Rational Design of an Antifungal Polyacrylamide Library with Reduced Host-Cell Toxicity.

Life-threatening invasive fungal infections represent an urgent threat to human health worldwide. The limited set of antifungal drugs has critical constraints such as resistance development and/or adverse side effects. One approach to overcome these limitations is to mimic naturally occurring antifungal peptides called defensins. Inspired by their advantageous amphiphilic properties, a library of 35 synthetic, linear, ternary polyacrylamides was prepared by controlled/living radical polymerization. The effect of the degree of polymerization (20, 40, and 100) and varying hydrophobic functionalities (branched, linear, cyclic, or aromatic differing in their number of carbons) on their antifungal activity was investigated. Short copolymers with a calculated log P of ∼1.5 revealed optimal activity against the major human fungal pathogen Candida albicans and other pathogenic fungal species with limited toxicity to mammalian host cells (red blood cells and fibroblasts). Remarkably, selected copolymers outperformed the commercial antifungal drug amphotericin B, with respect to the therapeutic index, highlighting their potential as novel antifungal compounds.

More than skin deep: using polymers to facilitate topical delivery of nitric oxide.

Skin, the largest organ in the human body, provides several important functions, including providing protection from mechanical impacts, micro-organisms, radiation and chemicals; regulation of body temperature; the sensations of touch and temperature; and the synthesis of several substances including vitamin D, melanin, and keratin. Common dermatological disorders (CDDs) include inflammatory or immune-mediated skin diseases, skin infection, skin cancer, and wounds. In the treatment of skin disorders, topical administration has advantages over other routes of administration, and polymers are widely used as vehicles to facilitate the delivery of topical therapeutic agents, serving as matrices to keep therapeutic agents in contact with the skin. Nitric oxide (NO), a cellular signalling molecule, has attracted significant interest in treating a broad spectrum of diseases, including various skin disorders. However, there are a number of challenges in effectively delivering NO. It must be delivered in a controlled manner at sufficient concentrations to be efficacious and the delivery system must be stable during storage. The use of polymer-based systems to deliver NO topically can be an effective strategy to overcome these challenges. There are three main approaches for incorporating NO with polymers in topical delivery systems: (i) physical incorporation of NO donors into polymer bases; (ii) covalent attachment of NO donors to polymers; and (iii) encapsulation of NO donors in polymer-based particles. The latter two approaches provide the greatest control over NO release and have been used by numerous researchers in treating CDDs, including chronic wounds and skin cancer.

Historical review on development of environmental quality standards and guideline values for air pollutants in Japan.

Environmental quality standards (EQSs) have been established as desirable levels to be maintained for protection of human health and the conservation of the living environment by Basic Environment Law. EQSs in ambient air had been set for 10 substances (sulfur dioxide (SO(2)), carbon monoxide (CO), suspended particulate matter (SPM), nitrogen dioxide (NO(2)) and photochemical oxidants (Ox), benzene, tetrachloroethylene, trichloroethylene, dioxins and dichloromethane) and guideline values for 7 (acrylonitorile, vinyl chloride monomer, mercury, nickel compounds, 1,3-butadiene, chloroform and 1,2-dichloromethane) in Japan by 2009. EQSs for the classical (or traditional) air pollutants, SO(2), CO, SPM, NO(2) and Ox, were set according to the minimal requirement to protect human health, based on evidence from epidemiological studies conducted before the 1970s. In 1996, the Central Environment Council designated substances which may be hazardous air pollutants and substances requiring priority action, and adopted the concept of risk assessment to set EQSs and guideline values. A life-long risk level (virtually safe dose) of 10(-5) was used to set EQS for benzene, and guideline values for vinyl chloride monomer, nickel compounds, and 1,3-butadiene. EQSs for trichloroethylene, tetrachloroethylene and dichloromethane, and guideline values for acrylonitorile and mercury were set using uncertain factors and lowest observed adverse effect (LOAEL)/no observed adverse effect level (NOAEL). The results of animal experiments were utilized to set guideline values for chloroform and 1,2-dichloroethane. The benchmark approach and human equivalent concentration (HEC) were adopted for 1,2-dichloroethane. The history of setting EQSs and guideline values for hazardous air pollutants is one of adopting new concepts into risk assessment.

Formation of acetaldehyde-derived DNA adducts due to alcohol exposure.

Epidemiological studies have identified chronic alcohol consumption as a significant risk factor for cancers of the upper aerodigestive tract, including the oral cavity, pharynx, larynx and esophagus, and for cancer of the liver. Ingested ethanol is mainly oxidized by the enzymes alcohol dehydrogenase (ADH), cytochrome P-450 2E1 (CYP2E1), and catalase to form acetaldehyde, which is subsequently oxidized by aldehyde dehydrogenase 2 (ALDH2) to produce acetate. Polymorphisms of the genes which encode enzymes for ethanol metabolism affect the ethanol/acetaldehyde oxidizing capacity. ADH1B*2 allele (ADH1B, one of the enzyme in ADH family) is commonly observed in Asian population, has much higher enzymatic activity than ADH1B*1 allele. Otherwise, approximately 40% of Japanese have single nucleotide polymorphisms (SNPs) of the ALDH2 gene. The ALDH2 *2 allele encodes a protein with an amino acid change from glutamate to lysine (derived from the ALDH2*1 allele) and devoid of enzymatic activity. Neither the homozygote (ALDH2*2/*2) nor heterozygote (ALDH2*1/*2) is able to metabolize acetaldehyde promptly. Acetaldehyde is a genotoxic compound that reacts with DNA to form primarily a Schiff base N(2)-ethylidene-2'-deoxyguanosine (N(2)-ethylidene-dG) adduct, which may be converted by reducing agents to N(2)-ethyl-2'-deoxyguanosine (N(2)-ethyl-dG) in vivo, and strongly blocked translesion DNA synthesis. Several studies have demonstrated a relationship between ALDH2 genotypes and the development of certain types of cancer. On the other hand, the drinking of alcohol induces the expression of CYP2E1, resulting in an increase in reactive oxygen species (ROS) and oxidative DNA damage. This review covers the combined effects of alcohol and ALDH2 polymorphisms on cancer risk. Studies show that ALDH2*1/*2 heterozygotes who habitually consume alcohol have higher rates of cancer than ALDH2*1/*1 homozygotes. Moreover, they support that chronic alcohol consumption contributes to formation of various DNA adducts. Although some DNA adducts formation is demonstrated to be an initiation step of carcinogenesis, it is still unclear that whether these alcohol-related DNA adducts are true factors or initiators of cancer. Future studies are needed to better characterize and to validate the roles of these DNA adducts in human study.

Effects of acetaldehyde inhalation in mitochondrial aldehyde dehydrogenase deficient mice (Aldh2-/-).

Human body might be exposed to acetaldehyde from smoking or occupational environment, which is known to be associated with cancer through the formation of DNA adducts, in particular, N2-ethylidene-2'- deoxyguanosine (N2-ethylidene-dG). Aldehyde dehydrogenase 2 (ALDH2) is the major enzyme that contribute to the detoxification of acetaldehyde in human body. In this study, wild type (Aldh2+/+) and Aldh2KO (Aldh2-/-) mice were exposed to the air containing 0, 125, 500 ppm acetaldehyde for 2 weeks. After inhalation, levels of N2- ethylidene-dG in the chromosomal DNA were analyzed by liquid chromatography tandem mass spectrometry (LC/MS/MS). N2-ethylidene-dG levels in livers of Aldh2-/- mice were always lower than those of Aldh2+/+ mice, suggesting that Aldh2 deficiency might cause the induction of acetaldehyde metabolizing enzymes in the liver such as P450s. The differences between Aldh2-/- and Aldh2+/+ mice were greater in the order of nasal epithelium > lung > dorsal skin, suggesting that nasal epithelium and lung are the major target sites for acetaldehyde. Acetaldehyde inhalation may cause a high risk in nasal epithelium and lung cancers for individuals with inactive ALDH2.

Characteristics of aldehyde dehydrogenase 2 (Aldh2) knockout mice.

Acetaldehyde is an intermediate of ethanol oxidation. It covalently binds to DNA, and is known as a carcinogen. Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme that oxidizes acetaldehyde. Approximately 45% of Chinese and Japanese individuals have the inactive ALDH2 genotypes (ALDH2*2/*2 and ALDH2*1/*2), and Aldh2 knockout mice appear to be a valid animal model for humans with inactive ALDH2. This review gives an overview of published studies on Aldh2 knockout mice, which were treated with ethanol or acetaldehyde. According to these studies, it was found that Aldh2 -/- mice (Aldh2 knockout mice) are more susceptible to ethanol and acetaldehyde-induced toxicity than Aldh2 +/+ mice (wild type mice). When mice were fed with ethanol, the mortality was increased. When they were exposed to atmospheres containing acetaldehyde, the Aldh2 -/- mice showed more severe toxic symptoms, like weight loss and higher blood acetaldehyde levels, as compared with the Aldh2 +/+ mice. Thus, ethanol and acetaldehyde treatment affects Aldh2 knockout mice more than wild type mice. Based on these findings, it is suggested that ethanol consumption and acetaldehyde inhalation are inferred to pose a higher risk to ALDH2-inactive humans. These results also support that ALDH2-deficient humans who habitually consume alcohol have a higher rate of cancer than humans with functional ALDH2.

Hazardous environmental factors enhance impairment of liver function in HBV and HCV hepatitis.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) often cause chronic liver disease. We hypothesized that environmental factors adversely impact the liver function in workers with these types of hepatitis. We used liver function tests including aspartate aminotransferase, alanine aminotransferase, and g -glutamyltransferase to evaluate whether hazardous work conditions increase the incidence of chronic liver disease among HBV and HCV infected workers. Organic solvent, night work, visual display terminals, dust, lead, vibrations, and ionizing radiation all led to increased impairment of liver function in patients with hepatitis as compared to the control group that were not exposed to such agents. Therefore, hazardous working conditions have to be carefully considered in the progress of chronic liver disease in workers infected with HBV and HCV.

Application of tryptophan fluorescence to assess sensitizing potentials of chemicals.

There are too many chemical substances around our living space. However, the toxicity of most of them has not been reported, especially regarding their sensitizing potentials. We aimed to develop a simple in vitro method to quantitatively predict the sensitizing potentials of chemicals by measuring the fluorescence of chemical-human serum albumin (HSA) complexes. HSA was treated with test chemicals and then analyzed by tryptophan fluorescence and protein concentration measurement. Four commonly designated sensitizers, two possible sensitizers, and two nonsensitizers were examined using the tryptophan fluorescence assay. HSA fluorescence at 280 nm excitation and 340 nm emission was reduced by toluene 2,4-diisocyanate (TDI), dose dependently. The addition of TDI immediately reduced the fluorescence, and it was stable for 6 h to 21 days after treatment, with a slight decrease. The reduction of HSA fluorescence by chemicals was in the order: commonly designated sensitizers > possible sensitizers > nonsensitizers. Chemical treatment at 0.05 and 0.5 mM led to optimal separation among the three groups. o-Phthalaldehyde (OPA), which has not been evaluated regarding its sensitization potential by any of the authorized organizations, reduced HSA fluorescence as much as the commonly designated sensitizer at final concentrations of the chemical of 0.05 and 0.5 mM. According to our method, OPA is evaluated as a commonly designated sensitizer. The treatment of all test chemicals did not lead to marked differences in the total protein concentrations by either the Lowry or the Bradford method. The assay utilizing tryptophan fluorescence loss of HSA after chemical treatment is a promising method to evaluate the sensitizing potentials of chemicals.

[International comparison of sensitizing chemical substances].

Some occupational and environmental chemicals cause allergic diseases. To prevent chemical allergies, it is essential to identify the chemical substances that cause sensitization and to eliminate such sensitizers from daily life. As an occupational countermeasure, information for evaluating sensitization of chemical substances is needed. The aims of this article are to compare the criteria for sensitizers among national organizations in various countries and international organizations, and to make out a list of these chemical substances. The definition of sensitizing chemicals and the designation of respective sensitizers according to the PRTR law, Japan Society for Occupational Health (JSHO), American Conference of Governmental Industrial Hygienists (ACGIH), European Union (EU), Deutsche Forschungsgemeinshaft (DFG) and Japanese Society of Occupational and Environmental Allergy were studied. There are 1,389 chemical substances which are designated as sensitizers by any of the laws and five organizations. We specify each chemical substance in the list.