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ALS-linked C9orf72 dipeptide repeats inhibit starvation-induced autophagy through modulating BCL2–BECN1 interaction

Acta Pharmaceutica Sinica B 2024年第5期14卷 2026-2038页

作者： Shiqiang Xu Qilian Ma Junwen Shen Ningning Li Shan Sun Nana Wang Yang Chen Chunsheng Dong Kin Yip Tam Jochen H.M.Prehn Hongfeng Wang Zheng Ying Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences Soochow UniversitySuzhou 215123China MOE Key Laboratory of Geriatric Diseases and Immunology College of Pharmaceutical SciencesSuzhou Medical College of Soochow UniversitySuzhou 215123China Jiangsu Province Engineering Research Center of Precision Diagnostics and therapeutics Development Soochow UniversitySuzhou 215123China Dept.of Physiology&Medical Physics and FUTURE-NEURO Research Centre Royal College of Surgeons in IrelandDublin D02 YN77Ireland Faculty of Health Sciences University of MacaoTaipaMacao 999078China Insititutes of biology and Medical Science Soochow UniversitySuzhou 215123China

Growing evidences indicate that dysfunction of autophagy contributes to the disease pathogenesis of amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD),two neurodegenerative *** GGGGCC·GGCCCC repeat RNA expansion in chromosome 9 open reading frame 72(C9orf72)is the most genetic cause of both ALS and *** to the previous studies,GGGGCC·GGCCCC repeat undergoes the unconventional repeat-associated non-ATG translation,which produces dipeptide repeat(DPR)*** there is a growing understanding that C9orf72 DPRs have a strong ability to harm neurons and induce C9orf72-linked ALS/FTD,whether these DPRs can affect autophagy remains *** the present study,we find that poly-GR and poly-PR,two arginine-containing DPRs which display the most cytotoxic properties according to the previous studies,strongly inhibit starvation-induced ***,our data indicate that arginine-rich DPRs enhance the interaction between BCL2 and BECN1/Beclin 1 by inhibiting BCL2 phosphorylation,therefore they can impair autophagic clearance of neurodegenerative disease-associated protein aggregates under starvation condition in ***,our study not only highlights the role of C9orf72 DPR in autophagy dysfunction,but also provides novel insight that pharmacological intervention of autophagy using SW063058,a small molecule compound that can disrupt the interaction between BECN1 and BCL2,may reduce C9orf72 DPR-induced neurotoxicity.

关键词： Amyotrophic lateral sclerosis Frontotemporal dementia C9orf72 Autophagy BCL2 BECN1/Beclin 1 Dipeptide repeat Neurodegeneration

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Utilizing zebrafish and okadaic acid to study Alzheimer's disease

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Neural Regeneration Research 2018年第9期13卷 1538-1541页

作者： Daniel Koehler Frederick E.Williams Department of Pharmacology and Experimental therapeutics University of Toledo

Despite the many years of extensive research using rodent models to study Alzheimer＇s disease （AD）, no cure or disease halting drug exists. An increasing number of people are suffering from the disease and a therapeutic intervention is needed. Therefore, it is necessary to have complementary models to aid in the drug discovery. The zebrafish animal model is emerging as a valuable model for the investigation of AD and neurodegenerative drug discovery. The main genes involved in human AD have homologous counter- parts in zebrafish and have conserved function. The basic brain structure of the zebrafish is also conserved when compared to the mammalian brain. Recently an AD model was established by administering okadaic acid to zebrafish. It was used to test the efficacy of a novel drug, lanthionine ketimine-5-ethyl ester, and to elucidate its mechanism of action. This demonstrated the ability of the okadaic acid-induced AD zebrafish model to be implemented in the drug discovery process for therapeutics against AD.

关键词： Alzheimer's disease Zebrafish okadaic acid protein phosphatase 2A learning and memory lanthionine ketimine-5-ethyl ester

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Quantitative and qualitative subgenomic RNA profiles of SARS-CoV-2 in respiratory samples: A comparison between Omicron BA.2 and non-VOC-D614G

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Virologica Sinica 2024年第2期39卷 218-227页

作者： Zigui Chen Rita Way Yin Ng Grace Lui Lowell Ling Agnes S.Y.Leung Chit Chow Siaw Shi Boon Wendy C.S.Ho Maggie Haitian Wang Renee Wan Yi Chan Albert Martin Li David Shu Cheong Hui Paul Kay Sheung Chan Department of Microbiology Faculty of MedicineThe Chinese University of Hong KongHong KongChina Department of Medicine and therapeutics Faculty of MedicineThe Chinese University of Hong KongHong KongChina Department of Anaesthesia and Intensive Care Faculty of MedicineThe Chinese University of Hong KongHong KongChina Department of Paediatrics Faculty of MedicineThe Chinese University of Hong KongHong KongChina Department of Anatomical and Cellular Pathology Faculty of MedicineThe Chinese University of Hong KongHong KongChina Jockey Club School of Public Health and Primary Care Faculty of MedicineThe Chinese University of Hong KongHong KongChina Stanley Ho Centre for Emerging Infectious Diseases Faculty of MedicineThe Chinese University of Hong KongHong KongChina

The SARS-CoV-2 Omicron variants are notorious for their transmissibility,but little is known about their subgenomic RNA(sgRNA)*** study applied RNA-seq to delineate the quantitative and qualitative profiles of canonical sgRNA of 118 respiratory samples collected from patients infected with Omicron BA.2 and compared with 338 patients infected with non-variant of concern(non-VOC)-D614G.A unique characteristic profile depicted by the relative abundance of 9 canonical sgRNAs was reproduced by both BA.2 and non-VOCD614G regardless of host gender,age and presence of ***,such profile was lost in samples with low viral load,suggesting a potential application of sgRNA pattern to indicate viral activity of individual patient at a specific time point.A characteristic qualitative profile of canonical sgRNAs was also reproduced by both BA.2 and *** presence of a full set of canonical sgRNAs carried a coherent correlation with crude viral load(AUC¼0.91,95%CI 0.88–0.94),and sgRNA ORF7b was identified to be the best surrogate marker allowing feasible routine application in characterizing the infection status of individual *** potentials in using sgRNA as a target for vaccine and antiviral development are worth pursuing.

关键词： Coronavirus SARS-CoV-2 Omicron BA.2 Non-VOC-D614G RNA-seq Subgenomic RNA(sgRNA)

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Bridging academic science and clinical research in the search for novel targeted anti-cancer agents

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Cancer biology & Medicine 2015年第4期12卷 316-327页

作者： Alex Matter Experimental therapeutics Center & D3 A*STAR

This review starts with a brief history of drug discovery & development, and the place of Asia in this worldwide effort discussed. The conditions and constraints of a successful translational R&D involving academic basic research and clinical research are discussed and the Singapore model for pursuit of open R&D described. The importance of well-characterized, validated drug targets for the search for novel targeted anti-cancer agents is emphasized, as well as a structured, high quality translational R&D. Furthermore, the characteristics of an attractive preclinical development drug candidate are discussed laying the foundation of a successful preclinical development. The most frequent sources of failures are described and risk management at every stage is highly recommended. Organizational factors are also considered to play an important role. The factors to consider before starting a new drug discovery & development project are described, and an example is given of a successful clinical project that has had its roots in local universities and was carried through preclinical development into phase I clinical trials.

关键词： Drug discovery drug development translational R&D targeted anti-cancer agents

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Thrombus migration in patients with acute ischaemic stroke undergoing endovascular thrombectomy

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Stroke & Vascular Neurology 2024年第2期9卷 126-133,I0006-I0395页

作者： ZeFeng Tan Lei Zhang Li'an Huang Hongyu Qiao Min Guan Bing Yang Pengfei Yang Yongwei Zhang Hongjian Shen Yu Zhou Bo Hong Huaizhang Shi Hongxing Han Xinyi Leng Yi Dong Changlin Lian Wenhuo Chen Anding Xu Jianmin Liu Neurology First People's Hospital of FoshanFoshanGuangdongChina Department of Neurology Jinan University First Affiliated HospitalGuangzhouGuangdongChina Neurovascular Center Changhai HospitalNaval Medical UniversityShanghaiChina Department of Neurosurgery First Affiliated Hospital of Harbin Medical UniversityHarbinChina Department of Neurology Linyi People's HospitalLinyiShandongChina Medicine&therapeutics The Chinese University of Hong KongHong KongChina Neurology Huashan Hospital Fudan UniversityShanghaiChina Neurology Zhangzhou Municipal Hospital of Fujian Province and Zhangzhou Affiliated Hospital of Fujian Medical UniversityZhangzhouFujianChina Stroke Center Jinan University First Affiliated HospitalGuangzhouGuangdongChina

Objective The impact of thrombus migration(TM)prior to endovascular thrombectomy(EVT)on clinical outcomes and revascularisation rates remains *** aimed to examine whether preinterventional TM modifies the treatment effects of direct EVT versus bridging EVT in acute large vessel occlusion *** All patients undergoing catheter angiography in the Direct Intra-arterial thrombectomy in order to Revascularise acute ischaemic stroke patients with large vessel occlusion Efficiently in Chinese Tertiary hospitals:A Multicentre randomised clinical Trial were *** was determined by radiologists unaware of the study by analysing discrepancies between computed tomographic angiography at baseline and first-run digital subtraction angiography before *** primary outcome was the score on the modified Rankin scale(mRS)assessed at 90 *** Of 627 included patients,the TM rate was 11.3%(71/627).In the multivariable logistic regression model,baseline National Institutes of Health Stroke Scale score(adjusted OR 0.956,95%CI 0.916 to 0.999;p=0.043)and intravenous thrombolysis(adjusted OR 2.614,95%CI 1.514 to 4.514;p<0.001)were independently associated with *** patients with TM were less likely to be completely recanalised than those without TM(21.27%vs 36.23%,p=0.040).The interaction of TM and the EVT treatment effect did not significantly affect mRS shift analysis(p=0.687)or mRS scores of 0 to 1(p=0.436).Conclusion Preinterventional TM does not modify the treatment effects of direct versus bridging EVT on functional outcomes in patients with acute ischaemic stroke with anterior large vessel *** leads to a lower complete recanalisation rate.

关键词： patients throm acute

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Nanomaterial-assisted wearable glucose biosensors for noninvasive real-time monitoring:Pioneering point-of-care and beyond

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Nano Materials Science 2024年第3期6卷 263-283页

作者： Moein Safarkhani Abdullah Aldhaher Golnaz Heidari Ehsan Nazarzadeh Zare Majid Ebrahimi Warkiani Omid Akhavan YunSuk Huh Navid Rabiee Nanobio High-Tech Materials Research Center Department of Biological Sciences and BioengineeringInha UniversityIncheon22212Republic of Korea Department of Chemistry Sharif University of TechnologyTehranIran School of Natural Sciences Massey UniversityPrivate Bag 11222Palmerston North4410New Zealand School of Chemistry Damghan UniversityDamghan36716-45667Iran School of biomedical Engineering University of Technology SydneySydneyNSW2007Australia Department of Physics Sharif University of TechnologyP.O.Box 11155-9161TehranIran Centre for Molecular Medicine and Innovative therapeutics Murdoch UniversityPerthWA 6150Australia School of Engineering Macquarie UniversitySydneyNew South Wales2109Australia

This review explores glucose monitoring and management strategies,emphasizing the need for reliable and userfriendly wearable sensors that are the next generation of sensors for continuous glucose *** addition,examines key strategies for designing glucose sensors that are multi-functional,reliable,and cost-effective in a variety of *** unique features of effective diabetes management technology are highlighted,with a focus on using nano/biosensor devices that can quickly and accurately detect glucose levels in the blood,improving patient treatment and control of potential diabetes-related *** potential of next-generation wearable and touch-sensitive nano biomedical sensor engineering designs for providing full control in assessing implantable,continuous glucose monitoring is also *** challenges of standardizing drug or insulin delivery doses,low-cost,real-time detection of increased blood sugar levels in diabetics,and early digital health awareness controls for the adverse effects of injectable medication are identified as unmet ***,the market for biosensors is expected to expand significantly due to the rising need for portable diagnostic equipment and an ever-increasing diabetic *** paper concludes by emphasizing the need for further research and development of glucose biosensors to meet the stringent requirements for sensitivity and specificity imposed by clinical diagnostics while being cost-effective,stable,and durable.

关键词： Glucose sensor biosensor Wearable devices Noninvasive Real-time monitoring

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Small molecule conjugates with selective estrogen receptor β agonism promote anti-aging benefits in metabolism and skin recovery

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2137-2152页

作者： Tarik Zahr Vijay K.Boda Jian Ge Lexiang Yu Zhongzhi Wu Jianwen Que Wei Li Li Qiang Naomi Berrie Diabetes Center Columbia UniversityNew YorkNY 10032USA Department of Molecular Pharmacology and therapeutics Columbia UniversityNew YorkNY 10032USA Department of Pharmaceutical Sciences College of PharmacyUniversity of Tennessee Health Science CenterMemphisTN 38163USA Drug Discovery Center College of PharmacyUniversity of Tennessee Health Science CenterMemphisTN 38163USA Division of Digestive and Liver Diseases Columbia UniversityNew YorkNY 10032USA Center for Human Development Columbia UniversityNew YorkNY 10027USA Department of Pathology and Cell biology Columbia UniversityNew YorkNY 10032USA Department of Medicine Columbia UniversityNew YorkNY 10032USA

Estrogen is imperative to mammalian reproductivity,metabolism,and ***,the hormone activating estrogen receptor(ERs)αcan cause major safety concerns due to the enrichment of ERαin female tissues and certain *** contrast,ERβis more broadly expressed in metabolic tissues and the ***,it is desirable to generate selective ERβagonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ERα***,we report the design and production of small molecule conjugates containing selective non-steroid ERβagonists Gtx878 or *** of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity,visceral adipose integrity,skeletal muscle function,and skin health,with validation in *** further uncovered the benefits of ERβconjugates in the skin using two inducible skin injury mouse models,showing increased skin basal cell proliferation,epidermal thickness,and wound ***,our ERβ-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.

关键词： Estrogen receptorβ Aging Metabolism Skin injury Muscle metabolism Small molecule conjugates Regeneration Adiposity

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Cellular zinc metabolism and zinc signaling:from biological functions to diseases and therapeutic targets

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Signal Transduction and Targeted Therapy 2024年第2期9卷 401-441页

作者： Bonan Chen Peiyao Yu Wai Nok Chan Fuda Xie Yigan Zhang Li Liang Kam Tong Leung Kwok Wai Lo Jun Yu Gary M.K.Tse Wei Kang Ka Fai To Department of Anatomical and Cellular Pathology State Key Laboratory of Translational OncologyPrince of Wales HospitalThe Chinese University of Hong KongHong KongChina State Key Laboratory of Digestive Disease Institute of Digestive DiseaseThe Chinese University of Hong KongHong KongChina CUHK-Shenzhen Research Institute The Chinese University of Hong KongShenzhenChina Department of Pathology Nanfang Hospital and Basic Medical CollegeSouthern Medical UniversityGuangdong Province Key Laboratory of Molecular Tumor PathologyGuangzhouChina Institute of biomedical Research Taihe HospitalHubei University of MedicineShiyanChina Department of Pediatrics The Chinese University of Hong KongHong KongChina Department of Medicine and therapeutics The Chinese University of Hong KongHong KongChina

Zinc metabolism at the cellular level is critical for many biological processes in the body.A key observation is the disruption of cellular homeostasis,often coinciding with disease *** an essential factor in maintaining cellular equilibrium,cellular zinc has been increasingly spotlighted in the context of disease *** research suggests zinc’s involvement in promoting malignancy and invasion in cancer cells,despite its low tissue *** has led to a growing body of literature investigating zinc’s cellular metabolism,particularly the functions of zinc transporters and storage mechanisms during cancer *** transportation is under the control of two major transporter families:SLC30(ZnT)for the excretion of zinc and SLC39(ZIP)for the zinc ***,the storage of this essential element is predominantly mediated by metallothioneins(MTs).This review consolidates knowledge on the critical functions of cellular zinc signaling and underscores potential molecular pathways linking zinc metabolism to disease progression,with a special focus on *** also compile a summary of clinical trials involving zinc *** the main localization of zinc transporters at the cell membrane,the potential for targeted therapies,including small molecules and monoclonal antibodies,offers promising avenues for future exploration.

关键词： metabolism invasion involvement

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Evaluation of the antidiabetic activity and toxicological properties of Jaundea pinnata(***.)

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Clinical Traditional Medicine and Pharmacology 2024年第2期5卷 25-31页

作者： Farouk Adedeji Oladoja Emmanuel S.Irokosu Elijah O.Oyinloye Akanji A.Murtala Marcus D.Ayoola Fatimah O.Lasisi Oyinkansola T.Aderibigbe Department of Pharmacology and Toxicology Faculty of PharmacyOlabisi Onabanjo UniversityAgo-IwoyeOgun-State 121102Nigeria Department of Pharmacology and therapeutics Faculty of Basic Medical ScienceOlabisi Onabanjo UniversityAgo-IwoyeOgun-State 121102Nigeria Department of Pharmacognosy Faculty of PharmacyObafemi Awolowo University Ile-IfeOsun-State 220282Nigeria

Background:Jaundea pinnata(JP),is a new plant native to North Africa,East Africa,Southern Nigeria,and *** is traditionally used as an anti-rheumatic,anti-inflammatory,antibacterial and antidiabetic herb,thus making it a potential source for modern antidiabetic ***:This investigation aimed to assess the toxicological profile and the antidiabetic potentials of the methanol extract of the Jaundea pinnata(JP)leaf in mice and ***:Preliminary phytochemical screening of JP leaf was conducted using standard *** plant extract’s acute and sub-chronic toxicity was evaluated using a modified OECD *** normal and streptozotocin-induced diabetic rats,its anti-diabetic action was tested over 28 days at doses of 100 mg/kg,200 mg/kg,and 400 mg/kg,with glibenclamide(10 mg/kg)and distilled water serving as the positive and negative controls,*** organs’histopathological analysis was also ***:According to the preliminary phytochemical analysis of the leaf extract,JP contains flavonoids,saponins,alkaloids,tannins,terpenoids,deoxy-sugars,and *** extract demonstrated an LD50 of above 2000 mg/kg in *** days 14,21,and 28 in streptozotocin-induced diabetic rats,the extract showed a dosedependent antidiabetic effect;nevertheless,the activity of the extract at 400 mg/kg on day 28 was barely comparable to that of glibenclamide(10 mg/kg).At 250 mg/kg,500 mg/kg,and 1500 mg/kg,respectively,the extract was appreciably non-toxic to the liver and kidney,while inducing a significant change in haematological ***:The study found that JP presented antihyperglycemic properties and was relatively safe at normal dosages(<2000 mg/kg).

关键词： Jaundea pinnata Diabetes mellitus Haematological and biochemical parameters

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Hydrogen sulfide prodrugs—a review

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Acta Pharmaceutica Sinica B 2015年第5期5卷 367-377页

作者： Yueqin Zheng Xingyue Ji Kaili Ji Binghe Wang Department of Chemistry and Center for Diagnostics and therapeutics Georgia State University

Hydrogen sul fi de(H_2S) is recognized as one of three gasotransmitters together with nitric oxide(NO) and carbon monoxide(CO). As a signaling molecule, H_2S plays an important role in physiology and shows great potential in pharmaceutical applications. Along this line, there is a need for the development of H_2S prodrugs for various reasons. In this review, we summarize different H_2S prodrugs, their chemical properties, and some of their potential therapeutic applications.

关键词： Hydrogen sulfide(H2S) Gasotransmitters H2S prodrugs H2S-hybrid nonsteroidal anti-inflammatory drugs Controllable H2S prodrugs Hydrolysis-based H2S prodrugs

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