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This randomized controlled study aimed to evaluate whether adding bismuth to the standard first-line triple therapy could improve the eradication rate of Helicobacter pylori. A total of 162 patients with Helicobacter pylori infection were randomly assigned to either the 7-day triple therapy group (RAK regimen: rabeprazole 20 mg, amoxicillin 1 g, and clarithromycin 500 mg bid; n=81) or the bismuth plus triple therapy group (n=81). In the RBAK group, bismuth subcitrate 360 mg twice daily was added to the RAK regimen. A follow-up endoscopy or urea breath test was performed at least 4 weeks after eradication to confirm the treatment efficacy. Comparable compliance and Helicobacter pylori eradication rates were observed in both groups in either intention-to-treat [RAK 72.8% (59/81) versus RBAK 77.8% (63/81); p=0.47] or per protocol analysis [RAK 74.7% (59/79) versus RBAK 81.8% (63/77); p=0.26]. Adverse effects were commonly reported (50.6% for both groups) although most of these did not cause cessation of treatment. The resistance rate was 27.2% for metronidazole and 12.3% for clarithromycin. Adding bismuth to the standard 7-day triple therapy did not substantially increase the eradication rate. Further study is needed clarifying whether extending the duration of RBAK regimen to 10–14 days can lead to a better result.

Gender differences in terms of mortality among many solid organ malignancies have been proved by epidemiological data. Estrogen has been suspected to cast a protective effect against cancer because of the lower mortality of gastric cancer in females and the benefits of hormone replacement therapy (HRT) in gastric cancer. Hence, it suggests that 17β-estradiol (E2) may affect the behavior of cancer cells. One of the key features of cancer-related mortality is metastasis. Accumulating evidences suggest that human bone marrow mesenchymal stem cells (HBMMSCs) and its secreted CCL-5 have a role in enhancing the metastatic potential of breast cancer cells. However, it is not clear whether E2 would affect HBMMSCs-induced mobility in gastric cancer cells. In this report, we show that CCL-5 secreted by HBMMSCs enhanced mobility in human AGS gastric cancer cells via activation of Src/Cas/Paxillin signaling pathway. Treatment with specific neutralizing antibody of CCL-5 significantly inhibited HBMMSCs-enhanced mobility in human AGS gastric cancer cells. We further observe that 17β-estradiol suppressed HBMMSCs-enhanced mobility by down-regulating CCL5-Src/Cas/paxillin signaling pathway in AGS cells. Collectively, these results suggest that 17β-estradiol treatment significantly inhibits HBMMSCS-induced mobility in human AGS gastric cancer cells.

Different types of proton pump inhibitor (PPI)-based triple therapies could result in different Helicobacter pylori eradication rates. This study aimed to compare the efficacy and safety of rabeprazole- and lansoprazole-based triple therapies in primary treatment of H. pylori infection. From September 2005 to July 2008, 426 H. pylori -infected patients were randomly assigned to receive a 7-day eradication therapy with either rabeprazole 20mgbid (RAC group, n =222) or lansoprazole 30mgbid (LAC group, n =228) in combination with amoxicillin 1gbid and clarithromycin 500mgbid. The patients received follow-up esophagogastroduodenoscopy (EGD) and/or 13 C-urea breath test 12–16 weeks later to define H. pylori status. Their personal and medical history, compliance and side effects were obtained by using a standardized questionnaire. Intention-to-treat analysis revealed that the eradication rate was 87.84% in the RAC group and 85.96% in the LAC group ( p =0.56). All patients returned for assessment of compliance (100% in the LAC group vs. 99.50% in the RAC group; p =0.32) and adverse events (7.20% in the RAC group vs. 5.70% in the LAC group, p =0.51). Univariate analysis suggested that patients with nonsteroid anti-inflammatory agent (NSAID) use had lower eradication rates than those without (76.71% vs. 88.74%; p =0.006). Our results showed that efficacy and safety were similar in rabeprazole- and lansoprazole-based primary therapies. The influence of NSAID usage on H. pylori eradication needs to be further investigated.

To study the mechanisms of gastric tumorigenesis, we have established CSN cell line from human normal gastric mucosa, and CS12, a tumorigenic and invasive gastric cancer cell line from CSN passages. Many stem cell markers were expressed in both CSN and CS12 cells, but LGR5 and NANOG were expressed only in CS12 cells. Increased expression of homeobox A13 (HoxA13) and its downstream cascades was significant for the tumorigenic activity of CS12 cells, and was associated with recruitment of E2F-1 to HoxA13 promoter accompanied with increased trimethylation of histone H3 lysine 4 (H3K4me3) at the hypomethylated E2F motifs. Knockdown of HoxA13 caused the downregulation of long non-coding RNA HOTTIP and insulin growth factor-binding protein 3 (IGFBP-3) genes, indicating that both were targets of HoxA13. Concurrent regulation of HoxA13-HOTTIP was mediated by the mixed lineage leukemia-WD repeat domain 5 complex, which caused the trimethylation of H3K4 and then stimulated cell proliferation. HoxA13 transactivated the IGFBP-3 promoter through the HOX-binding site. Activation of IGFBP-3 stimulated the oncogenic potential and invasion activity. Increased expression of HoxA13 (63.2%) and IGFBP-3 (28.6%) was detected in human gastric cancer tissues and was found in the gastric cancer data of The Cancer Genome Atlas. Taken together, the HoxA13-HOTTIP-IGFBP-3 cascade is critical for the carcinogenic characteristics of CS12 cells.

Objectives This prospective study was designed to compare the efficacies of levofloxacin-containing and high-dose metronidazole-containing quadruple therapies after failure of standard triple therapies. Methods A total of 150 Helicobacter pylori-infected patients were enrolled in our study and randomly assigned to levofloxacin-containing quadruple therapy (EBTL group) (40 mg of esomeprazole twice daily, 300 mg of bismuth subcitrate four times daily, 500 mg of tetracycline four times daily and 500 mg of levofloxacin once daily for 10 days) (n = 76) or high-dose metronidazole-based quadruple therapy (EBTM group) (40 mg of esomeprazole twice daily, 300 mg of bismuth subcitrate four times daily, 500 mg of tetracycline four times daily and 500 mg of metronidazole four times daily for 10 days) (n = 74). Follow-up endoscopy or urea breath test was done 16 weeks later to assess the treatment response. Patients' responses, CYP2C19 genotypes and antibiotic resistances were also examined. All participants, caregivers and those assessing the outcomes were blinded to group assignment. Results Intention-to-treat analysis revealed that both groups showed similar eradication rates: EBTL, 78.9% (60/76) (95% CI 69.7%-88.1%) and EBTM, 79.7% (59/74) (95% CI 70.5%-88.7%) [risk ratio (RR) 0.97, 95% CI 0.44-2.14]. Per-protocol results were EBTL = 87.0% (60/69) (95% CI 79.4%-94.9%) and EBTM = 90.8% (59/65) (95% CI 83.8%-97.8%) (RR 0.68, 95% CI 0.23-2.0). We did not find significant differences in compliance (RR 0.5, 95% CI 0.54-2.3) and adverse events (RR 1.11, 95% CI 0.54-2.3) between the two groups. Logistic regression analysis showed that only compliance was an important predictor for eradication failure. CYP2C19 polymorphism did not influence the eradicating effect. Conclusions The 10 day bismuth quadruple therapies with high-dose metronidazole or levofloxacin were effective even in areas with high resistance. These two therapies were equally safe and tolerated. Besides this, the metronidazole-containing therapy was cheaper. So it is persuasive that high-dose metronidazole-containing quadruple therapy could be a good choice for second-line H. pylori eradication in areas with high resistance.

Epidemiological studies demonstrate that the incidence and mortality rates of colorectal cancer in women are lower than in men. However, it is unknown if 17β-estradiol (E2) treatment is sufficient to inhibit cell proliferation and cell migration in human colon cancer cells. Up-regulation of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and matrix metallopeptidases (MMPs) is reported to associate with the development of cancer cell mobility, metastasis, and subsequent malignant tumor. In the present study, we treated human LoVo colon cancer cells with E2 to explore whether E2 down-regulates cell proliferation and migration, and to identify the precise molecular and cellular mechanisms behind the down-regulatory responses. Here, we found that E2 treatment decreased cell proliferation and cell cycle-regulating factors such as cyclin A, cyclin D1 and cyclin E. At the same time, E2 significantly inhibited cell migration and migration-related factors such as uPA, tPA, MMP-2, and MMP-9. However, E2 treatment showed no effects on upregulating expression of plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinase-1, -2, -3, and -4 (TIMP-1, -2, -3, and -4). After administration of inhibitors including QNZ (NFκB inhibitor), LY294002 (Akt activation inhibitor), U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor) or SP600125 (JNK1/2 inhibitor), E2-downregulated cell migration and expression of MMP-2 and MMP-9 in LoVo cells is markedly inhibited only by p38 MAPK inhibitors, SB203580. Application of specific target gene siRNA (ERα, ERβ, p38α, and p38β) to LoVo cells further confirmed that p38 MAPK mediates E2/ERs inhibition of MMP-2 and -9 expression and cell motility in LoVo cells. Collectively, these results suggest that E2 treatment down-regulates cell proliferation by modulating the expression of cyclin A, cyclin D1 and cyclin E. E2 treatment simultaneously impaired cell migration by inhibiting the expression of uPA, tPA, MMP-2, and MMP-9 through E2/ERs − p38α MAPK signaling pathway in human LoVo colon cancer cells. J. Cell. Physiol. 227: 3648–3660, 2012. © 2012 Wiley Periodicals, Inc.

Hepatoma-derived growth factor (HDGF) plays a critical role in tumor cell proliferation, anti-apoptosis, VEGF expression, lymph node metastasis and poor prognosis in human gastric cancer. Gastric cancer, as one of the most prevalent cancers worldwide, is the second leading cause of cancer-related mortality in the world for the prognosis of gastric cancer is generally poor, especially in patients with advanced stage. Helicobacter pylori (H. pylori) infection causes the chronic inflammation of stomach as well as the development of gastric cancer, with a three to six-fold increased risk of gastric cancer. Carcinoma-associated fibroblasts (CAFs) are myofibroblasts in tumor microenvironment, which possess various abilities to promote the progression of cancer by stimulating neoangiogenesis, proliferation, migration, invasion and therapy resistance of tumor cell. Mesenchymal stem cells (MSCs) are reported to promote tumor malignance through differentiation of MSCs toward CAFs. In the present study, we demonstrated that H. pylori infection promotes HDGF expression in human gastric cancer cells. HBMMSCs treated with HDGF assume properties of CAF-like myofibroblastic phenotypes, including expression of myofibroblast markers (α-smooth muscle actin (α-SMA), procollagen α1, tropomyoson I, desmin, fibroblast activation protein (FAP)), and fibroblast markers (prolyl-4-hydroxylase A1 (PHA1) and fibroblast specific protein-1 (FSP-1)/S100A4). HDGF recruits HBMMSCs, and then HBMMSCs further contributes to cell survival and invasive motility in human gastric cancer cells. Treatment of HDGF neutralizing antibody (HDGF-NAb) and serum significantly inhibit HDGF-regulated differentiation and recruitment of HBMMSCs. These findings suggest that HDGF might play a critical role in gastric cancer progress through stimulation of HBMMSCs differentiation to myofibroblast-like cells.

Improvement of methods for reliable and early diagnosis of the cellular diseases is necessary. A biological selectivity probe, such as an aptamer, is one of the candidate recognition layers that can be used to detect important biomolecules. Lung cancer is currently a typical cause of cancer-related deaths. In this work, an electrical sensing platform is built based on amine-terminated aptamer modified-gold electrodes for the specific, label-free detection of a human lung carcinoma cell line (A549). The microdevice, that includes a coplanar electrodes configuration and a simple microfluidic channel on a glass substrate, is fabricated using standard photolithography and cast molding techniques. A procedure of self-assembly onto the gold surface is proposed. Optical microscope observations and electrical impedance spectroscopy measurements confirm that the fabricated microchip can specifically and effectively identify A549 cells. In the experiments, the capacitance element that is dominant in the change of the impedance is calculated at the appropriate frequency for evaluation of the sensitivity of the biosensor. Therefore, a simple, inexpensive, biocompatible, and selective biosensor that has the potential to detect early-stage lung cancer would be developed.

Cross-sectional study.To analyze the predictors of severe neurogenic bowel dysfunction (NBD) in persons with spinal cord injury (SCI).The Kaohsiung Medical University Hospital, Taiwan.Two questionnaires-the NBD score and the Beck Depression Inventory second edition-were sent to 232 persons with SCI by mail. The demographic factors and injury-related factors were recorded to evaluate any relationships with severe NBD. The associations between the severity of NBD and psychological condition were also measured.In all, 39.4% of the respondents suffered from severe NBD. Multiple logistic regression analysis showed that those with a cervical injury (odds ratios (OR)=10.5, 95% confidence interval (CI) 1.6-67.7) or a thoracic injury (OR=7.1, 95% CI 1.2-40.3) had a higher risk of severe NBD than those with a lumbar injury. Persons with American Spinal Injury Association (ASIA) A had a 12.8-fold higher risk of severe NBD than persons with ASIA D (OR=12.8, 95% CI 3.3-50.1). Longer duration of injury (or =10 years) was another risk factor of severe NBD. Moderate-to-severe depression was associated with reduced bowel function.This study showed that high level of cord lesion, completeness of cord injury and longer duration of injury (or =10 years) could predict the severity of NBD in patients with SCI.

Cross-sectional study.(1) To assess the relationship between bladder management methods and the health-related quality of life (HRQL) in patients with spinal cord injury (SCI). (2) To identify any correlation between the two questionnaires used to assess the quality of life (one validated for SCI and one validated for bladder symptoms).Spinal Cord Injury Centre, Royal National Orthopaedic Hospital, Middlesex, UK.This study is based on two questionnaires with results collected from 142 people with SCI. The two questionnaires were based on information from the Short-Form 36-Item Health Survey (SF-36) and the King's Health Questionnaire and included demographic characteristics, bladder management methods and the frequency of incontinence.There is a moderate correlation between the results of the SF-36 and the King's Health Questionnaire. Only 21% SCI patients report normal voiding without any other form of bladder management. The type of bladder management may influence the HRQL in patients with SCI. Clean intermittent catheterization by attendant, indwelling transurethral catheterization and indwelling suprapubic catheterization are the three groups with the worst mental status. In addition, the frequency of incontinence is a strong influence on HRQL.The results of this study may provide a general baseline HRQL for patients with SCI. Our findings show the relationships between bladder management methods and quality of life in patients with SCI. In addition, the impact of incontinence on quality of life was also confirmed.

Evidence shows that women have lower tumour necrosis factor-alpha (TNF-alpha) levels and lower incidences of heart dysfunction and sepsis-related morbidity and mortality. To identify the cardioprotective effects and precise cellular/molecular mechanisms behind estrogen and estrogen receptors (ERs), we investigated the effects of 17beta-estradiol (E(2)) and estrogen receptor alpha (ERalpha) on LPS-induced apoptosis by analyzing the activation of survival and death signalling pathways in doxycycline (Dox)-inducible Tet-On/ERalpha H9c2 myocardial cells and ERalpha-transfected primary cardiomyocytes overexpressing ERalpha. We found that LPS challenge activated JNK1/2, and then induced IkappaB degradation, NFkappaB activation, TNF-alpha up-regulation and subsequent myocardial apoptotic responses. In addition, treatments involving E(2), membrane-impermeable BSA-E(2) and/or Dox, which induces ERalpha overexpression, significantly inhibited LPS-induced apoptosis by suppressing LPS-up-regulated JNK1/2 activity, IkappaB degradation, NFkappaB activation and pro-apoptotic proteins (e.g. TNF-alpha, active caspases-8, t-Bid, Bax, released cytochrome c, active caspase-9, active caspase-3) in myocardial cells. However, the cardioprotective properties of E(2), BSA-E(2) and ERalpha overexpression to inhibit LPS-induced apoptosis and promote cell survival were attenuated by applying LY294002 (PI3K inhibitor) and PI3K siRNA. These findings suggest that E(2), BSA-E(2) and ERalpha expression exert their cardioprotective effects by inhibiting JNK1/2-mediated LPS-induced TNF-alpha expression and cardiomyocyte apoptosis through activation of Akt.

In previous studies, we have found that IGF-II and IGF-II receptor (IGF-IIR) dose dependently correlated with the progression of pathological hypertrophy after complete abdominal aorta ligation, which may play a critical role in angiotensin II-induced cardiomyocyte apoptosis. However, the detail mechanisms of IGF-IIR in the regulation of cell apoptosis in response to IGF-II remain unclear. By using IGF-IR short hairpin RNA to inhibit IGF-IR expression and using Leu27 IGF-II analog to activate specifically the IGF-IIR, we investigated the role of IGF-II/IGF-IIR activation and its downstream signaling. Our results revealed that IGF-II synergistically increased the cell apoptosis induced by suppressing of IGF-IR in neonatal rat ventricular myocytes. After binding of Leu27IGF-II, IGF-IIR became associated with alpha-q polypeptide, acted like a protein-coupled receptor to activate calcineurin, led to the translocation of Bad into mitochondria and release of cytochrome c into cytoplasm, and contributed to mitochondrial-dependent apoptosis in neonatal rat ventricular myocytes. Furthermore, inhibition of IGF-IIR, alpha-q polypeptide, or calcineurin by RNA interference could block the Leu27IGF-II-induced cell apoptosis. Together, this study provides a new insight into the effects of the IGF-IIR and its downstream signaling in myocardial apoptosis. Suppression of IGF-IIR signaling pathways may be a good strategy for both the protection against myocardial cell apoptosis and the prevention of heart failure progression.

Anion exchangers (AEs) of the Cl(-)/HCO3(-) exchanger family contribute to the regulation of intracellular acid-base balance. Recently, we found that anion exchanger 2 (AE2) was significantly expressed in human hepatocellular carcinoma (HCC) and in poorly-differentiated human HCC HA22T/VGH cells. In the present study, we further explored the pharmacological function of AE in four human HCC cell lines (SK-Hep-1, HA22T/VGH, HepG2, and Hep3B) following the treatment of 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), an AEs specific inhibitor. After administrations with 400-1000 microM of DIDS, cell proliferation was greatly inhibited in a dose-dependent manner from 47.5 to 65.0% in higher malignant HA22T/VGH cells, but not in other cell lines. The results of 4,6-diamidino-2-phenylindole (DAPI) staining, DNA fragmentation and flow cytometric analysis further revealed that cell apoptosis induced by DIDS was also observed in HA22T/VGH cells. Therefore, these findings suggested that AE may be involved, in part, in the proliferation and survival of HA22T cells and could be a new potential therapeutic target against specific human HCC.

Accurate diagnosis of Helicobacter pylori (H. pylori) infection is a crucial part in the effective management of many gastroduodenal diseases. Several invasive and non-invasive diagnostic tests are available for the detection of H. pylori and each test has its usefulness and limitations in different clinical situations. Although none can be considered as a single gold standard in clinical practice, several techniques have been developed to give the more reliable results. Invasive tests are performed via endoscopic biopsy specimens and these tests include histology, culture, rapid urease test as well as molecular methods. Developments of endoscopic equipment also contribute to the real-time diagnosis of H. pylori during endoscopy. Urea breathing test and stool antigen test are most widely used non-invasive tests, whereas serology is useful in screening and epidemiological studies. Molecular methods have been used in variable specimens other than gastric mucosa. More than detection of H. pylori infection, several tests are introduced into the evaluation of virulence factors and antibiotic sensitivity of H. pylori, as well as screening precancerous lesions and gastric cancer. The aim of this article is to review the current options and novel developments of diagnostic tests and their applications in different clinical conditions or for specific purposes.

The bismuth-based quadruple regimen has been applied inHelicobacter pylorirescue therapy worldwide. The non-bismuth-based quadruple therapy or “concomitant therapy” is an alternative option in first-line eradication but has not been used in second-line therapy. Discovering a valid regimen for rescue therapy in bismuth-unavailable countries is important. We conducted a randomized controlled trial to compare the efficacies of the standard quadruple therapy and a modified concomitant regimen. One hundred and twenty-four patients were randomly assigned into two groups: RBTM (rabeprozole 20 mg bid., bismuth subcitrate 120 mg qid, tetracycline 500 mg qid, and metronidazole 250 mg qid) and RATM (rabeprozole 20 mg bid., amoxicillin 1 g bid., tetracycline 500 mg qid, and metronidazole 250 mg qid) for 10 days. The eradication rate of the RBTM and RATM regimen was 92.1% and 90.2%, respectively, in intention-to-treat analysis. Patients in both groups had good compliance (~96%). The overall incidence of adverse events was higher in the RATM group (42.6% versus 22.2%,P=0.02), but only seven patients (11.5%) experienced grades 2-3 events. In conclusion, both regimens had good efficacy, compliance, and acceptable side effects. The 10-day RATM treatment could be an alternative rescue therapy in bismuth-unavailable countries.

Although IGF-II activating the IGF-II receptor signaling pathway has been found to stimulate cardiomyocyte hypertrophy, the role of IGF-II in cardiac cell apoptosis remains unclear. This study aimed to identify the roles of IGF-II and/or IGF-II receptors (IGF-II/IIR) in cardiomyoblast apoptosis and in hypertensive rat hearts with abdominal aorta ligation. Cultured rat heart-derived H9c2 cardiomyoblasts and excised hearts from Sprague-Dawley rats with 0- to 20-day complete abdominal aorta ligation, a model of ANG II elevation and hypertension, were used. IGF-II/IIR expression, caspase activity, DNA fragmentation, and apoptotic cells were measured by RT-PCR, Western blot, agarose gel electrophoresis, and TUNEL assay following various combinations of ANG II, IGF-II/IIR antibody, CsA (calcineurin inhibitor), SP-600125 (JNK inhibitor), SB-203580 (p38 inhibitor), U-0126 (MEK inhibitor), or Staurosporine (PKC inhibitor) in H9c2 cells. ANG II-induced DNA fragmentation and TUNEL-positive cells were blocked by IGF-II/IIR antibodies and antisense IGF-II, but not by IGF-II sense. IGF-II-induced apoptosis was blocked by IGF-IIR antibody and CsA. The increased gene expressions of IGF-II and -IIR induced by ANG II were reversed by U-0126 and Sp600125, respectively. Caspase 8 activities induced by ANG II were attenuated by U-0126, SP-600125, and CsA. DNA fragmentation induced by ANG II was totally blocked by SP-600125, and CsA and was attenuated by U-0126. In rats with 0- to 20-day complete abdominal aorta ligation, the increases in IGF-II/IIR levels in the left ventricle were accompanied by hypertension as well as increases in caspase 9 activities and TUNEL-positive cardiac myocytes. ANG II-induced apoptosis was reversed by IGF-II/IIR blockade and coexisted with increased transactivation of IGF-II and -IIR, which are mediated by ERK and JNK pathways, respectively, both of which further contributed to cardiomyoblast apoptosis via calcineurin signaling. The increased cardiac IGF-II, IGF-IIR, caspase 9, and cellular apoptosis were also found in hypertensive rats with abdominal aorta ligation.

Background Serum iron overload or iron deficiency appears to be associated with atherosclerosis and ischemic myocardial damage. Roles of low or high serum iron in patients with ischemic heart diseases are still controversial. Methods Serum samples for biochemical and immunologic analyses were collected from the 73 normal subjects and the 90 patients with ischemic heart disease (IHD), the latter of which were selected from 142 patients and classified by low, normal and high serum iron. Results Tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), high sensitive C-Reactive protein (hsCRP), and interleukin-10 (IL-10) were increased and insulin-like growth factor (IGF)-I was decreased in IHD patients with low serum iron, whereas these parameters were not changed in IHD patients with normal or high serum iron, compared with normal subjects. Total bilirubin was increased in IHD patients with high serum iron but was not changed in IHD patients with low or normal serum iron, compared with normal subjects. Conclusion The IHD patients with low serum iron were associated with a pro-inflammatory state, such as increased TNF-α, IL-6, and hsCRP; increased anti-inflammatory activities, such as increased IL-10; decreased cardiac protective factor, such as decreased IGF-I. These findings may imply that IHD patients with low serum irons were associated with less cardiac protection and more pro-inflammatory states than normal subjects or IHD patients with either normal or high serum iron.

Background Controversial effects of intermittent hypobaric hypoxia such as cardiac damage or cardiac protection are still mysterious. It is unclear if short-term and long-term intermittent hypobaric hypoxic challenges exert different effects on cytochrome c oxidase and Bcl-2 family in rat heart. Methods Sixty Sprague–Dawley rats were randomized assigned into two groups: first, short-term intermittent hypobaric hypoxia (STIHH)-normobaric normoxia ( n =10), hypobaric hypoxia (380 mmHg, 12% O 2 , 8 hr/day) for 1 day ( n =10), and for 4 days ( n =10) and second, long-term intermittent hypobaric hypoxia (LTIHH)-normobaric normoxia ( n =10), hypobaric hypoxia for 1 week ( n =10) and 2 weeks ( n =10). After STIHH or LTIHH challenge, myocardial morphology, cytochrome c oxidase and pro-apoptotic Bcl-2 family in the excised left ventricle were determined by histological analysis, Western blotting, and RT-PCR. Results Increased wall thickness and abnormal myocardial architecture were observed after LTIHH. Cytochrome c oxidase and anti-apoptotic Bcl-2 protein were significantly increased after STIHH, but were decreased after LTIHH. Pro-apoptotic BNIP3 and Bad proteins were significantly decreased after STIHH but increased after LTIHH. Conclusions STIHH appeared to exert protective effects on hearts whereas LTIHH appeared to exert deleterious effects, which imply that deleterious or advantageous effect of cardiac adaptation after intermittent hypobaric hypoxia is tightly time–course dependent.

This study was designed to determine the effects of 17beta-estradiol (E2) in overcoming the cardiac over-loading and cardiac fibrosis in rats. E2 (100 ng/kg) or oil was applied in female Sprague-Dawley rats with or without bilateral ovariectomy and with or without coarctation of the abdominal aorta after 4 or 8 days. By post-operative day 4, the heart weight, the left ventricular weight, the latent form of MMP-2 in rat hearts with or without the ovary intact had significantly increased while these changes were reversed after E2 treatment. Although animals with the ovaries intact overcame the hypertrophic effects and the consumption of MMP-2, these effects were not restored in ovariectomized animals in which more fibrosis could be found by day 8. Among the IGF-I signaling, the levels of IGF-I, the activities of PI3K-Akt for cardiomyocyte survival, and MEK-ERKs for non-cardiomyocyte proliferation pathways had significantly increased by day 4. These increasing trends were enhanced by E2 treatment. However, down-regulation was only observed on day 8 in ovariectomized animals. Similarly, elevated expressions of the steady-state mRNA of IGF-I, IGF-IR, and Cox vb were observed on day 4 in animals with the ovaries intact and these expressions were enhanced by E2 treatment. In contrast, down-regulation on day 8 in ovariectomized animals was not enhanced by E2. The calcineurin/NFAT-3 pathway was suppressed on day 4 but was elevated on day 8 in ovariectomized animals. These findings indicate that signaling pathways may be plausible mechanisms for the cardiac protective effects of E2 administration.

The known factors that have contributed to the decline of Helicobacter pylori (H. pylori) eradication rate include antibiotic resistance, poor compliance, high gastric acidity, high bacterial load, and cytochrome P450 2C19 (CYP2C19) polymorphism. Proton pump inhibitor (PPI) is important in the eradication regimen. The principal enzyme implicated in the metabolism of PPIs is CYP2C19. The effects of PPI depend on metabolic enzyme, cytochrome P450 enzymes, and CYP2C19 with genetic differences in the activity of this enzyme (the homozygous EM, heterozygous EM (HetEM), and poor metabolizer). The frequency of the CYP2C19 polymorphism is highly varied among different ethnic populations. The CYP2C19 genotype is a cardinal factor of H. pylori eradication in patients taking omeprazole- based or lansoprazole-based triple therapies. In contrast, the CYP2C19 polymorphism has no significant effect on the rabeprazole-based or esomeprazole-based triple therapies. The efficacy of levofloxacin-based rescue triple therapy might be also affected by the CYP2C19 polymorphism, but CYP2C19 genotypes did not show obvious impact on other levofloxacin-based rescue therapies. Choice of different PPIs and/or increasing doses of PPIs should be individualized based on the pharmacogenetics background of each patient and pharmacological profile of each drug. Other possible factors influencing gastric acid secretion (e.g., IL-1β- 511 polymorphism) would be also under consideration.

Objective. This study was designed to compare the effect ofHelicobacter pylori(H. pylori) infection treatment on serum zinc, copper, and selenium levels.Patients and Methods. We measured the serum zinc, copper, and selenium levels inH. pylori-positive andH. pylori-negative patients. We also evaluated the serum levels of these trace elements afterH. pylorieradication. These serum copper, zinc, and selenium levels were determined by inductively coupled plasma mass spectrometry.Results. Sixty-threeH. pylori-positive patients and thirtyH. pylori-negative patients were studied. Serum copper, zinc, and selenium levels had no significant difference betweenH. pylori-positive andH. pylori-negative groups. There were 49 patients with successfulH. pylorieradication. The serum selenium levels were lower after successfulH. pylorieradication, but not significantly (P=0.06). There were 14 patients with failedH. pylorieradication. In this failed group, the serum selenium level afterH. pylorieradication therapy was significantly lower than that beforeH. pylorieradication therapy (P<0.05). The serum zinc and copper levels had no significant difference between before and afterH. pylorieradication therapies.Conclusion.H pylorieradication regimen appears to influence the serum selenium concentration (IRB number: KMUH-IRB-20120327).

Background. It is urgent to find alternative agents due to increasing failure rate ofHelicobacter pylori (H. pylori) eradication. The study surveyed the long-term effect of silver nanoparticles (AgNP) onH. pyloribased on Mongolian gerbil’s model.Materials and Methods. Fifty gerbils were randomly allocated to six groups (A–F). Group (Gr) A: the gerbils were fed with broth; Gr B and D: the gerbils were fed with AgNP/clay complex (0.1% of weight); Gr C and E: the gerbils were fed with AgNP/clay complex(1% of weight); and Gr D, E, and F: the gerbils were inoculated withH. pylori. At the 20th experimental week, the gerbils were sacrificed. Histology was evaluated according to the classification of the Sydney system.P<0.05was considered to be statistically significant.Results. The AgNP/clay has more obvious inhibitory effect onH. pyloriin vitro. There was a trend of higher concentrations of AgNP with stronger inhibitory effect onH. pylorigrowth(P=0.071). There were no significant differences of inflammation among groups D, E, and F(P=0.688).Conclusion. AgNP/clay would be a potential and safe agent for inhibitingH. pylori. It should be helpful for eradication ofH. pyloriinfection.

Epidemiological studies demonstrate that the incidence and mortality of gastric cancer in women are lower than in men worldwide. Many studies have reported the delayed menopause and hormone replacement therapy are associated with a reduced risk for gastric cancer. It has been reported that endogenous estrogen lowers gastric cancer incidence in women, and cancer patients treated with estrogens have a lower subsequent risk of gastric cancer. It has been reported that estrogen decreases the progression of gastric cancer by inhibiting erbB-2 oncogene expression. Overexpression of estrogen receptor might inhibit the proliferation and invasion of MKN28 gastric cancer cells. Accumulating evidence suggests that bone marrow mesenchymal stem cells contribute to the progression of gastric cancer. However, it is unknown if 17β-estradiol (E2) treatment is sufficient to inhibit human bone marrow mesenchymal stem cells (HBMMSCs)-mediated cell motility in human gastric cancer cells. The results from human cytokine arrays have shown that HBMMSCs notably secrete interleukin 6 (IL-6) protein. Administration of IL-6–specific neutralizing antibody significantly inhibits HBMMSCs-mediated motility activity in human gastric cancer cells. Treatment of recombinant IL-6 soluble protein confirmed the role of IL-6 in mediating HBMMSCs-upregulated cell motility. IL-6 mainly upregulates motility activity via activation of Src signaling pathway in human gastric cancer cells. We further observed that E2 treatment inhibits HBMMSCs-induced cellular motility via suppressing the activation of IL-6−Src/Cas/paxillin signaling pathway in human gastric cancer cells. Collectively, these results suggest that E2 treatment significantly inhibits HBMMSCs-induced cellular motility in human gastric cancer cells.

Background. The suppression ofHelicobacter pylori(H. pylori) decreasesH. pylori-related diseases. The probiotics have an inhibitory effect onH. pylori.Aim. We investigated the effects of long-term use of yogurt onH. pyloribased on Mongolian gerbils’ model.Materials and Methods. Yogurt (containing a supplement ofLactobacillus acidophilus, Bifidobacterium lactis, etc.) was used. Forty-six gerbils were divided into five groups. All groups were inoculated withH. pylorifor 5 to 8 weeks. The yogurt was given as follows: Group (Gr.) A: from 1st to 4th week; Gr. B from 5th to 8th week; Gr. C: from 17th week to sacrifice; Gr. D: from 5th week to sacrifice. Gerbils were sacrificed on the 52nd week. Histology was evaluated according to the Sydney system.Results. The positive rates ofH. pyloriwere 60% (Gr. A), 75% (Gr. B), 67% (Gr. C), 44% (Gr. D), and 100% (Gr. E). Gr. D showed lower inflammatory score. Only Gr. E (60%) had intestinal metaplasia. Gr. D showed higher IL-10 and lower TNF-αexpression than Gr. E.Conclusion.Long-term intake of yogurt could decreaseH. pyloriinfection. The long-term use of yogurt would be an alternative strategy to manageH. pyloriinfection.

Because Helicobacter pylori (H pylori) would cause carcinogenesis of the stomach, we need sufficient information for deciding on an appropriate strategy of eradication. Many factors affect the efficacy of eradication including antimicrobial resistance (especially clarithromycin resistance) and CYP2C19 polymorphism. This study was to survey the efficiency of gastric juice for detecting H pylori infection, clarithromycin resistance, and CYP2C19 polymorphism. The specimens of gastric juice were collected from all patients while receiving gastroscopy. DNA was extracted from gastric juice and then urease A and cag A were amplified by polymerase chain reaction (PCR) for detecting the existence of H pylori. By PCR-restriction fragment length polymorphism (PCR-RFLP), the 23S rRNA of H pylori and CYP2C19 genotypes of host were examined respectively. During endoscopy examination, biopsy-based specimens were also collected for rapid urease test, culture, and histology. The blood samples were also collected for analysis of CYP2C19 genotypes. We compared the results of gastric juice tests with the results of traditional clinical tests. When compared with the results from traditional clinical tests, our results from gastric juice showed that the sensitivity (SEN), specificity (SPE), positive predictive value (PPV), negative predictive value (NPV), and accuracy to detect H pylori infection were 92.1% (105/114), 92.9% (143/154), 90.5% (105/116), 94.1% (143/152), and 92.5% (248/268), respectively. The SEN, SPE, PPV, and NPV to detect clarithromycin resistance were 97.3% (36/37), 91.5% (43/47), 90.0% (36/40), and 97.7% (43/44), respectively. By using PCR-RFLP, the consistency of human CYP2C19 gene polymorphism from blood samples and gastric juice was as high as 94.9% (149/157). The manipulated gastric juice is actually an effective diagnostic sample for evaluation of H pylori existence, clarithromycin resistance, and host CYP2C19 polymorphism.

This paper reviews the literature about first-line therapies forH. pyloriinfection in recent years. First-line therapies are facing a challenge because of increasing treatment failure due to elevated antibiotics resistance. Several new treatment strategies that recently emerged to overcome antibiotic resistance have been surveyed. Alternative first-line therapies include bismuth-containing quadruple therapy, sequential therapy, concomitant therapy, and hybrid therapy. Levofloxacin-based therapy shows impressive efficacy but might be employed as rescue treatment due to rapidly raising resistance. Rifabutin-based therapy is also regarded as a rescue therapy. Several factors including antibiotics resistance, patient compliance, and CYP 2C19 genotypes could influence the outcome. Clinicians should use antibiotics according to local reports. It is recommended that triple therapy should not be used in areas with high clarithromycin resistance or dual clarithromycin and metronidazole resistance.

Garlic oil has been reported to protect the cardiovascular system; however, the effects and mechanisms behind the cardioprotection of garlic oil on diabetes-induced cardiaomyopathy are unclear. In this study, we used streptozotocin (STZ)-induced diabetic rats to investigate whether garlic oil could protect the heart from diabetes-induced cardiomyopathy. Wistar STZ-induced diabetic rats received garlic oil (0, 10, 50 or 100 mg kg−1body weight) by gastric gavage every 2 days for 16 days. Normal rats without diabetes were used as control. Cardiac contractile dysfunction and cardiac pathologic hypertrophy responses were observed in diabetic rat hearts. Cardiac function was examined using echocardiography. In addition to cardiac hypertrophy-related mitogen-activated protein kinases (MAPK) pathways (e.g., p38, c-Jun N-terminal kinases (JNK) and extracellularly responsive kinase (ERK1/2)), the IL-6/MEK5/ERK5 signaling pathway was greatly activated in the diabetic rat hearts, which contributes to the up-regulation of cardiac pathologic hypertrophy markers including atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), and leads to cardiac contractile dysfunction. Garlic oil treatment significantly inhibited the up-regulation in MAPK (e.g., p38, JNK and ERK1/2) and IL-6/MEK5/ERK5 signaling pathways in the diabetic rat hearts, reducing the levels of cardiac pathologic hypertrophy markers such as ANP and BNP, and improving the cardiac contractile function. Collectively, data from these studies demonstrate that garlic oil shows the potential cardioprotective effects for protecting heart from diabetic cardiomyopathy.

Upregulation of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and matrix metallopeptidases (MMPs) is associated with the development of myocardial infarction (MI), dilated cardiomyopathy, cardiac fibrosis, and heart failure (HF). Evidences suggest that lipopolysaccharide (LPS) participates in the inflammatory response in the cardiovascular system; however, it is unknown if LPS is sufficient to upregulate expressions and/or activity of uPA, tPA, MMP-2, and MMP-9 in myocardial cells. In this study, we treated H9c2 cardiomyoblasts with LPS to explore whether LPS upregulates uPA, tPA, MMP-2, and MMP-9, and further to identify the precise molecular and cellular mechanisms behind this upregulatory responses. Here, we show that LPS challenge increased the protein levels of uPA, MMP-2 and MMP-9, and induced the activity of MMP-2 and MMP-9 in H9c2 cardiomyoblasts. However, LPS showed no effects on the expression of tissue inhibitor of metalloproteinase-1, -2, -3, and -4 (TIMP-1, -2, -3, and -4). After administration of inhibitors including U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor), CsA (calcineurin inhibitor), and QNZ (NFkappaB inhibitor), the LPS-upregulated expression and/or activity of uPA, MMP-2, and MMP-9 in H9c2 cardiomyoblasts are markedly inhibited only by ERK1/2 inhibitors, U0126. Collectively, these results suggest that LPS upregulates the expression and/or activity of uPA, MMP-2, and MMP-9 through ERK1/2 signaling pathway in H9c2 cardiomyoblasts. Our findings further provide a link between the LPS-induced cardiac dysfunction and the ERK1/2 signaling pathway that mediates the upregulation of uPA, MMP-2 and MMP-9.

Evidences suggest that lipopolysaccharide (LPS) participates in the inflammatory response in the cardiovascular system; however, it is unknown if LPS is sufficient to cause the cardiac hypertrophy. In the present study, we treated H9c2 myocardiac cells with LPS to explore whether LPS causes cardiac hypertrophy, and to identify the precise molecular and cellular mechanisms behind hypertrophic responses. Here we show that LPS challenge induces pathological hypertrophic responses such as the increase in cell size, the reorganization of actin filaments, and the upregulation of hypertrophy markers including atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in H9c2 cells. LPS treatment significantly promotes the activation of GATA-4 and the nuclear translocation of NFAT-3, which act as transcription factors mediating the development of cardiac hypertrophy. After administration of inhibitors including U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor), CsA (calcineurin inhibitor), FK506 (calcineurin inhibitor), and QNZ (NFkappaB inhibitor), LPS-induced hypertrophic characteristic features, such as increases in cell size, actin fibers, and levels of ANP and BNP, and the nuclear localization of NFAT-3 are markedly inhibited only by calcineurin inhibitors, CsA and FK506. Collectively, these results suggest that LPS leads to myocardiac hypertrophy through calcineurin/NFAT-3 signaling pathway in H9c2 cells. Our findings further provide a link between the LPS-induced inflammatory response and the calcineurin/NFAT-3 signaling pathway that mediates the development of cardiac hypertrophy.

Background Epidemiological studies demonstrate that the incidence and mortality rates of colorectal cancer in women are lower than in men. However, it is unknown if 17β-estradiol treatment is sufficient to inhibit prostaglandin E2 (PGE2)-induced cellular motility in human colon cancer cells. Methods We analyzed the protein expression of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), matrix metallopeptidases (MMPs), plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinases (TIMPs), and the cellular motility in PGE2-stimulated human LoVo cells. 17β-Estradiol and the inhibitors including LY294002 (Akt activation inhibitor), U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor), QNZ (NFκB inhibitor) and ICI 182 780 were further used to explore the inhibitory effects of 17β-estradiol on PGE2-induced LoVo cell motility. Student's t-test was used to analyze the difference between the two groups. Results Upregulation of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA) and matrix metallopeptidases (MMPs) is reported to associate with the development of cancer cell mobility, metastasis, and subsequent malignant tumor. After administration of inhibitors including LY294002, U0126, SB203580, SP600125 or QNZ, we found that PGE2 treatment up-regulated uPA and MMP-9 expression via JNK1/2 signaling pathway, thus promoting cellular motility in human LoVo cancer cells. However, PGE2 treatment showed no effects on regulating expression of tPA, MMP-2, plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinase-1, -2, -3 and -4 (TIMP-1, -2, -3 and -4). We further observed that 17β-estradiol treatment inhibited PGE2-induced uPA, MMP-9 and cellular motility by suppressing activation of JNK1/2 in human LoVo cancer cells. Conclusions Collectively, these results suggest that 17β-estradiol treatment significantly inhibits PGE2-induced motility of human LoVo colon cancer cells.

Background The acid-suppressive agents have been linked with an increased risk of infectious disease. The relationship between these drugs and Mycobacterium Tuberculosis (TB) was not been reported. Methods We conducted a case–control study using data from National Health Insurance research database of Taiwan. From 1996 till 2008, and 6541 cases were defined as TB infection/activation (ICD-9 coding plus prescription two of four first-line anti-TB regimen for at least one month). Control subjects who were matched to the TB cases by age and sex were selected with 10:1 ratio. Medical records including acid-suppressive agent prescription and comorbidity, and socioeconomic status were analyzed. Results TB infection/activation was more frequent to comorbidity with chronic diseases, alcohol abuse, malignancy, immune deficient/suppression status and acid-related disease (peptic ulcer, reflux esophagitis). Among the TB cases, there was higher exposure record to acid-suppressive agents within 3 months before TB index date (OR 2.43(2.06-2.88) and 1.90 (1.68-2.14) for proton pump inhibitor (PPI) and histamine 2 receptor antagonist (H2RA) respectively). After adjusting confounding factors, PPIs prescription 3 months before TB index date had an association of TB infection/activation (adjusted OR 1.63(1.61-1.63)). Similar result was found in H2RA user (adjusted OR 1.51(1.50-1.52)). The association of acid-suppressive agents in TB infection/activation was fade gradually when the drug prescription period extended. Conclusions Recent prescription of acid-suppressive agent seems to associate the TB infection/activation. In the society where TB was prevalent, evaluation of pulmonary TB before prescription of PPI or H2RA is warranted.