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Protein & Cell 2017年第11期8卷 791-795页

作者： Xiang Jin Kang Chiong Isabella Noelle Caparas boon seng soh Yong Fan Key Laboratory for Major Obstetric Diseases of Guangdong Province Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes Center for Reproductive Medicine The Third Affiliated Hospital of Guangzhou Medical University Guangzhou 510150 China Disease Modeling and Therapeutics Laboratory ASTAR Institute of Molecular and Cell Biology 61 Biopolis Drive Proteos Singapore 138673 Singapore

The recently developed RNA-guided clustered regularly interspaced short palindromic repeat （CRISPR）/CRISPR-associated 9 （Cas9） nuclease system has progressed to be an invaluable technology for genome manipulation in somatic cell types and germline model organisms. While the unprecedented advance in human embryo gene editing research has great potential in next-generation therapeutics, it raises various ethical concerns that need to be addressed before being translated for clinical use. Here, we discuss the current and potential applications of CRISPR/Cas9 technology and its limitations in clinical applications, as well as ethical and legal considerations in the treatment, disease prevention or disability in somatic cells or human embryo via gene editing.

关键词： Addressing challenges clinical applications associated CRISPR/Cas9 technology ethical questions prevent its misuse

Human germline editing: Insights to future clinical treatment of diseases

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Protein & Cell 2019年第7期10卷 470-475页

作者： Yanni Li Xiang Jin Kang Jeremy Kah Sheng Pang boon seng soh Yang Yu Yong Fan Key Laboratory for Major Obstetric Diseases of Guangdong Province Center of Reproductive Medicine The Third Affiliated Hospital of Guangzhou Medical University Guangzhou 510150 China Disease Modeling and Therapeutics Laboratory A*STAR Institute of Molecular and Cell Biology 61 Biopolis Drive Proteos Singapore 138673 Singapore Center of Reproductive Medicine Department of Obstetrics and Gynecology Peking University Third Hospital Beijing 100191 China

Last year, the first attempt to genetically modify human embryos in the United States was reported and sparked a huge debate (Ma et al., 2017). Although the first human germline modification was only performed two years ago, the study showed that rapid adva nces in tech no logy has allowed the rate of off-target effects and mosaicism to be reduced considerably (Liang et al., 2015). Recently, Vertex and CRISPR therapeutics collaborated and developed CTX001, the first CRISPR/Cas9-based therapy, targeting patients with P-thalassemia and have begun phase 1/2 clinical trials. With policies and technologies regarding genome editing both developing rapidly, explorations into the possibility of clinical gene editing for hundreds of hereditary diseases are starting to become achievable. Here, we address the progress of huma n embryo editi ng tech no logies so far and its promise and risks in advancing therapy for hereditary diseases.

关键词： Human germline editing Insights diseases

Site-directed deuteration of dronedarone preserves cytochrome P4502J2 activity and mitigates its cardiac adverse effects in canine arrhythmic hearts

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Acta Pharmaceutica Sinica B 2022年第10期12卷 3905-3923页

作者： Aneesh V.Karkhanis Gopalakrishnan Venkatesan Ryuichi Kambayashi Jacqueline Wen Hui Leow Marcus Qingrui Han Hiroko Izumi-Nakaseko Ai Goto Jeremy Kah Sheng Pang boon seng soh Pipin Kojodjojo Atsushi Sugiyama Eric Chun Yong Chan Department of Pharmacy Faculty of ScienceNational University of SingaporeSingapore 117543Singapore Department of Pharmacology Faculty of MedicineToho UniversityTokyo 143-8540Japan Institute of Molecular and Cell Biology Agency for ScienceTechnology and ResearchSingapore 138673Singapore Department of Biological Sciences Faculty of ScienceNational University of SingaporeSingapore 117558Singapore Department of Medicine Yong Loo Lin School of MedicineNational University of SingaporeSingapore 119228Singapore

Cytochrome P4502J2(CYP2J2)metabolizes arachidonic acid(AA)to cardioprotective epoxyeicosatrienoic acids(EETs).Dronedarone,an antiarrhythmic drug prescribed for treatment of atrial fibrillation(AF)induces cardiac adverse effects(AEs)with poorly understood *** previously demonstrated that dronedarone inactivates CYP2J2 potently and irreversibly,disrupts AA-EET pathway leading to cardiac mitochondrial toxicity rescuable via EET *** this study,we investigated if mitigation of CYP2J2 inhibition prevents dronedarone-induced cardiac *** first synthesized a deuterated analogue of dronedarone(termed poyendarone)and demonstrated that it neither inactivates CYP2J2,disrupts AA-EETs metabolism nor causes cardiac mitochondrial toxicity in *** patch-clamp experiments demonstrated that pharmacoelectrophysiology of dronedarone is unaffected by ***,we show that dronedarone treatment or CYP2J2 knockdown in spontaneously beating cardiomyocytes indicative of depleted CYP2J2 activity exacerbates beat-to-beat(BTB)variability reflective of proarrhythmic *** contrast,poyendarone treatment yields significantly lower BTB variability compared to dronedarone in cardiomyocytes indicative of preserved CYP2J2 ***,poyendarone and dronedarone display similar antiarrhythmic properties in the canine model of persistent AF,while poyendarone substantially reduces beat-to-beat variability of repolarization duration suggestive of diminished proarrhythmic *** findings prove that deuteration of dronedarone prevents CYP2J2 inactivation and mitigates dronedarone-induced cardiac AEs.

关键词： Arachidonic acid Atrial fibrillation CYP2J2 Drug-induced proarrhythmia Epoxyeicosatrienoic acids Mechanism-based inactivation Dronedarone

Fargeted elimination of mutant mitochondria DNA in MELAS-iPSCs by mitoTALENs

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Protein & Cell 2018年第3期9卷 283-297页

作者： Yi Yang Han Wu Xiangjin Kang Yanhui Liang Ting Lan Tianjie Li Tao Tan Jiangyun Peng Quanjun Zhang Geng An Yali Liu Qian Yu Zhenglai Ma Ying Lian boon seng soh Qingfeng Chen Ping Liu Yaoyong Chen Xiaofang Sun Rong Li Xiumei Zhen Yang Yu Xiaoping Li Yong Fan Key Laboratory for Major Obstetric Diseases of Guangdong Province Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes The Third Affiliated Hospital of Guangzhou Medical University Guangzhou 510150 China Key Laboratory of Regenerative Biology of the Chinese Academy of Sciences and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine South China Institute for Stem Cell Biology and Regenerative Medicine Guangzhou Institutes of Biomedicine and Health Chinese Academy of Sciences Guangzhou 510530 China Center of Reproductive Medicine Department of Obstetrics and Gynecology Peking University Third Hospital Beijing 100191 China Yunnan Key Laboratory of Primate Biomedical Research Institute of Primate Translational Medicine Kunming University of Science and Technology Kunming 650500 China Disease Modeling and Therapeutics Laboratory A'STAR Institute of Molecular and Cell Biology 61 Biopolis Drive Proteos Singapore 138673 Singapore Department of Biological Sciences National University of Singapore Singapore 117543 Singapore

Mitochondrial diseases are maternally inherited hetero- geneous disorders that are primarily caused by mitochondrial DNA （mtDNA） mutations. Depending on the ratio of mutant to wild-type mtDNA, known as heteroplasmy, mitochondrial defects can result in a wide spectrum of clinical manifestations. Mitochondria-targeted endonucleases provide an alternative avenue for treating mitochondrial disorders via targeted destruc- tion of the mutant mtDNA and induction of heteroplasmic shifting. Here, we generated mitochondrial disease patient-specific induced pluripotent stem cells （MiPSCs） that harbored a high proportion of m.3243A〉G mtDNA mutations and caused mitochondrial encephalomyopathy and stroke-like episodes （MELAS）. We engineered mitochondrial-targeted transcription activator-like effector nucleases （mitoTALENs） and successfully eliminated the m.3243A〉G mutation in MiPSCs. Off-target mutagenesis was not detected in the targeted MiPSC clones. Utilizing a dual fluorescence iPSC reporter cell line expressing a 3243G mutant mtDNA sequence in the nuclear genome, mitoTALENs displayed a significantly limited ability to target the nuclear genome compared with nuclear-localized TALENs. Moreover, genetically rescued MiPSCs displayed normal mitochondrial respiration and energy production. Moreover, neuronal progenitor cells differentiated from the rescued MiPSCs also demonstrated normal metabolic profiles. Further- more, we successfully achieved reduction in the human m.3243A〉G mtDNA mutation in porcine oocytes via injection of mitoTALEN mRNA. Our study shows the great potential for using mitoTALENs for specific targeting of mutant mtDNA both in iPSCs and mammalian oocytes, which not only provides a new avenue for studying mitochondrial biology and disease but also suggests a potential therapeutic approach for the treatment of mitochondrial disease, as well as the prevention of germline transmission of mutant mtDNA.

关键词： mitochondria iPSCs TALEN MELAS

Reassessment of functional dyspepsia:From the editor

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World Journal of Gastroenterology 2006年第17期12卷 2660-2666页

作者： Andrew seng boon Chua MD

Dyspepsia refers to group of upper gastrointestinal symptoms that occur commonly in adults. Dyspepsia is known to result from organic causes, but the majority of patients suffer from non-ulcer or functional dyspepsia. Epidemiological data from population-based studies of various geographical locations have been reviewed, as they provide more realistic information. Population-based studies on true functional dyspepsia （FD） are few, due to the logistic difficulties of excluding structural disease in large numbers of people. Globally, the prevalence of uninvestigated dyspepsia （UD） varies between 7%- 45%, depending on definition used and geographical location, whilst the prevalence of FD has been noted to vary between 11%-29.2%. Risk factors for FD have been shown to include females and underlying psychological disturbances, whilst environmental/lifestyle habits such as poor socio-economic status, smoking, increased caffeine intake and ingestion of non-steroidal anti-inflammatory drugs appear to be more relevant to UD. It is clear that dyspepsia and FD in particular are common conditions globally, affecting most populations, regardless of location.

关键词： Dyspepsia Functional dyspepsia Geographical variation Uninvestigated dyspepsia Prevalence Epidemiology

Reassessment of functional dyspepsia:A topic review

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World Journal of Gastroenterology 2006年第17期12卷 2656-2659页

作者： Andrew seng boon Chua Ipoh Gastro Centre 31 Lebuhraya Taman Ipoh Ipoh Garden South31400IpohPerakMalaysia

Dyspepsia itself is not a diagnosis but stands for a constellation of symptoms referable to the upper gastrointestinal tract. It consists of a variable combination of symptoms including abdominal pain or discomfort, postprandial fullness, abdominal bloating, early satiety, nausea, vomiting, heartburn and acid regurgitation. Patients with heartburn and acid regurgitation invariably have gastroesophageal reflux disease and should be distinguished from those with dyspepsia. There is a substantial group of patients who do not have a definite structural or biochemical cause for their symptoms and are considered to be suffering from functional dyspepsia （FD）. Gastrointestinal motor abnormalities, altered visceral sensation, dysfunctional central nervous system-enteral nervous system （CNS- ENS） integration and psychosocial factors have all being identified as important pathophysiological correlates. It can be considered as a biopsychosocial disorder with dysregulation of the brain-gut axis being central in origin of disease. FD can be categorizeo into different subgroups based on the predominant single symptom identified by the patient. This subgroup classification can assist us in deciding the appropriate symptomatic treatment for the patient.

关键词： Dyspepsia Epidemiology H pylori Subgroups Cholecystokinin Visceral hypersensitivity Psychosocial Central receptors Therapy

Functional dyspepsia and irritable bowel syndrome,are they different entities and does it matter?

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World Journal of Gastroenterology 2006年第17期12卷 2708-2712页

作者： Kok-Ann Gwee Andrew seng boon Chua Stomach Liver & Bowel Clinic Gleneagles Hospital Singaporeand the Department of MedicineNational University of SingaporeSingapore Ipoh Gastro Centre 31 Lebuh Raya Taman Ipoh Ipoh Garden South31400 IpohPerakMalaysia

A high prevalence of overlap between functional dyspepsia and irritable bowel syndrome has been consistently and universally reported. Recent studies demonstrating shared common pathophysiological disturbances including delayed gastric emptying and visceral hypersensitivity involving more than one region, suggest that these patients have a generalised rather than regional, disorder of the gut. Furthermore, a study of the natural history of dyspepsia suggests that with time, a substantial proportion will evolve into IBS. The recognition of IBS in dyspeptic patients has potentially profound therapeutic importance. It could help to reduce the risk of unnecessary cholecystectomy in IBS patients. The ability to appreciate the extent of involvement could allow us to address the disturbances more comprehensively, and thereby achieve greater patient satisfaction with their treatment.

关键词： Functional dyspepsia Irritable bowel syndrome Common pathophysiology Asian Epidemiology

Role of cholecystokinin and central serotonergic receptors in functional dyspepsia

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World Journal of Gastroenterology 2006年第9期12卷 1329-1335页

作者： Andrew seng boon Chua PWN Keeling TG Dinan Ipoh Gastro Centre Ipoh Malaysia Department of Medicine Trinity College Dublin Ireland Departments of Psychiatry and Alimentary Phar-mabiotic Centrev University College Cork Ireland

Symptoms of functional dyspepsia are characterized by upper abdominal discomfort or pain, early satiety, postprandial fullness, bloating, nausea and vomiting. It is a chronic disorder, with symptoms more than 3 mo per year, and no evidence of organic diseases. Dysfunctional motility, altered visceral sensation, and psychosocial factors have all been identified as major pathophysiological mechanisms. It is believed that these pathophysiological mechanisms interact to produce the observed symptoms. Dyspepsia has been categorized into three subgroups based on dominant symptoms. Dysmotility-like dyspepsia describes a subgroup of patients whose symptom complex is usually related to a gastric sensorimotor dysfunction. The brain-gut peptide cholecystokinin （CCK） and serotonin （5-HT） share certain physiological effects. Both have been shown to decrease gastric emptying and affect satiety. Furthermore the CCK induced anorexia depended on serotonergic functions probably acting via central pathways. We believe that abnormalities of central serotonergic receptors functioning together with a hyper responsiveness to CCK or their interactions may be responsible for the genesis of symptoms in functional dyspepsia （FD）.

关键词： Functional dyspepsia Cholecystokinin Serotonin Gastric emptying

Rome Ⅲ survey of irritable bowel syndrome among ethnic Malays

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World Journal of Gastroenterology 2012年第44期18卷 6475-6480页

作者： Yeong Yeh Lee Anuar Waid Huck Joo Tan Andrew seng boon Chua William E Whitehead Department of Medicine School of Medical SciencesUniversity Sains MalaysiaKubang Kerian 16150Malaysia Department of Gastroenterology Sunway Medical CenterPetaling Jaya 46150Malaysia 31 Lebuh Raya Raman Ipoh Ipoh Garden SouthIpoh 31400Malaysia Center for Functional Gastrointestinal and Motility Disorders University of North Carolina at Chapel HillChapel HillCA 27599-7080United States

AIM:To survey irritable bowel syndrome(IBS) using Rome Ⅲ criteria among Malays from the north-eastern region of Peninsular ***:A previously validated Malay language Rome Ⅲ IBS diagnostic questionnaire was used in the current study.A prospective sample of 232 Malay subjects(80% power) was initially *** a stratified random sampling strategy,a total of 221 Malay subjects(112 subjects in a "full time job" and 109 subjects in "no full time job") were *** were visitors(friends and relatives) within the hospital compound and were representative of the local *** flags and psychosocial alarm symptoms were also assessed in the current study using previously translated and validated *** with IBS were sub-typed into constipation-predominant,diarrhea-predominant,mixed type and *** and multivariable analyses were used to test for association between socioeconomic factors and presence of red flags and psychosocial alarm features among the Malays with ***:IBS was present in 10.9%(24/221),red flags in 22.2%(49/221) and psychosocial alarm features in 9.0%(20/221).Red flags were more commonly reported in subjects with IBS(83.3%) than psychosocial alarm features(20.8%,P < 0.001).Subjects with IBS were older(mean age 41.4 years vs 36.9 years,P = 0.08),but no difference in gender was noted(P = 0.4).Using univariable analysis,IBS was significantly associated with a tertiary education,high individual income above RM1000,married status,exsmoker and the presence of red flags(all P < 0.05).In multiple logistic regression analysis,only the presence of red flags was significantly associated with IBS(odds ratio:0.02,95%CI:0.004-0.1,P < 0.001).The commonest IBS sub-type was mixed type(58.3%),followed by constipation-predominant(20.8%),diarrheapredominant(16.7%) and un-subtyped(4.2%).Four of 13 Malay females(30.8%) with IBS also had menstrual *** subjects with IBS had at least one red flag(70.8%)

关键词： Irritable bowel syndrome Malays Preva-lence Rome Ⅲcriteria Malaysia

Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome： a double blind randomized controlled trial

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Asian Journal of Andrology 2012年第4期14卷 604-611页

作者： seng-Fah Tong Chirk-Jenn Ng boon-Cheok Lee Verna-KM Lee Ee-Ming Khoo Eng-Giap Lee Hui-Meng Tan Universiti Kebangsaan Malaysia Kuala Lumpur 56000Malaysia University of Malaya Lumpur 56000Malaysia Sime Darby Medical Centre Selangor 47500Malaysia International Medical University Kuala Lumpur 57000Malaysia

This study aimed to investigate the effect of intramuscular injection of testosterone undecanoate on overall quality of life （QoL） in men with testosterone deficiency syndrome （TDS）. A randomized controlled trial over a 12-month period was carried out in 2009. One hundred and twenty men aged 40 years and above with a diagnosis of TDS （serum total testosterone 〈12 nmol 1-1 and total Aging Male Symptom （AMS） scores ≥ 27） were invited to participate. Interventions comprised intramuscular injection of either placebo or 1000 mg testosterone undecanoate, given at weeks O, 6, 18, 30 and 42. This paper presents the secondary analysis of QoL changes measured in the scores of Short-Form-12 （SF-12） scale at baseline, weeks 30 and 48 after the first injection. A total of 56/60 and 58/60 men from the active treatment and placebo group, respectively, completed the study. At week 48, before adjusting for baseline differences, the QoL of men in the treatment group improved significantly in five out of the eight domains on SF-12. The physical health composite scores improved 4.0 points from a baseline of 41.9±7.0 in the treatment group compared to 0.8 point from a baseline of 43.7--7.1 in the placebo group （F=3.652, P=0.027）. The mental health composite scores improved 4.4 points from a baseline of 37.1±9.0 in the treatment group compared to 1.0 points from a baseline of 37.6±7.9 in the placebo group （F=4.514, P=-0.018）. After adjusting for baseline differences, significant improvement was observed in mental health composite scores, but not in physical health composite scores. LQng-acting testosterone undecanoate significanUy improved the mental health component of QoL in men with TDS.

关键词： hypogonadism randomized controlled trial quality of life testosterone deficiency syndrome (TDS) testosterone therapy