[Application of three methods in occupational health risk assessment of automobile 4S shop].

Objective: To choose various occupational health risk assessment of the mature methods at home and abroad respectively occupational health risk assessment was carried out on the 4s stores, to explore different risk assessment methods on the 4 s shop the applicability of the occupational health risk assessment. Methods: Chemical was applied on the harmful factors of occupational health risk assessment technology guideline in the composite index method, quantitative cancer risk assessment method using the guidelines for the harmful factors of occupational health risk assessment of chemical technology of composite index method, quantitative cancer risk assessment method, international commission on mining and metals (ICMM) occupational health risk assessment quantitative method and the occupational-disease-inductive operation classification to evaluate chemical factors in 4S store, Combined with on-site occupational health investigation to compare with the result of risk assessment and analysis of international mining and metals (ICMM) committee occupational health risk assessment quantitative method and the occupational-disease-inductive operation classification of 4S store to evaluate chemical factors, combined with on-site occupational health investigation comparison and analysis the result of the risk assessment. Results: Except for 6 times, the results of ICMM matrix method and comprehensive index method were consistent, which were all higher than job classification. The other results were job classification of >of ICMM matrix method >comprehensive index method or job classification of >of ICMM matrix method. Conclusion: When the concentration of occupational-disease-inductive factors is lower than 1/2 limit, the risk assessment results tend to be ICMM quantitative >composite index method >operation classification. When the occupational-disease-inductive factors were involved with triphenyl, the quantitative non-carcinogenic risk assessment method was more likely to reach the conclusion that the occupational health risk was unacceptable.

Effects of methotrexate on the quality of oocyte maturation in vitro.

Methotrexate (MTX), an antifolate drug, is widely used for clinical treatment of malignancies and ectopic pregnancy. Many studies have documented that MTX has strong side-effects on rapidly dividing somatic cells. However, its side-effects on female reproductive cells have not been widely reported. Combined with in vitro culture, two-photon fluorescence imaging and three-dimensional reconstruction, this study analyzed the effects of MTX on oocyte maturation time, chromosome arrangement, karyotype, spindle morphology, and the localization of microtubule organizing centers (MTOCs). Compared with a control group (84%), the rate of germinal vesical breakdown in the MTX group dropped to 73% (P < 0.05). The rate of the first polar body extrusion in the MTX group (53%) was also below the control group (63%; P < 0.05). The rate of abnormal chromosomal arrangement in the MTX group was 60%, but 24% in the control group (P < 0.05). The matured oocyte karyotypes showed 20 univalents in both control and MTX groups, while point-shaped DAPI signals were detected in the MTX group. The rate of abnormal spindle in the MTX group was 49%, but 17% in the control group (P < 0.05). MTOCs in oocytes with normal spindles concentrated at the poles, while MTOCs in oocytes with abnormal spindles were scattered around the poles or in the ooplasm. MTX changes the structures of chromosomes and spindles, potentially by interfering with DNA methylation. The above results indicate a basis for understanding negative effects of MTX on oocyte maturation quality, and provide information for the clinical application of MTX in female patients.

A new method for estimating the number of non-differentially expressed genes.

Control of the false discovery rate is a statistical method that is widely used when identifying differentially expressed genes in high-throughput sequencing assays. It is often calculated using an adaptive linear step-up procedure in which the number of non-differentially expressed genes should be estimated accurately. In this paper, we discuss the estimation of this parameter and point out defects in the original estimation method. We also propose a new estimation method and provide the error estimation. We compared the estimation results from the two methods in a simulation study that produced a mean, standard deviation, range, and root mean square error. The results revealed that there was little difference in the mean between the two methods, but the standard deviation, range, and root mean square error obtained using the new method were much smaller than those produced by the original method, which indicates that the new method is more accurate and robust. Furthermore, we used real microarray data to verify the conclusion. Finally we provide a suggestion when analyzing differentially expressed genes using statistical methods.

A method for simultaneously delineating multiple targets in 3D-FISH using limited channels, lasers, and fluorochromes.

Many studies have suggested a link between the spatial organization of genomes and fundamental biological processes such as genome reprogramming, gene expression, and differentiation. Multicolor fluorescence in situ hybridization on three-dimensionally preserved nuclei (3D-FISH), in combination with confocal microscopy, has become an effective technique for analyzing 3D genome structure and spatial patterns of defined nucleus targets including entire chromosome territories and single gene loci. This technique usually requires the simultaneous visualization of numerous targets labeled with different colored fluorochromes. Thus, the number of channels and lasers must be sufficient for the commonly used labeling scheme of 3D-FISH, "one probe-one target". However, these channels and lasers are usually restricted by a given microscope system. This paper presents a method for simultaneously delineating multiple targets in 3D-FISH using limited channels, lasers, and fluorochromes. In contrast to other labeling schemes, this method is convenient and simple for multicolor 3D-FISH studies, which may result in widespread adoption of the technique. Lastly, as an application of the method, the nucleus locations of chromosome territory 18/21 and centromere 18/21/13 in normal human lymphocytes were analyzed, which might present evidence of a radial higher order chromatin arrangement.

Nerve growth factor regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes via PI3K/mTOR pathway.

Decades of research have provided the data to confirm the hypothesis that there is bidirectional communication between the central nervous system and the immune system in psoriasis pathogenesis, but the contribution of the cutaneous neural system remains underexplored. In this study, we evaluated the molecular mechanisms by which nerve growth factor (NGF) regulates hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) production. The mRNA and protein levels of VEGF secretion from HaCaT cells by NGF were increased in a concentration-dependent manner. In addition, the NGF- induced increase in VEGF is accompanied by an increase in HIF-1α, but not HIF-2α or HIF-1ß. However, this increase is abrogated by pretreatment with a mammalian target of rapamycin (mTOR) inhibitor rapamycin. Pharmacologic inhibitors of the Trk tyrosine kinase, PI-3 kinase, and mTOR pathways prevent NGF-stimulated increases in HIF-1α and VEGF. Mutation of the siRNA-mediated silencing of HIF-1α expression blocks NGF-induced increases in VEGF transcription. Our study indicates that NGF regulates the expression of VEGF through the PI3K/mTOR signaling pathway in human HaCaT keratinocytes.

Performance of homeostasis model assessment and serum high-sensitivity C-reactive protein for prediction of isolated post-load hyperglycaemia.

AIMS: To evaluate whether homeostasis model assessment and high-sensitivity C-reactive protein improve the prediction of isolated post-load hyperglycaemia. METHODS: The subjects were 1458 adults without self-reported diabetes recruited between 2006 and 2010. Isolated post-load hyperglycaemia was defined as fasting plasma glucose < 7 mmol/l and 2-h post-load plasma glucose ≥ 11.1 mmol/l. Risk scores of isolated post-load hyperglycaemia were constructed by multivariate logistic regression. An independent group (n = 154) was enrolled from 2010 to 2011 to validate the models' performance. RESULTS: One hundred and twenty-three subjects (8.28%) were newly diagnosed as having diabetes mellitus. Among those with undiagnosed diabetes, 64 subjects (52%) had isolated post-load hyperglycaemia. Subjects with isolated post-load hyperglycaemia were older, more centrally obese and had higher blood pressure, HbA(1c), fasting plasma glucose, triglycerides, LDL cholesterol, high-sensitivity C-reactive protein and homeostasis model assessment of insulin resistance and lower homeostasis model assessment of ß-cell function than those without diabetes. The risk scores included age, gender, BMI, homeostasis model assessment, high-sensitivity C-reactive protein and HbA(1c). The full model had high sensitivity (84%) and specificity (87%) and area under the receiver operating characteristic curve (0.91), with a cut-off point of 23.81; validation in an independent data set showed 88% sensitivity, 77% specificity and an area under curve of 0.89. CONCLUSIONS: Over half of those with undiagnosed diabetes had isolated post-load hyperglycaemia. Homeostasis model assessment and high-sensitivity C-reactive protein are useful to identify subjects with isolated post-load hyperglycaemia, with improved performance over fasting plasma glucose or HbA(1c) alone.

A numerical investigation of the effect of vertex geometry on localized surface plasmon resonance of nanostructures.

Advances in nanofabrication and nano-scale measurement methods now allow for fabrication of highly detailed nanometer-scale topographic features. As geometric features greatly impact the formation of an electromagnetic field in response to incident light, this in turn calls for the study of the effects of new features of nanostructures on their performance in applications such as localized surface plasmon resonance (LSPR) sensing. This paper studies the effects of vertex features of a single nanostructure on its LSPR properties. A general relationship between the LSPR spectra and the vertex features of a nanoparticle is established. The results of electrodynamics calculations show that a delta-star with a relatively small vertex angle exhibits a bigger resonant wavelength than one with a large vertex angle. Moreover, the sensing performance initially increases, and then decreases as angular size of the vertices increases, with a turning point of 30 degrees. It is also shown that for nanostars with different numbers of vertices, the resonant wavelength undergoes a blue shift and the sensing performance grows poorer as the number of vertices increases. A regular vertex angle of 30 degrees displays the greatest figure of merit (FOM) value for LSPR applications, approximately 9.5 RIU(-1).

Effects of vertex truncation of polyhedral nanostructures on localized surface plasmon resonance.

Polyhedral nanostructures are widely used to enable localized surface plasmon resonance (LSPR). In practice, vertices of such structures are almost always truncated due to limitations of nanofabrication processes. This paper studies the effects of vertex truncation of polyhedral nanostructures on the characteristics of LSPR sensing. The optical properties and sensing performance of triangular nanoplates with truncated vertices are investigated using electrodynamics analysis and verified by experiment. The experimental results correlated with simulation analysis demonstrate that the fabricated triangular nanoplate array has a truncation ratio, defined as the length of truncation along an edge of the triangle over the edge length, of approximately 12.8%. This significantly influences optical properties of the nanostructures, resulting in poorer sensing performance. These insights can be used to guide the design and fabrication of nanostructures for high performance LSPR sensors.

Immediate effects of coloured overlays on the reading performance of preschool children with an autism spectrum disorder using eye tracking.

BACKGROUND: Coloured overlays have often been used to improve reading performance in preschool children with an autism spectrum disorder (ASD), however, previous evidence shows conflicts in its application. AIMS: To investigate the immediate effects of coloured overlays on reading performance using eye tracking in preschool children with ASD and their typical development (TD) counterparts closely matched by chronological age. METHODS: Forty participants with ASD (n = 20) or TD (n = 20) were recruited by convenience sampling and asked to read aloud numbers randomly arranged on paper. Participants' ocular performance (fixation duration, fixation count, total visit duration), reading speed and number of errors were recorded by eye tracker and digital stopwatch respectively throughout testing with and without coloured overlays. RESULTS: The findings show that coloured overlays had no significant immediate effect in improving ocular performance and reading speed of children with ASD or TD, although individual improvements were identified in some children with ASD. CONCLUSIONS: Use of coloured overlays may not be useful to improve reading and ocular performance in children with ASD in one single occasion. The potential effect on reading ability of using coloured overlays repetitively for a longer period needs further investigation.

Changes in cerebrovascular reactivity in healthy adults after acute exposure to high altitude.

OBJECTIVE: To study changes in the cerebrovascular reactivity (CVR) at different altitude area in healthy adults. SUBJECTS AND METHODS: CVR was tested using transcranial Doppler combined with CO2 inhalation, near-infrared spectroscopy (NIRS) was used to detect the regional cerebral oxygen saturation (rScO2). Blood samples were collected, and the vasoactive substances in serum were detected using the enzyme-linked immunosorbent assay. In this study, 59 healthy adults were divided into 3 groups: low altitude group, medium altitude group and high altitude group. All the indicators in low altitude group were tested at 24h before departure and after arrival from Beijing (at an altitude of 44.4 m) to Xining (at a medium altitude of 2200 m). Then, after resting for 48h, all the indicators were tested at 24h and 48h after arrival from Xining (at a medium altitude of 2200 m) to Yushu Jiegu town (at a high altitude of 3700 m) together with those at the medium altitude. Intergroup comparisons were made for the subjects in the three altitudes. RESULTS: There was an increase in the CVR in low altitude group after acute exposure to high altitude, and the difference was significant (CVR: 1.94re was vs. 0.91±0.53, p<0.001); the CVR index was increased, and the difference was significant [cerebrovascular reserve index (CVRI): 3.65he CVR vs. 1.37e CVR, p<0.001]; the rScO2 level was decreased with the increase of altitude, and the difference was significant [(66.78±4.61)% vs. (70.29±4.52)%, p<0.001]. The levels of vasoactive substances in low altitude group were decreased after acute exposure to high altitude compared with those before exposure: NO: [(79.14±9.54) µmol/L vs. (58.01±9.93) µmol/L, p<0.001]; serum eNOS level was increased, and the difference was significant [(77.23±6.20) pg/ml vs. (65.07±9.82) pg/ml, p<0.001]; EPO: [(84.68±13.16) pg/ml vs. (65.01±5.92) pg/ml, p<0.001]; VEGF: [(71.91±11.62) pg/ml vs. (54.92±11.86) pg/ml, p<0.001]; sFlt: [(384.18±42.73) pg/ml vs. (320.62±78.96) pg/ml, p<0.001]. There was also an increase in CVR in medium altitude group after acute exposure to high altitude, and the difference was significant [CVR: 2.00±0.79 vs. 0.91±0.66, p<0.001]; the difference of CVRI was significant [3.83±0.67 vs. 1.67±0.87, p<0.001]; rScO2 was slightly decreased with the increase of altitude, and the difference was not statistically significant [(67.53±4.61) % vs. (69.63±5.59) %, p<0.001]. Before exposure to high altitude area, the levels of NO, NOS, EPO, VEGF, and sFlt in low and medium altitude groups were higher than those in high altitude group. CVR level of subjects at different altitudes was negatively related to the ScO2 (r=-0.91) but positively related to NO and NOS levels (rs=0.89, r=0.75); CVR was moderately related to VEGF and EPO (rs=0.45, r=0.42). rScO2 was positively related to RBC, HB and VEGF levels (r=0.89, r=0.75, rs=0.86), but had a moderately negative correlation with NO and NOS levels (rs=-0.52, r=-0.57). CONCLUSIONS: After subjects at a low altitude are exposed to high altitude rapidly, CVR is increased, RBC and vasoactive substances in serum, such as NO, eNOS, and EPO, are dramatically increased, VEGF is increased first and then decreased, sFlt-1 level is increased gradually, and rScO2 level is gradually decreased with the increase of altitude, indicating the local brain anoxia of subjects at a high altitude.

[Application of Mohs microsurgery in nasal basal cell carcinoma].

Objective: To discuss the application of Mohs microsurgery in nasal and facial basal cell carcinoma (BCC) and analyze the pathological and clinical features. Methods: The clinical data of 127 patients who were diagnosed by pathology as nasal and facial BCC in Qilu Hospital of Shandong University from January 2010 to January 2015 were retrospectively analysed. The value of Mohs microsurgery was discussed and the nasal & facial sites of BCC lesions, clinical and histopathology features were summarized. Results: The proportion of male and female was 1.27︰1 in 127 patients, the ages ranged from 27 to 91 years. The top three inflicted area in nasal and facial was followed by nasal dorsum, nasal root and upper lip.The most frequent clinical type was nodular ulcerative type.The most common pathological type was nodular and pigmented. Routine surgical resection was performed in 62 cases (48.8%) while Mohs micrographic surgery in 38 cases (29.9%). Follow-up duration was 37 months on average. Local recurrence occurred in 5 cases in routine surgical resection group while there was no recurrence in Mohs micrographic surgery group. There was no distant metastasis in all cases. Conclusions: There are few specific clinical manifestation in nasal & facial BCC. Surgical treatment is prefered, especially by Mohs micrographic surgery, because it can strictly control the scope of surgical resection and obtain malformation repairment as well as beauty in nasal and facial region.

Requirement for phosphatidylinositol 3-kinase in epidermal growth factor-induced AP-1 transactivation and transformation in JB6 P+ cells.

Phosphatidylinositol 3-kinase (PI 3-kinase) plays a role in a variety of biological processes, including regulation of gene expression, cell growth, and differentiation. However, little is known about its role in the cytoplasmic events involved in epidermal growth factor (EGF)-induced transduction of signals to the transcriptional machinery of the nucleus and in EGF-induced cell transformation. In this study, we examined whether PI 3-kinase is a mediator for the activation of AP-1 and neoplastic transformation by EGF in the murine epidermal cell line JB6. The results showed the following. (i) EGF not only induced a high level of PI 3-kinase activity by itself but also enhanced insulin-induced PI 3-kinase activity in JB6 P+ cells, the EGF-induced PI-3 kinase activity could be blocked by constitutive overexpression of a dominant negative P85 subunit of PI 3-kinase (deltaP85), and insulin could markedly promote EGF-induced AP-1 activity in a dose-dependent manner in JB6 P+ cells as well as promote EGF-induced JB6 P+ cell transformation. (ii) Inhibition of PI-3 kinase with wortmannin or LY294002 markedly decreased the AP-1 activity induced by insulin, EGF, or EGF and insulin in a dose-dependent manner, while wortmannin did not block UVB-induced AP-1 activity. (iii) AP-1 activation by insulin, EGF, or EGF and insulin could be completely inhibited by overexpression of deltaP85 in all the dose and time courses studied. (iv) Inhibitors of PI 3-kinase (wortmannin and LY294002) and stable overexpression of deltaP85 inhibited EGF-induced transformation but had no significant inhibitory effect on cell proliferation induced by EGF or EGF and insulin. These results demonstrate for the first time that PI 3-kinase appears to be required for EGF- or insulin-induced AP-1 transactivation and cell transformation but not cell proliferation in JB6 cells.

The comparison of the rejuvenation effects on the skin of Wistar rats between 10600 nm CO2 fractional laser and retinoic acid.

OBJECTIVE: The fractional laser and topical retinoic acid treatment have been applied for skin rejuvenation; however, the possible molecular mechanism of promoting remodeling of dermis is not clearly. Here we aimed to compare the effects of 10600 nm CO2 fractional laser and topical retinoic acid formulation on the skin collagen proliferation of Wistar rats, and to further explore the possible molecular mechanism of promoting remodeling of dermis. MATERIALS AND METHODS: The hair on the back of Wistar rats was removed, and the back was divided equally into four regions with the cross-streaking method: A (the control group), B (the retinoic acid group), C (retinoic acid and fractional laser combination treatment group), and D (the fractional laser group). Specimens were collected at 3rd day and in 1-8 weeks after CO2 fractional laser irradiation; then they were used for detection of the changes of dermis thickness and content of hydroxyproline in the four regions of the rats' back. Real-time PCR method was used to detect the dynamic changes of the expression level of type III procollagen mRNA and the expression levels of miR-29a, Akt and transforming growth factor-ß (TGF-ß) mRNA at 3rd week in the skin tissue of Wistar rats. RESULTS: The thickness of dermis, content of hydroxyproline and expression level of type III procollagen mRNA in the treatment groups (B, C, and D) were found all significantly increased compared with those in the control group (A) (p<0.05); at 3rd week, up-regulation of Akt and TGF-ß mRNA expression and down-regulation of miR-29a mRNA expression were observed in the treatment groups (B, C, and D). The difference in the combination treatment group (C) was the most significant (p<0.05). CONCLUSIONS: These results demonstrate that retinoic acid formulation and CO2 fractional laser both can promote collagen proliferation and reconstruction, with the skin rejuvenation efficacy in group C > group D > group B. miR-29a/Akt/TGF-ß signal pathways may play a certain role in the promotion of collagen synthesis and proliferation.

Arsenic induces apoptosis through a c-Jun NH2-terminal kinase-dependent, p53-independent pathway.

Arsenic has been used as an effective chemotherapy agent for some human cancers, such as acute promyelocytic leukemia. In this study, we found that arsenic induces activation of c-Jun NH2-terminal kinases (JNKs) at a similar dose range for induction of apoptosis in JB6 cells. In addition, we found that arsenic did not induce p53-dependent transactivation. Similarly, there was no difference in apoptosis induction between cells with p53 +/+ or p53 -/-. In contrast, arsenic-induced apoptosis was almost totally blocked by expression of a dominant-negative mutant of JNK1. These results suggest that the activation of JNKs is involved in arsenic-induced apoptosis of JB6 cells. Taken together with previous findings that p53 mutations are involved in approximately 50% of all human cancers and nearly all chemotherapeutic agents kill cancer cells mainly by apoptotic induction, we suggest that arsenic may be a useful agent for the treatment of cancers with p53 mutation.

Inositol hexaphosphate inhibits cell transformation and activator protein 1 activation by targeting phosphatidylinositol-3' kinase.

Inositol hexaphosphate (InsP6) is the most abundant inositol phosphate found in plants. In mammalian cells, the concentrations of InsP6 are between 10 and 100 microM. Previous work has indicated that InsP6 is an effective cancer chemopreventive and chemotherapeutic agent. However, the molecular mechanisms involved in the inhibition of carcinogenesis by InsP6 remain unclear. In this study, we investigated the influence of InsP6 on tumor promoter-induced cell transformation and signal transduction pathways leading to activator protein 1 activation, which is considered to play a crucial role in tumor promotion. InsP6 markedly blocks epidermal growth factor-induced phosphatidylinositol-3 (PI-3) kinase activity in a dose-dependent manner in JB6 cells and directly in vitro. Blocking PI-3 kinase activity by InsP6 profoundly impairs epidermal growth factor- or phorbol ester-induced JB6 cell transformation and extracellular signal-regulated protein kinases activation, as well as activator protein 1 activation. These results provide the first evidence that the molecular mechanism of InsP6 antitumor promotion effect targets and blocks PI-3 kinase activation and demonstrate that PI-3 kinase can serve as a molecular target for the development of cancer chemopreventive agents.

Essential role of p53 in phenethyl isothiocyanate-induced apoptosis.

Phenethyl isothiocyanate (PEITC) is a natural product that is among the most effective cancer chemopreventive agents known. Mechanistic studies indicate that the chemopreventive activity of PEITC is associated with its favorable modification of carcinogen metabolism and its induction of apoptosis. Here, we found that PEITC blocks tumor promoter (12-O-tetradecanoylphorbol-13-acetate or epidermal growth factor)-induced cell transformation in mouse epidermal JB6 cells, and this inhibitory activity on cell transformation is correlated with induction of apoptosis. Most importantly, apoptosis induction by PEITC occurs through a p53-dependent pathway. This was demonstrated not only by results that PEITC induction of p53 protein expression and p53-dependent transactivation but also by PEITC-induced apoptosis in p53 +/+ cells but not in p53 -/- cells. In contrast, PEITC induced apoptosis in cells with both normal or deficient sphingomyelinase activity. Our results demonstrate for the first time that p53 elevation is required for PEITC-induced apoptosis, which may be involved in its cancer chemopreventive activity.

Inhibition of epidermal growth factor-induced cell transformation and activator protein 1 activation by [6]-gingerol.

Many spices, including plants of the ginger family, possess anticarcinogenic activity. However, the molecular mechanisms by which they exert their antitumorigenic effects are unknown. Activator protein 1 (AP-1) has a critical role in tumor promotion, and blocking of tumor promoter-induced activation of AP-1 inhibits neoplastic transformation. Epidermal growth factor induces cell transformation and AP-1 activity. The purpose of this study was to investigate the effect of two structurally related compounds of the ginger family, [6]-gingerol and [6]-paradol, on EGF-induced cell transformation and AP-1 activation. Our results provide the first evidence that both block EGF-induced cell transformation but act by different mechanisms.

Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase.

Resveratrol, a phytoalexin found in grapes, berries, and peanuts, is one of the most promising agents for cancer prevention. Our previous study showed that the antitumor activity of resveratrol occurs through p53-mediated apoptosis. In this study, we have elucidated the potential signaling components underlying resveratrol-induced p53 activation and induction of apoptosis. We found that in a mouse JB6 epidermal cell line, resveratrol activated extracellular-signal-regulated protein kinases (ERKs), c-Jun NH2-terminal kinases (JNKs), and p38 kinase and induced serine 15 phosphorylation of p53. Stable expression of a dominant negative mutant of ERK2 or p38 kinase or their respective inhibitor, PD98059 or SB202190, repressed the phosphorylation of p53 at serine 15. In contrast, overexpression of a dominant negative mutant of JNKI had no effect on the phosphorylation. Most importantly, ERKs and p38 kinase formed a complex with p53 after treatment with resveratrol. Strikingly, resveratrol-activated ERKs and p38 kinase, but not JNKs, phosphorylated p53 at serine 15 in vitro. Furthermore, pretreatment of the cells with PD98059 or SB202190 or stable expression of a dominant negative mutant of ERK2 or p38 kinase impaired resveratrol-induced p53-dependent transcriptional activity and apoptosis, whereas constitutively active MEK1 increased the transcriptional activity of p53. These data strongly suggest that both ERKs and p38 kinase mediate resveratrol-induced activation of p53 and apoptosis through phosphorylation of p53 at serine 15.

Two novel glycosides from the fruits of Morinda citrifolia (noni) inhibit AP-1 transactivation and cell transformation in the mouse epidermal JB6 cell line.

The fruit juice of Morinda citrifolia (noni), a plant originally grown in the Hawaiian and Tahitian islands, has long been used by islanders to treat diseases, including cancer. Two novel glycosides, 6-O-(beta-D-glucopyranosyl)-1-O-octanoyl-beta-D-glucopyranose and asperulosidic acid, extracted from the juice of noni fruits, were used to examine their effects on 12-O-tedtradecanoylphorbol-13-acetate (TPA)- and epidermal growth factor (EGF)-induced AP-1 transactivation and cell transformation in mouse epidermal JB6 cells. The results indicated that both compounds were effective in suppressing TPA- or EGF-induced cell transformation and associated AP-1 activity. TPA- or EGF-induced phosphorylation of c-Jun, but not extracellular signal-regulated kinases or p38 kinases, was also blocked by the compounds, indicating that c-Jun N-terminal kinases were critical in mediating TPA- or EGF-induced AP-1 activity and subsequent cell transformation in JB6 cells.

Organ-specific activation of activator protein-1 in transgenic mice by 12-o-tetradecanoylphorbol-13-acetate with different administration methods.

12-O-Tetradecanoylphorbol-13-acetate (TPA) is widely used as a tumor promoter with organotropy in skin and esophagus. TPA-induced, organ-specific tumor promotion is not correlated with the distribution of its receptor, protein kinase C (PKC). Using five administration methods (painting, drinking, gavage feeding, i.p. injection, and i.v. injection), we analyzed TPA-stimulated activator protein-1 (AP-1) activity in various organs (liver, kidney, brain, lung, spleen, heart, stomach, colon, esophagus, and skin) from transgenic mice expressing the AP-1 luciferase reporter gene. Topical application of TPA by painting the skin on the back of mice raised AP-1 activity 122.6-fold, and the highest peak of AP-1 activity was at 12 h after administration of TPA. Drinking water containing TPA caused a 25.8-fold induction of AP-1 activity in the skin, whereas gavage feeding with TPA caused a 34.2-fold induction of AP-1 in the skin. Intraperitoneal or i.v. injection of TPA induced a 49.56-fold or 20.4-fold increase in AP-1 activity in the skin, respectively. The highest peaks of AP-1 activity in the skin were at 12 h after drinking, feeding, or injection of TPA. More interesting, in the esophagus, i.p. injection of TPA raised AP-1 activity 13.9-fold, drinking TPA raised AP-1 activity 8.4-fold, and painting with TPA caused a 2.4-fold induction of AP-1 activity. In the colon, i.p. injection of TPA raised AP-1 activity 3.9-fold, drinking TPA induced a 1.2-fold increase in AP-1 activity, but painting with TPA had no effect. AP-1 activity in other organs was not detectable after administration of TPA by painting, drinking, or injection. Phosphorylation of extracellular signal-regulated kinases in the skin increased at 12 h after painting, drinking, or i.p. injection of TPA. In addition, phosphorylation of p38 kinase was raised slightly after TPA administration, but phosphorylation of c-Jun NH(2)-terminal kinases was not detected at any time point after TPA administration. Similar changes in MAP kinases were also seen in the esophagus after TPA administration. These results indicate that the skin is the most sensitive organ to TPA induction of AP-1 activity. The data suggest that the organ-specific, tumor-promoting effect of TPA may be through AP-1 activation and phosphorylation of ERKs and p38 kinase.