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Compared to normal cells, tumour cells exhibit an upregulation of glucose transporters and an increased rate of glycolytic activity. In previous research, we successfully identified a promising hit compound BH10 through a rigorous screening process, which demonstrates a potent capacity for inhibiting cancer cell proliferation by targeting glucose metabolism. In the current study, we identify Kelch-like ECH-associated protein 1 (Keap1) as a potential protein target of BH10via avidin pull-down assays with biotinylated-BH10. Subsequently, we present a comprehensive analysis of a series of BH10 analogues characterized by the incorporation of a naphthoimidazole scaffold and the introduction of a triazole ring with diverse terminal functional groups. Notably, compound 4d has emerged as the most potent candidate, exhibiting better anti-cancer activities against HEC1A cancer cells with an IC 50 of 2.60 μM, an extended biological half-life, and an improved pharmacokinetic profile (compared to BH10) in mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Ocular infections caused by antibiotic-resistant pathogens can result in partial or complete vision loss. The development of pan-resistant microbial strains poses a significant challenge for clinicians as there are limited antimicrobial options available. Synthetic peptoids, which are sequence-specific oligo-N-substituted glycines, offer potential as alternative antimicrobial agents to target multidrug-resistant bacteria., Methods: The antimicrobial activity of synthesised peptoids against multidrug-resistant (MDR) ocular pathogens was evaluated using the microbroth dilution method. Hemolytic propensity was assessed using mammalian erythrocytes. Peptoids were also incubated with proteolytic enzymes, after which their minimum inhibitory activity against bacteria was re-evaluated., Results: Several alkylated and brominated peptoids showed good inhibitory activity against multidrug-resistant Pseudomonas aeruginosa strains at concentrations of ≤15 μg mL -1 (≤12 µM). Similarly, most brominated compounds inhibited the growth of methicillin-resistant Staphylococcus aureus at 1.9 to 15 μg mL -1 (12 µM). The N-terminally alkylated peptoids caused less toxicity to erythrocytes. The peptoid denoted as TM5 had a high therapeutic index, being non-toxic to either erythrocytes or corneal epithelial cells, even at 15 to 22 times its MIC. Additionally, the peptoids were resistant to protease activity., Conclusions: Peptoids studied here demonstrated potent activity against various multidrug-resistant ocular pathogens. Their properties make them promising candidates for controlling vision-related morbidity associated with eye infections by antibiotic-resistant strains., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Respiratory health problems in poultry production are frequent and knotty and thus attract the attention of farmers and researchers. The breakthrough of gene sequencing technology has revealed that healthy lungs harbor rich microbiota, whose succession and homeostasis are closely related to lung health status, suggesting a new idea to explore the mechanism of lung injury in broilers with pulmonary microbiota as the entry point. This study aimed to investigate the succession of pulmonary microbiota in healthy broilers during the growth cycle. Fixed and molecular samples were collected from the lungs of healthy broilers at 1, 3, 14, 21, 28, and 42 d of age. Lung tissue morphology was observed by hematoxylin and eosin staining, and the changes in the composition and diversity of pulmonary microbiota were analyzed using 16S rRNA gene sequencing. The results showed that lung index peaked at 3 d, then decreased with age. No significant change was observed in the α diversity of pulmonary microbiota, while the β diversity changed regularly with age during the broilers' growth cycle. The relative abundance of dominant bacteria of Firmicutes and their subordinate Lactobacillus increased with age, while the abundance of Proteobacteria decreased with age. The correlation analysis between the abundance of differential bacteria and predicted function showed that dominant bacteria of Firmicutes, Proteobacteria and Lactobacillus were significantly correlated with most functional abundance, indicating that they may involve in lung functional development and physiological activities of broilers. Collectively, these findings suggest that the lung has been colonized with abundant microbiota in broilers when they were just hatched, and their composition changed regularly with day age. The dominant bacteria, Firmicutes, Proteobacteria, and Lactobacillus, play crucial roles in lung function development and physiological activities. It paves the way for further research on the mechanism of pulmonary microbiota-mediated lung injury in broilers., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The MYCN oncogene and histone deacetylases (HDACs) are key driver genes in the childhood cancer, neuroblastoma. We recently described a novel pyridobenzimidazole analogue, SE486-11, which enhanced the therapeutic effectiveness of HDAC inhibitors by increasing MYCN ubiquitination through effects on the deubiquitinase, ubiquitin-specific protease 5 (USP5). Here we describe the synthesis of a novel series of pyrimido[1,2-a]benzimidazole derivatives, and an evaluation of their cytopathic effects against non-malignant and human neuroblastoma cell lines. Among the tested analogues, 4-(4-methoxyphenyl)benzo[4,5]imidazo[1,2-a]pyrimidine (3a) was the most active compound against neuroblastoma cells (IC 50  ≤ 2 µM), with low cytotoxicity (IC 50  ≥ 15 µM) to normal cells. We show compound 3a bound to USP5 protein (K d  = 0.47 µM) in vitro and synergistically enhanced the efficacy of HDAC inhibitors against neuroblastoma cells. Moreover, knockdown of USP5 and MYCN in treated neuroblastoma cells showed that both USP5 and MYCN expression was necessary for the cytopathic activity of compound 3a, thus providing a clinically relevant rationale for further development of this of pyrimido[1,2-a]benzimidazole., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Co-culture of microalgae-activated sludge has the potential to purify wastewater while reduce energy demand from aeration. In this work, a mechanically stirred membrane photobioreactor (stirred-MPBR) was used to evaluate the impact of the biomass retention time (BRT) on the treatment performance and membrane fouling. Results showed that stirred-MPBR was affected by BRT during treating domestic wastewater at a flux of 16.5 L m -2 h -1 . The highest productivity was attained at BRT 7d (102 mg L -1 d -1 ), followed by BRT 10d (86 mg L -1 d -1 ), BRT 5d (85 mg L -1 d -1 ), and BRT 3d (83 mg L -1 d -1 ). Statistical analysis results showed that BRT 7d had a higher COD removal rate than BRT 10d, however, there is no difference in total nitrogen removal rate. The highest TP removal occurred when the biomass operated at BRT as short as 3d. Reduced BRTs caused a change in the microalgae-activated sludge biomass fraction that encouraged nitrification activity while simultaneously contributing to a higher fouling rate. The bound protein concentrations dropped from 31.35 mg L -1 (BRT 10d) to 10.67 mg L -1 (BRT 3d), while soluble polysaccharides increased from 0.99 to 1.82 mg L -1 , respectively. The concentrations of extracellular polymeric substance fractions were significantly altered, which decreased the mean floc size and contributed to the escalating fouling propensity. At the optimum BRT of 7d, the stirred-MPBR showed sufficient access to light and nutrients exchange for mutualistic interactions between the microalgae and activated sludge., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

It is well established that the quorum sensing (QS) in Pseudomonas aeruginosa is primarily responsible for the synthesis and the release of several virulence factors including pyocyanin and are involved in biofilm formation. In the Pseudomonas quinolone signal (PQS) system, autoinducers such as PQS and HHQ bind and activate the transcription regulator protein receptor PqsR (MvfR). Targeting PqsR with competitive inhibitors could be a promising strategy to inhibit QS in P. aeruginosa to overcome antimicrobial resistance. In this study, we have designed and synthesized a series of novel quinazolinone disulfide-containing competitive inhibitor of PqsR. The most potent analogue 8q efficiently inhibited the pqs system with an IC 50 value of 4.5 µM. It also showed complete suppression of pyocyanin production and a significant reduction in biofilm formation by P. aeruginosa (PAO1) with low cytotoxicity. Additionally, 8q produced synergy in combination with known antibiotics such as ciprofloxacin and tobramycin. Finally, molecular docking analysis suggested that compound 8q could bind with the ligand-binding domain of PqsR in a similar fashion to the native ligand., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The Irrawaddy (Ayeyarwaddy) and Salween (Thanlwin) globally rank among the largest rivers for supplying dissolved and particulate material to the ocean. Along with the Sittaung and Kaladan rivers they have societal importance to Myanmar in terms water sources and food production. Despite their importance for global biogeochemical cycles and the ~50 million people who live in their catchments, the chemistry of these rivers is poorly known. This study presents a comprehensive survey of dissolved (<0.22 μm) trace element concentrations (Sr, Fe, Al, Ba, Mn, V, Rb, Cu, Zn, As, Li, Ni, Mo, Cr, U, Pb, Sb, Co, Cs, Tl and Cd) at 38 locations within these river catchments, spanning a period of 2 years. The results highlight the global importance of the Irrawaddy and Salween rivers for trace element global biogeochemical cycles; contributing between 1 and 17 % of global dissolved riverine fluxes to the land-ocean interface for the studied elements. Area normalized dissolved fluxes in these catchments are ~2 to 10 times higher than global average values for most elements, consistent with high rates of chemical weathering. In general, anthropogenic activities have yet to significantly perturb dissolved trace element fluxes in these river systems. The presented dataset should therefore serve as a useful 'natural' baseline, against which future perturbations driven by climate change and/or the development of Myanmar's mining industry could be assessed. Exceptions to this include As in the Sittaung River and Sb, Zn, Pb and As in the Salween River, which may already be significantly impacted by anthropogenic inputs. The former represents a water quality issue of concern for public health, and so constraining the exact sources of As in the Sittaung River should be considered a priority for future research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Novel phycosphere associated bacteria processes are being regarded as a potential and cost-effective strategy for controlling anthropogenic contaminants in wastewater treatment. However, the underlying concern with the process is its vulnerability to improper organic or nutrient intake. This study established a synergistic interaction between microalgae and activated sludge in a three-photobioreactor system (without external aeration) to understand how pollutants could be mitigated whilst simultaneously yielding biomass under different C/N ratios of 1:1, 5:1 and 10:1. The result showed that the superior biomass productivity was facilitated at a C/N ratio of 5:1 (106 mg L -1 d -1 ), and the high degradation rate constants (k COD = 0.25 d -1 , k TN = 0.29 d -1 , k TP = 0.35 d -1 ) was approximated using a first-order kinetic model. The removal of pollutants was remarkably high, exceeding 90% (COD), 93% (TN), and 96% (TP). Nevertheless, the C/N ratio of 1:1 resulted in a threefold drop in biomass-specific growth rate (μ = 0.07 d -1 ). Microalgal assimilation, followed by bacterial denitrification, is the major pathway of removing total nitrogen when the C/N ratio exceeds 5:1. Activated sludge plays an important role in improving microalgae tolerance to high concentration of ammonia nitrogen and boosting nitrification (light phase) and denitrification (dark phase). The use of phycosphere associated bacteria could be a promising strategy for controlling nutrients pollution and other environmental considerations in wastewater., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Canine vector-borne pathogens can act as zoonotic agents in humans; however, it poorly understood whether dogs play a role as reservoirs of vector-borne parasites in livestock animals. Here, we report the unexpected detection of 18S rRNA gene (rDNA) sequences of five ruminant Theileria species from the peripheral blood of dogs in Myanmar, in addition to those of two canine Babesia species. Using novel BTH primers capable of amplifying the 18S rDNA of Babesia, Theileria, and Hepatozoon spp., approximately 1,500 bp nested PCR products were detected in 19% (17/91) of local or imported dog breeds in different regions of Myanmar. Among the sequences of the 17 PCR products, ten were determined as Theileria 18S rDNA, including three as Theileria orientalis, three as Theileria buffeli, two as Theileria cf. velifera, one as Theileria luwenshuni, and one as Theileria sp. Most of these sequences showed higher identities with Theileria sequences determined in previous studies of cattle, water buffaloes, and goats in Myanmar. Six PCR products were identified as Babesia vogeli and one sample was determined as Babesia gibsoni. Furthermore, we obtained approximately 900 bp thrombospondin-related adhesive protein (TRAP) gene fragments from three dog blood DNA samples. Phylogenetic analysis of the TRAP gene showed that B. gibsoni parasites in Myanmar were considerably related to isolates from China, Korea, Japan, and Taiwan, but clearly separated from those from Bangladesh and India. These results provide new insights into a possible role of dogs in maintaining and spreading tick-borne pathogens among livestock and canine populations in Myanmar., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

This study aims to offer insights into how ciprofloxacin (CIP) impact bacterial community structures in the Sponge-MBR process when CIP is spiked into hospital wastewater. We found that the CIP toxicity decreased richness critical phylotypes such as phylum class ẟ-, β-, ɣ-proteobacteria, and Flavobacteria that co-respond to suppress denitrification and cake fouling to 37% and 28% respectively. Cluster analysis shows that the different community structures were formed under the influence of CIP toxicity. CIP decreased attached growth biomass by 2.3 times while increasing the concentration of permeate nitrate by 3.8 times, greatly affecting TN removal by up to 26%. Ammonia removal was kept stable by inflating the ammonia removal rate (p < 0.003), with the wealthy Nitrospira genus guaranteeing the nitrification activity. In addition, we observed an increasing richness of Chloroflexi and Planctomycetes, which may play a role in fouling reduction in the Sponge-MBR. Therefore, if the amount of antibiotics in hospital wastewater continues to increase, it is so important to extend biomass retention for denitrification recovery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: To investigate the relationship between anticipated delay in help-seeking and cancer symptom recognition and the extent to which this relationship varied according to socio-demographic and health-related characteristics., Methods: A cross-sectional telephone survey was conducted of 1895 adults aged ≥40 years who were randomly selected across Malaysia and interviewed using the Awareness and Beliefs about Cancer questionnaire, which was previously validated and culturally adapted by the research team. Logistic regression analysis was used to test the associations between anticipated delay for help seeking >2 weeks and socio-demographic and health-related variables., Results: Anticipated delay in help-seeking was reported for persistent cough (19.3 %), rectal bleeding (6.1 %) and breast changes (2.5 %). Difficulty in accessing a doctor was associated with anticipated delayed help-seeking for breast changes and rectal bleeding (adjusted ORs 7.58; 95 % CI 1.98, 28.94 and 2.37; 95 % CI 1.21, 4.66, respectively); not recognising the symptom 'unexplained bleeding' as a colorectal cancer warning sign was associated with anticipated delayed help-seeking for rectal bleeding (adjusted OR 1.54; 95 % CI 1.03, 2.31); and ethnicity was associated with anticipated delay for rectal bleeding and persistent cough., Conclusions: Generally, anticipated delay to help-seeking for cancer symptoms in Malaysia (a middle-income country) appeared to be a less significant problem compared to other countries including high-income countries. There appeared to be a significant association between social variation indicators in Malaysia and anticipated delay in help-seeking., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: As the surgical burden of diseases grows higher than ever, the development of skilled surgeons and surgery teams is of fundamental importance. However, there is scarce evidence of the effectiveness of surgical training programs. Our study aims to evaluate the effectiveness of a global surgery fellowship program., Design: In 2018, Myanmar subspecialty surgeons were trained for a 3-month in tertiary hospital of Korea. We evaluated the reactions, learning, and transfer of the 11 trainees using Kirkpatrick's Evaluation Model., Setting: Myanmar and Korean tertiary hospital., Participants: Eleven participants of fellowship from Myanmar., Results: Participants' overall reaction scores were 4.45 ± 0.52 out of 5.00. Regarding overall competency, the trainees assessed themselves as at an "advanced beginner level" (3.63 ± 1.38 out of 10.00) at the beginning and at a "competent level" (5.40 ± 1.70 out of 10.00) after the training (p for difference = 0.014). The trainees stated that their transfer in clinical practice was between "quite applicable" and "I am very sure that I can do this" (3.39 ± 0.61 out of 4.00). Their transfer in education was second, ranked around "quite applicable" (3.21 ± 0.77 out of 4.00), and their transfer in research was last and ranked "applicable, but just a little" (2.81 ± 0.67 out of 4.00). However, in our online survey, native and foreign trainers had mixed opinions about the transfer of training and were not entirely confident in the trainees' competency. Trainees felt that there were multifactorial challenges for transfer and cited infrastructure, facilities, human resources, perioperative care, and financing., Conclusions: Surgical trainees reported high-level satisfaction and increased knowledge after training. However, further onsite surgical experiences are necessary for a successful transfer to the real setting. Challenges for such transfers were multifactorial, and surgical care must be systemically strengthened., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Decabromodiphenyl ether (decaBDE) is a brominated flame retardant used in plastic and textile articles. It has become a ubiquitous environmental contaminant, however; the relationship between decaBDE and obesity remains to be elucidated. We aimed to clarify if oral decaBDE exposure can be a factor in obesity and its related metabolic dysfuctions. Male C57BL/6 J mice were fed a normal (ND, 9.0 kcal% fat) or high-fat (HFD, 62.2 kcal% fat) diet and treated with decaBDE (the equivalent of three doses of 0, 0.5 (L-DecaBDE), and 10 (H-DecaBDE) μg/kg body weight/day) ad libitum in drinking water from 5 to 20 weeks of age. In HFD-fed mice, decaBDE exposure markedly increased both fasting blood glucose levels compared with vehicle exposure, which was more prominent in H-DecaBDE-exposed mice. DecaBDE exposure significantly reduced mRNA levels of glucose transporter 4 and thyroid hormone receptor alpha in skeletal muscle and mechanistic target of rapamycin complex 2 in brown adipose tissue compared with vehicle exposure under HFD-feeding. The tendency for hyperglycemia and the remarkable activation of insulin signaling pathway-related genes were observed in ND + DecaBDE mice compared to the ND + Vehicle mice. These results demonstrate that decaBDE can contribute to the enhancement of diet-induced hyperglycemia through disruption of glucose homeostasis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Lifestyle factors, such as diet, body weight, and physical activity, are linked to better survival after breast cancer (BC) diagnosis. A high percentage of the Malaysian population is overweight or obese. In addition, studies have shown a disparity in survival among Malaysian women compared with other higher-income countries. The Malaysian Breast Cancer Survivorship Cohort (MyBCC) study aims to study lifestyle factors that affect survival in BC survivors. These are the preliminary findings on the nutritional status of Malaysian BC survivors., Objective: Our aim was to evaluate the nutritional status of BC survivors at 1 year after diagnosis., Design: This was a cross-sectional study of 194 participants from the MyBCC study, recruited within 1 year of their diagnosis. Participants completed a 3-day food diary., Participants: Malaysian women (aged 18 years and older) who were newly diagnosed with primary BC, managed at the University Malaya Medical Center, and able to converse either in Malay, English, or Mandarin were included., Main Outcome Measures: Dietary intake and prevalence of overweight or obesity among participants 1 year after diagnosis were measured., Statistical Analyses Performed: Student's t test and analysis of variance or its equivalent nonparametric test were used for association in continuous variables., Results: About 66% (n=129) of participants were overweight or obese and >45% (n=86) had high body fat percentage 1 year after diagnosis. The participants' diets were low in fiber (median=8.7 g/day; interquartile range=7.2 g/day) and calcium (median=458 mg/day; interquartile range=252 mg/day). Ethnicity and educational attainment contributed to the differences in dietary intake among participants. Higher saturated fat and lower fiber intake were observed among Malay participants compared with other ethnic groups., Conclusions: Overweight and obesity were highly prevalent among BC survivors and suboptimal dietary intake was observed. Provision of an individualized medical nutrition therapy by a qualified dietitian is crucial as part of comprehensive BC survivorship care., (Copyright © 2018 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Dendrimers are highly branched spherical nanomaterials produced for use in diagnostic and therapeutic applications such as a drug delivery system. The toxicological profiles of dendrimers are largely unknown. We investigated the in vivo effects of nasal exposure to polyamidoamine (PAMAM) dendrimers on their effects on neurological biomarkers in the mouse brain. A single dose of PAMAM dendrimers (3 or 15μg/mouse) was intranasally administered to 8-week old male BALB/c mice. Twenty-four hours after administration, the olfactory bulb, hippocampus, and cerebral cortex were collected and potential biomarkers in the blood and brain were examined using blood marker, microarray and real-time RT-PCR analyses. No remarkable changes in standard serum biochemical markers were observed in the blood. A microarray analysis showed the alterations of the genes expression level related to pluripotent network, serotonin-anxiety pathway, TGF-beta receptor signaling, prostaglandin synthesis-regulation, complement-coagulation cascades, and chemokine-signaling pathway and non-odorant GPCR signaling pathways in brain tissues. Brain derived-neurotrophic factor mRNA was up-regulated in the hippocampus and cerebral cortex in mice treated with a high dose of dendrimers. These findings suggest that PAMAM dendrimers may reach the brain via the systemic circulation or an olfactory nerve route after intranasal instillation, and indicate that a single intranasal administration of PAMAM dendrimers may potentially lead to neuronal effects by modulating the gene expression of brain-derived neurotrophic factor signaling pathway., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

We investigated the effects of low-level toluene exposure on immunological biomarkers during different developmental stages in infant mice. Fetuses in utero in the pregnant mice on gestational day (GD) 14 as well as male pups on postnatal day (PND) 2 and PND 8 were exposed either to filtered air (control; 0 ppm), or to 5 ppm or to 50 ppm of toluene for 5 consecutive days in the whole body exposure chamber. Immunological biomarkers in the blood and spleen of PND 21 male mice were examined by ELISA, real-time RT-PCR, flow cytometry, and histological analysis. Plasma total IgG1 levels were markedly reduced in PND 21 mice exposed to 5 ppm of toluene during all developmental stages. Splenic T lymphocyte subsets and mRNA expression levels of Th1 cytokine IL-12, transcription factor T-bet, and Foxp3 were significantly suppressed in PND 21 male mice exposed to toluene during PNDs 8-12. There were changes in some immunological biomarkers in PND 42 mice exposed to toluene during PNDs 8-12. These findings indicate developmental stage-specific changes in non-specific immunological biomarkers in mice after early life toluene exposure., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The cytotoxic effect of ionizing radiation makes it a popular therapeutic tool against cancer. It is, however, a double-edged sword. Radiation exposure unleashes a plethora of protective and survival mechanisms that include increased proliferation, remodeling of the vasculature and altered cell motility. These mechanisms can play a pro-survival role in remaining cells, contributing to repopulation of tumors after radiation treatment. Understanding these mechanisms and finding ways to minimize their impact would improve the outcome of radiotherapy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

To investigate the effect of low-level toluene inhalation on immune regulation in an allergic mouse model, C3H/HeN mice were exposed to 0, 5, 50, or 500ppm of toluene for 6h/day, 5 days/week for 3 or 6 weeks. For allergic mouse model, half of the mice in each group were immunized with ovalbumin (OVA). Allergic mice exposed to toluene for 3 weeks did not exhibit any changes in their plasma, lung or spleen samples. Although exposure to toluene alone for 6 weeks did not increase the number of inflammatory cells in bronchoalveolar lavage (BAL) fluid, coexposure to 50ppm toluene and OVA increased the number of BAL cells. Histological changes and increased amounts of fibronectin were observed in the lungs of OVA-immunized, 50-ppm-toluene-exposed mice. Exposure to 500ppm significantly increased the expressions of transcription factors STAT3, STAT4 and STAT5a mRNAs in spleen. In spleens from the allergic mouse model, the expressions of STAT3, STAT4, STAT5a, STAT6, GATA3 and Foxp3 mRNAs were significantly enhanced following exposure to 50ppm toluene for 6 weeks, but the expression of T-bet mRNA was not increased. Regarding the Th1/Th2 balance, the expressions of IL-4 and IL-12 mRNAs were enhanced in the spleens of toluene-exposed mice. Total IgG1 antibody production in the plasma was significantly increased in the 50-ppm-toluene-exposed allergic mouse model. These results indicate that low-level toluene exposure might dysregulate the allergic responses to OVA in C3H/HeN mice., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Chemical susceptibility is triggered by a large range of chemicals present both indoors and outdoors including pesticides, cleaning products, perfumes, scented products and cigarette smoke. Health risk after chemical exposure depends on age, sex, genetic factors, socioeconomic status, nutritional status, and environmental factors. Toluene is one of volatile organic chemicals that causes different sensitivity in individuals. Although neurotoxic and immunotoxic effects of toluene have been studied extensively, the underlying mechanism remains obscure. This review highlights the possible neuroimmune factors influencing toluene sensitivity and neurotoxicity in a mouse model., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

The ability of ionizing radiation (IR) to induce apoptosis independent of p53 is crucial for successful therapy of cancers bearing p53 mutations. p53-independent apoptosis, however, remains poorly understood relative to p53-dependent apoptosis. IR induces both p53-dependent and p53-independent apoptoses in Drosophila melanogaster, making studies of both modes of cell death possible in a genetically tractable model. Previous studies have found that Drosophila E2F proteins are generally pro-death or neutral with regard to p53-dependent apoptosis. We report here that dE2F1 promotes IR-induced p53-independent apoptosis in larval imaginal discs. Using transcriptional reporters, we provide evidence that, when p53 is mutated, dE2F1 becomes necessary for the transcriptional induction of the pro-apoptotic gene hid after irradiation. In contrast, the second E2F homolog, dE2F2, as well as the net E2F activity, which can be depleted by mutating the common cofactor, dDp, is inhibitory for p53-independent apoptosis. We conclude that p53-dependent and p53-independent apoptoses show differential reliance on E2F activity in Drosophila., (Copyright © 2010 Elsevier Inc. All rights reserved.)

In Drosophila, heterozygosity in the pro-apoptotic gene hid significantly reduces apoptosis that is induced by ionizing radiation (IR). Therefore, mechanisms that regulate Hid levels can potentially contribute to life-or-death decision of an irradiated cell. 3'UTR of hid mRNA contains 5 potential binding sites for bantam microRNA. Ectopic expression of ban attenuated apoptosis that results from ectopic expression of hid but the significance of this regulation under physiological conditions remained to be investigated. We report here that ban is needed to limit IR-induced apoptosis in larval imaginal discs. Using tubulin-EGFP ban sensors with ban consensus sequences in the 3'UTR, we find that EGFP decreases following IR, indicating that IR activates ban. Likewise, a tubulin-EGFP reporter with hid-3'UTR is repressed in irradiated discs and this repression requires ban consensus sites in the hid 3'UTR. ban mutant larvae show increased sensitivity to killing by IR, which is suppressed by a mutation in hid. These results can fit into a model in which IR activates ban and ban represses hid to limit IR-induced apoptosis. miRNAs have been shown previously to be induced by radiation but this is the first report that a miRNA is functionally important for radiation responses.

Expression of hemolin, which generates an immune protein, was up-regulated in wandering fifth instar larval stage of Plodia interpunctella. The mRNA level peaked in the middle of the wandering stage. Major expression was in the epidermis, rather than in the fat body or gut. To test a possible ecdysteroid effect on hemolin induction we treated with RH-5992, an ecdysteroid agonist, and KK-42, which inhibits ecdysteroid biosynthesis in both feeding and wandering fifth instar larvae. When feeding larvae were treated with RH-5992 the hemolin mRNA level was increased. When wandering larvae were treated with KK-42 its level was reduced. In addition, when KK-42-treated larvae were subsequently treated with RH-5992 the hemolin mRNA level was recovered. These results strongly suggest that ecdysteroid up-regulates the expression of hemolin mRNA. Hormonal and bacterial effects on hemolin induction were further analyzed at the tissue level. Major induction of hemolin mRNA was detected following both RH-5992 treatment and bacterial injection in the epidermis of both feeding and wandering larvae. Minor induction of hemolin was detected in the fat body following a bacterial injection, but not RH-5992 treatment. We infer that in P. interpunctella larvae, the epidermis is the major tissue for hemolin induction in naïve insects and in insects manipulated with bacterial and hormonal treatments.

Toluene, a widely used aromatic organic solvent, has been well characterized as a neurotoxic chemical. Although the neurobehavioral effects of toluene have been studied substantially, the mechanisms involved are not clearly understood. Hippocampus, which is one of the limbic areas of brain associated with neuronal plasticity, and learning and memory functions, may be a principal target of toluene. In the present study, to establish a mouse model for investigating the effects of acute toluene exposure on the amino acid neurotransmitter levels in the hippocampus, in vivo microdialysis study was performed in freely moving mice after a single intraperitoneal administration of toluene (150 and 300 mg/kg). Amino acid neurotransmitters in microdialysates were measured by a high performance liquid chromatography system. The extracellular levels of glutamate and taurine were rapidly and reversibly increased within 30 min after the toluene administration in a dose-dependent manner and returned to the basal level by 1h. Conversely, the extracellular level of glycine and GABA were stable, and no significant change was observed after the toluene administration. To further investigate the brain toluene level in the hippocampus of toluene-administered mice, we used a solid-phase microextraction (SPME) method and examined the time course changes of toluene in the hippocampus of living mice. The brain toluene level reached the peak at 30 min after injection and returned to the basal level after 2h. In the present study, we observed the relationship between brain toluene levels and amino acid neurotransmitter glutamate and taurine levels in the hippocampus. Therefore, we suggest that toluene may mediate its action through the glutamatergic and taurinergic neurotransmission in the hippocampus of freely moving mice.

Oxidative stress is a persistent threat to the genome and is associated with major causes of human mortality, including cancer, atherosclerosis, and aging. Here we established a method to generate libraries of genomic DNA fragments containing oxidatively modified bases by using specific monoclonal antibodies to immunoprecipitate enzyme-digested genome DNA. We applied this technique to two different base modifications, 8-hydroxyguanine and 1,N6-propanoadenine (acrotein-Ade), in a ferric nitrilotriacetate-induced murine renal carcinogenesis model. Renal cortical genomic DNA derived from 10- to 12-week-old male C57BL/6 mice, of untreated control or 6 hours after intraperitoneal injection of 3 mg iron/kg ferric nitrilotriacetate, was enzyme digested, immunoprecipitated, cloned, and mapped to each chromosome. The results revealed that distribution of the two modified bases was not random but differed in terms of chromosomes, gene size, and expression, which could be partially explained by chromosomal territory. In the wild-type mice, low GC content areas were more likely to harbor the two modified bases. Knockout of OGG1, a repair enzyme for genomic 8-hydroxyguanine, increased the amounts of acrolein-Ade as determined by quantitative polymerase chain reaction analyses. This versatile technique would introduce a novel research area as a high-throughput screening method for critical genomic loci under oxidative stress.

We have recently identified in Drosophila melanogaster a new gene encoding a nuclear protein, DIP1. Here we report the developmental expression and the finding that DIP1 subcellular localization is in the nucleus and at the nuclear periphery during interphase in embryos. Interestingly, in humans, DIP1 antibody identified signals in nuclei from cultured cells and reacted with a rough 30kDa protein in Western blotting experiments, demonstrating evolutionary conservation.