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The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

Mitophagy, a mitochondria-specific form of autophagy, removes dysfunctional mitochondria and is hence an essential process contributing to mitochondrial quality control. PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin are critical molecules involved in stress-induced mitophagy, but the intracellular signaling mechanisms by which this pathway is regulated are unclear. We tested the hypothesis that signaling through RhoA, a small GTPase, induces mitophagy via modulation of the PINK1/Parkin pathway as a protective mechanism against ischemic stress. We demonstrate that expression of constitutively active RhoA as well as sphingosine-1-phosphate induced activation of endogenous RhoA in cardiomyocytes result in an accumulation of PINK1 at mitochondria. This is accompanied by translocation of Parkin to mitochondria and ubiquitination of mitochondrial proteins leading to recognition of mitochondria by autophagosomes and their lysosomal degradation. Expression of RhoA in cardiomyocytes confers protection against ischemia, and this cardioprotection is attenuated by siRNA-mediated PINK1 knockdown. In vivo myocardial infarction elicits increases in mitochondrial PINK1, Parkin, and ubiquitinated mitochondrial proteins. AAV9-mediated RhoA expression potentiates these responses and a concurrent decrease in infarct size is observed. Interestingly, induction of mitochondrial PINK1 accumulation in response to RhoA signaling is neither mediated through its transcriptional upregulation nor dependent on depolarization of the mitochondrial membrane, the canonical mechanism for PINK1 accumulation. Instead, our results reveal that RhoA signaling inhibits PINK1 cleavage, thereby stabilizing PINK1 protein at mitochondria. We further show that active RhoA localizes at mitochondria and interacts with PINK1, and that the mitochondrial localization of RhoA is regulated by its downstream effector protein kinase D. These findings demonstrate that RhoA activation engages a unique mechanism to regulate PINK1 accumulation, induce mitophagy and protect against ischemic stress, and implicates regulation of RhoA signaling as a potential strategy to enhance mitophagy and confer protection under stress conditions., (© 2022. The Author(s).)

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

The available COVID-19 literature has focused on specific disease manifestations, infection control, and delivery or prioritization of services for specific patient groups in the setting of the acute COVID-19 pandemic. Local health systems aim to contain the COVID-19 pandemic and hospitals and health-care providers rush to provide the capacity for a surge of COVID-19 patients. However, the short, medium-term, and long-term outcomes of patients with gastrointestinal (GI) diseases without COVID-19 will be affected by the ability to develop locally adapted strategies to meet their service needs in the COVID-19 setting. To mitigate risks for patients with GI diseases, it is useful to differentiate three phases: (i) the acute phase, (ii) the adaptation phase, and (iii) the consolidation phase. During the acute phase, service delivery for patients with GI disease will be curtailed to meet competing health-care needs of COVID-19 patients. During the adaptation phase, GI services are calibrated towards a "new normal," and the consolidation phase is characterized by rapid introduction and ongoing refinement of services. Proactive planning with engagement of relevant stakeholders including consumer representatives is required to be prepared for a variety of scenarios that are dictated by thus far undefined long-term economic and societal impacts of the pandemic. Because substantial changes to the delivery of services are likely to occur, it is important that these changes are embedded into quality and research frameworks to ensure that data are generated that support evidence-based decision-making during the adaptation and consolidation phases., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Preservation of mitochondrial integrity is critical for maintaining cellular homeostasis. Mitophagy is a mitochondria-specific type of autophagy which eliminates damaged mitochondria thereby contributing to mitochondrial quality control. Depolarization of the mitochondrial membrane potential is an established mechanism for inducing mitophagy, mediated through PINK1 stabilization and Parkin recruitment to mitochondria. Hexokinase-II (HK-II) which catalyzes the first step in glucose metabolism, also functions as a signaling molecule to regulate cell survival, and a significant fraction of cellular HK-II is associated with mitochondria (mitoHK-II). We demonstrate here that pharmacological interventions and adenoviral expression of a mitoHK-II dissociating peptide which reduce mitoHK-II levels lead to robust increases in mitochondrial Parkin and ubiquitination of mitochondrial proteins in cardiomyocytes and in a human glioblastoma cell line 1321N1, independent of mitochondrial membrane depolarization or PINK1 accumulation. MitoHK-II dissociation-induced mitophagy was demonstrated using Mito-Keima in cardiomyocytes and in 1321N1 cells. Subjecting cardiomyocytes or the in vivo heart to ischemia leads to modest dissociation of mitoHK-II. This response is potentiated by expression of the mitoHK-II dissociating peptide, which increases Parkin recruitment to mitochondria and, importantly, provides cardioprotection against ischemic stress. These results suggest that mitoHK-II dissociation is a physiologically relevant cellular event that is induced by ischemic stress, the enhancement of which protects against ischemic damage. The mechanism which underlies the effects of mitoHK-II dissociation can be attributed to the ability of Bcl2-associated athanogene 5 (BAG5), an inhibitor of Parkin, to localize to mitochondria and form a molecular complex with HK-II. Overexpression of BAG5 attenuates while knockdown of BAG5 sensitizes the effect of mitoHK-II dissociation on mitophagy. We suggest that HK-II, a glycolytic molecule, can function as a sensor for metabolic derangements at mitochondria to trigger mitophagy, and modulating the intracellular localization of HK-II could be a novel way of regulating mitophagy to prevent cell death induced by ischemic stress.

In Parkinson's disease (PD), several genes have been identified as the PD-related genes, however, the regulatory mechanisms of these gene expressions have not been fully identified. In this study, we investigated the effect of inflammation, one of the major risk factors in PD on expressions of the PD-related genes. Lipopolysaccharide (LPS) was intraperitoneally administered to mature male zebrafish and gene expressions in the brains were examined by real-time PCR. In the inflammation-related genes, expressions of tnfb, il1b and il6 were increased at 2 days post administration in the 10 μg group, and tnfb expression was also increased at 4 days post administration in the 1 μg and 10 μg group. In the PD-related genes, pink1 expression was significantly decreased at 4 days, atp13a2 expression was significantly increased at 7 days, and uchl1 expression was significantly decreased at 7 days. This suggests that pink1, atp13a2 and uchl1 expressions are regulated by inflammation, and this regulatory mechanism might be involved in the progress of PD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: There is an escalation of frequency and magnitude of dengue epidemics in Malaysia, with a concomitant increase in patient hospitalization. Prolonged hospitalization (PH) due to dengue virus (DENV) infections causes considerable socioeconomic burden. Early identification of patients needing PH could optimize resource consumption and reduce health care costs. This study aims to identify clinicopathological factors present on admission that are associated with PH among patients with DENV infections. Methods: This study was conducted in a tertiary referral hospital in Southern Malaysia. Relevant clinical and laboratory data upon admission were retrieved from medical records of 253 consecutive DENV nonstructural protein 1 (NS1) antigen and PCR-positive hospitalized patients. The DENV serotype present in each patient was determined. Patients were stratified based on duration of hospital stay (<4 vs. ≥4 days). Data were analyzed using IBM ® SPSS ® 25.0. Multivariate logistic regression was performed to examine the association between PH and admission parameters. Results: Of 253 DENV hospitalized patients, 95 (37.5%) had PH (≥4 days). The mean duration of hospital stay was 3.43 ± 2.085 days (median = 3 days, interquartile range = 7 days). Diabetes mellitus (adjusted odds ratio [AOR] = 6.261, 95% confidence interval [CI] = 2.130-18.406, p  = 0.001), DENV-2 serotype (AOR = 2.581, 95% CI = 1.179-5.650, p  = 0.018), duration of fever ≤4 days (AOR = 2.423, 95% CI = 0.872-6.734, p  = 0.09), and a shorter preadmission fever duration (AOR = 0.679, 95% CI = 0.481-0.957, p  = 0.027) were independently associated with PH. However, PH was not found to be associated with symptoms on admission, secondary DENV infections or platelet count, hematocrit, or liver enzyme levels on admission. Conclusions: Early identification of these factors at presentation may alert clinicians to anticipate and recognize challenges in treating such patients, leading to more focused management plans that may shorten the duration of hospitalization.

Cardiac ischemia/reperfusion, loss of blood flow and its subsequent restoration, causes damage to the heart. Oxidative stress from ischemia/reperfusion leads to dysfunction and death of cardiomyocytes, increasing the risk of progression to heart failure. Alterations in mitochondrial dynamics, in particular mitochondrial fission, have been suggested to play a role in cardioprotection from oxidative stress. We tested the hypothesis that activation of RhoA regulates mitochondrial fission in cardiomyocytes. Our studies show that expression of constitutively active RhoA in cardiomyocytes increases phosphorylation of Dynamin-related protein 1 (Drp1) at serine-616, and leads to localization of Drp1 at mitochondria. Both responses are blocked by inhibition of Rho-associated Protein Kinase (ROCK). Endogenous RhoA activation by the GPCR agonist sphingosine-1-phosphate (S1P) also increases Drp1 phosphorylation and its mitochondrial translocation in a RhoA and ROCK dependent manner. Consistent with the role of mitochondrial Drp1 in fission, RhoA activation in cardiomyocytes leads to formation of smaller mitochondria and this is attenuated by inhibition of ROCK, by siRNA knockdown of Drp1 or by expression of a phosphorylation-deficient Drp1 S616A mutant. In addition, activation of RhoA prevents cell death in cardiomyocytes challenged by oxidative stress and this protection is blocked by siRNA knockdown of Drp1 or by Drp1 S616A expression. Taken together our findings demonstrate that RhoA activation can regulate Drp1 to induce mitochondrial fission and subsequent cellular protection, implicating regulation of fission as a novel mechanism contributing to RhoA-mediated cardioprotection., (Copyright © 2018. Published by Elsevier Inc.)

Physical activity is essential for optimal bone strength accrual, but we know little about interactions between physical activity, sedentary time, and bone outcomes in older adolescents. Physical activity (by accelerometer and self-report) positively predicted bone strength and the distal and midshaft tibia in 15-year-old boys and girls. Lean body mass mediated the relationship between physical activity and bone strength in adolescents., Purpose: To examine the influence of physical activity (PA) and sedentary time on bone strength, structure, and density in older adolescents., Methods: We used peripheral quantitative computed tomography to estimate bone strength at the distal tibia (8% site; bone strength index, BSI) and tibial midshaft (50% site; polar strength strain index, SSI p ) in adolescent boys (n = 86; 15.3 ± 0.4 years) and girls (n = 106; 15.3 ± 0.4 years). Using accelerometers (GT1M, Actigraph), we measured moderate-to-vigorous PA (MVPA Accel ), vigorous PA (VPA Accel ), and sedentary time in addition to self-reported MVPA (MVPA PAQ-A ) and impact PA (ImpactPA PAQ-A ). We examined relations between PA and sedentary time and bone outcomes, adjusting for ethnicity, maturity, tibial length, and total body lean mass., Results: At the distal tibia, MVPA Accel and VPA Accel positively predicted BSI (explained 6-7% of the variance, p < 0.05). After adjusting for lean mass, only VPA Accel explained residual variance in BSI. At the tibial midshaft, MVPA Accel , but not VPA Accel , positively predicted SSI p (explained 3% of the variance, p = 0.01). Lean mass attenuated this association. MVPA PAQ-A and ImpactPA PAQ-A also positively predicted BSI and SSI p (explained 2-4% of the variance, p < 0.05), but only ImpactPA PAQ-A explained residual variance in BSI after accounting for lean mass. Sedentary time did not independently predict bone strength at either site., Conclusion: Greater tibial bone strength in active adolescents is mediated, in part, by lean mass. Despite spending most of their day in sedentary pursuits, adolescents' bone strength was not negatively influenced by sedentary time.

Functional dyspepsia (FD) is a common disorder in East and Southeast Asia where subjects experience post prandial fullness/bloating, early satiety, belching, epigastric pain, and/or burning. A subset of patients with FD experience triggers exclusively related to meals, defined as the post prandial distress syndrome in the Rome IV guidelines. There is significant overlap of symptoms and implicated pathogenic factors with another common functional gastrointestinal disorder, irritable bowel syndrome (IBS) and in fact, a significant proportion of subjects have FD/IBS overlap. The introduction of the low-FODMAP diet has changed the paradigm of treatment for IBS. Like IBS, dietary management appears to be important to patients with FD and clinicians treating the condition. This review aims to examine the current role of diet in the management of FD in East and Southeast Asia, with an exploration of the likely efficacy and mechanisms of action of the low-FODMAP diet in this region., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Gut dysbiosis may contribute to pain and bloating in patients with functional gastrointestinal disease., Aims: To determine if treatment with rifaximin would improve the symptoms of functional dyspepsia in Chinese patients in a double-blinded, randomised, placebo-controlled trial., Methods: Consecutive subjects with a diagnosis of functional dyspepsia as per the Rome III criteria were randomised to receive rifaximin 400 mg or placebo, all taken three times daily for 2 weeks. The investigators and study subjects were blinded to the treatment allocation. Subjects were followed up for 8 weeks. The primary end point was adequate relief of global dyspeptic symptoms (GDS). Secondary endpoints were relief of individual dyspeptic symptoms., Results: Eighty-six subjects were recruited. At week 8, there were significantly more subjects in the rifaximin than in the placebo group who experienced adequate relief of GDS (78% vs. 52%, P = 0.02). A trend favouring rifaximin group was also noted in the preceding 4 weeks. Rifaximin was also superior to placebo in providing adequate relief of belching and post-prandial fullness/bloating (PPF) in subjects at week 4. Subgroup analysis revealed that female subjects had more significant response to rifaximin treatment (adequate relief of GDS at week 4: 76% vs. 42%, P = 0.006; week 8: 79% vs. 47%, P = 0.008), as well as improvements in their belching and PPF at week 4. The incidences of adverse effects were similar in both groups., Conclusions: Treatment with 2 weeks of rifaximin led to adequate relief of global dyspeptic symptoms, belching and post-prandial fullness/bloating in subjects with functional dyspepsia. The difference was more marked in females. (clinicaltrials.org NCT01643083)., (© 2017 John Wiley & Sons Ltd.)

The ability of adult cardiomyocytes to regenerate is limited, and irreversible loss by cell death plays a crucial role in heart diseases. Autophagy is an evolutionarily conserved cellular catabolic process through which long-lived proteins and damaged organelles are targeted for lysosomal degradation. Autophagy is important in cardiac homeostasis and can serve as a protective mechanism by providing an energy source, especially in the face of sustained starvation. Cellular metabolism is closely associated with cell survival, and recent evidence suggests that metabolic and autophagic signaling pathways exhibit a high degree of crosstalk and are functionally interdependent. In this review, we discuss recent progress in our understanding of regulation of autophagy and its crosstalk with metabolic signaling, with a focus on the nutrient-sensing mTOR complex 1 (mTORC1) pathway., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background and Aims: The prevalence of gastroesophageal reflux disease (GERD) is consistently lower in the Chinese than in white populations. Population-based data tracking the time trend of GERD prevalence in Chinese subjects is conflicting. This study examines the population prevalence, risk factors, and time trend associated with GERD in a Chinese population., Methods: A population-based cross-sectional study utilizing a validated GERD questionnaire administered by a telephone survey was performed on 3360 Chinese subjects from Hong Kong. GERD prevalence rates in 2011 were compared with prevalence rates in 2002 and 2006. Multiple logistic regressions were performed to determine the risk factors associated with weekly GERD., Results: A total of 2074 subjects (mean age, 48.1±18.2 y; range 18 to 94; 63.1% female) completed the survey (response rate 61.7%). The prevalence of GERD as defined by the Montreal definition was 3.8%. The prevalence of weekly GERD had increased by 1.3% between 2002 and 2011, which represents an at least 50% relative increase (P<0.0005). A diagnosis of weekly GERD was associated with noncardiac chest pain [odds ratio (OR), 1.7; 95% confidence interval (CI), 1.034-2.9; P=0.037], dyspepsia (OR, 5.1; 95% CI, 3.0-8.8; P<0.005), and an acid feeling in the stomach (OR, 3.0; 95% CI, 1.8-5.1)., Conclusions: GERD rates in the ethnic Chinese have risen over the last decade. Despite this, variables associated with a survey diagnosis of GERD remain ostensibly unchanged. GERD research in East Asia should focus on the factors driving the rapid rise in prevalence rates and the association with more atypical symptoms of GERD.

Hexokinases (HKs) catalyze the first step of glucose metabolism, phosphorylating glucose to glucose 6-phosphate (G6P). HK2/hexokinase-II is a predominant isoform in insulin-sensitive tissues such as heart, skeletal muscle, and adipose tissues and is also upregulated in many types of tumors associated with enhanced aerobic glycolysis (the Warburg effect). Accumulating evidence indicates that HK2 plays an important role not only in glycolysis but also in cell survival. Although there is increasing recognition that cellular metabolism and cell survival are closely related, the molecular link between metabolism and autophagic pathways has not been fully elucidated. We recently discovered that HK2 facilitates autophagy in response to glucose deprivation (HK substrate deprivation) to protect cardiomyocytes, and suggest that HK2 functions as a molecular switch from glycolysis to autophagy to ensure cellular energy homeostasis under starvation conditions.

Multiple reports have documented unsuspected inguinal hernias which result in difficulties during the colonoscopic examinations of patients. In most cases, the colonoscopy can be delayed until a surgical consult has further evaluated the inguinal hernia. This case report documents a patient who required a colonoscopy but surgical intervention for the detected inguinal hernia was not appropriate due to his co-morbid medical conditions. With the use of the combination of an enteroscope fitted with a cap and fluoroscopy, the inguinal hernia was able to be negotiated and the diagnosis of a cecal carcinoma was able to be confirmed.

A preponderance of evidence from systematic reviews supports the effectiveness of weight-bearing exercises on bone mass accrual, especially during the growing years. However, only one systematic review (limited to randomized controlled trials) examined the role of physical activity (PA) on bone strength. Thus, our systematic review extended the scope of the previous review by including all PA intervention and observational studies, including organized sports participation studies, with child or adolescent bone strength as the main outcome. We also sought to discern the skeletal elements (eg, mass, structure, density) that accompanied significant bone strength changes. Our electronic-database, forward, and reference searches yielded 14 intervention and 23 observational studies that met our inclusion criteria. We used the Effective Public Health Practice Project (EPHPP) tool to assess the quality of studies. Due to heterogeneity across studies, we adopted a narrative synthesis for our analysis and found that bone strength adaptations to PA were related to maturity level, sex, and study quality. Three (of five) weight-bearing PA intervention studies with a strong rating reported significantly greater gains in bone strength for the intervention group (3% to 4%) compared with only three significant (of nine) moderate intervention studies. Changes in bone structure (eg, bone cross-sectional area, cortical thickness, alone or in combination) rather than bone mass most often accompanied significant bone strength outcomes. Prepuberty and peripuberty may be the most opportune time for boys and girls to enhance bone strength through PA, although this finding is tempered by the few available studies in more mature groups. Despite the central role that muscle plays in bones' response to loading, few studies discerned the specific contribution of muscle function (or surrogates) to bone strength. Although not the focus of the current review, this seems an important consideration for future studies., (© 2014 American Society for Bone and Mineral Research.)

Awareness is increasing that risk of venous thromboembolism and development of atherosclerosis is elevated in patients with some chronic inflammatory diseases. This review aimed to examine the risk of vascular disease in patients with inflammatory bowel disease (IBD) and to identify potential pathogenic mechanisms and therapeutic approaches. An extensive literature search was conducted using MEDLINE database, Cochrane Library and international conference abstracts for studies pertaining to venous and arterial thromboembolism in adult IBD patients. There is a 1.1-3.6 fold risk of venothromboembolism in IBD, affecting 0.55-6.15% of patients. Risks are increased during a flare or with chronically active inflammation. Evidence is building that there may be a modestly increased risk of arterial disease overall, despite evidence that traditional risk factors may be reduced. Multiple pathogenic factors have been identified including endothelial dysfunction, inflammation-mediated calcium deposition in the media of arteries, hyperhomocysteinemia, platelet activation, and altered coagulation and fibrinolysis. The key to active and preventive therapy is to effectively treat inflammation. Recommendations for prophylaxis of venothromboembolism have followed guidelines where they exist and have been extrapolated from studies of other at-risk conditions, as have those for arterial disease, where screening for risk factors and actively treating abnormalities is encouraged. In conclusion, patients with IBD are at considerably increased risk of venothromboembolism and probably of arterial disease, in particular mesenteric ischemia and ischemic heart disease. Increased penetration of gaps between this knowledge and clinical therapeutic action to prevent thromboembolic events into IBD clinical practice is needed., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Incarceration of an endoscope in an inguinal hernia may occur during the course of routine colonoscopy. The incarceration may occur on insertion or withdrawal and frequently the hernia is not suspected prior to the colonoscopy. Most commonly, a left sided inguinal hernia is involved, however right inguinal hernias may be implicated in subjects with altered anatomy post abdominal surgery. Incarceration of an endoscope in an inguinal hernia has been seldom reported in the literature which is likely to be related to under reporting. A range of techniques have been suggested by various authors over the last four decades to manage this unusual complication of colonoscopy. These techniques include utilizing fluoroscopy, manual external pressure and/or the fitting of a cap onto the tip of the colonoscope to facilitate colonoscopic navigation. The authors present a case report of incarceration of the colonoscope on withdrawal in an unsuspected left inguinal hernia with a review of the literature on the management of this colonoscopic complication. A management strategy is suggested.

Chemoprevention may form the cornerstone in the management of gastric adenocarcinoma of the future. Helicobacter pylori eradication and aspirin and/or nonsteroidal anti-inflammatory drug therapy have emerged as front-runner chemotherapeutic agents due to the putative pathogenic mechanisms that they address. Before a population-based chemopreventive strategy can be recommended on a large scale, randomized controlled trials with follow-up of more than 10 years of these 2 agents in populations at high gastric adenocarcinoma risk is urgently awaited., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aim: To evaluate sertraline, a selective serotonin reuptake inhibitor in the treatment of patients with functional dyspepsia., Methods: Consecutive tertiary hospital patients with a clinical diagnosis of functional dyspepsia (FD) according to the Rome II criteria with a Hong Kong dyspepsia index (HKDI) of greater than 16 were recruited. Patients commenced enrolment prior to the inception of the Rome III criteria for functional dyspepsia. All patients were ethnic Chinese, had a normal upper endoscopy and were Helicobacter pylori negative prior to enrolment. Study patients were randomized to receive sertraline 50 mg or placebo daily for 8 wk. HKDI symptom scores, quality of life, hospital anxiety and depression (HAD) scale and global symptom relief were evaluated before, during and after treatment. Adverse effects were monitored during and after treatment., Results: A total of 193 patients were randomized in the intention to treat (ITT), and 150 patients were included in the per protocol (PP) analysis. In both the ITT and PP, there was no difference in the primary outcome of global dyspepsia symptoms between the sertraline and placebo groups at week 8. In the ITT analysis, 98 and 95 patients were randomized to the sertraline and placebo groups respectively. A total of 43 patients withdrew from the study (22.3%) by week 8, with 23 of the 24 drop-outs in the sertraline group occurring prior to week 4 (95.8%). In contrast, in the placebo arm, 11 of 19 patients dropped out by week 4 (57.9%). Utilizing the last response carried forward to account for the drop-outs, there were no differences between the sertraline and placebo groups at baseline in terms of the HKDI, HKDI 26.08 ± 6.19 vs 26.70 ± 5.89, P = 0.433; and at week 8, HKDI 22.41 ± 6.36 vs 23.25 ± 7.30, P = 0.352 respectively. In the PP analysis, 74 and 76 patients were randomized to the sertraline and placebo groups respectively. At baseline, there were no statistically significant differences between the sertraline and placebo groups, HKDI 25.83 ± 6.313 vs 27.19 ± 5.929 respectively, P = 0.233; however by week 8, patients in the sertraline group demonstrated a statistically significant difference in their Hong Kong Dyspepsia Index compared to placebo, HKDI 20.53 ± 6.917 vs 23.34 ± 7.199, P = 0.02, respectively). There was also no statistically significant difference in overall quality of life measures or the HAD scale related to treatment in either the ITT or PP analysis at week 8., Conclusion: This pilot study, the first to examine sertraline, a selective serotonin reuptake inhibitor, for the management of FD, did not find that it was superior to placebo.

The role of X chromosome-linked inhibitor of apoptosis protein (XIAP)-associated factor 1 (XAF1) in mediating apoptosis has been reported but the underlying mechanism remains unclear. The present study was designed to examine the putative interaction between XAF1 and p53 and the functional importance of this interaction in regulation of apoptosis in human gastric and colon cancer cells. We first identified XAF1 as a novel target gene of p53 by the chromatin immunoprecipitation (CHIP) assay and demonstrated that wild-type p53, but not mutant p53, down-regulated XAF1 at both mRNA and protein levels, which acted mostly under the condition of high expression of XAF1 and was associated with the physical interaction between p53 and the XAF1 promoter. We also found that the over-expression of XAF1 led to activation of wild-type p53 via post-translational modification in cells with or without DNA damage, which resulting in p53 nuclear accumulation and its increased transcriptional activity and enhancing p53-dependent apoptosis. These findings suggest that a potential novel feedback loop exists between XAF1 and wild-type p53., (Copyright © 2011 Wiley Periodicals, Inc.)

Xanthomonas oryzae pv. oryzae (Xoo) is a plant bacterial pathogen that causes bacterial blight (BB) disease, resulting in serious production losses of rice. The crystal structure of malonyl CoA-acyl carrier protein transacylase (XoMCAT), encoded by the gene fabD (Xoo0880) from Xoo, was determined at 2.3 Å resolution in complex with N-cyclohexyl-2-aminoethansulfonic acid. Malonyl CoA-acyl carrier protein transacylase transfers malonyl group from malonyl CoA to acyl carrier protein (ACP). The transacylation step is essential in fatty acid synthesis. Based on the rationale, XoMCAT has been considered as a target for antibacterial agents against BB. Protein-protein interaction between XoMCAT and ACP was also extensively investigated using computational docking, and the proposed model revealed that ACP bound to the cleft between two XoMCAT subdomains.

Clopidogrel is a pro-drug which is converted to an active metabolite that selectively blocks ADP-dependent platelet activation and aggregation. The main enzyme responsible for activating clopidogrel is the cytochrome P450 (CYP) isoenzyme CYP2C19, which is polymorphic. There is a growing body of literature showing that carriers of variant CYP2C19 alleles have impaired ability to metabolize clopidogrel (i.e. poor metabolizers), which is associated with decreased inhibition of platelet aggregation and increased cardiovascular risk. Some proton pump inhibitors are also metabolized by the CYP2C19 enzyme and often given together with clopidogrel to reduce gastrointestinal side effects. In particular, omeprazole has been shown to inhibit the CYP-mediated metabolism of clopidogrel, and some studies have shown that the combination was associated with a higher incidence of cardiovascular adverse reactions than clopidogrel given alone. However, a recent randomized controlled trial demonstrated no significant difference in adverse cardiovascular events for patients on the combination of clopidogrel and omeprazole compared with clopidogrel alone. This current review aims to summarize the role of pharmacogenetics and drug interactions in determining variability in response to clopidogrel., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Background: Evidence suggests that rates of gastroesophageal reflux disease are increasing in the Asia-Pacific region, where patients tend to have predominantly non-erosive reflux disease as opposed to erosive (reflux) esophagitis. At present, data for the responsiveness of non-erosive reflux disease to proton pump inhibition are scant. We aimed to study esomeprazole for the treatment of non-erosive reflux disease in Chinese patients., Methods: Patients with a clinical diagnosis of gastroesophageal reflux, and a locally validated reflux index, the Chinese GerdQ, of equal to or greater than 12 were recruited and randomized to receive esomeprazole 20 mg daily or placebo for 8 weeks. Reflux index scores, quality of life (SF-36), and the hospital anxiety and depression (HAD) scale and symptom relief were evaluated before, during, and after treatment., Results: A total of 175 patients were randomized. Patients in the esomeprazole group (n = 85) demonstrated statistically significant reductions in their GerdQ index, from 19.45 to 15.37 and to 14.32 (p = 0.013, p = 0.005) at weeks 4 and 8, respectively. Compared to placebo at week 8, 57.1% of patients on esomeprazole found that their symptoms had resolved or were acceptable compared with 37.2% in the placebo group (p = 0.001). There were no statistically significant differences in overall quality-of-life measures or the HAD scale related to treatment., Conclusions: This study suggests that esomeprazole is efficacious in treating Chinese patients with non-erosive reflux disease.

XIAP-associated factor 1(XAF1) is a tumor suppressor with its functional mechanisms not fully understood. The zinc-finger cluster located at the N-terminus is the only domain structure. Four and a half LIM domain protein 2 (FHL2) also contains a tandem zinc finger structure, and its protein functions as an important adaptor and modifier in protein-protein interactions. Both of their structures are relatively simple, while the association between them is still unclear. In this study, we detected the interaction between XAF1 and FHL2 by using the yeast two-hybrid system. We identified FHL2 as a XAF1 binding protein. Furthermore, both XAF1 and FHL2 localized to the cytoplasm, mitochondria, and nucleus of gastric cancer cells. Over-expression of XAF1 excluded FHL2 from the nucleus and suppressed the trans-activity of FHL2 in stimulating the transcriptional activities of β-catenin and AP-1. In conclusion, our findings unraveled an antagonistic mechanism between a tumor suppressor and an oncoprotein in cancer cells., (Copyright © 2010 Wiley-Liss, Inc.)

E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT), which plays a crucial role in cancer metastasis. We previously demonstrated that four and a half LIM protein 2 (FHL2) inhibited E-cadherin expression and promoted invasive potential and EMT in colon cancer. Here, we aim to further define the mechanism underlying the inhibition of E-cadherin by FHL2 in colon cancer. The expression profiles of FHL2 and Snail1 were first observed by Western blot, immunofluorescence and immunohistochemistry. We found that both the protein level and the cellular localisation of Snail1 were quite similar to FHL2 in colon cancer; reciprocal co-immunoprecipitation assay showed that FHL2 was able to bind Snail1 and its intact structure was required. The expression of FHL2 was positively correlated to Snail1 while negatively to E-cadherin and phospho-Snail1. FHL2 over-expression induced the accumulation of Snail1 in the nucleus. Moreover, dual luciferase assay revealed that FHL2 over-expression decreased while FHL2 siRNA increased the transcriptional activities of two E-cadherin promoter constructs which contained E-box sites (Snail1-binding elements). Mutation of E-boxes increased the transcriptional activities and FHL2 expression was involved in the function of mutation. These results suggested that FHL2 negatively regulated E-cadherin transcriptional activity through interaction with Snail1. Our study established a novel regulatory function of FHL2 and revealed a potential mechanism on promoting the process of EMT., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Since its' introduction by Warren and Marshall 27 years ago, Helicobacter pylori (HP) has become the linchpin in our understanding of important gastric conditions including gastritis, intestinal metaplasia (IM), gastric/duodenal ulcers (GU/DU), Mucosal Associated Lymphoid Tumour (MALToma) and gastric cancer. Initially named Campylobacter pyloridis, it was re-named HP when biochemical and genetic characterization of the organism showed that it was not a member of the Campylobacter genus. The finding in 1983 was seminal. It is now recognized that HP is the most common chronic human bacterial infection and it is the most common cause of gastritis. It is strongly implicated in the development of peptic ulcer disease and gastric neoplasms. In the years since its' discovery, much headway has been made in the understanding of this ubiquitous organism that had remained elusive, with much work focused on eradication, in part driven by pharmaceutical research and development. Standard triple therapy emerged to eradicate HP. However, with the emergence of HP resistance, newer regimes have been put forth that include quadruple therapy, sequential therapy and a dizzying array of other combinations bent on eradicating HP. Much less is known about the natural history of HP, the different faces of HP internationally, HP eradication and its effect on gastritis, IM, GU/DU and gastric cancer. This review will address the changing face of HP in 2011., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background & Aims: There is controversy about the efficacy of treating patients with laryngopharyngeal reflux (LPR) using proton pump inhibitors (PPIs). We assessed the effects of high doses of the PPI rabeprazole in patients with LPR., Methods: Patients with LPR symptoms were assigned randomly to receive rabeprazole (20 mg, twice daily, n = 42) or placebo (n = 40) for 12 weeks. All patients completed symptom questionnaires; these provided demographic information and the reflux symptom index before, during, and 6 weeks after cessation of treatment. Videolaryngostroboscopy was used to document the laryngeal findings and determine the reflux finding score., Results: Twenty-four patients (57.1%) in the rabeprazole group and 27 patients (67.5%) in the placebo group had pH-documented LPR. The total reflux symptom index score decreased significantly in the group given rabeprazole, compared with patients given placebo, at weeks 6 and 12, but not at week 18. However, there were no significant differences in reflux finding scores between the rabeprazole and placebo groups at any of the time points., Conclusions: Twelve weeks of treatment with rabeprazole (20 mg, twice daily) significantly improved reflux symptoms, compared with placebo, in patients with LPR. Relapse of symptoms was observed 6 weeks after stopping PPI therapy, indicating the requirement for longer treatment duration in patients with LPR., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The expression of pancreatic-duodenal homeobox 1 (PDX1) in gastric cancer is aberrantly reduced. The aim of this study was to elucidate the regulation of DNA methylation and histone acetylation at the promoter for PDX1 silencing in gastric cancer., Methods: PDX1 expression in response to demethylation and acetylation was detected in human gastric cancer cell lines by reverse transcription-polymerase chain reaction (PCR) and western blot. Four CpG islands within the 5'-flanking region of PDX1 gene were analyzed with their transcription activities being detected by dual luciferase assay. Promoter hypermethylation was identified in gastric cancer cell lines and cancer tissues by methylation-specific PCR or bisulfite DNA sequencing PCR analysis. Histone acetylation was determined by chromatin immunoprecipitation (ChIP) assay., Results: Demethylation by 5'-aza-2'-deoxycytidine (5'-aza-dC) and/or acetylation by trichostatin A (TSA) restored PDX1 expression in gastric cancer cells. Hypermethylation was found in four CpG islands in six of seven cancer cell lines. However, only the distal CpG island located in the promoter fragment of PDX1, F383 (c.-2063 to -1681 nt upstream of the ATG start codon) displayed significant transcriptional activity that could be suppressed by SssI methylase and increased by 5'-aza-dC and TSA. More than 70% of the single CpG sites in F383 were methylated with hypermethylation of F383 fragment more common in gastric cancerous tissues compared with the paired normal tissues (P < 0.05). ChIP assay showed F383 was also associated with low hypoacetylation level of the histones., Conclusion: Promoter hypermethylation and histone hypoacetylation contribute to PDX1 silencing in gastric cancer.

Clopidogrel is an integral part of the management of several important vascular diseases. However the medium to long term clinical outcomes are poorer for these patients if they experience gastro-intestinal bleeding, hence patients with risk factors for gastro-intestinal bleeding are frequently prescribed proton pump inhibitors. Conflicting evidence exists as to the existence of an adverse interaction between clopidogrel and proton pump. This review examines the original studies, which suggested the adverse interaction, the subsequent and most recent studies, the pharmaco-dynamics of the two drugs and suggests an algorithm for the use of clopidogrel with proton pump inhibitors.

Background and Aims: Cancer invasion and metastasis may associate with the phenotype transition called epithelial-mesenchymal transition (EMT). We aim to evaluate the impact of four-and-a-half LIM protein 2 (FHL2) on EMT and invasion of colon cancer., Methods: The functional role of FHL2 in EMT was determined by overexpression or small interfering RNA-mediated depletion of FHL2. Mechanisms of FHL2 on expression or activity of E-cadherin and beta-catenin were assessed., Results: FHL2 was highly expressed in primary and metastatic colon cancer but not in normal tissues. FHL2 was critical for cancer cell adhesion to extracellular matrix, migration and invasion. FHL2 expression was stimulated by transforming growth factor (TGF)-beta1. Moreover, FHL2 acted as a potent EMT inducer by stimulating vimentin and matrix metalloproteinase-9 expressions and causing a loss of E-cadherin, whereas those alterations of EMT markers were not affected by silencing of Smad molecules (typical TGF-beta signal mediators) in FHL2 stable transfectant cells. Therefore, FHL2 induced EMT in a TGF-beta-dependent and Smad-independent manner. FHL2 downregulated E-cadherin expression and inhibited the formation of membrane-associated E-cadherin-beta-catenin complex. FHL2 also stabilized nuclear beta-catenin, resulting in enforcement of beta-catenin transactivation activity., Conclusion: FHL2 is a potent EMT inducer and might be an important mediator for invasion and/or metastasis of colon cancer.

Recent evidence suggests that a subpopulation of cancer cells, cancer stem cells (CSCs), is responsible for tumor growth in colorectal cancer. However, the role of CSCs in colorectal cancer metastasis is unclear. Here, we identified a subpopulation of CD26(+) cells uniformly present in both the primary and metastatic tumors in colorectal cancer patients with liver metastasis. Furthermore, in patients without distant metastasis at the time of presentation, the presence of CD26(+) cells in their primary tumors predicted distant metastasis on follow-up. Isolated CD26(+) cells, but not CD26(-) cells, led to development of distant metastasis when injected into the mouse cecal wall. CD26(+) cells were also associated with enhanced invasiveness and chemoresistance. Our findings have uncovered a critical role of CSCs in metastatic progression of cancer. Furthermore, the ability to predict metastasis based on analysis of CSC subsets in the primary tumor may have important clinical implication as a selection criterion for adjuvant therapy., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background and Aim: The incidence of colorectal cancer (CC) is increasing in many Asian countries, but decreasing in western countries. The present study examined the local incidence of CC in the past few decades., Methods: A population based study, using data from Hong Kong (HK) Cancer Registry, was carried out to examine the trends of CC in different age groups in HK. Comparison with other countries was made., Results: The crude rate of CC in HK increased from 29.6/100,000 in 1983 to 57.1/100,000 in 2006. Age standardized rate (ASR) increased by less than 20%. It was markedly smaller than the 190% increase in crude rate. ASR progressively increased in males. In females, ASR peaked in 1994 and declined in the last decade. In most countries, the risk of CC was higher and increasing in males, but stable or decreasing in females. With respect to age, increasing risk was noted in males above 60 years old and females above 70 years old. However, a declining rate was noted in those below 50 years old. The decrease was over 40% in the 30-34 years group over the past two decades., Conclusions: Increasing incidence of CC in HK was mostly in the older and male population, but not in the younger age group.

Colorectal cancer (CRC) is the second most common lethal cancer in the Western world. There is a 10 to 20 years lead time from normal mucosa to carcinoma which offers a window of opportunity to modify and prevent the outcome of CRC, with its incipient morbidity and mortality. The objective of this paper is to review the evidence for chemoprophylaxis in CRC, identify currently used agents and determine their role in the current management algorithm of CRC. Large cohort-control and randomised controlled trials in the most studied chemoprophylaxis agents are reviewed. Currently, the role for chemoprophylaxis in CRC remains a niche area, with celecoxib the only recommended agent for use in patients with familial polyposis syndromes. However, the role of chemoprophylaxis is likely to grow significantly in the next decade as understanding of the stepwise tumorigenesis cascade becomes better understood and current clinical trials are completed.

Screening for coeliac disease is confined to subgroups at greater risk for the disease, including type 1 diabetes mellitus, autoimmune thyroid disease and family members of affected individuals. This study examined the hypothesis that patients taking antidepressants or presenting with fractures could represent new subgroups at higher risk for coeliac disease. A total of 105 and 199 consecutive patients presenting to hospital taking antidepressants and/or with a fracture was screened with IgA tissue transglutaminase and had their IgA serum levels quantified. Patients with positive serology were offered further diagnostic and management follow up. No patients taking antidepressants had positive serology. Seven with fractures had elevated titres of IgA tissue transglutaminase. All of these patients had presented with non-axial fractures, representing a prevalence of 5.2% (95% confidence interval: 1.4-8.9%). Uptake of further investigation and management was poor. Patients presenting with non-axial fractures may be a subgroup in whom coeliac screening may be indicated. There needs to be greater awareness of atypical presentations of coeliac disease.

Dual antiplatelet therapy with aspirin and clopidogrel has been shown to reduce subsequent cardiac events in patients with acute coronary syndrome or coronary artery stenting. Clopidogrel, a thienopyridine, is a prodrug that is transformed in vivo to an active metabolite by the cytochrome P450 (CYP) enzyme system. The genes encoding CYP enzymes are polymorphic. Recent data demonstrated patients carrying a genetic variant of CYP enzymes (e.g. CYP2C19) would have a higher rate of ischemic events than non-carriers due to an attenuation of the pharmacokinetic and pharmacodynamic responses to clopidogrel. Furthermore, concomitant gastrointestinal ulcer prophylaxis with a proton pump inhibitor (PPI) is commonly prescribed to patients because of the increased risk of bleeding with dual antiplatelet therapy. PPIs are extensively metabolized by the cytochrome P450 system and have been associated with decreased antiplatelet activity of clopidogrel. In this review, we will discuss the impact of CYP450 enzymes genetic variation and CYP450 pathway drug-drug interactions in pharmacological and clinical response to clopidogrel., (2009 Elsevier Inc. All rights reserved.)

The prevalence of colorectal cancer is increasing in Asia. However, the age-standardized rate has reached a plateau in some countries. Some studies have shown a male predominance difference and increasing risk in the elderly, but not in the younger population. 'Right shifting' of colorectal cancer, not accountable by difference in age or the indications for endoscopic examination, has also been noted. Westernized diet is associated with colorectal cancer, but controversy remains on how it causes colorectal cancer. Alcohol consumption, obesity, diabetes mellitus, consumption of red and processed meat and cigarette smoking are linked to bowel cancer epidemiologically. Only high dietary calcium has a consistent negative (or 'protective') effect. The efficacy of fish oil, vitamin D, soy, phytoestrogens, folate, methionine, riboflavin and vitamin B6 has not been established. Aspirin and non-steroidal anti-inflammatory drugs use decrease risk of colorectal cancer after 5-10 years of use. There is no evidence for a detrimental effect of proton pump inhibitors or benefit of statins in colorectal cancer. In conclusion, there is a rising trend and prevalence of colorectal cancer in Asia. Dietary modification or supplementation may not be effective in preventing colorectal cancer. Surveillance of colorectal cancer in high-risk groups, according to current recommendation, is probably most effective.

Our previous studies and those of others have indicated that X-linked inhibitor of apoptosis protein (XIAP) holds promise as a target gene in colon cancer gene therapy. In this study, we constructed an adenoviral vector to deliver small hairpin RNA (shRNA) against XIAP (XIAP-shRNA) into colon cancer cells and tested its therapeutic efficacy in vitro and in vivo. We first confirmed an overexpression of XIAP in colon cancer cells and human cancer tissues. We then designed XIAP-small interfering RNA (siRNA) and confirmed the knockdown effect of these siRNAs in colon cancer cells. The sequences of the effective siRNAs were converted into shRNA and then packed into replication-deficient adenoviral vectors using BLOCK-iT Adenoviral RNAi Expression System to generate Adv-XIAP-shRNA. Infection of HT29 and HCT116 cells with Adv-XIAP-shRNA led to enhanced caspase-3 activity, which was associated with increased apoptosis and reduced cell proliferation. The therapeutic effect of Adv-XIAP-shRNA was then tested in xenograft tumors in nude mice. We showed that treatment of the xenograft tumors derived from HCT116 cells with Adv-XIAP-shRNA resulted in a retardation of tumor growth, which was associated with enhanced apoptosis, increased caspase-3 activity, and reduced expression of proliferating cell nuclear antigen in the tumor tissues. Treatment of xenograft tumors with Adv-XIAP-shRNA did not affect the expressions of inflammatory cytokines in tumor-bearing mice. Thus, Adv-XIAP-shRNA-mediated down-regulation of XIAP exerts a therapeutic effect in colon cancer by promoting apoptosis and inhibiting proliferation of colon cancer cells, and the antitumor effect of Adv-XIAP-shRNA was unlikely to be related to virus-induced immune response.

Prolonged dual-antiplatelet therapy with aspirin and clopidogrel is mandatory after drug-eluting stent implantation because of the potential increased risk of late stent thrombosis. The concern regarding prolonged antiplatelet therapy is the increased risk of bleeding. Gastrointestinal bleeding is the most common site of bleeding and presents a serious threat to patients due to the competing risks of gastrointestinal hemorrhage and stent thrombosis. Currently, there are no guidelines and little evidence on how best to manage these patients who are at high risk of morbidity and mortality from both the bleeding itself and the consequences of achieving optimum hemostasis by interruption of antiplatelet therapy. Managing gastrointestinal bleeding in a patient who has undergone recent percutaneous coronary intervention requires balancing the risk of stent thrombosis against further catastrophic bleeding. Close combined management between gastroenterologist and cardiologist is advocated to optimize patient outcomes.