Room-temperature CO Thermoelectric Gas Sensor based on Au/Co3O4 Catalyst Tablet.

A carbon monoxide (CO) thermoelectric (TE) gas sensor was fabricated by affixing a Au/Co3O4 catalyst tablet on a TE film layer. The Au/Co3O4 catalyst tablet was prepared by a co-precipitation and tablet compression method and its possible catalytic mechanism was discussed by means of x-ray diffraction, field emission scanning electron microscopy, high resolution transmission electron microscopy, x-ray photoelectron spectroscopy, temperature-programmed reduction of hydrogen, Fourier transform infrared spectroscopy and Brunauer-Emmett-Teller analysis. The optimal catalyst, with a Au content of 10 wt%, was obtained at a calcination temperature between 200 and 300 °C. The small size of the Au nanoparticles, high specific surface, the existence of Co3+ and water-derived species contributed to  high catalytic activity. Based on the optimal Au/Co3O4 catalyst tablet, the CO TE gas sensor worked at room temperature and showed a response voltage signal (ΔV) of 23 mV, high selectivity among hydrogen and methane, high stability, and a fast response time of 106 s for 30 000 ppm CO/air. In addition, a CO concentration in the range of 5000-30 000 ppm could obviously be detected and exhibited a linear relationship with ΔV. The CO TE gas sensor provides a promising option for the detection of CO gas at room temperature.

High-Temperature Syngas Desulfurization and Particulate Filtration by ZnO/Ceramic Filters.

Combustible gas (e.g., gasification syngas) cleaning at high temperatures can obtain further gains in energy efficiency for power generation and importantly leads to a simplified process and lower cost as a commercially viable source of clean energy. Thus, a feasibility study for high-temperature desulfurization (HTDS) and additional high-temperature particulate filtration (HTPF) of a raw syngas using ZnO sorbent-dispersed Raney CuO (ZnO/R-CuO) and ceramic filter (ZnO/CF) has been carried out. By synchrotron X-ray absorption near-edge structure (XANES) spectroscopy, mainly Zn(II) and Cu(II) are found in the ZnO/R-CuO sorbents. Both ZnO and R-CuO in the sorbents are involved in HTDS (1% H2S) at 873 K to form ZnS, Cu2S, and a small amount of CuS and reach relatively high HTDS efficiencies (82-90%). In addition, regeneration of the sulfurized sorbent by oxidation with O2 at 873 K (HTRG) for 1 h can restore ZnO and CuO for continuous and repetitive HTDS-HTRG cycles. To facilitate the HTDS engineering applications by the ZnO/R-CuO sorbents, their reaction rate constant (8.35 × 104 cm3/g/min) and activation energy (114.8 kJ/mol) at 873 K have also been determined. Furthermore, the ZnO/CF sorbent/filter can perform HTDS and additional HTPF at 873 K with very high particulate removal efficiencies (>98%). This demonstrates the feasibility for hot-syngas cleaning with a much better energy efficiency and lesser cost for cleaner power generation.

Cytotoxicity of arsenic trioxide is enhanced by (-)-epigallocatechin-3-gallate via suppression of ferritin in cancer cells.

Arsenic trioxide (ATO) treatment is a useful therapy against human acute promyelocytic leukemia (APL), however, it concomitantly brings potential adverse consequences including serious side effect, human carcinogenicity and possible development of resistance. This investigation revealed that those problems might be relaxed by simultaneous application with (-)-epigallocatechin-3-gallate (EGCG), one of the major components from green tea. EGCG significantly lowered down the ATO concentration required for an effective control of APL cells, HL-60. The simultaneous treatment of ATO with EGCG induced a mitochondria-dependent apoptosis in HL-60 cells significantly, which accounted for more than 70% of the cell death in the treatment. The mechanism of apoptosis induction was elucidated. EGCG in HL-60 cells acted as a pro-oxidant enhancing intracellular hydrogen peroxide significantly. ATO, on the other hand, induced heme oxygenase-1 (HO-1) to catalyze heme degradation, thereby provided ferrous iron for EGCG-induced hydrogen peroxide to precede Fenton reaction, which in turn generated deleterious reactive oxygen species to damage cell. In addition, EGCG inhibited expression of ferritin, which supposedly to sequester harmful ferrous iron, thereby augmented the occurrence of Fenton reaction. This investigation also provided evidence that ATO, since mainly acted to induce HO-1 in simultaneous treatment with EGCG, could be replaced by other HO-1 inducer with much less human toxicity. Furthermore, several of our preliminary investigations revealed that the enhanced cytotoxicity induced by combining heme degradation and Fenton reaction is selectively toxic to malignant but not non-malignant cells.

Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy.

Helicobacter pylori is causally associated with gastritis and gastric cancer. Some developing countries with a high prevalence of infection have high gastric cancer rates, whereas in others, these rates are low. The progression of helicobacter-induced gastritis and gastric atrophy mediated by type 1 T-helper cells may be modulated by concurrent parasitic infection. Here, in mice with concurrent helminth infection, helicobacter-associated gastric atrophy was reduced considerably despite chronic inflammation and high helicobacter colonization. This correlated with a substantial reduction in mRNA for cytokines and chemokines associated with a gastric inflammatory response of type 1 T-helper cells. Thus, concurrent enteric helminth infection can attenuate gastric atrophy, a premalignant lesion.

Embolization of a ruptured lenticulostriate artery aneurysm.

Aneurysms arising from the lenticulostriate artery (LSA) are rare. So far, only 23 cases have been reported in the literature (Ahn et al. 2007 [1], Gandhi et al. 2008 [2], Harreld et al. 2010 [3]). Early detection and treatment of these aneurysms is difficult because of their small size, deep location and complex surrounding vasculature. The majority of reported cases were treated surgically, and only two were treated with endovascular embolization (Harreld et al. 2010 [3], Larrazabal et al. 2001 [4]). We present here a case of an LSA aneurysm that was successfully embolized with n-butyl cyanoacrylate (n-BCA) with no recurrence after 1 year of follow-up.

Pulmonary toxicity in mice exposed to low and medium doses of water-soluble multi-walled carbon nanotubes.

Carbon nanotubes (CNTs) are a class of new allotrope of carbon. Different functionalized CNTs may vary from their physical and chemical properties to the biological property. In this study, the toxicity of water-soluble taurine multi-walled CNTs (tau-MWNTs), raw MWNTs and positive control crystalline silicon dioxide particles on mouse lungs via intratracheal instillation (i.t.) was investigated. The dosages we used were 0.125, 0.25, 0.5 or 1 mg/kg of tau-MWNTs and raw MWNTs, and 1 mg/kg of silicon dioxide particles; Serum and lungs were collected at 1, 7, 14 or 28 days postexposure. The biochemical and cellular parameters were assessed, which include the ratio of the lung weight and body weight (lung indices), lactate dehydrogenase (LDH), alkaline phosphatase (ALP) and angiotensin converting enzyme (ACE) in serum, and malondialdehyde (MDA), reduced glutathione (GSH), total sulfhydryl group (TSH) in lung tissue homogenates as well as the hydroxyproline in lungs. The characteristic recovery of the lung injury at 28 days postexposure was examined by the assessment of LDH, ALP, lung indices, and histopathology. ACE, MDA, GSH, TSH and histopathological changes showed that tau-MWNTs were less toxic than the raw MWNTs. Histopathological and ultrastructural investigation indicated that the acute pulmonary inflammation in lungs alleviated after 7d postexposure, and were greatly recovered within 28d. Meanwhile, the entrapment of tau-MWNTs reduced greatly by the 28d postexposure. Whereas the heavier pathologic changes induced by raw MWNTs lasted 7 days more than that of tau-MWNTs. Notably, no occurrence of granulomas and fibrosis were found in this study both in the two CNTs samples through 28d postexposure. Silicon dioxide particles, on the contrary, produced more severe damage to lungs than CNTs did in lung index, as well as other biochemical and cellular parameters. These findings indicate that water-soluble tau-MWNTs in low and medium doses induce slight and recoverable pulmonary inflammation in mice, and are less toxic than the insoluble raw MWNTs.

Multiple factors conferring high radioresistance in insect Sf9 cells.

Sf9, a lepidopteran cell line isolated from the fall armyworm, Spodoptera frugiperda, was shown to be significantly more resistant to growth inhibition and apoptosis induction effects of x-ray irradiation than several human cell lines of different origins. The single-cell electrophoresis technique revealed that Sf9 cells showed lower x-ray irradiation-induced DNA damage as well as better efficiency at repairing these damages. In addition, Sf9 cells were lower in both background and x-ray irradiation-induced intracellular oxidative stress, in which the higher intracellular level of reduced glutathione seemed to play a major role. The significance of oxidative stress in determining the radioresistance of Sf9 cells was confirmed by their being more resistant to hydrogen peroxide while equally susceptible to other non-reactive oxygen species of N-nitroso alkylating agents when compared with a human cell line. Although the Sf9 and human cell lines were equally susceptible to the lethal effects of N-nitroso alkylating agents, the components of DNA damage-induced and the repair enzymes involved significantly differ. This phenomenon is also discussed in this report.

First Report of Soybean Pod and Stem Blight Caused by Diaporthe phaseolorum var. sojae in Taiwan.

Genera, Diaporthe and Phomopsis, from an important pathogenic complex of soybean (Glycine max) throughout the world, cause reductions in plant stands, yield, and seed health and quality (1). In a study of the Diaporthe/Phomopsis complex in Taiwan in March 2008, four stem samples with black fruiting structures in linear rows on senescent soybean were collected from the research fields at AVRDC, Shanhua, Tainan, Taiwan. Unidentified fungal isolates were obtained by surface disinfection of infected stems and plating excised tissues on potato dextrose agar (PDA). Colonies of the isolates showed ropelike white mycelia with yellowish tonalities. Small and scattered black stromata were observed frequently in the medium. Mutic pycnidia were found solitarily or aggregated in conidiomata on PDA plates after 10 days of incubation at 24°C with a 12-h photoperiod with near-UV light. All isolates produced α-conidia that measured 8.78 × 3.32 (7.00 to11.00 × 3.00 to 4.00) µm, and sporadically, ß-conidia of 30.58 × 0.85 (26.00 to 33.00 × 0.60 to 1.20) µm. Perithecia were not observed in the collected stem samples or the fungal cultures on PDA. Restriction fragment length polymorphism patterns of the PCR products amplified by ITS4 and ITS5 primers for all isolates were identical to the patterns reported for Diaporthe phaseolorum var. sojae (3). Thus, all isolates were identified as D. phaseolorum var. sojae on the basis of morphologic and genetic characteristics (2,3). Pathogenicity was confirmed through inoculations during the V2 growth stage of soybean seedlings by atomizing conidial suspensions (1 × 107 α-conidia/ml) of each isolate on soybean seedlings as well as by injecting the inoculum into soybean stems separately. Four plants in each of three replications were inoculated for each method and six noninoculated plants served as controls. Plants were incubated in a growth chamber at 25°C and maintaining relative humidity at 100% by a humidifier for 48 h in darkness; thereafter, plants were maintained in the greenhouse at temperatures ranging from 23 to 34°C. Seven days after inoculation, red-brown leaf spots and coalescent lesions were observed on seedlings atomized by inoculum suspensions, as well as brown lesions and black pycnida in linear rows observed on plants inoculated by stem injection. No symptoms were observed on noninoculated plants. The fungal isolates obtained from inoculated soybeans were morphologically identical to those used as inoculum. The pathogenicity test was repeated twice. To our knowledge, this is the first explicit report identifying the causal agent of soybean pod and stem blight in Taiwan. The vouchers of infected specimens are available at AVRDC-The World Vegetable Center. Reference: (1) R. P. Mulrooney. Plant Dis. 70:600, 1988. (2) R. N. Pioli et al. Phytopathology 93:136, 2003. (3) A. W. Zhang et al. Phytopathology 88:1306, 1998.

First Report of the A2 Mating Type of Phytophthora capsici Infecting Peppers (Capsicum annuum) in Taiwan.

Phytophthora capsici Leonion was first identified on pepper (Capsicum annuum L) in Taiwan in 1976. At that time, only the A1 mating type was present (2). In 2007, the A2 mating type of P. capsici was identified on tomato and eggplant in the central part of the country (1). During an excessively rainy period in mid-2008, many chili and sweet pepper fields in Taiwan suffered severe losses due to P. capsici. Symptoms included a foliar blight and stem, root, and fruit rot. Plants eventually wilted and died. Symptomatic plants were collected from chili- and sweet pepper-production areas in central, southern, and eastern Taiwan. Fifty-three isolates from single zoospores were identified by PCR using species-specific primers CAPFW/CAPRV2 (4). Mating type was determined by co-inoculating rape seed agar plates (3) with mycelial plugs of the tester and a known isolate. Pc134, maintained by the mycology unit at The World Vegetable Center, and 27220, provided by P. J. Ann at the Taiwan Agricultural Research Institute, were used as reference isolates of A1 and A2 mating types, respectively. Plates were examined microscopically for oospores after 5 to 7 days of incubation at 24°C in the dark. Of the 53 isolates, 15 were identified as the A2 mating type and the remaining 38 isolates were identified as A1. The A2 mating type was found in the central and southern regions while the A1 mating type was widely distributed across all three regions. The sporangia of the A2 mating type were 60.4 to 73.4 × 40.9 to 51.8 µm (average 69.2 × 44.7 µm), whereas sporangia of the A1 mating type were 50.1 to 73.9 × 37.9 to 48.1 µm (average 61.4 × 44.1 µm). In general, the A2 mating type produced longer sporangia and only a few isolates produced chlamydospores in V8 broth and on agar. To our knowledge, this is the first report of the A2 mating type of P. capsici infecting peppers in Taiwan. The presence of both mating types in the same field has been observed. References: (1) P. J. Ann et al. Plant Pathol. Bull. 17:69, 2008. (2) L. S. Leu and C. W. Kao. Plant Prot. Bull. (Taiwan) 23:59, 1981. (3) M. M. Sautor. Mycologia 59:161, 1967. (4) C. Silvar et al. Eur. J. Plant Pathol. 112:43, 2005.

Role of bone marrow-derived cells in experimental chronic pancreatitis.

BACKGROUND: Chronic pancreatitis is a known risk factor for pancreatic adenocarcinoma. Recent work has pointed to a role for bone marrow-derived progenitor cells (BMDCs) in chronic inflammation-based carcinogenesis. Consequently, the role of BMDCs in chronic pancreatitis was investigated. METHODS: The fate of BMDCs was followed using green fluorescent protein and the Y chromosome as bone marrow markers in gender-mismatched transplanted mice treated with repeated injections of cerulein for up to 45 weeks. The phenotype of engrafted BMDCs was assessed based on the co-expression of bone marrow and pancreatic markers. RESULTS: After 45 weeks of cerulein treatment, mice developed severe chronic pancreatitis but no preneoplastic lesions. BMDCs did engraft in the pancreas. Most of the BMDCs were desmin positive and contributed to 5.12% (1.12%) (mean (SEM)) of the pancreatic stellate cell population. Pancreatic stellate cells derived from the bone marrow could be activated, as demonstrated by alpha-smooth muscle actin expression, suggesting a role in tissue repair. BMDCs could also be found in pancreatic ducts, based on dolichos biflorus agglutinin and cytokeratin 19 stainings, but at a much lower frequency (0.62% (0.11%)). CONCLUSION: BMDCs contribute to the pancreatic stellate cell population, suggesting a role in pancreatic tissue repair. In the absence of preneoplastic lesions, BMDCs contribute at a very low level to the ductal epithelium of the chronically inflamed pancreas. The role of BMDCs in pancreatic carcinogenesis remains to be defined.

Optically modulated internal strain in InGaN quantum dots grown on SiN(x) nano masks.

Optically modulated internal strain has been observed in InGaN quantum dots (QDs) deposited on SiN(x) nano masks. The modulated internal strain can induce a number of intriguing effects, including the change of refractive index and the redshift of InGaN A(1)(LO) phonon. The underlying mechanism can be well accounted for in terms of the variation of internal strain through the converse piezoelectric effect arising from the screening of the internal electric field due to spatial separation of photoexcited electrons and holes. Our results point out a convenient way for the fine tuning of physical properties in nitride-based semiconductor nanostructures, which is very important for high quality optoelectronic devices.

Hypergastrinemia increases gastric epithelial susceptibility to apoptosis.

Plasma concentrations of the hormone gastrin are elevated by Helicobacter pylori infection and by gastric atrophy. It has previously been proposed that gastrin acts as a cofactor during gastric carcinogenesis and hypergastrinemic transgenic INS-GAS mice are prone to developing gastric adenocarcinoma, particularly following H. pylori infection. We hypothesised that the increased risk of carcinogenesis in these animals may partly result from altered susceptibility of gastric epithelial cells to undergo apoptosis. Gastric corpus apoptosis was significantly increased 48 h after 12Gy gamma-radiation in mice rendered hypergastrinemic by transgenic (INS-GAS) or pharmacological (omeprazole treatment of FVB/N mice) methods and in both cases the effects were inhibited by the CCK-2 receptor antagonist YM022. However, no alteration in susceptibility to gamma-radiation-induced gastric epithelial apoptosis was observed in mice overexpressing progastrin or glycine-extended gastrin. Apoptosis was also significantly increased in gastric corpus biopsies obtained from H. pylori-infected humans with moderate degrees of hypergastrinemia. We conclude that hypergastrinemia specifically renders cells within the gastric corpus epithelium more susceptible to induction of apoptosis by radiation or H. pylori. Altered susceptibility to apoptosis may therefore be one factor predisposing to gastric carcinogenesis in INS-GAS mice and similar mechanisms may also be involved in humans.

Genotoxicity of low dose N-nitroso propoxur to human gastric cells.

Propoxur is among the most popular insect control agents in subtropical countries such as Taiwan. As a member of the N-methylcarbamate insecticide group, propoxur is notorious for its potential for conversion into highly genotoxic N-nitroso derivatives. Due to the fact that the stomach has been identified as the major target for N-nitroso N-methylcarbamates, this investigation used a human gastric cell line, SC-M1, in order to obtain results pertinent to the authentic adverse effects of this compound on human health. This report reveals that at dose levels inhibiting < or = 10% cell growth, a 2-h pulsed treatment of N-nitroso propoxur induced significant amounts of DNA damage. Most of the damaged DNA was repaired within 24 h after treatment removal, such that an outcome with a significant induction of chromosomal aberrations was not observed. Gene mutations and anchorage independence, on the other hand, were significantly induced by this same treatment. In conclusion, exposure to low doses of N-nitroso propoxur is not cytotoxic nor clastogenic, nevertheless, has the potential to increase genetic instability and, possibly as a result, to enhance the malignant potential of treated cells. We suggest that although the damaged DNA was repaired during the transient G2/M arrest period, it was probably not done in an appropriate way which would preserve the original genetic stability.

First Report of the A2 Mating Type of Phytophthora infestans on Tomato Crops in Taiwan, Republic of China.

In a study of the Phytophthora infestans population in Taiwan, samples with symptoms typical of late blight were collected from field crops in an important potato- (Solanum tuberosum) and tomato-(Lycopersicon esculentum) production area in the central highlands region. Isolates were obtained by surface disinfecting leaf sections and plating them onto antibiotic-amended rye A agar (1). After subculturing, the pathogen was confirmed as P. infestans on the basis of morphological characters (2). Mating type was determined by co-inoculating unamended rye agar plates with mycelial plugs of the test isolate and a reference P. infestans isolate of either the A1 or A2 mating type (four plates per test isolate, two with different A1, and two with different A2 reference isolates). After incubation (15°C darkness, 7 to 14 days), plates were examined microscopically for the presence of oospores where the colonies interacted. In 2004, one isolate of 200 tested, and in 2006, one isolate of 102 tested, produced oospores only with A1 reference isolates and were concluded to be A2 mating type. In vitro testing showed the two A2 isolates were metalaxyl-resistant (ED50 values >100 mg of metalaxyl per liter on rye grain agar), which is typical of recent P. infestans isolates from potato and tomato in this area (2). Twenty-one single-sporangial isolates from each of the two A2 strains were tested for mating type against two different A1 isolates of P. infestans and confirmed as A2. These isolates were characterized using the techniques described by Deahl et al. (1) and had the allozyme genotype 100/100/111, 100/100 at the loci coding for glucose-6-phosphate isomerase and peptidase, respectively, and were mitochondrial haplotype IIb. This multi-locus genotype is characteristic of recent P. infestans isolates from tomato and potato in Taiwan, but all previous such isolates were A1 mating type and attributed to the US-11 clonal lineage (1). When evaluated on differential hosts, both A2 isolates were tomato race PH-1 and complex potato race R 0,1,2,3,4,7,9,11. RG57 fingerprinting showed that the A2 isolates had fingerprints identical to each other and to A1 P. infestans isolates of the US-11 clonal lineage from tomato in Taiwan (101 011 100 100 110 101 011 001 1). Koch's postulates were completed and the two A2 isolates were found to be highly aggressive on cultivars of potato and tomato. To our knowledge, this is the first report of A2 mating type strains of P. infestans in the field in Taiwan, but currently, their incidence is very low (<1%). One crop from which an A2 isolate was obtained also yielded an A1 isolate, while A1 isolates were obtained from crops in the vicinity of the other. The concurrent presence of the two mating types of P. infestans poses a risk of sexual reproduction and oospore formation in tomato or potato in Taiwan. References: (1) K. L. Deahl et al. Pest Manag. Sci. 58:951, 2002. (2). D. C. Erwin and O. K. Ribeiro, Page 346 in: Phytophthora Diseases Worldwide. The American Phytopathological Society. St. Paul, MN, 1996.

The gastrin gene promoter is regulated by p73 isoforms in tumor cells.

p73, a new p53 family member, is a transcription factor that is increasingly recognized in cancer research as an important player in tumorigenesis as well as in chemotherapeutic drug sensitivity. Despite the substantial structural and functional similarities to p53, accumulating evidence suggests that p53 and p73 may differently regulate their transcriptional targets. In this study, we have investigated the role of p73 in regulation of the gastrin gene promoter. Gastrin is a peptide hormone and an important factor in determining the progression of a number of human malignancies. Our results show that p73 can bind to the gastrin promoter. This leads to transcriptional upregulation of gastrin mRNA. We also found that the levels of gastrin and p73 transcripts correlate in primary gastric tumors. Taken together, our results demonstrate a novel mechanism for regulation of gastrin gene transcription and support a concept that p53 and p73 may have different biological roles in tumors.

Gastrin is a target of the beta-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis.

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene occur in most colorectal cancers and lead to activation of beta-catenin. Whereas several downstream targets of beta-catenin have been identified (c-myc, cyclin D1, PPARdelta), the precise functional significance of many of these targets has not been examined directly using genetic approaches. Previous studies have shown that the gene encoding the hormone gastrin is activated during colon cancer progression and the less-processed forms of gastrin are important colonic trophic factors. We show here that the gastrin gene is a downstream target of the beta-catenin/TCF-4 signaling pathway and that cotransfection of a constitutively active beta-catenin expression construct causes a threefold increase in gastrin promoter activity. APC(min-/+) mice overexpressing one of the alternatively processed forms of gastrin, glycine-extended gastrin, show a significant increase in polyp number. Gastrin-deficient APC(min-/+) mice, conversely, showed a marked decrease in polyp number and a significantly decreased polyp proliferation rate. Activation of gastrin by beta-catenin may therefore represent an early event in colorectal tumorigenesis and may contribute significantly toward neoplastic progression. The identification of gastrin as a functionally relevant downstream target of the beta-catenin signaling pathway provides a new target for therapeutic modalities in the treatment of colorectal cancer.

Transgenic expression of tpr-met oncogene leads to development of mammary hyperplasia and tumors.

Receptor tyrosine kinases are important in cell signal transduction and proliferation. Abnormal expression of tyrosine kinases often leads to malignant transformation. C-met is a tyrosine kinase receptor and its ligand is hepatocyte growth factor (HGF). HGF/c-met plays diverse role in regulation of cell growth, shape and movement. Constitutively activated met, such as tpr-met, is a potent oncogene in vitro, but its carcinogenic role in vivo remains unclear. Our study demonstrates that expression of tpr-met leads to development of mammary tumors and other malignancies in transgenic mice, and suggests that deregulated met expression may be involved in mammary carcinogenesis.

The trefoil gene family are coordinately expressed immediate-early genes: EGF receptor- and MAP kinase-dependent interregulation.

The trefoil gene family of mucus cell-secreted proteins is a critical mediator of gastrointestinal mucosal restitution. Transcription of trefoil genes is induced during mucosal repair, but the regulatory mechanisms involved are unknown. Mice deficient in the intestine-specific peptide intestinal trefoil factor (ITF), in which colonic restitution is lethally impaired, showed reduced expression of the gastric trefoil genes SP and pS2, suggesting that trefoil peptides may individually regulate transcription of the entire family. In gastric cell lines, the trefoils were shown to act in a manner suggestive of immediate-early genes capable of auto- and cross-induction through cis-acting regulatory regions. Trefoil-mediated transcriptional regulation required activation of the Ras/MEK/MAP kinase signal transduction pathway. EGF receptor (EGF-R) activation was also necessary for trefoil auto- and cross-induction, and both spasmolytic polypeptide (SP) and ITF stimulation of gastric cell lines led to phosphorylation of EGF-R. Nevertheless, ITF and ITF-thioredoxin cell surface binding at 4 degrees C colocalized not with EGF-R, but with CD71, which is found in clathrin-coated pits, suggesting that integration of trefoil peptide responses may occur after internalization. As EGF-R expression is itself strongly induced after mucosal damage, the trefoil/EGF-R relationship may be pivotal in the generation and maintenance of the mucosal repair phenotype.

Processing and proliferative effects of human progastrin in transgenic mice.

Incompletely processed gastrins have been postulated to play a role in growth of the gastrointestinal tract, but few studies have examined the effects of progastrin on mucosal proliferation in vivo. Human gastrin gene expression and progastrin processing were therefore studied in transgenic mice containing a human gastrin (hGAS) minigene, and compared to processing in mice bearing an insulin gastrin (INS-GAS) transgene that overexpresses amidated gastrin. Progastrin processing was studied using region-specific antisera and radioimmunoassays, biosynthetic labeling, immunoprecipitation, and HPLC. Proliferative effects due to overexpression of processed and unprocessed gastrin in INS-GAS and hGAS mice, respectively, were determined using routine histology and BrdU incorporation. The pancreatic islets of INS-GAS mice were able to produce carboxyamidated G-17, resulting in a twofold elevation of serum amidated gastrin, marked thickening of the oxyntic mucosa, and an increased BrdU labeling index (LI) of the gastric body. In contrast, livers of adult hGAS mice expressed abundant human gastrin mRNA and human progastrin but were unable to process this peptide to the mature amidated form, resulting in markedly elevated serum progastrin levels and normal amidated gastrin levels. Nevertheless, there was a marked increase in the BrdU labeling index of the colon in hGAS mice (LI 7.46+/-1.90%), as well as in INS-GAS mice (LI 6.16+/-1.17%), compared to age-matched, wild type control mice (LI 4.01+/-0.98%, P < 0.05). These studies suggest that incompletely processed gastrin precursors may contribute to colonic mucosal proliferation in vivo.

Pancreatic gastrin stimulates islet differentiation of transforming growth factor alpha-induced ductular precursor cells.

Gastrin is transiently expressed in fetal islets during a critical period of their development from protodifferentiated islet precursors in fetal pancreatic ducts. To examine the possible role of gastrin as an islet cell growth factor, postnatal islet growth was studied in transgenic mice which overexpress gastrin and TGF alpha in their pancreas. Overexpression of a TGF alpha transgene causes metaplastic ductules containing numerous insulin expressing cells that resemble protodifferentiated precursors of the fetal pancreas. However, islet mass of the TGF alpha transgenic mice was not increased. Pancreatic overexpression of gastrin from a chimeric insulin/gastrin transgene transcribed from the insulin promoter markedly decreased the TGF alpha-stimulated increase in pancreatic duct mass. Furthermore, pancreatic coexpression of both gastrin and TGF alpha significantly increased islet mass in mice expressing both transgenes. These findings indicate that TGF alpha and gastrin can act synergistically to stimulate islet growth, although neither peptide alone is sufficient. Islet growth may possibly be stimulated through gastrin promoting the differentiation of insulin-positive cells in the TGF alpha-induced metaplastic ducts. This transgenic study suggests that islet neogenesis can be reactivated in the ductular epithelium of the adult pancreas by local expression of two growth factors, gastrin and TGF alpha.