emergence and commercialization of this novel synthetic tryptamine 5-MeO-DALT points to the importance of health care and forensic professionals keeping abreast of the latest drugs of abuse and their clinical features. The authors hope this report leads the way in disseminating the potential risks associated with unscheduled and unregulated substances, synthetic tryptamines such as 5-MeO-DALT in particular.

Chk1, but not Chk2, is responsible for G2/M phase arrest induced by diallyl disulfide in human gastric cancer BGC823 cells.

Diallyl disulfide (DADS) has been shown to cause G2/M phase cell cycle arrest in several human cancers. Here we demonstrate a mechanism by which DADS induces G2/M phase arrest in BGC823 human gastric cancer cells via Chk1. From cell cycle gene array results, we next confirmed that cyclin B1 expression was decreased by DADS, while the expression of p21, GADD45α and p53 were increased. Despite the lack of change in Chk1 gene expression in response to DADS according to the array analysis, intriguingly overexpression of Chk1, but not Chk2, exhibited increased accumulation in G2/M phase. Moreover, overexpression of Chk1 promoted the effect of DADS-induced G2/M arrest. Augmented phosphorylation of Chk1 by DADS was observed in Chk1-transfected cells, followed by downregulation of Cdc25C and cyclin B1 proteins. In contrast, phosphorylated Chk2 showed no obvious change in Chk2-transfected cells after DADS treatment. Furthermore, knockdown of Chk1 by siRNA partially abrogated DADS-induced downregulation of Cdc25C and cyclin B1 proteins and G2/M arrest. In contrast, knockdown of Chk2 did not show these effects. Therefore, these data indicate that DADS may specifically modulate Chk1 phosphorylation, and DADS-induced G2/M phase arrest in BGC823 cells could result in part from Chk1-mediated inhibition of the Cdc25C/cyclin B1 pathway.