Multicenter Prospective Observational Study to Evaluate the Therapeutic Effect and Safety of a Combination of Montelukast and Levocetirizine for Allergic Rhinitis when Administered to Patients with Allergic Rhinitis and Asthma.

INTRODUCTION: Allergic rhinitis and asthma share a common inflammatory mechanism and are closely related, recognized as "one airway disease." Thus, the guidelines recommend allergic rhinitis and asthma be treated together, and leukotriene antagonists and antihistamines have been administered simultaneously; however, there are few reports of the use of combination drugs so far. METHODS: The aim of the study was to evaluate the treatment effects and adverse events of Monterizine® (a combination of montelukast and levocetirizine); a total of 2,254 patients with perennial allergic rhinitis and asthma were prospectively enrolled from 60 hospitals nationwide in Korea. They were followed up for 3 (Period 1) or 6 months (Period 2). Total nasal symptom score (TNSS), satisfaction, and safety data were collected and compared to baseline. RESULTS: TNSS scores were analyzed for 2,254 subjects. At Period 1 (n = 2,024) and 2 (n = 1,861), the scores decreased significantly from baseline (-1.20 ± 2.49 and -1.63 ± 2.78, p < 0.001). The mean quality of life (QoL) was significantly improved at Period 1 and 2 relative to baseline (-3.75 ± 6.58, -4.83 ± 7.11, both p < 0.0001). There were no serious adverse drug reactions, but there were some minor reactions including nasopharyngitis (2.92%), rhinitis (0.37%), and somnolence (0.34%). CONCLUSIONS: TNSS score and QoL were significantly improved by 3-6 months' treatment with Monterizine without significant adverse reactions. These results indicate that Monterizine, as a combination drug, is effective and safe for improving nasal symptoms and quality of life in patients with allergic rhinitis who also have asthma.

Association between diabetes mellitus and anemia among Korean adults according to sex: a cross-sectional analysis of data from the Korea National Health and Nutrition Examination Survey (2010-2016).

BACKGROUND: There are many conflicting opinions regarding the association between anemia and diabetes mellitus (DM), and the mechanism by which DM influences anemia remains uncertain. Therefore, we aimed to investigate the association between anemia and DM in Korean adults and to analyze the risk factors for anemia among these patients according to sex. METHODS: This retrospective cross-sectional survey was conducted using data from the Korea National Health and Nutrition Examination Survey V, VI, and VII between January 2010 and December 2016. In total, 25,597 Korean adults aged ≥19 years (10,117 men, 15,480 women) were included. Patients with a fasting blood sugar level of ≥126 mg/dL or who have been diagnosed with DM were classified as the DM group. Anemia was defined as hemoglobin levels of < 13 g/dL in men and < 12 g/dL in women. Logistic regression analysis was used to adjust for demographic characteristics and lifestyle-, disease-, and health-related factors. RESULTS: Approximately 11.3% of patients had DM. The prevalence of anemia was significantly higher in the DM group than in the non-DM group. After adjusting for confounding factors, the odds of the prevalence of anemia in men were higher in the DM group than in the non-DM group (odds ratio [OR] 1.87, 95% confidence interval [CI] 1.42-2.50, p < 0.0001). When investigated according to the serum creatinine level, the association was significantly stronger among women (OR 42.63, 95% CI 17.25-105.36, p < 0.0001) than among men (OR 6.30, 95% CI 3.08-12.90, p < 0.0001). CONCLUSIONS: We found a strong association between DM and anemia that was more prominent among men than among women. We also determined that the serum creatinine level had a greater influence on DM and anemia in women than in men.

Early discontinuation of ethambutol in pulmonary tuberculosis treatment based on results of the GenoType MTBDRplus assay: A prospective, multicenter, non-inferiority randomized trial in South Korea.

No studies have investigated whether discontinuation of ethambutol (EMB) based on the susceptibility to isoniazid and rifampin as determined by the GenoType MTBDRplus assay would be appropriate. We aimed to determine the feasibility of discontinuing EMB before the end of intensive phase treatment based on the result of MTBDRplus assay in patients with pulmonary tuberculosis (PTB). This prospective, multicenter non-inferiority randomized trial was conducted at 12 referral centers in South Korea in drug-susceptible PTB patients who initiated the standard four-drug regimen for PTB. Based on the results of the assay, EMB was discontinued in the MTBDRplus group after the confirmation that M. tuberculosis isolate was susceptible to isoniazid and rifampin. The timepoint for EMB discontinuation in the Guideline group was determined using the results of the phenotypic drug susceptibility test based on the Korean National TB Guidelines. The primary outcome was treatment success. Secondary outcomes included the 1-year rates of recurrence and adverse events. Of 600 randomized patients, the treatment outcome analysis was performed for 493 patients (MTBDRplus group, 244; Guideline group, 249). Treatment success rates were 93.9% (229/224) in the MTBDRplus group and 93.6% (233/249) in the Guideline group and did not differ between groups; relative risk 1.00 (95% CI 0.95-1.06). The 1-year recurrence rate between the two groups (0.9% vs. 0.5%, respectively) and differences in adverse drug reactions did not differ between groups. In conclusion, early discontinuation of EMB based on the results of the MTBDRplus assay did not affect the treatment outcomes in PTB.

Genomic and Proteomic Evidences for Exopolysaccharide Biosynthesis in Sphingobium chungbukense DJ77.

Sphingobium chungbukense DJ77 is a Gram-negative bacterium has metabolic capability of producing exopolysaccharide (EPS) as a potential reducing and stabilizing agent for metallic nanoparticle synthesis. In this study, we investigated the genomic and proteomic analysis to verify metabolic pathway and involved genes and enzymes related to EPS biosynthesis in S. chungbukense DJ77. End-sequencing results of randomly selected fosmid library, which were prepared from high molecular weight DNA of S. chungbukense DJ77, showed identity to sequences from genes related the EPS biosynthesis pathways in several bacteria. We also observed that proteomic responses in S. chungbukense DJ77 by heterogeneously expressing gelA and gelN involved in gellan biosynthesis in Sphingomonas elodea. Comparative two-dimensional gel electrophoresis revealed that both GelA and GelN altered internal expression levels of proteins involved in EPS biosynthesis in S. chungbukense DJ77. The results might provide the genomic and proteomic evidences for presence of EPS biosynthesis pathways in S. chungbukense DJ77.

The co-expression of Neogenin with SOX2 in hippocampal neurons.

Dementia has been shown to be closely related with neuronal degeneration and/or a decrease in the activity of neural stem cells in many brain regions, including the hippocampus. It has been recently established that Neogenin is involved in the cell fate determination by regulating Oct3/4, SOX and Nanog, notable embryonic cell markers, expressions in pre-implantation mouse embryos. Further, Neogenin expression at both mRNA and protein levels is manifest in many brain regions in mice, but it remains unclear whether Neogenin expression is prerequisite for the maintenance of neural stem cells, particularly, playing a critical role in the hippocampus, a brain region known to be involved in memory generation and consolidation. Here, we provide evidence that supports that Neogenin is implicated in the maintenance of neural stem cells in the hippocampus by enhancing PCNA expressions. We have performed RT-PCR analysis, Western blotting, and immunohistochemistry with fetal rat brain tissues at E18 for Neogenin mRNA and protein profiling. Neuronal cells obtained from the hippocampus were subjected to FACS analysis for the identification of Neogenin-positive and/or neuronal stem cell marker-positive cells. Western blotting results showed that Neogenin expression was higher in the hippocampal region compared to the cortical region. FACS analysis results indicated that a significant population of fetal rat neuronal cells exhibiting Neogenin expression also displayed SOX2 expression, implying co-expression of Neogenin and SOX2 in the hippocampus. Next, we investigated the role of Neogenin through gain- and loss-of-function studies with cultured rat hippocampal neurons. Neogenin down-regulation by small hairpin RNAs led to a dramatic decrease in SOX2 expression while its up-regulation by overexpression caused an increase in PCNA expression, a cell proliferation marker, compared with none-transfected cells. From this study, we propose a model whereby Neogenin could maintain neural stem cell population and control cell proliferation.

Quercetin 3,7-O-dimethyl ether from Siegesbeckia pubescens suppress the production of inflammatory mediators in lipopolysaccharide-induced macrophages and colon epithelial cells.

Siegesbeckia pubescens (Compositae) is an annual herb indigenous to Korean mountainous regions. Recent reports have been issued on some compounds derived from S. pubescens for its anti-inflammatory activity or mode of action. The quercetin 3,7-O-dimethyl ether (QDE) isolated from the herbs of S. pubescens suppressed the lipopolysaccharide (LPS)-induced nitric oxide and inducible nitric oxide synthase (iNOS) protein production in mouse macrophages. QDE downregulated pro-inflammatory cytokines such as interleukin (IL)-6, IL-1ß, tumor necrosis factor -α levels in LPS-stimulated macrophages. Also, QDE decreased the expression of LPS-induced iNOS and cyclooxygenase-2 (COX-2) protein and the production of IL-8 in LPS-induced HT-29 cells. Macrophages and colon epithelial cells are important for regulating the colon immune systems, thus QDE may regulate inflammatory colon disease via LPS-induced inflammation in macrophages and colon epithelial cells. QDE, anti-inflammatory constituent of S. pubescens herbs, can be expected to be a potential candidate for therapeutics against inflammatory bowel disease.

Visible-light-initiated thiol-acrylate photopolymerization of heparin-based hydrogels.

An in situ heparin-based forming hydrogel that cures under visible-light is formulated using eosin Y as a photoinitiator with triethanolamine as an electron donor to initiate reaction of thiolated-heparin with acrylate-ended poly(ethylene glycol). Formulations and irradiation conditions are presented for control of heparin content (1.6 to 3.3% w/v), modulus (100-10,000 Pa), and gelation time (30-600 s). Encapsulation of 3T3 fibroblasts in the hydrogel gave over 96% viability for all conditions examined. In vitro characterization of epidermal growth factor released from the hydrogel confirmed that the growth factor remains bioactive. The ability to deliver growth factors, fast gelation kinetics under visible light, and independent control of physical and biochemical properties makes this system a promising candidate for use in regenerative medicine. In particular, irradiation conditions that achieve gelation in 150s are compatible with the stringent light exposure limits of the retina, which affords a wide safety margin for use with other tissues.

Academic Helplessness and Life Satisfaction in Korean Adolescents: The Moderated Mediation Effects of Leisure Time Physical Activity.

This study examined whether depression mediates a relationship between academic helplessness and life satisfaction and whether the mediating effect differs depending on participation in leisure time physical activity (LTPA) from a sample of 2384 middle school students in South Korea. Identifying these factors could help in developing intervention strategies for promoting life satisfaction. Structural equation modeling analyses were employed to understand how various factors influence adolescents' life satisfaction. First, the effect of academic helplessness on life satisfaction was mediated by depression. Second, the mediating effect of depression was moderated according to participation in LTPA: the size of the negative mediating effect of depression on the relationship between academic helplessness and life satisfaction was reduced in the LTPA group compared to the non-LTPA group. The current findings suggest that encouraging engagement in physical activity may be a crucial vehicle for affecting academic helplessness, depression, and life satisfaction among early adolescents. Implications and future directions are discussed.

Alleviation of hippocampal necroptosis and neuroinflammation by NecroX-7 treatment after acute seizures.

Temporal lobe epilepsy (TLE) is one of the most common neurological disorders, but still one-third of patients cannot be properly treated by current medication. Thus, we investigated the therapeutic effects of a novel small molecule, NecroX-7, in TLE using both a low [Mg2+]o-induced epileptiform activity model and a mouse model of pilocarpine-induced status epilepticus (SE). NecroX-7 post-treatment enhanced the viability of primary hippocampal neurons exposed to low [Mg2+]o compared to controls in an MTT assay. Application of NecroX-7 after pilocarpine-induced SE also reduced the number of degenerating neurons labelled with Fluoro-Jade B. Immunocytochemistry and immunohistochemistry showed that NecroX-7 post-treatment significantly alleviated ionized calcium-binding adaptor molecule 1 (Iba1) intensity and immunoreactive area, while the attenuation of reactive astrocytosis by glial fibrillary acidic protein (GFAP) staining was observed in cultured hippocampal neurons. However, NecroX-7-mediated morphologic changes of astrocytes were seen in both in vitro and in vivo models of TLE. Finally, western blot analysis demonstrated that NecroX-7 post-treatment after acute seizures could decrease the expression of mixed lineage kinase domain-like pseudokinase (MLKL) and phosphorylated MLKL (p-MLKL), markers for necroptosis. Taken all together, NecroX-7 has potential as a novel medication for TLE with its neuroprotective, anti-inflammatory, and anti-necroptotic effects.

Composite system of PLCL scaffold and heparin-based hydrogel for regeneration of partial-thickness cartilage defects.

Delivering isolated chondrocytes with matrix is a promising approach to promote the cartilage repair. The present study attempted to combine the advantages of porous scaffold and hydrogel in delivering chondrocytes to partial-thickness cartilage defects. An electrospun, gelatin-incorporated PLCL scaffold mechanically similar to natural cartilage was fabricated, and chondrocytes were seeded using an injectable heparin-based hydrogel for efficient cell seeding. The scaffold/hydrogel composite showed more enhanced expression of chondrogenic genes and production of GAGs than those prepared without hydrogel. In addition, significant cartilage formation showing good integration with surrounding, similar to natural cartilage, was observed by scaffold/hydrogel composite system in partial-thickness defects of rabbit knees while no regeneration was observed in control defects. Although no exogenous chondrogenic factors were added, it was evident that the scaffold/hydrogel composite system was highly effective and better than the scaffold alone system without hydrogel for cartilage regeneration both in vitro and in vivo.

Electrochemical release of hepatocyte-on-hydrogel microstructures from ITO substrates.

This paper describes a novel platform that utilizes micropatterning and electrochemistry to release cells-on-hydrogel microstructures from conductive indium tin oxide (ITO) substrates. In this approach, UV photopolymerization was employed to micropattern heparin-based hydrogels onto glass substrates containing ITO electrodes. ITO/glass substrates were first functionalized with acrylated silane to promote attachment of hydrogel structures. The surfaces containing hydrogel micropatterns were further functionalized with poly(ethylene glycol) thiol, rendering the regions around the hydrogel structures non-fouling to proteins and cells. After incubating surfaces with collagen (I), primary rat hepatocytes were shown to selectively attach on top of the hydrogel and not on surrounding glass/ITO regions. Electrical activation of specific ITO electrodes (-1.8 V vs. Ag/AgCl reference) was then used to release cells-on-hydrogel microstructures from the substrate. Immunostaining and reverse transcription polymerase chain reaction analysis of albumin, an important indicator of hepatic function, showed that the hepatocyte-on-hydrogel microstructures released from the surface maintained their function at levels similar to hepatocytes remaining on the culture substrate. In the future, switchable conductive substrates described here may be to collect cell samples at different time points and may also be used for harvesting cell-carrying vehicles for transplantation studies.

Maternal lead exposure induces sex-dependent cerebellar glial alterations and repetitive behaviors.

Lead (Pb) is one of the most prevalent heavy metals we encounter daily. Although there are many reports regarding their toxic effects on humans, the effects of exposure to low lead concentrations throughout the pregnancy period on the offspring are not fully elucidated yet. This study aimed to investigate the cellular mechanisms that occur in response to lead exposure. To this end, we administered lead-containing water to pregnant mice from the day of conception till delivery or till day 28 postnatally. Furthermore, we performed neurodevelopmental disorder-related behavior tests and RNA-sequencing analysis. We used both genders for all experiments because neurodevelopmental disorders usually show several sex-dependent differences. The results revealed increased levels of gliosis in the cerebella of lead-exposed pups compared to those in littermates belonging to the control group. Additionally, we observed altered behaviors of male mice in the autism spectrum disorder-related tests. RNA-sequencing results revealed changes in gamma-aminobutyric acid (GABA) signaling in the lead-exposed mouse model. Specifically, the lead-exposed male mice showed decreased monoamine oxidase B and increased levels of diamine oxidase enzyme, which is related to the synthesis of GABA in astrocytes. These findings demonstrate sex-dependent basal developmental changes in glial cells and an increased prevalence of autistic-like behaviors in the young pups of mothers exposed to lead during pregnancy.

Sex-related Differences in Glial Fibrillary Acidic Protein-positive GABA Regulate Neuropathology Following Pilocarpine-induced Status Epilepticus.

Status epilepticus (SE) is a life-threatening neurological disorder that causes neuronal death and glial activation. Studies have explained the clinical side effects and lack of effectiveness of neurological disorder treatments based on sex-related differences in brain structure and function. However, the sex-specific outcomes of seizure disorders and the underlying mechanisms remain unknown. We compared SE-induced behavioral and pathophysiological changes in male and female mice. The time taken to reach stage 6 seizure following pilocarpine injection was shorter in male mice than in female mice, and the prevalence of SE was higher in male mice than in female mice. Fluoro-Jade B staining revealed more extensive SE-induced hippocampal neuronal death in male mice than in female mice. Glial cells were more activated in male mice than in female mice. In contrast, astrocyte-derived γ-aminobutyric acid (GABA)-immunostaining was less expressed in male mice than in female mice. Moreover, the mRNA levels of inflammatory cytokines released from activated glial cells were higher in male mice than in female mice. Notably, the mRNA level of astrocytic γ-aminobutyric acid transporter (GAT-3) involved in extracellular GABA uptake was lower in female mice than in male mice, while the mRNA levels of glutamate/aspartate transporter (GLAST (EAAT1)) and glutamate transporter (GLT-1 (EAAT2)) involved in extracellular glutamate uptake were higher in female mice. Our findings suggest that male mice are more vulnerable to SE than female mice, resulting in more extensive neuronal cell death and glial activation in male mice, partly due to increased GAT-3 expression that subsequently leads to reduced glial fibrillary acidic protein (GFAP)-positive GABA content assessed with anti-GABA antibodies.

Truncated Neogenin Promotes Hippocampal Neuronal Death after Acute Seizure.

Protecting hippocampal neurons from death after seizure activity is critical to prevent an alteration of neuronal circuitry and hippocampal function. Here, we present a novel target, a truncated form of neogenin that is associated with seizure-induced hippocampal necroptosis, and novel use of the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) as a pharmacological regulator of neogenin truncation. We show that 3 days after pilocarpine-induced status epilepticus in mice, when hippocampal cell death is detected, the level of truncated neogenin is increased, while that of full-length neogenin is decreased. Moreover, phosphorylation of mixed lineage kinase domain-like pseudokinase, a crucial marker of necroptosis, was also markedly upregulated at 3 days post-status epilepticus. In cultured hippocampal cells, kainic acid treatment significantly reduced the expression of full-length neogenin. Notably, treatment with DAPT prevented neogenin truncation and protected cultured neurons from N-methyl-D-aspartate (NMDA)-induced death. These data suggest that seizure-induced hippocampal necroptosis is associated with the generation of truncated neogenin, and that prevention of this by DAPT treatment can protect against NMDA-induced excitotoxicity.

Real-time ultrafast oscilloscope with a relativistic electron bunch train.

The deflection of charged particles is an intuitive way to visualize an electromagnetic oscillation of coherent light. Here, we present a real-time ultrafast oscilloscope for time-frozen visualization of a terahertz (THz) optical wave by probing light-driven motion of relativistic electrons. We found the unique condition of subwavelength metal slit waveguide for preserving the distortion-free optical waveform during its propagation. Momentary stamping of the wave, transversely travelling inside a metal slit, on an ultrashort wide electron bunch enables the single-shot recording of an ultrafast optical waveform. As a proof-of-concept experiment, we successfully demonstrated to capture the entire field oscillation of a THz pulse with a sampling rate of 75.7 TS/s. Owing to the use of transversely-wide and longitudinally-short electron bunch and transversely travelling wave, the proposed "single-shot oscilloscope" will open up new avenue for developing the real-time petahertz (PHz) metrology.

Zerumbone, a tropical ginger sesquiterpene, inhibits colon and lung carcinogenesis in mice.

Zerumbone (ZER), present in subtropical ginger Zingiber zerumbet Smith, possesses anti-growth and anti-inflammatory properties in several human cancer cell lines. ZER also down-regulates the cyclooxygenase-2 and inducible nitric oxide synthase expression via modulation of nuclear factor (NF)-kappaB activation in cell culture systems. These findings led us to investigate whether ZER is able to inhibit carcinogenesis in the colon and lung, using 2 different preclinical mouse models. In Exp. 1, a total of 85 male ICR mice were initiated using a single intraperitoneal (i.p.) injection with azoxymethane (AOM, 10 mg/kg bw) and promoted by 1.5% dextran sulfate sodium (DSS) in drinking water for 7 days for rapid induction of colonic neoplasms. Animals were then fed the diet containing 100, 250 or 500 ppm ZER for 17 weeks. In Exp. 2, a total of 50 female A/J mice were given a single i.p. injection of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (10 micromol/mouse) to induce lung proliferative lesions. They were then fed the diet mixed with 100, 250 or 500 ppm ZER for 21 weeks. At the termination of the experiments (wk 20 of Exp. 1 and wk 22 of Exp. 2), all animals were subjected to complete necropsy examination to determine the pathological lesions in both tissues. Oral administration of ZER at 100, 250 and 500 ppm significantly inhibited the multiplicity of colonic adenocarcinomas. The treatment also suppressed colonic inflammation. In the lung carcinogenesis, ZER feeding at 250 and 500 ppm significantly inhibited the multiplicity of lung adenomas in a dose-dependent manner. Feeding with ZER resulted in inhibition of proliferation, induction of apoptosis, and suppression of NFkappaB and heme oxygenase (HO)-1 expression in tumors developed in both tissues. Our findings suggest that dietary administration of ZER effectively suppresses mouse colon and lung carcinogenesis through multiple modulatory mechanisms of growth, apoptosis, inflammation and expression of NFkappaB and HO-1 that are involved in carcinogenesis in the colon and lung.

Higher Acid-Base Imbalance Associated with Respiratory Failure Could Decrease the Survival of Patients with Scrub Typhus during Intensive Care Unit Stay: A Gene Set Enrichment Analysis.

Ninety percent of patients with scrub typhus (SC) with vasculitis-like syndrome recover after mild symptoms; however, 10% can suffer serious complications, such as acute respiratory failure (ARF) and admission to the intensive care unit (ICU). Predictors for the progression of SC have not yet been established, and conventional scoring systems for ICU patients are insufficient to predict severity. We aimed to identify simple and robust indicators to predict aggressive behaviors of SC. We evaluated 91 patients with SC and 81 non-SC patients who were admitted to the ICU, and 32 cases from the public functional genomics data repository for gene expression analysis. We analyzed the relationships between several predictors and clinicopathological characteristics in patients with SC. We performed gene set enrichment analysis (GSEA) to identify SC-specific gene sets. The acid-base imbalance (ABI), measured 24 h before serious complications, was higher in patients with SC than in non-SC patients. A high ABI was associated with an increased incidence of ARF, leading to mechanical ventilation and worse survival. GSEA revealed that SC correlated to gene sets reflecting inflammation/apoptotic response and airway inflammation. ABI can be used to indicate ARF in patients with SC and assist with early detection.

A novel rasH2 mouse carcinogenesis model that is highly susceptible to 4-NQO-induced tongue and esophageal carcinogenesis is useful for preclinical chemoprevention studies.

We investigated the susceptibility of 4-nitroquinoline 1-oxide (4-NQO)-induced tongue carcinogenesis in male CB6F1-Tg-rasH2 @Jcl mice (Tg mice). The Tg mice were administered 4-NQO (20 p.p.m. in drinking water) for 2, 4, 6 or 8 weeks, and thereafter they were untreated up to week 24. At week 24, a higher incidence (80%) of tongue neoplasm with dysplasia was noted in the mice that received 4-NQO for 8 weeks in comparison with the other groups (20% incidence for each) treated with 4-NQO for 2, 4 and 6 weeks. Esophageal tumors also developed in the Tg mice were 4-NQO. Immunohistochemical observation revealed that the EP receptors, especially EP(1) and EP(2), expressed in the tongue and esophageal lesions induced by 4-NQO, thus suggesting the involvement of prostaglandin (PG) E(2) and EP(1,2) receptors in the tongue and esophageal carcinogenesis. Using this animal model, we investigated the potential chemopreventive ability of pitavastatin (1, 5 and 10 p.p.m. in diet for 15 weeks), starting 1 week after the cessation of 4-NQO-exposure (20 p.p.m. in drinking water for 8 weeks). Dietary pitavastatin at 10 p.p.m. significantly reduced the incidence and multiplicity of the tongue, but not esophageal neoplasms by the modulation of prostaglandin E2 biosynthesis, EP(1) and EP(2) expression and proliferation. Our results thus suggest that a rasH2 mouse model of 4-NQO-induced tongue and esophageal carcinogenesis can be utilized for investigating the pathogenesis of cancer development in these tissues and may well prove to be useful for identifying candidate cancer chemopreventive agents for the upper digestive organs.

A novel prodrug of 4'-geranyloxy-ferulic acid suppresses colitis-related colon carcinogenesis in mice.

The inhibitory effects of a novel prodrug, 3-(4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoyl-L-alanyl-L-proline (GAP), of the secondary metabolite 4'-geranyloxy-3'-methoxyphenyl)-2-trans-propenoic acid (4'-geranyloxy-ferulic acid), on colon carcinogenesis was investigated using an azoxymetahen (AOM)/dextran sodium sulfate (DSS) model. GAP was synthetically derived from ferulic acid. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of azoxymethane (10 mg/kg body weight) were promoted by 1% (wt/vol) DSS in drinking water for 7 days. They were then given modified AIN-76A diet containing 0.01% or 0.05% GAP for 17 wk. At Week 20, the development of colonic adenocarcinoma was significantly inhibited by GAP feeding at dose levels of 0.01% [60% incidence (P = 0.0158) with a multiplicity of and 1.13 +/- 1.13 (P < 0.05)] and 0.05% [53% incidence (P = 0.0057) with a multiplicity of 0.08 +/- 1.08 (P < 0.01)], when compared to the AOM/DSS group (95% incidence with a multiplicity of 3.10 +/- 3.06). Dietary GAP modulated the mitotic and apoptotic indexes in the crypt cells and lowered 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells in the colonic mucosa. Urinary level of 8-OHdG was lowered by GAP feeding. Additionally, dietary GAP elevated the immunoreactivity of an inducible form of heme oxygenase 1 in the colonic mucosa. Our results indicate that GAP is able to inhibit colitis-related colon carcinogenesis by modulating proliferation and oxidative stress in mice.

Aqueous and ethanolic extract fractions from the Brazilian propolis suppress azoxymethane-induced aberrant crypt foci in rats.

We investigated the effects of the two fractions, aqueous (AEP) and ethanolic extracts of propolis (EEP) of the Brazilian propolis on azoxymethane (AOM)-induced aberrant crypt foci (ACF). Male Wistar Hannover (GALAS) rats were administered two weekly subcutaneous injections of AOM (20 mg/kg bw) and fed with diets mixed with AEP (100, 500 and 1,000 ppm) or EEP (500 and 1,000 ppm) for 4 weeks, starting one week before the first dosing of AOM. The modifying effects of the test extracts on ACF formation were assessed by counting the incidence and multiplicity of ACF at week 4. Proliferation cell nuclear antigen (PCNA)-labeling nuclei and apoptotic index were also immunohistochemically determined. Dietary supplementation with AEP and EEP significantly reduced the multiplicity of ACF with the effect of EEP being more potent than AEP. In the ACF and their surrounding non-lesional crypts, significantly lowered cell proliferation was observed in the rats, administered with AOM, and the extracts, while neither fraction affected the apoptotic index. Our findings suggest that AEP and EEP possess a chemopreventive ability in the early phase of colon carcinogenesis through the modulation of cell proliferation.