Improvement in Radiative Efficiency Via Intramolecular Charge Transfer in ortho-Carboranyl Luminophores Modified with Functionalized Biphenyls.

In this study, we found that the electronic effects of the functional groups on aromatic units attached to o-carboranyl species can enhance the efficiency of intramolecular charge transfer (ICT)-based radiative decay processes. Six o-carboranyl-based luminophores having attached functionalized biphenyl groups with CF3, F, H, CH3, C(CH3)3, and OCH3 substituents were prepared and fully characterized by multinuclear magnetic resonance spectroscopy. In addition, their molecular structures were determined by single-crystal X-ray diffractometry, which revealed that the distortion of the biphenyl rings and the geometries around the o-carborane cages were similar. All compounds exhibited ICT-based emissions in the rigid state (solution at 77 K and film). Intriguingly, the quantum efficiencies (Φem) of five compounds (that of the group with CF3 could not be measured because of its extremely weak emissions) in the film state increased gradually as the electron-donating power of the terminal functional group modifying the biphenyl moiety increased. Furthermore, the nonradiative decay constants (knr) for the group with OCH3 were estimated to be one-tenth of those for the group with F, whereas the radiative decay constants (kr) for the five compounds were similar. The dipole moments (µ) calculated for the optimized first excited state (S1) structures gradually increased, from that of the group with CF3 to that of the group with OCH3, implying that the inhomogeneity of the molecular charge distribution was enhanced by electron donation. The electron-rich environment formed as a result of electron donation led to efficient charge transfer to the excited state. Both experimental and theoretical findings revealed that the electronic environment of the aromatic moiety in o-carboranyl luminophores can be controlled to accelerate or interrupt the ICT process in the radiative decay of excited states.

Assessment of Safety, Effects, and Muscle-Specific Accumulation of Dietary Butylated Hydroxytoluene (BHT) in Paralichthys olivaceus.

Butylated hydroxytoluene (BHT) is a commonly used antioxidant added to animal/fish feed to limit lipid autoxidation and peroxidation. Although there have been reviews and reports of BHT toxicity in animals, limited information is available with respect to the toxic effects and accumulation of BHT due to oral exposure in aquaculture species. Therefore, 120 days of feeding trial was conducted to evaluate the effects of dietary BHT on the marine fish olive flounder Paralichthys olivaceus. Graded levels of BHT were added to the basal diet in increments of 0, 10, 20, 40, 80, and 160 mg BHT/kg, corresponding to 0 (BHT0), 11 (BHT11), 19 (BHT19), 35 (BHT35), 85 (BHT85), and 121 (BHT121) mg BHT/kg diets, respectively. Fish with an average weight of 77.5 ± 0.3 g (mean ± SD) were fed one of the six experimental diets in triplicate groups. Growth performance, feed utilization, and survival rate were not significantly affected by the dietary BHT levels among all experimental groups, whereas BHT concentration in the muscle tissue was found to increase in a dose-dependent manner up to 60 days of the experimental period. Thereafter, BHT accumulation in muscle tissue showed a declining trend among all treatment groups. Furthermore, the whole-body proximate composition, nonspecific immune responses, and hematological parameters (except triglycerides) were not significantly influenced by the dietary levels of BHT. Blood triglyceride content was significantly higher in fish fed the BHT-free diet compared to all other treatment groups. Thus, this study demonstrates that dietary BHT (up to 121 mg/kg) is a safe and effective antioxidant without exhibiting any adverse effects on the growth performance, body composition, and immune responses in the marine fish olive flounder, P. olivaceus.

Relationship between the Molecular Geometry and the Radiative Efficiency in Naphthyl-Based Bis-Ortho-Carboranyl Luminophores.

The efficiency of intramolecular charge transfer (ICT)-based emission on π-aromatic-group-appended closo-ortho-carboranyl luminophores is known to be affected by structural fluctuations and molecular geometry, but investigation of this relationship has been in progress to date. In this study, four naphthyl-based bis-o-carboranyl compounds, in which hydrogen (15CH and 26CH) or trimethysilyl groups (15CS and 26CS) were appended at the o-carborane cage, were synthesized and fully characterized. All the compounds barely displayed an emissive trace in solution at 298 K; however, 15CH and 26CH distinctly exhibited a dual emissive pattern in rigid states (in solution at 77 K and in films), attributed to locally excited (LE) and ICT-based emission, while 15CS and 26CS showed strong ICT-based greenish emission. Intriguingly, the molecular structures of the four compounds, analyzed by single X-ray crystallography, showed that the C-C bond axis of the o-carborane cage in the trimethysilyl group-appended compounds 15CS and 26CS were more orthogonal to the plane of the appended naphthyl group than those in 15CH and 26CH. These features indicate that 15CS and 26CS present an efficient ICT transition based on strong exo-π-interaction, resulting in a higher quantum efficiency (Φem) for ICT-based radiative decay than those of 15CH and 26CH. Moreover, the 26CS structure revealed most orthogonal geometry, resulting in the highest Φem and lowest knr values for the ICT-based emission. Consequently, all the findings verified that efficient ICT-based radiative decay of aromatic group-appended o-carboranyl luminophores could be achieved by the formation of a specific geometry between the o-carborane cage and the aromatic plane.

Rheumatoid arthritis in low-level toluene-exposed workers based on nationwide medical surveillance data in Korea.

BACKGROUND: There is growing evidence that exposure to organic solvents can play a role in the etiology of rheumatoid arthritis (RA). This prospective cohort study aimed to investigate the association between RA and toluene exposure. METHODS: The study cohort consisted of Korea Occupational Safety and Health Agency data from male workers exposed to toluene who had undergone a toluene-associated special medical examination at least once between January 1, 2000 and December 31, 2004 (n = 148,870). The morbidity from RA based on hospital admission records was estimated from 2000 to 2005 using National Health Insurance Claim Data. The standardized admission ratio (SAR) for RA was calculated with reference to the general population. Levels of urinary hippuric acid (HA), a metabolite of toluene, were measured and used for exposure assessment. RESULTS: Toluene-exposed workers were at an elevated risk of seropositive rheumatoid arthritis (ICD-10 code M05) with an SAR of 2.38 (95% confidence interval [CI]: 1.14-4.37) and other rheumatoid arthritis (M06) with an SAR of 1.22 (95% CI: 0.91-1.59). When data were stratified according to the duration of toluene exposure and by tertiles of urinary HA level, no significant difference was apparent. CONCLUSION: SARs of the toluene-exposed workers are higher than that of the general reference population, indicating that exposure to toluene may contribute to an increased risk of RA. Further studies of toluene-exposed workers with longer follow-up are needed.

Inhibition of MAGEA2 regulates pluripotency, proliferation, apoptosis, and differentiation in mouse embryonic stem cells.

Mouse embryonic stem cells (mESCs) exhibit self-renewal and pluripotency, can differentiate into all three germ layers, and serve as an essential model in stem cell research and for potential clinical application in regenerative medicine. Melanoma-associated antigen A2 (MAGEA2) is not expressed in normal somatic cells but rather in different types of cancer, especially in undifferentiated cells, such as in the testis, differentiating cells, and ESCs. However, the role of MAGEA2 in mESCs remains to be clarified. Accordingly, in this study, we examined the expression and functions of MAGEA2 in mESCs. MAGEA2 messenger RNA (mRNA) expression was decreased during mESCs differentiation. MAGEA2 function was then evaluated in knockdown mESC. MAGEA2 knockdown resulted in decreased pluripotency marker gene expression in mESCs consequent to increased Erk1/2 phosphorylation. Decreased MAGEA2 expression inhibited mESC proliferation via S phase cell cycle arrest with a subsequent decrease in cell cycle-associated genes Cdk1, Cdk2, Cyclin A1, Cyclin D1, and Cdc25a. Apoptotic mESCs markedly increased along with cleaved forms of caspases 3, 6, and 7 and PARP expression, confirming caspase-dependent apoptosis. MAGEA2 knockdown significantly decreased embryoid body size in vitro when cells were differentiated naturally and teratoma size in vivo, concomitant with decreased ectoderm marker gene expression. These findings suggested that MAGEA2 regulates ESC pluripotency, proliferation, cell cycle, apoptosis, and differentiation. The enhanced understanding of the regulatory mechanisms underlying diverse mESC characteristics will facilitate the clinical application of mESCs.

Deboronation-Induced Ratiometric Emission Variations of Terphenyl-Based Closo-o-Carboranyl Compounds: Applications to Fluoride-Sensing.

Closo-o-carboranyl compounds bearing the ortho-type perfectly distorted or planar terphenyl rings (closo-DT and closo-PT, respectively) and their nido-derivatives (nido-DT and nido-PT, respectively) were synthesized and fully characterized using multinuclear NMR spectroscopy and elemental analysis. Although the emission spectra of both closo-compounds exhibited intriguing emission patterns in solution at 298 and 77 K, in the film state, closo-DT mainly exhibited a π-π* local excitation (LE)-based emission in the high-energy region, whereas closo-PT produced an intense emission in the low-energy region corresponding to an intramolecular charge transfer (ICT) transition. In particular, the positive solvatochromic effect of closo-PT and theoretical calculation results at the first excited (S1) optimized structure of both closo-compounds strongly suggest that these dual-emissive bands at the high- and low-energy can be assigned to each π-π* LE and ICT transition. Interestingly, both the nido-compounds, nido-DT and nido-PT, exhibited the only LE-based emission in solution at 298 K due to the anionic character of the nido-o-carborane cages, which cannot cause the ICT transitions. The specific emissive features of nido-compounds indicate that the emissive color of closo-PT in solution at 298 K is completely different from that of nido-PT. As a result, the deboronation of closo-PT upon exposure to increasing concentrations of fluoride anion exhibits a dramatic ratiometric color change from orange to deep blue via turn-off of the ICT-based emission. Consequently, the color change response of the luminescence by the alternation of the intrinsic electronic transitions via deboronation as well as the structural feature of terphenyl rings indicates the potential of the developed closo-o-carboranyl compounds that exhibit the intense ICT-based emission, as naked-eye-detectable chemodosimeters for fluoride ion sensing.

Reductively Caged, Photoactivatable DNA-PAINT for High-Throughput Super-resolution Microscopy.

In DNA points accumulation in nanoscale topography (DNA-PAINT), capable of single-molecule localization microscopy with sub-10-nm resolution, the high background stemming from the unbound fluorescent probes in solution limits the imaging speed and throughput. Herein, we reductively cage the fluorescent DNA probes conjugated with a cyanine dye to hydrocyanine, acting as a photoactivatable dark state. The additional dark state from caging lowered the fluorescent background while enabling optically selective activation by total internal reflection (TIR) illumination at 405 nm. These benefits from "reductive caging" helped to increase the localization density or the imaging speed while preserving the image quality. With the aid of high-density analysis, we could further increase the imaging speed of conventional DNA-PAINT by two orders of magnitude, making DNA-PAINT capable of high-throughput super-resolution imaging.

Co-expression of MDM2 and CDK4 in transformed human mesenchymal stem cells causes high-grade sarcoma with a dedifferentiated liposarcoma-like morphology.

Amplification and overexpression of MDM2 and CDK4 are well-known diagnostic criteria for well-differentiated liposarcoma (WDLPS)/dedifferentiated liposarcoma (DDLPS). Although it was reported that the depletion of MDM2 or CDK4 decreased proliferation in DDLPS cell lines, whether MDM2 and CDK4 induce WDLPS/DDLPS tumorigenesis remains unclear. We examined whether MDM2 and/or CDK4 cause WDLPS/DDLPS, using two types of transformed human bone marrow stem cells (BMSCs), 2H and 5H, with five oncogenic hits (overexpression of hTERT, TP53 degradation, RB inactivation, c-MYC stabilization, and overexpression of HRASv12). In vitro functional experiments revealed that the co-overexpression of MDM2 and CDK4 plays a key role in tumorigenesis by increasing cell growth and migration and inhibiting adipogenic differentiation potency when compared with the sole expression of MDM2 or CDK4. Using mouse xenograft models, we found that the co-overexpression of MDM2 and CDK4 in 5H cells with five additional oncogenic mutations can cause proliferative sarcoma with a DDLPS-like morphology in vivo. Our results suggest that the co-overexpression of MDM2 and CDK4, along with multiple genetic factors, increases the tendency for high-grade sarcoma with a DDLPS-like morphology in transformed human BMSCs by accelerating their growth and migration and blocking their adipogenic potential.

Adipogenesis induces growth inhibition of dedifferentiated liposarcoma.

Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are the most common types of liposarcoma. Although WDLPS and DDLPS patients receive intensive treatment including radical surgery and systemic therapy, their overall 5-year survival rates are 90% and 30%, respectively, indicating that DDLPS is clinically more aggressive. We examined whether adipogenic stimulation induces adipogenesis in human WDLPS/DDLPS cells by using dexamethasone, indomethacin, insulin, and 3-isobutyl-1-methylxanthine (IBMX), all putative medications or drugs. Functional in vitro experiments showed that treatment with these four compounds induced adipogenic potency by transcriptional and translational upregulation of genes related to the maintenance of stemness and adipogenic differentiation. Using in vivo xenograft models, we found that the induction of stemness and adipogenesis inhibited the tumorigenic potency of DDLPS. This study suggests a potential application of drug repositioning in which adipogenesis-inducing compounds could be used to treat DDLPS patients in a clinical setting.

High mobility group box 1 secretion blockade results in the reduction of early pancreatic islet graft loss.

Pancreatic islet transplantation has been known as the best cure for patients suffering from severe type 1 diabetes mellitus (T1DM). Despite meaningful advances in human allogeneic islet transplantation field, significant amounts of islet loss in early post-transplantation periods is still a big concern for clinicians. One of the major factors determining the fate of the islets is the danger-associated molecular patterns (DAMPs) secreted by activated immune cells or islets themselves under hypoxic stress. High mobility group box 1 (HMGB1) protein is one of the best characterized DAMP molecules associated with islets. HMGB1 is known to be passively released by transplanted murine islet cells after taking damages from cytokines, reactive oxygen species, and other DAMPS, and the released HMGB1 harms neighboring islet cells by interacting with receptors expressed on murine islets such as toll-like receptor 2 (TLR2) and TLR4, thereby forming a vicious cycle. Here, we show that a small molecule inhibitor inflachromene (ICM) was capable of blocking the secretion of HMGB1 from murine islet cells during the normoxic and hypoxic post-isolation period. Notably, the treatment of ICM during the islet isolation process resulted in decreased HMGB1 levels during the subsequent cell culture. ICM's in vivo efficacy was evaluated in murine syngeneic islet transplantation model, and it significantly reduced the serum and graft level of HMGB1. Ultimately, the intraperitoneal administration of ICM prevented the loss of marginal-mass islet grafts and reversed the diabetes in mice.

PRPF4 is a novel therapeutic target for the treatment of breast cancer by influencing growth, migration, invasion, and apoptosis of breast cancer cells via p38 MAPK signaling pathway.

Pre-mRNA processing factor 4 (PRPF4), a core protein in U4/U6 snRNP, maintains snRNP structures by interacting with PRPF3 and cyclophilin H. Expression of the PRPF4 gene affects cell survival as well as apoptosis and is responsible for retinitis pigmentosa (RP). Proteomics analysis shows that PRPF4 may be a therapeutic target in human cancers. Nevertheless, the exact function and role of the PRPF4 gene are unclear. In this study, we assessed the expression of PRPF4 gene in human breast cancer cells. First, we confirmed that the PRPF4 gene was overexpressed in various breast cancer cell lines. Next, using breast cancer cell lines MCF7 and MDA-MB-468, we established stable cell lines with PRPF4 gene knockdown. We also performed microarray analysis to investigate molecular mechanisms underlying PRPF4 activity. All cell lines with PRPF4 gene knockdown exhibited reduced cell proliferation, remarkable reduction in anchorage-independent colony formation capacity, and reduction of PCNA protein, which is a marker cell of proliferation. Reduced expression of the PRPF4 gene induced apoptosis and changes in the expression of associated apoptotic markers in breast cancer cell lines. Knockdown of the PRPF4 gene reduced cellular capacity for migration and invasion (the key hallmarks of human cancers) and decreased the expression of genes involved in epithelial-mesenchymal transition (EMT). Microarray results showed that the expression of PPIP5K1, PPIPK2, and YWHAE genes was reduced at the transcriptional level, leading to reduced phosphorylation of p38 MAPK. These findings suggest that knockdown of PRPF4 gene slows down breast cancer progression via suppression of p38 MAPK phosphorylation. In conclusion, the PRPF4 gene plays an important role in the growth of breast cancer cells and is therefore a potential therapeutic target.

Suppression of PRPF4 regulates pluripotency, proliferation, and differentiation in mouse embryonic stem cells.

Mouse embryonic stem cells (mESCs) are characterized by their self-renewal and pluripotency and are capable of differentiating into all three germ layers. For this reason, mESCs are considered a very important model for stem cell research and clinical applications in regenerative medicine. The pre-mRNA processing factor 4 (PRPF4) gene is known to have a major effect on pre-mRNA splicing and is also known to affect tissue differentiation during development. In this study, we investigated the effects of PRPF4 knockdown on mESCs. First, we allowed mESCs to differentiate naturally and observed a significant decrease in PRPF4 expression during the differentiation process. We then artificially induced the knockdown of PRPF4 in mESCs and observed the changes in the phenotype. When PRPF4 was knocked down, various genes involved in mESC pluripotency showed significantly decreased expression. In addition, mESC proliferation increased abnormally, accompanied by a significant increase in mESC colony size. The formation of mESC embryoid bodies and teratomas was delayed following PRPF4 knockdown. Based on these results, the reduced expression of PRPF4 affects mESC phenotypes and is a key factor in mESC. SIGNIFICANCE OF THE STUDY: Our results indicate that PRPF4 affects the properties of mESCs. Suppression of PRPF4 resulted in a decrease in pluripotency of mESC and promoted proliferation. In addition, suppression of PRPF4 also resulted in decreased apoptosis. Moreover, the inhibition of PRPF4 reduced the ability to differentiate and formation of teratoma in mESC. Our results demonstrated that PRPF4 is a key factor of controlling mESC abilities.

Status of programmed death-ligand 1 expression in sarcomas.

BACKGROUND: Sarcomas are challenging to study because of their rarity and histomorphological complexity. PD1 and PD-L1 inhibitors showed a promising anti-tumor effect in solid tumors, where a relationship between PD-L1 expression and the objective response has been evidenced. METHODS: In this study, we examined PD-L1 expression in 16 bone and soft tissue sarcoma cell lines of 11 different subtypes by means of western blot, flow cytometry and immunocytochemistry, and in 230 FFPE patient-derived tumor tissues by means of immunohistochemistry using three different antibody clones. The association between PD-L1 expression and clinicopathological features was evaluated. RESULTS: We demonstrated that PD-L1 protein is highly expressed in pleomorphic rhabdomyosarcoma, fibrosarcoma, and dedifferentiated liposarcoma (DDLPS) cell lines. From the tissue microarray, undifferentiated pleomorphic sarcoma showed ≥ 1% immunoreactivity in 20%, 17.6%, and 16.3% of the cases with PD-L1 22C3, SP263, and SP142 antibodies, respectively. In whole sections stained with a PD-L1 22C3 antibody, DDLPS showed ≥ 1% immunoreactivity in 21.9% of the cases. In DDLPS group, cases with ≥ 1% PD-L1 expression showed statistically significantly worse recurrence-free survival (P = 0.027) and overall survival (P = 0.017) rates. Upon interferon-gamma treatment, the mRNA expression levels of PD-L1 were elevated in the HS-RMS-1, LIPO-224B, MLS1765, RH30, and RH41 cell lines. CONCLUSIONS: We found that the expression of PD-L1 in sarcoma differs depending on the histologic subtype and the PD-L1 antibody clones. These results may serve as primary data for the selection of appropriate patients when applying PD1/PD-L1 inhibitor therapy in sarcoma.

Molecular breakdown: a comprehensive view of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer.

Most anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLCs) show good clinical response to ALK inhibitors. However, some ALK-rearranged NSCLC patients show various primary responses with unknown reasons. Previous studies focused on the clinical aspects of ALK fusions in small cohorts, or were conducted in vitro and/or in vivo to investigate the function of ALK. One of the suggested theories describes how echinoderm microtubule-associated protein-like 4 (EML4)-ALK variants play a role towards different sensitivities in ALK inhibitors. Until now, there has been no integrated comprehensive study that dissects ALK at the molecular level in a large scale. Here, we report the largest extensive molecular analysis of 158 ALK-rearranged NSCLCs and have investigated these findings in a cell line construct experiment. We discovered that NSCLCs with EML4-ALK short forms (variant 3/others) had more advanced stage and frequent metastases than cases with the long forms (variant 1/others) (p = 0.057, p < 0.05). In vitro experiments revealed that EML4-ALK short forms show lower sensitivity to ALK inhibitors than do long forms. Clinical analysis also showed a trend for the short forms showing worse PFS. Interestingly, we found that breakpoints of ALK are evenly distributed mainly in intron 19 and almost all of them undergo a non-homologous end-joining repair to generate ALK fusions. We also discovered four novel somatic ALK mutations in NSCLC (T1151R, R1192P, A1280V, and L1535Q) that confer primary resistance; all of them showed strong resistance to ALK inhibitors, as G1202R does. Through targeted deep sequencing, we discovered three novel ALK fusion partners (GCC2, LMO7, and PHACTR1), and different ALK fusion partners showed different intracellular localization. With our findings that the EML4-ALK variants, new ALK somatic mutations, and novel ALK-fusion partners may affect sensitivity to ALK inhibitors, we stress the importance of targeted therapy to take the ALK molecular profiling into consideration. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Clinical significance of serum apolipoproteins as a predictor of coronary heart disease risk in Korean men.

OBJECTIVE: Although serum apolipoprotein measurement is known to be associated with coronary heart disease (CHD) risk, there is only limited information about the clinical significance of lipid profiles such as ApoA, ApoB and A/B ratio in predicting CHD risk in Asians. Therefore, this cohort study was conducted to evaluate the longitudinal effects of baseline serum apolipoprotein measurements on CHD risk in Korean men. DESIGN: Initially, an intermediate and high Framingham risk score (FRS)-free cohort of 23 918 healthy Korean men was followed until 2010. FRS was calculated for each man and divided into three levels of risk <10% (low), 10-19% (intermediate) and ≥20% (high). More-than-a-moderate CHD risk group (participants with FRS ≥ 10%) and high CHD risk group (participants with FRS ≥ 20%) were defined as our two dependent variables. Cox proportional hazards models were performed. RESULTS: In the more-than-a-moderate CHD risk group, the total and average follow-up periods were 83340·2 and 3·48 person-years, respectively, and 3763 (15·7%) incident cases developed between 2006 and 2010. In the high CHD risk group, the total and average follow-up periods were 87868·8 and 3·67 person-years, respectively, and 344 (1·4%) incident cases developed between 2006 and 2010. Multivariate-adjusted analyses showed a strong statistically significant relationship between the quintile groups of apolipoprotein B (ApoB), apolipoprotein A-1 (ApoA-1) and apolipoprotein B/apolipoprotein A-1 (ApoB/A-1) ratio and both the more-than-a-moderate CHD risk and high CHD risk. CONCLUSIONS: Serum ApoB, ApoA-1 and ApoB/A-1 ratio levels are independently associated with CHD risk in Korean men.

In Vivo Expression of Reprogramming Factors Increases Hippocampal Neurogenesis and Synaptic Plasticity in Chronic Hypoxic-Ischemic Brain Injury.

Neurogenesis and synaptic plasticity can be stimulated in vivo in the brain. In this study, we hypothesized that in vivo expression of reprogramming factors such as Klf4, Sox2, Oct4, and c-Myc would facilitate endogenous neurogenesis and functional recovery. CD-1® mice were induced at 1 week of age by unilaterally carotid artery ligation and exposure to hypoxia. At 6 weeks of age, mice were injected GFP only or both four reprogramming factors and GFP into lateral ventricle. Passive avoidance task and open field test were performed to evaluate neurobehavioral function. Neurogenesis and synaptic activity in the hippocampus were evaluated using immunohistochemistry, qRT-PCR, and/or western blot analyses. Whereas BrdU+GFAP+ cells in the subgranular zone of the hippocampus were not significantly different, the numbers of BrdU+ßIII-tubulin+ and BrdU+NeuN+ cells were significantly higher in treatment group than control group. Expressions of synaptophysin and PSD-95 were also higher in treatment group than control group. Importantly, passive avoidance task and open field test showed improvement in long-term memory and decreased anxiety in treatment group. In conclusion, in vivo expression of reprogramming factors improved behavioral functions in chronic hypoxic-ischemic brain injury. The mechanisms underlying these repair processes included endogenous neurogenesis and synaptic plasticity in the hippocampus.

Larvicidal activity of naturally occurring naphthalenedione and its structurally related analogs against three mosquito species.

The objective of this study was to determine the larvicidal activity of an active compound isolated from Cercis chinensis heartwood and its structurally related analogs against 4th-stage Aedes aegypti, Culex pipiens pallens, and Ae. togoi. The larvicidal compound of C. chinensis was isolated with the use of various chromatographic techniques and identified as analogs of 1,4-naphthalenedione. Based on the median lethal concentration (LC(50)) values of commercially procured analogs against Ae. aegypti larvae, the most toxic analog was 2-bromo-1,4-naphthalenedione (1.19 µg/ml); followed by 5-hydroxy-1,4-naphthalenedione (1.72 µg/ml); 2-methyl-1,4-naphthalenedione (9.12 µg/ml); 2-hydroxy-1,4-naphthalenedione (10.76 µg/ml); and 2-methoxy-1,4-naphthalenedione (12.50 µg/ml). Similar results were observed against Cx. p. pallens and Ae. togoi larvae with 1,4-naphthalenedione analogs. These results also showed that 1,4-naphthalenedione analogs were less toxic than the organophosphate pirimiphos-methyl. Nonetheless, naturally occurring C. chinensis-derived materials and 1,4-naphthalenedione analogs have potential for development as mosquito larvicidal agents.

Acaricidal activities against house dust mites of spearmint oil and its constituents.

The aim of this study was to evaluate the acaricidal activities of spearmint oil and carvone derivatives against house dust mites using contact and fumigant toxicity bioassays to replace benzyl benzoate as a synthetic acaricide. Based on the LD50 values, the contact toxicity bioassay revealed that dihydrocarvone (0.95 and 0.88 µg/cm2) was 7.7 and 6.8 times more toxic than benzyl benzoate (7.33 and 6.01 µg/cm2) against Dermatophagoides farinae and Dermatophagoides pteronyssinus, respectively, followed by carvone (3.78 and 3.23 µg/cm2), spearmint oil (5.16 and 4.64 µg/cm2), carveol (6.00 and 5.80 µg/cm2), and dihydrocarveol (8.23 and 7.10 µg/cm2). Results of the fumigant toxicity bioassay showed that dihydrocarvone (2.73 and 2.16 µg/cm2) was approximately 4.0 and 4.8 times more effective than benzyl benzoate (11.00 and 10.27 µg/cm2), followed by carvone (6.63 and 5.78 µg/cm2), carveol (7.58 and 7.24 µg/cm2), spearmint oil (9.55 and 8.10 µg/cm2), and dihydrocarveol (9.79 and 8.14 µg/cm2). Taken together, spearmint oil and carvone derivatives are a likely viable alternative to synthetic acaricides for managing house dust mites.

Acaricidal activities of bicyclic monoterpene ketones from Artemisia iwayomogi against Dermatophagoides spp.

The acaricidal properties of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one isolated from Artemisia iwayomogi and its structural analogues were evaluated against Dermatophagoides farinae and D. pteronyssinus, and their effects were compared with that of the commercial acaricide benzyl benzoate. Based on the 50 % lethal dose (LD50) values against D. farinae, 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (0.82 µg/cm(2)) was 9.71 times more effective than benzyl benzoate (7.96 µg/cm(2)), followed by (1R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (1.03 µg/cm(2)), (1S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one (1.58 µg/cm(2)), and (1R)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one oxime (3.05 µg/cm(2)) in a filter paper bioassay. The acaricidal activities of 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one and its structural analogues against D. pteronyssinus were similar to those against D. farinae. These results demonstrate that naturally occurring A. iwayomogi-isolated 1,7,7-trimethylbicyclo[2.2.1]heptan-2-one and its structural analogues are suitable for the production of natural acaricides against house dust mites.

Antimicrobial potentials of active component isolated from Citrullus colocynthis fruits and structure-activity relationships of its analogues against foodborne bacteria.

BACKGROUND: Synthetic preservatives have been consistently used to maintain the quality of food products. However, the degree of danger to human health cannot be ignored. In this study, the antimicrobial activities of Citrullus colocynthis fruits and 4-methylquinoline analogues were investigated to develop natural preservatives against foodborne bacteria. RESULTS: Antimicrobial activities of the methanol extract and five fractions derived from C. colocynthis fruits were evaluated against five foodborne bacteria. The chloroform fraction possessed strong activities against five foodborne bacteria. 4-Methylquinoline was isolated by chromatographic analyses. To establish the structure-activity relationships, the antimicrobial activities of 4-methylquinoline analogues (2-hydroxyquinoline, 4-hydroxyquinoline, 6-hydroxyquinoline, 2-methylquinoline, 6-methyquinoline, 8-methylquinoline and 2-methyl-8-hydroxyquinoline) were tested against food-borne bacteria. When employing the agar diffusion method, 2-methyl-8-hydroxyquinoline was found to have potent activities against the five foodborne bacteria. In terms of minimum bactericidal concentration or minimum inhibitory concentration, 2-methyl-8-hydroxyquinoline had significantly higher antimicrobial activity against the five foodborne bacteria. CONCLUSION: Citrullus colocynthis fruits and 4-methylquinoline analogues could be useful for the development of eco-friendly food supplemental agents and pharmaceuticals.