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Mitochondria targeting drugs for neurodegenerative diseases——Design, mechanism and application

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2778-2789页

作者： Jiajia Xu Wei Du Yunhe Zhao Kahleong Lim Li Lu Chengwu Zhang Lin Li Key Laboratory of Flexible Electronics(KLOFE)&Institute of Advanced Materials(IAM) Jiangsu National Synergetic Innovation Center for Advanced Materials(SICAM)Nanjing Tech University(NanjingTech)Nanjing 211816China Department of Anatomy Shanxi Medical UniversityTaiyuan 030001China Lee Kang Chian School of Medicine Nanyang Technological UniversitySingapore 308232Singapore school of Basic Medical Sciences Shanxi Medical UniversityTaiyuan 030001China The Institute of Flexible Electronics(IFE Future Technologies)Xiamen UniversityXiamen 361005China

Neurodegenerative diseases(NDDs) such as Alzheimer’s disease(AD) and Parkinson ’s disease(PD) are a heterogeneous group of disorders characterized by progressive degeneration of neurons.NDDs threaten the lives of millions of people worldwide and regretfully remain incurable.It is well accepted that dysfunction of mitochondria underlies the pathogenesis of NDDs.Dysfunction of mitochondria results in energy depletion,oxidative stress,calcium overloading,caspases activation,which dominates the neuronal death of NDDs.Therefore,mitochondria are the preferred target for intervention of NDDs.So far various mitochondria-targeting drugs have been developed and delightfully some of them demonstrate promising outcome,though there are still some obstacles such as targeting specificity,delivery capacity hindering the drugs development.In present review,we will elaborately address 1) the strategy to design mitochondria targeting drugs,2) the rescue mechanism of respective mitochondria targeting drugs,3) how to evaluate the therapeutic effect.Hopefully this review will provide comprehensive knowledge for understanding how to develop more effective drugs for the treatment of NDDs.

关键词： Neurodegenerative diseases Mitochondria Targeting drug Apoptosis Reactive oxygen species Adenosine triphosphate Mitochondrial membrane potential Evaluation

Who Supports Redistribution? Subjective Income Inequality in Japan and China

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Economic and Political Studies 2015年第2期3卷 30-59页

作者： STEPHEN TAY the lee Kong chian school of medicine Nanyang Technological University

Governments reduce income inequality with redistribution policies. These policies are often contentious because people who live in the same country have different preferences for redistribution. Some prefer the government to do more while others prefer the government to do less. Hence what explains the difference in preferences? Using the methodologically suitable cases of Japan and China, this paper contributes to the redistributive preference literature by proposing an alternative theory of how a person's subjective evaluation of and experiences with income inequality—subjective income inequality—affect his/her redistributive preferences. Specifically, a person who feels that his/her country's level of income inequality is too high is more likely to support government redistribution. But contrary to extant studies, this paper finds that a spatial locality's level of objective income inequality does not systematically affect its citizens' preference for redistribution. This finding has implications for redistribution policies because government policies in Japan and China—as with other countries—narrowly frame income inequality in the objective dimensions by pegging it to "objective" income inequality indices(e.g., Gini ratio), thereby ignoring the more important subjective dimensions of income inequality.

关键词： redistributive preferences subjective income inequ

Role of metabolic dysfunction and inflammation along the liver-brain axis in animal models with obesity-induced neurodegeneration

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Neural Regeneration Research 2025年第4期20卷 1069-1076页

作者： Evridiki Asimakidou Eka Norfaishanty Saipuljumri Chih Hung Lo Jialiu Zeng Department of Clinical Neurosciences University of CambridgeCambridgeUK school of Applied Science Republic PolytechnicSingaporeSingapore lee Kong chian school of medicine Nanyang Technological UniversitySingaporeSingapore

The interaction between metabolic dysfunction and inflammation is central to the development of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.Obesity-related conditions like type 2 diabetes and non-alcoholic fatty liver disease exacerbate this relationship.Peripheral lipid accumulation,particularly in the liver,initiates a cascade of inflammatory processes that extend to the brain,influencing critical metabolic regulatory regions.Ceramide and palmitate,key lipid components,along with lipid transporters lipocalin-2 and apolipoprotein E,contribute to neuroinflammation by disrupting blood–brain barrier integrity and promoting gliosis.Peripheral insulin resistance further exacerbates brain insulin resistance and neuroinflammation.Preclinical interventions targeting peripheral lipid metabolism and insulin signaling pathways have shown promise in reducing neuroinflammation in animal models.However,translating these findings to clinical practice requires further investigation into human subjects.In conclusion,metabolic dysfunction,peripheral inflammation,and insulin resistance are integral to neuroinflammation and neurodegeneration.Understanding these complex mechanisms holds potential for identifying novel therapeutic targets and improving outcomes for neurodegenerative diseases.

关键词： Alzheimer’s disease inflammatory cytokines insulin resistance lipid

EpiMix:A novel method to estimate effective reproduction number

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Infectious Disease Modelling 2023年第3期8卷 704-716页

作者： Shihui Jin Borame lee Dickens Jue Tao Lim Alex R.Cook Saw Swee Hock school of Public Health National University of Singapore and National University Health SystemSingapore lee Kong chian school of medicine Nanyang Technological UniversitySingapore Department of Statistics and Data Science National University of SingaporeSingapore

Transmission potential of a pathogen,often quantified by the time-varying reproduction number R t,provides the current pace of infection for a disease and indicates whether an emerging epidemic is under control.In this study,we proposed a novel method,EpiMix,for R t estimation,wherein we incorporated the impacts of exogenous factors and random effects under a Bayesian regression framework.Using Integrated Nested Laplace Approx-imation,EpiMix is able to efficiently generate reliable,deterministic R t estimates.In the simulations and case studies performed,we further demonstrated the method's robust-ness in low-incidence scenarios,together with other merits,including its flexibility in selecting variables and tolerance of varying reporting rates.All these make EpiMix a potentially useful tool for real-time R t estimation provided that the serial interval distri-bution,time series of case counts and external influencing factors are available.

关键词： Epidemics INLA Regression Reproduction number SARS-CoV-2 Transmission dynamics

Can we omit systematic biopsies in patients undergoing MRI fusion-targeted prostate biopsies?

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Asian Journal of Andrology 2023年第1期25卷 43-49页

作者： Jeffrey J Leow Soon Hock Koh Marcus WL Chow Wayren Loke Rolando Salada Seok Kwan Hong Yuyi Yeow Chau Hung lee Cher Heng Tan Teck Wei Tan Department of Urology Tan Tock Seng HospitalSingapore 308433Singapore lee Kong chian school of medicine Nanyang Technological UniversitySingapore 308232Singapore Department of Diagnostic Radiology Tan Tock Seng HospitalSingapore 308433Singapore

Magnetic resonance imaging(MRI)-targeted prostate biopsy is the recommended investigation in men with suspicious lesion(s)on MRI.The role of concurrent systematic in addition to targeted biopsies is currently unclear.Using our prospectively maintained database,we identified men with at least one Prostate Imaging-Reporting and Data System(PI-RADS)≥3 lesion who underwent targeted and/or systematic biopsies from May 2016 to May 2020.Clinically significant prostate cancer(csPCa)was defined as any Gleason grade group≥2 cancer.Of 545 patients who underwent MRI fusion-targeted biopsy,222(40.7%)were biopsy naïve,247(45.3%)had previous prostate biopsy(s),and 76(13.9%)had known prostate cancer undergoing active surveillance.Prostate cancer was more commonly found in biopsy-naïve men(63.5%)and those on active surveillance(68.4%)compared to those who had previous biopsies(35.2%;both P<0.001).Systematic biopsies provided an incremental 10.4%detection of csPCa among biopsy-naïve patients,versus an incremental 2.4%among those who had prior negative biopsies.Multivariable regression found age(odds ratio[OR]=1.03,P=0.03),prostate-specific antigen(PSA)density≥0.15 ng ml^(−2)(OR=3.24,P<0.001),prostate health index(PHI)≥35(OR=2.43,P=0.006),higher PI-RADS score(vs PI-RADS 3;OR=4.59 for PI-RADS 4,and OR=9.91 for PI-RADS 5;both P<0.001)and target lesion volume-to-prostate volume ratio≥0.10(OR=5.26,P=0.013)were significantly associated with csPCa detection on targeted biopsy.In conclusion,for men undergoing MRI fusion-targeted prostate biopsies,systematic biopsies should not be omitted given its incremental value to targeted biopsies alone.The factors such as PSA density≥0.15 ng ml^(−2),PHI≥35,higher PI-RADS score,and target lesion volume-to-prostate volume ratio≥0.10 can help identify men at higher risk of csPCa.

关键词： prostate biopsy prostate cancer prostate health index prostate-specific antigen software fusion Uronav

Lung cancer management during the COVID-19 pandemic:experience of a medical oncology unit at a tertiary hospital in Singapore

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Journal of Cancer Metastasis and Treatment 2020年第1期6卷 707-717页

作者： Elise KY Vong Puey-Ling Chia Alex Y.Chang Department of Medical Oncology Tan Tock Seng HospitalSingapore lee Kong chian school of medicine Singapore Johns Hopkins University school of medicine BaltimoreMD 21836USA

Coronavirus disease 2019(COVID-19),caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),was declared a pandemic by the World Health Organisation(WHO)on 11 March 2020.The pandemic has had profound effects on healthcare systems across the world,and also poses unique challenges for oncology services.Singapore saw its first imported case of COVID-19 on 23 January 2020,and there has since been 52,000 confirmed cases and 27 deaths as of early August 2020 locally.Oncologists have a special duty to our patients to ensure patient safety and provide optimum care without undue disruption which may compromise long-term cancer-specific outcomes.We herein examine the impact that the COVID-19 pandemic has had on our clinical services,and share our experience with regards to manpower reconfiguration,infection control measures,diagnostic evaluation of patients with suspected COVID-19,oncological management of lung cancer patients,as well as changes in the education and training of juniors,from our unique position as a Medical Oncology department in Tan Tock Seng Hospital,a tertiary hospital affiliated with the National Centre of Infectious Diseases in Singapore.

关键词： COVID-19 lung cancer thoracic cancer

Cilostazol for secondary stroke prevention:systematic review and meta-analysis

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Stroke & Vascular Neurology 2021年第3期6卷 410-423,I0035-I0053页

作者： Choon Han Tan Andrew GR Wu Ching-Hui Sia Aloysius ST Leow Bernard PL Chan Vijay Kumar Sharma Leonard LL Yeo Benjamin YQ Tan Department of medicine Lee Kong Chian School of MedicineNanyang Technological UniversitySingapore Department of medicine Yong Loo Lin School of MedicineNational University of SingaporeSingapore Department of Cardiology National University Heart CentreSingapore Division of Neurology Department of MedicineNational University Health SystemSingapore

Background Stroke is one of the leading causes of death worldwide.Cilostazol,an antiplatelet and phosphodiesterase 3 inhibitor,has not been clearly established for ischaemic stroke use.We aim to determine the efficacy and safety of cilostazol for secondary stroke prevention.Methods MEDLINE,EMBASE,Cochrane Library,Web of Science and ClinicalTrials.gov were searched from inception to 25 September 2020,for randomised trials comparing the efficacy and safety of cilostazol monotherapy or dual therapy with another antiplatelet regimen or placebo,in patients with ischaemic stroke.Version 2 of the Cochrane risk-of-bias tool for randomised trials(RoB 2)was used to assess study quality.This meta-analysis was reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA)statement.Results Eighteen randomised trials comprising 11429 participants were included in this meta-analysis.Most trials possessed low risk of bias and were of low heterogeneity.Cilostazol significantly reduced the rate of ischaemic stroke recurrence(risk ratio,RR=0.69,95%CI 0.58 to 0.81),any stroke recurrence(RR=0.64,95%CI 0.54 to 0.74)and major adverse cardiovascular events(RR=0.67,95%CI 0.56 to 0.81).Cilostazol did not significantly decrease mortality(RR=0.90,95%CI 0.64 to 1.25)or increase the rate of good functional outcome(Modified Rankin Scale score of 0–1;RR=1.07,95%CI 0.95 to 1.19).Cilostazol demonstrated favourable safety profile,significantly reducing the risk of intracranial haemorrhage(RR=0.46,95%CI 0.31 to 0.68)and major haemorrhagic events(RR=0.49,95%CI 0.34 to 0.70).Conclusions Cilostazol demonstrated superior efficacy and safety profiles compared with traditional antiplatelet regimens such as aspirin and clopidogrel for secondary stroke prevention but does not appear to affect functional outcomes.Future randomised trials can be conducted outside East Asia,or compare cilostazol with a wider range of antiplatelet agents.

关键词： prevention Cilostazol regimen

Autolysosomal acidification impairment as a mediator for TNFR1 induced neuronal necroptosis in Alzheimer’s disease

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Neural Regeneration Research 2024年第9期19卷 1869-1870页

作者： Evridiki Asimakidou Richard Reynolds Anna M.Barron Chih Hung Lo Department of Clinical Neurosciences University of CambridgeCambridgeUK Department of Brain Sciences Faculty of MedicineImperial College LondonLondonUK lee Kong chian school of medicine Nanyang Technological UniversitySingaporeSingapore

Neuronal necroptosis-an emerging form of regulated cell death associated with neuroinflammatory signaling:Alzheimer’s disease(AD)is characterized by the presence of extracellular amyloid-β(Aβ)plaques and intracellular tau neurofibrillary tangles as well as progressive neuronal loss.Recent evidence has suggested that prolonged neuroinflammation with increased levels of cytokines,arising from neuronal injury,innate immune responses from glial cells,and peripheral inflammation,leads to neuronal death and AD progression.

关键词： Alzheimer death tau Aβ

A Case Report of Pemphigoid Nodularis as Masquerader of Neurotic Excoriations

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International Journal of Dermatology and Venereology 2020年第4期3卷 239-241页

作者： Tan Chee Hian Tey Hong Liang National Skin Centre 308205Singapore Yong Loo Ling school of medicine National University of Singapore117597Singapore lee Kong chian school of medicine Nanyang Technological University308232Singapore

Introduction:Pemphigoid nodularis is a rare clinical variant of bullous pemphigoid characterized by both prurigo nodularis-like lesions and pemphigoid-like blisters.Case presentation:A 72-year-old Chinese man has been on follow-up at an outpatient Dermatology unit for extensive prurigo nodularis for past 4 to 5 years until an inpatient stay when he was admitted for labile mood and erratic behavior due to the intense pruritus and skin lesions.During the admission,the inpatient team noticed tense hemorrhagic blisters on his right thigh for which histological examination confirmed the diagnosis of bullous pemphigoid.He was treated with oral prednisolone,doxycycline,and nicotinamide,which led to clinical improvement.Discussion:Pemphigoid nodularis can be easily misdiagnosed as prurigo nodularis.We discuss clinical clues that can raise the suspicion of an underlying immunobullous disorder,including erythematous nodules with a much larger surface area affected by central erosions and ulceration.Pruritus associated with larger areas of erosions and ulceration is clues that lesions can be more than mere excoriations.Conclusion:It is important for clinicians to be aware of the presentation of prurigo nodularis in association with bullous pemphigoid such that effective treatment can be promptly instituted.This is especially illustrated in this case,as the treatment of bullous pemphigoid not only improved his skin condition but it also improved his psychological health and behavior with the resolution of itch.

关键词： bullous pemphigoid pemphigoid nodularis itch case report