Effects of styrene monomer on a mouse model of atopic dermatitis.

Aim: Styrene monomer (SM) is a basic chemical used as a raw material for polystyrene and unsaturated polyester resins and in the production of synthetic resins, synthetic rubbers, paints, and adhesives. To date, it is unclear whether SM is associated with the aggravation of atopic dermatitis. The aim was to investigate the effects of SM on atopic dermatitis-like skin lesions induced by mite allergen in NC/Nga mice.Methods: Male mice were injected intradermally with mite allergen on their right ears. In the presence of an allergen, SM (3.5 or 350 µg/animal/week) was administered by intraperitoneal injection. We evaluated clinical scores, ear thickening, histologic findings, and the protein expressions of cytokines and chemokines.Results: Macroscopic and microscopic examinations demonstrated that exposure to SM at a dose of 3.5 µg caused an exacerbation of atopic dermatitis-like skin lesions related to mite allergen. These changes were consistent with the level of histamine in the ear tissue as an overall trend. In contrast, 350-µg SM did not show significant enhancement effects.Conclusion: These results indicate that SM exacerbated atopic dermatitis-like skin lesions at hundred-fold lower levels than the level that causes no observed adverse effects as determined by histologic changes in rodent livers. SM could be at least partly responsible for the recent increase in atopic dermatitis.Impact statementStyrene monomer (SM) is classified as an International Agency for Research on Cancer group 2B carcinogen and includes neurotoxicity and respiratory disorders. However, the effects of SM as a chemical substance on existing allergic pathophysiology have not been elucidated yet. This study demonstrated that SM exacerbated murine atopic dermatitis-like skin lesions at hundred-fold lower levels than the level that causes no observed adverse effects as determined by histologic changes in rodent livers, which was concomitant with the local level of histamine. These data hasten a need for comprehensive research to clarify the chemical pollutants' effects of doses much lower than NOAEL on vulnerable pathophysiologies such as allergy/atopy.

Effects of Streamer Discharge on PM2.5 Containing Endotoxins and Polyaromatic Hydrocarbons and Their Biological Responses In Vitro.

Experimental and epidemiological studies have demonstrated that fine particulate matter with a diameter of <2.5 µm (PM2.5) affects both the respiratory and immune systems. However, effective approaches to reduce PM2.5-induced hazardous effects have not been discovered yet. Streamer discharge is a category of plasma discharge in which high-speed electrons collide with oxygen and nitrogen molecules. Although streamer discharge can reportedly eliminate bacteria, molds, chemical substances, and allergens, its ability to decontaminate PM2.5 has not been previously demonstrated. The present study explored whether streamer discharge treatment could reduce PM2.5-induced inflammatory responses by employing an in vitro system. PM2.5 was collected under four conditions (Bangkok (Sep.−Dec.), Bangkok (Dec.−Mar.), Singapore, and Taipei). Airway epithelial cells and antigen-presenting cells exposed to non-treated PM2.5 in several conditions resulted in inflammatory responses. Streamer-discharged PM2.5 (Bangkok (Sep.−Dec.)) decreased the expression of interleukin (IL)-6 and IL-8 compared to non-treated PM2.5. Moreover, composition analysis demonstrated that streamer discharge reduced some compounds, such as endotoxins and polycyclic aromatic hydrocarbons, included in PM2.5 that can elicit inflammatory responses. Streamer discharge treatment can reduce endotoxins, polycyclic aromatic hydrocarbons, and the subsequent inflammatory responses induced by PM2.5 in vitro.

PM2.5 collected using cyclonic separation causes stronger biological responses than that collected using a conventional filtration method.

Evaluation of the health effects of particulate matter with aerodynamic dias. ≤ 2.5 µm (PM2.5) should reflect realistic condition in ambient atmosphere. However, using conventional filtration methods, only extracts from PM2.5 collected on the filter can be analyzed and not the particle itself. Cyclonic separation is a technique that enables the direct analysis of the effects of the crude "powder form" of PM2.5 on respiratory health. Airway epithelial cells and antigen-presenting cells were exposed to PM2.5 collected during the same period using a conventional filtration method or cyclonic separation. PM2.5 collected using cyclonic separation led to a higher secretion of interleukins 6 and 8 (IL-6, IL-8) from airway epithelial cells, and IL-6, IL-1ß, tumor necrosis factor-α (TNF-α) secretion, cluster of differentiation 86 (CD86), and dendritic and epithelial cells 205 (DEC205) expression on antigen-presenting cells, compared with the effects of filter-collected PM2.5. Furthermore, PM2.5 collected using cyclonic separation increased inflammatory cytokine levels and induced lung inflammation in vivo. These results suggest that crude PM2.5 collected using cyclonic separation causes stronger biological responses than filter-collected PM2.5. Hence, PM2.5 collected using cyclonic separation can be utilized for a reliable evaluation of the health effects of ambient PM2.5.

Exposure to particulate matter upregulates ACE2 and TMPRSS2 expression in the murine lung.

Coronavirus disease (COVID-19) is currently a serious global issue. Epidemiological studies have identified air pollutants, including particulate matter (PM), as a risk factor for COVID-19 infection and severity of illness, in addition to numerous factors such as pre-existing conditions, aging and smoking. However, the mechanisms by which air pollution is involved in the manifestation and/or progression of COVID-19 is still unknown. In this study, we used a mouse model exposed to crude PM, collected by the cyclone method, to evaluate the pulmonary expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine type 2 (TMPRSS2), the two molecules required for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells. Multiplex immunohistochemical analysis revealed that exposure to PM increased the expression of these two molecules at the same site. Furthermore, image cytometry analysis revealed increased expression of these proteins, particularly, in the alveolar type 2 cells and macrophages, which are potential targets for SARS-CoV-2. Our findings provide an experimental evidence that exposure to PM may adversely affect the manifestation and progression of COVID-19, mediated by the impact of SARS-CoV-2 on the site of entry. The study results suggest that examining these effects might help to advance our understanding of COVID-19 and aid the development of appropriate social interventions.

4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP) Targets Estrogen Receptor ß, to Evoke the Resistance of Human Breast Cancer MCF-7 Cells to G-1, an Agonist for G Protein-Coupled Estrogen Receptor 1.

Bisphenol A (BPA) has been shown to induce the activation of nuclear estrogen receptor α/ß (ERα/ß) in both in vitro and in vivo settings. We originally obtained a 4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), a possible active metabolite of BPA, strongly activating the ERs-mediated transcription in MCF-7 cells with an EC50 of 2.8 nM (i.e., BPA's EC50 = 519 nM). Environmental estrogens can also target G protein-coupled estrogen receptor 1 (GPER1), a membrane-type ER. However, the effects of BPA/MBP on GPER1, have not yet been fully resolved. In this study, we used MCF-7, a ERα/ERß/GPER1-positive human breast cancer cell line, as a model to investigate the effects of the exposure to BPA or MBP. Our results revealed that at concentrations below 1 nM MBP, but not BPA, downregulates the expression of GPER1 mRNA via upregulated ERß, and the MCF-7 cells pre-treated with MBP display resistance to GPER1 agonist G-1-mediated anti-proliferative effects. Because GPER1 can act as a tumor suppressor in several types of cancer including breast cancer, the importance of MBP-mediated decrease in GPER1 expression in breast cancer cells is discussed.

[Influence of Vibration Waveform on MR Elastography].

The purpose of this study was to investigate an influence of vibration waveform on magnetic resonance elastography (MRE). MRE is an innovative imaging technique for the non-invasive quantification of the elasticity of soft tissues through the direct visualization of propagating shear waves in vivo using a special phase-contrast magnetic resonance imaging sequence. Since the elasticity of soft tissue calculates from the wavelength of propagating shear waves, it is necessary to propagate sine-wave-shape shear wave at the target soft tissue. However, due to the various factors; i.e. overload of vibration generator, poor contact between imaging object and vibration pad, etc.; it may be difficult to generate a simple sine wave. This work was focused on change vibration waveforms; i.e. square wave, triangle wave, saw-tooth wave; which is induced by the various factors. Phantom experimental results demonstrated that when square and saw-tooth waveforms of 25 Hz vibration frequency, into the phantom, the waveform of propagating wave was not similar to sine waveform. It may influence on the MRE that in case of the waveforms has low frequency and square or saw-tooth like waveforms.

Physiological effects of brominated flame retardants on NC/Nga mice.

PURPOSE: Brominated flame retardants (BFRs) are used as an additive or reactive components in various materials. Regarding their health concerns, their immunotoxicity have not been clarified yet. MATERIALS AND METHODS: In the current study, we examined the effects of systemic exposure to two types of BFRs, DE71 and DE79, on pathophysiologic traits of murine atopic dermatitis (AD). Male NC/Nga mice were repeatedly injected intraperitoneally with DE71 and DE79 and/or mite allergen (Dermatophagoides pteronyssinus: Dp) into their right ears. Thereafter, clinical scores, macroscopic findings of inflammatory foci, and Ig values in serum were examined. RESULTS: Both DEs significantly aggravated clinical scores induced by mite allergen including skin dryness and edema. Total IgE titer was significantly greater in the Dp + DE79 group than in the Dp group. CONCLUSIONS: Taken together, exposure to BFRs can exacerbate AD-like skin lesions related to mite allergen in mice. The accentuating effects may be mediated, at least in part, through hyperproduction of IgE.

In vivo immunoamplifying effects of di-(2-ethylhexyl) phthalate on cytokine response.

A recent epidemiological study has revealed the positive association between atopy morbidity in children and phthalate esters, environmental chemicals in house dust. Nonetheless, experimental and molecular evidences regarding the correlation between phthalates and allergic response/pathophysiology are not fully investigated. Among phthalate esters, di-(2-ethylhexyl) phthalate (DEHP) has been widely used for flexible polyvinyl chloride products including vinyl flooring and wall covering. In the present study, we examined the effects of exposure to DEHP on allergen (ovalbumin: OVA) -induced peritonitis in ICR mice. Repeated administration of OVA via intraperitoneal route induced peritoneal inflammation characterized by infiltration of granulocytes (neutrophils and eosinophils) into the cavity. DEHP synergistically exaggerated the OVA-related neutrophilic inflammation. Furthermore, DEHP + OVA profoundly amplified OVA-elicited inflammation- and allergy-related molecules such as interleukin-5, eotaxin, and keratinocyte-derived chemoattractant production/release in the peritoneal cavity. Taken together, DEHP aggravated OVA-related peritoneal inflammation, which is concomitant with local enhanced production/release of inflammation- and allergy-related molecules.

Effects of airway exposure to di-(2-ethylhexyl) phthalate on allergic rhinitis.

Recent epidemiological studies have suggested a positive link between atopy morbidity and exposure to phthalate esters, which are environmental chemicals mainly involved in house dust. Nevertheless, experimental studies applying several allergic in vivo models (in addition to epidemiological studies) are needed to prove the precise correlation between phthalates and facilitation of the allergic response/pathophysiology. Among the phthalate esters, di-(2-ethylhexyl) phthalate (DEHP) has been widely used in flexible polyvinyl chloride products, including vinyl flooring and wall covering, and has been widely suggested to have immunomodulating potential. In the present study, we examined the effects of airway exposure to DEHP on allergen (ovalbumin: OVA)-induced rhinitis in mice. The repeated administration of OVA via an intranasal route induced nasal inflammation characterized by the infiltration of granulocytes (neutrophils and eosinophils) into the nasal cavity. In this experimental setting, DEHP did not exaggerate OVA-related inflammatory pathology. However, local (nasal) IL-13 levels were significantly higher in mice treated with allergen plus DEHP than with allergen alone. Taken together, phthalate esters including DEHP have the potential to exacerbate the allergic milieu in the nasal system, as well as dermal and respiratory systems.

Dietary supplementation with fructooligosaccharides attenuates allergic peritonitis in mice.

Fructooligosaccharides (FOS) are a prebiotic supplement, which can enhance immunological responses in the host to activate mucosal immunity probably through regulation of gastrointestinal microflora. Nonetheless, the therapeutic potential of prebiotics on allergic pathologies has not been fully elucidated. Therefore, the purpose of this study was to evaluate the preventive and therapeutic effects of dietary supplementation with FOS on a murine model of allergic peritonitis induced by ovalbumin (OVA). Male C3H/HeN mice were intraperitoneally administrated with OVA (1 µg) bi-weekly (Day 0-42, total four times) and were fed a diet containing 0 or 2.5% FOS ad libitum (Day 7-43). At Day 43, mice were killed and several parameters were evaluated. As results, supplementation with FOS alleviated OVA-related peritoneal inflammation characterized by trafficking of polymorphonuclear leukocytes such as eosinophils and neutrophils in the peritoneal cavity. Also, FOS significantly suppressed the protein level of interleukin (IL)-5 and eotaxin in the peritoneal lavage fluid elicited by OVA. In addition, a FOS-supplemented diet significantly reduced the serum allergen specific-IgG(1) level, whereas it significantly increased total IgA levels in the cecal contents as compared with a control diet in the presence of OVA. These results suggest that dietary supplementation with FOS can prevent/ameliorate allergic peritoneal inflammation induced by OVA. The efficacy can at least partially be associated with the regulation of Ig class switching and inhibition of the local expression of IL-5 and eotaxin.

Expression of the bacterial heavy metal transporter MerC fused with a plant SNARE, SYP121, in Arabidopsis thaliana increases cadmium accumulation and tolerance.

The bacterial merC gene from the Tn21-encoded mer operon is a potential molecular tool for improving the efficiency of metal phytoremediation. Arabidopsis SNARE molecules, including SYP111, SYP121, and AtVAM3 (SYP22), were attached to the C-terminus of MerC to target the protein to various organelles. The subcellular localization of transiently expressed GFP-fused MerC-SYP111, MerC-SYP121, and MerC-AtVAM3 was examined in Arabidopsis suspension-cultured cells. We found that GFP-MerC-SYP111 and GFP-MerC-SYP121 localized to the plasma membrane, whereas GFP-AtVAM3 localized to the vacuolar membranes. These results demonstrate that SYP111/SYP121 and AtVAM3 target foreign molecules to the plasma membrane and vacuolar membrane, respectively. To enhance the efficiency and potential of plants to sequester and accumulate cadmium from contaminated sites, transgenic Arabidopsis plants expressing MerC, MerC-SYP111, MerC-SYP121, or MerC-AtVAM3 were generated. The transgenic plants that expressed MerC, MerC-SYP121, or MerC-AtVAM3 appeared to be normal, whereas the transgenic that expressed MerC-SYP111 exhibited severe growth defects. The transgenic plants expressing merC-SYP121 were more resistant to cadmium than the wild type and accumulated significantly more cadmium. Thus, the expression of MerC-SYP121 in the plant plasma membrane may provide an ecologically compatible approach for the phytoremediation of cadmium pollution.

Perfluorooctanoic acid (PFOA) as a stimulator of estrogen receptor-negative breast cancer MDA-MB-231 cell aggressiveness: Evidence for involvement of fatty acid 2-hydroxylase (FA2H) in the stimulated cell migration.

Detailed in vitro studies on the effects of perfluorooctanoic acid (PFOA) have demonstrated that activation of peroxisome proliferator-activated receptor α (PPARα) is a key process by which PFOA affects the malignancy of estrogen receptor α (ERα)-positive breast cancer cells. However, there is very little information on the PPARα-regulated genes responsible for the effects of PFOA in ERα-negative breast cancer cell malignancy. We recently demonstrated that fatty acid 2-hydroxylase (FA2H) stimulates the migration of ERα-negative human MDA-MB-231 cells, and PPARα is a key factor for the induction of FA2H in these cells. However, evidence for the relationship between PFOA exposure and PPARα-FA2H axis-driven migration has not been obtained. Here we analyzed the effects of PFOA on PPARα transcription and FA2H expression in relation to MDA-MB-231 cell migration. We found that simultaneously with stimulated migration, PFOA upregulated FA2H and activated the transcription of PPARα. FA2H-selective siRNA, but not siRNA control, clearly dampened PFOA-mediated cell migration. There is an inhibitory interaction between PPARα and PPARß/δ (i.e., PPARß/δ can suppress PPARα-mediated transcription) in MDA-MB-231 cells, but even in the presence of PPARß/δ expression, PFOA appeared to free PPARα to upregulate FA2H. Collectively, our findings show that i) PFOA activates PPARα-mediated transcription, ii) PFOA stimulates migration dependent on FA2H expression, and iii) mechanistically, PFOA relieves PPARß/δ suppression of PPARα activity to upregulate FA2H in MDA-MB-231 cells.

Di-(2-ethylhexyl) phthalate enhances cytokine release from group 2 innate lymphoid cells in the presence of interleukin-33.

Epidemiological and experimental studies have shown that di-(2-ethylhexyl) phthalate (DEHP), a plasticizer, can aggravate allergic diseases. DEHP promotes adaptive immune responses, although its effect on the innate immune system remains largely unknown. The present study investigated the effects of DEHP on group 2 innate lymphoid cells (ILC2) that produce Th2 cytokines in response to epithelial cell-derived cytokines, such as interleukin (IL)-33. ILC2 (lineage-negative, CD45.2+, Sca1+, KLRG1+) were isolated from the lungs of C57BL/6 J mice. Co-exposure to DEHP and IL-33 significantly increased IL-5 release from ILC2, whose level was higher than that of the vehicle and IL-33 alone. The effects of DEHP in the presence of IL-33 showed an inverted-U dose-response. The present is the first report showing that DEHP exacerbates allergy through the innate immune system.

Efficacy and Safety of Lipase Inhibitor Orlistat in Japanese with Excessive Visceral Fat Accumulation: 24-Week, Double-Blind, Randomized, Placebo-Controlled Study.

INTRODUCTION: Orlistat is an inhibitor of pancreatic lipase and is used as an anti-obesity drug in many countries. However, there are no data available regarding the effects of orlistat on visceral fat accumulation in Japanese subjects. Therefore, this comparative, placebo-controlled, double-blind, randomized study aimed to evaluate the efficacy and safety of orlistat in Japanese participants with excessive visceral fat accumulation and without dyslipidemia, diabetes mellitus, and hypertension ("metabolic diseases"). METHODS: The study population included Japanese participants with excessive visceral fat accumulation (waist circumference ≥ 85 cm in males and ≥ 90 cm in females, which corresponds to a visceral fat area of 100 cm2) and without metabolic diseases. Following a 12-week observation term, participants were randomized to the orlistat 60 mg group (n = 100) or placebo group (n = 100). Both drugs were administered orally three times daily for 24 weeks. Participants were also counseled to improve their diet and to maintain exercise throughout the study. Visceral fat area, subcutaneous fat area, waist circumference, body weight, body mass index, adverse reactions, laboratory tests, and blood pressure were regularly assessed. RESULTS: Visceral fat area, waist circumference, and body weight were significantly reduced in the orlistat group (mean ± standard error, - 13.50 ± 1.52%, - 2.51 ± 0.25%, and - 2.79 ± 0.30%, respectively) compared to the placebo group (- 5.45 ± 1.50%, - 1.55 ± 0.26%, and - 1.22 ± 0.28%, respectively) at the last assessment. The main adverse reactions were defecation-related symptoms including oily spotting and flatus with discharge, resulting from the pharmacological effects of orlistat. Most adverse reactions were mild, and none were serious or severe. CONCLUSION: Orlistat administration reduced visceral fat area, waist circumference, and body weight in Japanese participants with excessive visceral fat and without metabolic diseases. In addition, safety was confirmed with a tolerable profile. Orlistat may be useful to reduce excessive visceral fat accumulation when used in combination with diet and exercise. TRIAL REGISTRATION: Japan Pharmaceutical Information Center identifier, JapicCTI-184005. FUNDING: Taisho Pharmaceutical Co., Ltd.

Reduction of Excessive Visceral Fat and Safety with 52-Week Administration of Lipase Inhibitor Orlistat in Japanese: Long-Term Clinical Study.

INTRODUCTION: Orlistat is an inhibitor of pancreatic lipase and is used as an anti-obesity drug in many countries. However, there are no data available regarding the effects of orlistat on visceral fat (VF) accumulation in Japanese individuals. Therefore, this study aimed to analyze the efficacy and safety of 52 weeks of orlistat administration in Japanese individuals. METHODS: Orlistat 60 mg was administered orally three times daily for 52 weeks to Japanese participants with excessive VF accumulation and without dyslipidemia, diabetes mellitus, and hypertension (metabolic diseases). Participants were also counseled to improve their diet and to maintain exercise habits. We defined excessive VF accumulation as a waist circumference (WC) of ≥ 85 cm for males and ≥ 90 cm for females, which corresponds to a VF area of 100 cm2. Adverse reactions, clinical laboratory tests, VF, WC, body weight (BW), etc., were monitored throughout the study period. RESULTS: VF, WC, and BW were significantly reduced at week 52 from baseline; the mean ± standard error rate of change was - 21.52% ± 1.89%, - 4.89% ± 0.45%, and - 5.36% ± 0.56%, respectively, and continued to reduce throughout the 52 weeks; these significantly reduced at whole term compared with baseline. Most adverse reactions were defecation-related symptoms such as oily spotting and flatus with discharge (flatus with small amounts of stool or oil) due to the pharmacologic effects of the lipase inhibitor. These symptoms were mostly mild, reversible, and recognizable by the participants; none were serious or severe. No participants discontinued by medical judgment about adverse reactions, and the drug could be administered continuously. CONCLUSION: VF, WC, and BW were reduced from week 4 to week 52, indicating the effect of long-term orlistat administration. Moreover, it was well tolerated with an acceptable safety profile. Long-term administration of orlistat may be efficacious in reducing VF accumulation with safety when used in combination with diet and exercise. TRIAL REGISTRATION: This study is registered with the Japan Pharmaceutical Information Center (identifier: JapicCTI-184004). FUNDING: Funding for this study was provided by Taisho Pharmaceutical Co., Ltd.

Ambient fine and coarse particles in Japan affect nasal and bronchial epithelial cells differently and elicit varying immune response.

Ambient particulate matter (PM) epidemiologically exacerbates respiratory and immune health, including allergic rhinitis (AR) and bronchial asthma (BA). Although fine and coarse particles can affect respiratory tract, the differences in their effects on the upper and lower respiratory tract and immune system, their underlying mechanism, and the components responsible for the adverse health effects have not been yet completely elucidated. In this study, ambient fine and coarse particles were collected at three different locations in Japan by cyclone technique. Both particles collected at all locations decreased the viability of nasal epithelial cells and antigen presenting cells (APCs), increased the production of IL-6, IL-8, and IL-1ß from bronchial epithelial cells and APCs, and induced expression of dendritic and epithelial cell (DEC) 205 on APCs. Differences in inflammatory responses, but not in cytotoxicity, were shown between both particles, and among three locations. Some components such as Ti, Co, Zn, Pb, As, OC (organic carbon) and EC (elemental carbon) showed significant correlations to inflammatory responses or cytotoxicity. These results suggest that ambient fine and coarse particles differently affect nasal and bronchial epithelial cells and immune response, which may depend on particles size diameter, chemical composition and source related particles types.

Increased blood pressure in nesfatin/nuclebindin-2-transgenic mice.

Nesfatin/nucleobindin-2 (nesf/NUCB2), a precursor of the anorexigenic protein nesfatin-1, is selectively expressed in the hypothalamic nuclei, which are central to the regulation of the autonomic nervous system. The present study sought to investigate the involvement of nesf/NUCB2 in the regulation of blood pressure and ingestive behavior, by using nesf/NUCB2-transgenic (Tg) mice. Blood pressure and heart rates were measured under conscious and unconscious conditions. Twenty-four-hour water intake and urine volume of male nesf/NUCB2-Tg mice and their littermates in metabolic cages were measured. After killing, kidney weight was measured and the mRNA expression of epithelial sodium channel (ENaC)-α and ENaC-γ was measured in the hypothalamus and kidney with real-time PCR. Systolic, diastolic and mean blood pressure were significantly higher in nesf/NUCB2-Tg mice, but pulse rate was not affected in conscious mice. In contrast, isoflurane anesthesia prevented an increase in blood pressure in the nesf/NUCB2-Tg mice. Twenty-four-hour water intake and urine volume were significantly higher in the nesf/NUCB2-Tg mice than in their non-Tg littermates. Urine sodium concentration was significantly lower in the nesf/NUCB2-Tg mice, although the serum sodium concentration and urine sodium excretion were not different between the genotypes. Kidney weight was significantly higher in the nesf/NUCB2-Tg mice than their non-Tg littermates, although there were no clear differences in the kidney histological findings between genotypes. The mRNA expression of ENaC-γ, but not ENaC-α, was decreased in the hypothalami of nesf/NUCB2-Tg mice. Our data suggested that Nesf/NUCB2 is involved in the regulation of blood pressure in the brain.

Effects of exposure to nanoparticle-rich diesel exhaust on 8-OHdG synthesis in the mouse asthmatic lung.

It has been demonstrated that exposure to diesel exhaust (DE) is associated with the induction and exacerbation of respiratory disorders; however, the impacts of DE containing mainly nanoparticles have been less studied. We have previously demonstrated that inhalation exposure to nanoparticle-rich DE (NR-DE) exacerbated allergic pulmonary inflammation, in the context of enhanced local expression of proinflammatory molecules. However, the underlying mechanisms have not been fully elucidated. 8-Hydroxydeoxyguanosine (8-OHdG) is a marker of oxidative damage, particularly in DNA. This study examined the effects of NR-DE on 8-OHdG synthesis in the lung in the presence or absence of an allergen. Institute for Cancer Research (ICR) mice were exposed by inhalation to four different gas compositions (control air, low-concentration DE, high-concentration DE and high-concentration DE without particulate matter) for 8 weeks, in the presence or absence of repetitive intratracheal administration of ovalbumin (OVA). Thereafter, we assessed the levels of 8-OHdG synthesis and expression in the lungs by means of enzyme immunoassay (EIA) and immunohistochemistry. The EIA revealed that the level of 8-OHdG was significantly higher in the high-concentration NR-DE-exposed and allergen-sensitized/stimulated group compared with that in the control air-exposed and allergen-treated group. The immunohistochemistry results demonstrated that the level of immunoreactive 8-OHdG was higher in the NR-DE-exposed and allergen-treated lungs compared with that in the corresponding control air-exposed lungs. The results suggested that NR-DE exposure enhanced 8-OHdG formation in asthmatic lungs. This, at least in part, is involved in the NR-DE-mediated exacerbation of the allergic pathophysiology that was identified in our previous study.