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Small molecule deoxynyboquinone triggers alkylation and ubiquitination of Keap1 at Cys489 on Kelch domain for Nrf2 activation and inflammatory therapy

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Journal of Pharmaceutical Analysis 2024年第3期14卷 401-415页

作者： Ke-Gang Linghu Tian Zhang Guang-Tao Zhang Peng Lv Wen-Jun Zhang Guan-Ding Zhao Shi-hang Xiong Qiu-Shuo ma Ming-Ming Zhao Meiwan Chen Yuan-Jia Hu Chang-Sheng Zhang Hua Yu State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao SARChina macao Centre for Research and Development in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao SARChina Key Laboratory of Tropical marine Bio-resources and Ecology Guangdong Key Laboratory of Marine Materia MedicaRNAM Center for Marine MicrobiologySouth China Sea Institute of OceanologyChinese Academy of SciencesGuangzhou510301China State Key Laboratory of Functions and Applications of Medicinal Plants&School of Pharmaceutical Sciences Guizhou Medical UniversityGuiyang550025China

Activation of nuclear factor erythroid 2-related factor 2(Nrf2)by Kelch-like ECH-associated protein 1(Keap1)alkylation plays a central role in anti-inflammatory therapy.However,activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified.Deoxynyboquinone(DNQ)is a natural small molecule discovered from marine actinomycetes.The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1.DNQ exhibited significant anti-inflammatory properties both in vitro and in vivo.The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be theα,β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine.DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway.Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation.The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry.DNQ triggered the ubiquitination and subsequent degradation of Keap1 by alkylation of the cysteine residue 489(Cys489)on Keap1-Kelch domain,ultimately enabling the activation of Nrf2.Our findings revealed that DNQ exhibited potent anti-inflammatory capacity throughα,β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain,suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.

关键词： Deoxynyboquinone Anti-inflammation Target Keap1/Nrf2 Alkylation Ubiquitination

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Inhibition of the CDK9-cyclin T1 protein-protein interaction as a new approach against triple-negative breast cancer

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1390-1405页

作者： Sha-Sha Cheng Yuan-Qing Qu Jia Wu Guan-Jun Yang Hao Liu Wanhe Wang Qi Huang Feng Chen Guodong Li Chun-Yuen wong Vincent Kam Wai wong Dik-Lung ma Chung-hang Leung Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine University of MacaoMacao 999078China Dr.Neher’s Biophysics Laboratory for Innovative Drug Discovery State Key Laboratory of Quality Research in Chinese MedicineMacao University of Science and TechnologyMacao 999078China State Key Laboratory for managing Biotic and Chemical Threats to the Quality and Safety of Agro-products Ningbo UniversityKow loon TongHong Kong 999077China Laboratory of Biochemistry and Molecular Biology School of Marine SciencesNingbo UniversityNingbo 315211China Department of Chemistry Hong Kong Baptist UniversityNingbo 315211China Institute of Medical Research Northwestern Polytechnical UniversityXi'an 710072China Department of Chemistry City University of Hong KongHong Kong 999077China Department of Biomedical Sciences Faculty of Health SciencesUniversity of MacaoMacao 999078China

Cyclin-dependent kinase 9(CDK9) activity is correlated with worse outcomes of triplenegative breast cancer(TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein-protein interaction(PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CN ligand and tested their activity against the CDK9cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9-cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9-cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.

关键词： Metal complex Kinase inhibitor Protein-protein interaction Epigenetics Triple-negative breast cancer Metastasis

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The Hong Kong consensus recommendations on the diagnosis and management of pancreatic cystic lesions

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Hepatobiliary Surgery and Nutrition 2023年第5期12卷 715-735,I0019-I0020页

作者： Tan-To Cheung Yuk Tong Lee Raymond Shing-Yan Tang wong Hoi She Kai Chi Cheng Chin Cheung Cheung Keith Wan hang Chiu Kenneth Siu Ho Chok Wing Sun Chow Tak Wing Lai Wai-Kay Seto Thomas yau Department of Surgery Queen Mary HospitalThe University of Hong KongHong KongChina Gastroenterologist in private practice Hong KongChina Department of Medicine and Therapeutics The Chinese University of Hong KongHong KongChina Department of Surgery Kwong Wah HospitalHong KongChina Department of Surgery Tuen Mun HospitalHong KongChina Department of Radiology&Imaging Queen Elizabeth HospitalHong KongChina Department of Medicine The University of Hong KongHong KongChina Department of Surgery Princess Margaret HospitalHong KongChina Department of Medicine School of Clinical MedicineThe University of Hong KongHong KongChina State Key Laboratory of Liver Research The University of Hong KongHong KongChina

Background:The finding of pancreatic cystic lesions(PCL)on incidental imaging is becoming increasingly common.International studies report a prevalence of 2.2-44.7%depending on the population,imaging modality and indication for imaging,and the prevalence increases with age.Patients with PCL are at risk of developing pancreatic cancer,a disease with a poor prognosis.This publication summarizes recommendations for the diagnosis and management of PCL and post-operative pancreatic exocrine insufficiency(PEI)from a group of local specialists.Methods:Clinical evidence was consolidated from narrative reviews and consensus statements formulated during two online meetings in march 2022.The expert panel included gastroenterologists,hepatobiliary surgeons,oncologists,radiologists,and endocrinologists.Results:Patients with PCL require careful investigation and follow-up due to the risk of malignant transformation of these lesions.They should undergo clinical investigation and pancreas-specific imaging to classify lesions and understand the risk profile of the patient.Where indicated,patients should undergo pancreatectomy to excise PCL.Following pancreatectomy,patients are at risk of PEI,leading to gastrointestinal dysfunction and malnutrition.Therefore,such patients should be monitored for symptoms of PEI,and promptly treated with pancreatic enzyme replacement therapy(PERT).Patients with poor response to PERT may require increases in dose,addition of a proton pump inhibitor,and/or further investigation,including tests for pancreatic function.Patients are also at risk of new-onset diabetes mellitus after pancreatectomy;they should be screened and treated with insulin if indicated.Conclusions:These statements are an accurate summary of our approach to the diagnosis and management of patients with PCL and will be of assistance to clinicians treating these patients in a similar clinical landscape.

关键词： Pancreatic cystic lesions pancreatic endocrine insufficiency pancreatic enzyme replacement therapy

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Characterization of available automated external def ibrillators in the market based on the product manuals in 2014

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World Journal of Emergency Medicine 2016年第2期7卷 138-146页

作者： Chik Leung Ho Ka Wai Cheng tze hang ma.yau hang wong Ka Lok Cheng Chak Wah Kam Department of Accident and Emergency Medicine Tuen Mun Hospital

BACKGROUND: To popularize the wide-spread use of automated external defi brillator(AED) to save life in sudden cardiac arrest, we compared the strength and weakness of different types of AEDs to enable a sound selection based on regional requirement.METHODS: This was a retrospective descriptive study. Different types of AEDs were compared according to the information of AEDs from manuals and brochures provided by the manufacturers. Fifteen types of AEDs were divided into 3 groups, basic, intermediate and advanced.RESULTS: Lifeline? AUTO AED had the best performance in price, portability and user-friendly among AEDs of basic level. It required less time for shock charging. Samaritan PAD defi brillator was superior in price, portability, durability and characteristic among AEDs of intermediate level. It had the longest warranty and highest protection against water and dust. Lifeline? PRO AED had the best performance in most of the criteria among AEDs of advanced level and offered CPR video and manual mode for laypersons and clinicians respectively.CONCLUSION: Lifeline? AUTO AED, Samaritan PAD def ibrillator, Lifeline? PRO AED are superior in AEDs of basic, intermediate and advanced levels, respectively. A feasible AED may be chosen by users according to the regional requirement and the current information about the best available products.

关键词： Automated external defi brillator Electrodes Pads Cardiac arrest

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Intravenous fluid selection rationales in acute clinical management

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World Journal of Emergency Medicine 2018年第1期9卷 13-19页

作者： Wing Yan Shirley Cheung Wai Kwan Cheung Chun Ho Lam Yeuk Wai Chan Hau Ching Chow Ka Lok Cheng yau hang wong Chak Wah Kam Accident and Emergency Department Tuen Mun Hospital

BACKGROUND: Intravenous fluid(IVF) is commonly used in acute clinical management. This study aimed to review the choice and primary considerations in IVF prescriptions and to evaluate the adequacy of guidelines and trainings on it in the New Territories West Cluster(NTWC) of Hong Kong.METHODS: This is a descriptive study based on data collected from an online survey. Data were processed by SPSS for statistical analysis. This study focused on a general description and doctor-nurse between group comparison. Participants were asked the choice of IVF for nine acute clinical scenarios and provide reason. A 1–10 scale was used to assess the sufficiency of guideline, training and information, and time for revision on IVF prescription.RESULTS: 0.9% sodium chloride was the most familiar IVF(36%), followed by 5% Dextrose solution(26%). In the nine scenarios, the most chosen IVF was 0.9% sodium chloride(37%–61%). There was significant difference in the choice of IVF between doctors and nurses in 7 cases. The second most chosen IVF for doctors was Plasma-Lyte A while that for nurses was Gelofusine. Departmental practice was the most chosen reason to account for the prescription. The adequacy of guideline, information and training, and time for revision was rated 5. Doctors had significantly more time at work than nurses to update knowledge in IVF prescription(5.41 versus 4.57).CONCLUSION: 0.9% sodium chloride was mostly chosen. The choice of IVF was mainly based on departmental practice. Adequacy of guideline, information and training, and time for revision on IVF prescription were average, indicating significant training deficit.

关键词： Intravenous fluid Acute care Resuscitation

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Epidemiological Characteristics of Influenza A and B in macau,2010–2018

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Virologica Sinica 2021年第5期36卷 1144-1153页

作者： Hoi man Ng Teng Zhang Guoliang Wang Si Meng Kan Guoyi ma Zhe Li Chang Chen Dandan Wang Meng In wong Chio hang wong Jinliang Ni Xiaohua Douglas Zhang Clinical Laboratory Kiang Wu Hospital Faculty of Health Sciences University of Macau

Influenza is one of the major respiratory diseases in humans. macau is a tourist city with high density of population and special population mobility. The study on the epidemiological characteristics of influenza in macau should bring great value for preventing influenza in tourist cities like macau in the world. In this study, we collected a total of 104,874 samples with influenza-like illness(ILI) in macau from 2010 to 2018. Chi-square test and binary multivariable logistic regression were used to investigate the epidemiological characteristics of influenza A and B in macau. Among these ILI samples, the overall positive rate is 17.17% for influenza A and 6.97% for influenza B. The epidemics of influenza in three years(i.e., 2012, 2017 and 2018) differ from the remaining years(i.e., normal years). In a normal year, influenza A occurs year-round whereas influenza B is seasonal. Our research shows significant differences in influenza infections between different age groups in normal years. Interestingly, our analysis shows no significant difference between locals and tourists in influenza A and B infection in a normal year, whereas the odds of influenza A in tourists were significantly higher than those in locals in July 2017 and the odds of influenza B in tourists were significantly higher than those in locals in January–February 2012 and January–February 2018. This is possibly attributed by the policy of free vaccination to everyone in macau. These findings should be valuable for preventing influenza in not only macau but also the world.

关键词： Influenza Epidemiology Chi-square test Logistic regression macau

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Aurone derivatives as Vps34 inhibitors that modulate autophagy

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Acta Pharmaceutica Sinica B 2019年第3期9卷 537-544页

作者： Guodong Li Joshua William Boyle Chung-Nga Ko Wu Zeng Vincent Kam Wai wong Jian-Bo Wan Philip Wai Hong Chan Dik-Lung ma Chung-hang Leung State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacao999078China School of Chemistry Monash UniversityClayton3800Australia Department of Chemistry Hong Kong Baptist UniversityHong Kong999077China State Key Laboratory of Quality Research in Chinese Medicine Macao University of Science and TechnologyMacao999078China Department of Chemistry University of WarwickCoventry CV47ALUK

We report in this study the identification of a natural product-like antagonist(1a) of Vps34 as a potent autophagy modulator via structure-based virtual screening. Aurone derivative 1a strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, 1a prevents autophagy in human cells induced either by starvation or by an mT OR inhibitor. In silico modeling and kinetic data revealed that 1a could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy in vivo and without inducing heart or liver damage in mice. 1a could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases.

关键词： Autophagy Natural products Vps34 Inhibitor Structure-based virtual screening Vesicle trafficking Heart or liver damage Aurone derivative

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Long-Term Treatment with an Herbal Formula MCC Ameliorates Obesity-Associated Metabolic Dysfunction in High Fat Diet-Induced Obese Mice: A Comparative Study among MCC and Various Combinations of Its Constituents

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Chinese Medicine 2014年第1期5卷 34-46页

作者： Pou Kuan Leong Hoi Yan Leung Hoi Shan wong Ji hang Chen Wing man Chan Chung Wah ma Yi Ting Yang Kam Ming Ko Division of Life Science Hong Kong University of Science and Technology Hong Kong China Infinitus (China) Company Ltd. Guangzhou China

Obesity has been found to be associated with increased incidence of various metabolic disorders. Anti-obesity interventions are therefore urgently needed. An earlier study has demonstrated that treatment with an herbal formula MCC, which comprises the fruit of Momordica charantia (MC), the pericarpium of Citri reticulate (CR) and L-carnitine (CA), reduced the weight gain in high fat diet (HFD)-fed mice. In the present study, we investigated the effect of long-term treatment with MCC (6 g/kg/day × 40 doses) and various combinations of its constituents in HFD-fed female ICR mice. Body weight change was monitored during the course of the experiment. Total and differential adiposity, plasma lipid contents, metabolic enzyme activities and mitochondrial coupling efficiency in skeletal muscle were measured. Glucose homeostasis was also assessed. Results showed that HFD increased the body weight, total and differential adiposity, and plasma lipid contents as well as impaired metabolic status in skeletal muscle and glucose homeostasis. MCC and all combinations of its constituents reduced the weight gain in HFD-fed mice, which was accompanied with an improvement on glucose homeostasis. While MC, CA and CR independently suppressed the HFD-induced weight gain in mice, MC seems to be the most effective in weight reduction, all of which correlated with the induction of mitochondrial uncoupling in skeletal muscle. Only CA and CR, but not MC, significantly reduced the total adiposity and visceral adiposity as well as plasma cholesterol level. However, the two component combinations, MC + CR and MC + CA, decreased the degree of visceral adiposity and plasma cholesterol level, respectively. MCC treatment at 1.5 g/kg (but not a higher dose of 6 g/kg) suppressed visceral adiposity and induced mitochondrial uncoupling in skeletal muscle in HFD-fed mice. The finding suggests that MCC may offer a promising prospect for ameliorating the diet-induced obesity and metabolic disorders in humans.

关键词： High Fat Diet Obesity Weight Control Momordica Charantia Citri Reticulata L-Carnitine

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Acute and Long-Term Treatments with an Herbal Formula V-Vital Capsule Increase Exercise Endurance Capacity in Weight-Loaded Swimming Mice

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Chinese Medicine 2014年第3期5卷 153-164页

作者： Pou Kuan Leong Hoi Yan Leung Wing man Chan Ji hang Chen Hoi Shan wong Chung Wah ma Shi Yu Zou Kam Ming Ko Division of Life Science The Hong Kong University of Science & Technology Hong Kong SAR China Infinitus (China) Company Ltd. Guangzhou China

Fatigue is a self-limiting response arising from physical and/or mental weariness, with a consequent personal and economic morbidity on work performance and social relationships. Anti-fatigue intervention is therefore urgently sought. “Qi-invigorating” Chinese tonic herbs, which can improve the energy status in the body according to the theory of traditional Chinese medicine, may produce beneficial effects in fatigue individuals. The herbal formula V-Vital capsule (VVC), which comprises 3 “Qi-invigorating” herbs, namely the root of Rhodiola rosea, Eleutherococcus senticosus and Panax quinquefolium, may produce anti-fatigue effect. In the present study, we investigated the effect of acute/long-term VVC treatment (acute: 0.75, 0.2 and 3.75 kg/day × 1 dose;long-term: 0.075 and 0.25 g/kg/day × 14 doses) on weight-loaded swimming female ICR mice. The weight-loaded swimming time until exhaustion, indicative of exercise endurance capacity, was recorded. Plasma levels of glucose, non-esterified fatty acid (NEFA), lactate and reactive oxygen metabolites (ROM) were measured in the exhausted mice. Glycogen levels in skeletal muscle and liver tissues were also measured. Mitochondrial function status [such as adenine nucleotide translocase (ANT) activity and coupling efficiency] was assayed. Results showed that acute VVC treatment increased the exercise endurance capacity in weight-loaded swimming mice. The ability of acute VVC treatment to enhance the exercise endurance was associated with increases in plasma glucose levels as well as glycogen levels in skeletal muscles and liver tissues, presumably due to the utilization of plasma lactate for gluconeogenesis and/or glycogen synthesis in the liver. While acute VVC treatment reduced the plasma ROM level in weight-loaded swimming mice, it increased the ANT activity. In this regard, the enhancement in exercise endurance afforded by acute VVC treatment might be due to an increase in the glucose supply to the skeletal muscle, the amelioration of systemic oxidative stress and the

关键词： Fatigue Exercise Endurance Rhodiola rosea Eleutherococcus senticosus Panax quinquefolium

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How to secure the connection between thoracostomy tube and drainage system?

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World Journal of Emergency Medicine 2014年第4期5卷 259-263页

作者： Ka Ki Pat Li Kit Shing John wong yau hang Henry wong Ka Lok Cheng Fung Ling So Chu Leung Lau Chak Wah Kam Department of Accident and Emergency Medicine Pok Oi Hospital Department of Accident and Emergency Medicine Tuen Mun Hospital Clinical Skills Training Centre Tuen Mun Hospital

BACKGROUND: Thoracostomy tube insertion is one of the common bedside procedures in emergency medicine and many acute specialties. Dislodgement of thoracostomy tube from the connection tube of chest drainage system is an important problem with potential complications such as contamination, infection and pneumothorax. Besides, mere loosening can also lead to malfunction. It is a common practice to tape the connection of the system. This study aimed to evaluate the materials and methods of connection of chest drain system to minimize drainage dislodgement. METHODS: We conducted an experimental study to assess the tightness of the connection with various taping materials and methods. We selected three commonly used adhesive materials(3M^(tm) Transpore^(tm) Medical tape, 3M^(tm) Micropore^(tm) Medical tape, 3M^(tm) Soft Cloth Tape on Liner) and three different methods(cross method, straight method, nylon band) to secure the junction between the thoracostomy tube and the bi-conical adaptor in the drainage system. The measured outcome was the weight causing visible loosening of the junction between thoracotomy tube and the adaptor.RESULTS: For each taping material and taping method, 10 trials were performed. The median weight required to disconnect the junction is 26.22 lb for Transpore^(tm), 31.29 lb for Micropore^(tm) and 32.44 lb for Soft Cloth Tape on Liner. A smaller force was required to disconnect if Transpore^(tm) is used(Pmaterial for thoracostomy tub

关键词： Thoracostomy tube Drainage system Cross-taping

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