Diabetes has become a global concern at present,among which type 2 diabetes mellitus(T2DM)accounts for approximately 90%-95%of patients.T2DM is a type of metabolic disorder syndrome that results from a genetic defect,...Diabetes has become a global concern at present,among which type 2 diabetes mellitus(T2DM)accounts for approximately 90%-95%of patients.T2DM is a type of metabolic disorder syndrome that results from a genetic defect,and it is based on insulin resistance and an insulin secretion disorder.The occurrence of T2DM is usually the outcome of both genetic and environmental factors and their interactions.The etiology and pathogenesis of diabetes have not been fully elucidated,and no radical therapeutic cure has been found.Patients with T2DM suffer from complications such as the development of a chronic hyperglycemic condition and even serious metabolic disorders and organ damage in the body and depression and dementia,in addition to other chronic complications.Many studies have suggested that diet is crucial in the development of diabetes and the control of blood glucose.Natural substances have the characteristics of low toxicity and few side effects and may be key to the development of diabetic health products and preventive treatments.This paper reviews the etiology,pathogenesis,risks,treatments and diets related to T2DM to summarize the types of recently available natural products,from both local and foreign sources,for lowering blood glucose at home and their application in supplementary hypoglycemic foods.The key findings and conclusions suggest that there are various known T2DM-inducing factors,including genetic and environmental factors and three types of hybrid factors.展开更多
The protein–protein interaction between menin and mixed lineage leukemia(MLL)plays an important role in the development of human hepatocellular carcinogenesis(HCC)and is associated with poor prognosis of HCC patients...The protein–protein interaction between menin and mixed lineage leukemia(MLL)plays an important role in the development of human hepatocellular carcinogenesis(HCC)and is associated with poor prognosis of HCC patients.1,2 Hence,interrupting the menin-MLL interaction is an attractive strategy in cancer treatment,particularly for liver cancer.3,4 In this study,we identified complex C1 as the first rhodium(III)-based orally bioavailable selective inhibitor of the menin-MLL interaction for HCC.展开更多
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 t...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.展开更多
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 activit...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.展开更多
Triple-negative breast cancer(TNBC)is a highly aggressive and metastasizing cancer that has the worst prognosis out of all breast cancer subtypes.The epithelial emesenchymal transition(EMT)and cancer stem cells(CSCs)h...Triple-negative breast cancer(TNBC)is a highly aggressive and metastasizing cancer that has the worst prognosis out of all breast cancer subtypes.The epithelial emesenchymal transition(EMT)and cancer stem cells(CSCs)have been proposed as important mechanisms underlying TNBC metastasis.CDK9 is highly expressed in breast cancer,including TNBC,where it promotes EMT and induces cancer cell stemness.In this study,we have identified a tetrahydroisoquinoline derivative(compound 1)as a potent and selective CDK9-cyclin T1 inhibitor via virtual screening.Interestingly,by targeting the ATP binding site,compound 1 not only inhibited CDK9 activity but also disrupted the CDK9-cyclin T1 proteineprotein interaction(PPI).Mechanistically,compound 1 reversed EMT and reduced the ratio of CSCs by blocking the CDK9-cyclin T1 interaction,leading to reduced TNBC cell proliferation and migration.To date,compound 1 is the first reported tetrahydroisoquinoline-based CDK9-cyclin T1 ATP-competitive inhibitor that also interferes with the interaction between CDK9 and cyclin T1.Compound 1 may serve as a promising scaffold for developing more selective and potent anti-TNBC agents.Our work also provides insight into the role of the CDK9-cyclin T1 PPI on EMT and CSCs and highlights the feasibility and significance of targeting CDK9 for the treatment of TNBC.展开更多
While the function of DNA in biology is for storage of genetic information,chemists have developed methods to obtain DNA sequences with catalytic and molecular recognition functions.Thus,DNA is a highly attractive mol...While the function of DNA in biology is for storage of genetic information,chemists have developed methods to obtain DNA sequences with catalytic and molecular recognition functions.Thus,DNA is a highly attractive molecule for developing biosensors.DNA probes are known for their detection of complementary DNA and RNA.In addition,DNA aptamers allow for the detection of,essentially,any type of molecule.By coupling DNA with biological elements such as CRISPR-Cas12,highly sensitive detection with signal amplification can also be achieved.Overall,using DNA as a sensor component and as a target are hot areas of research for biomedical diagnosis,environmental monitoring,and food safety.展开更多
基金supported by the Educational Department o f Liaoning Province(LQN201713)Liaoning University(LDQN2019017)+1 种基金Liaoning Provincial Science and Technology Department(2020-bs-080)the Ministry of Science and Technology,Taiwan(MOST 109-2221-E-005-012)。
文摘Diabetes has become a global concern at present,among which type 2 diabetes mellitus(T2DM)accounts for approximately 90%-95%of patients.T2DM is a type of metabolic disorder syndrome that results from a genetic defect,and it is based on insulin resistance and an insulin secretion disorder.The occurrence of T2DM is usually the outcome of both genetic and environmental factors and their interactions.The etiology and pathogenesis of diabetes have not been fully elucidated,and no radical therapeutic cure has been found.Patients with T2DM suffer from complications such as the development of a chronic hyperglycemic condition and even serious metabolic disorders and organ damage in the body and depression and dementia,in addition to other chronic complications.Many studies have suggested that diet is crucial in the development of diabetes and the control of blood glucose.Natural substances have the characteristics of low toxicity and few side effects and may be key to the development of diabetic health products and preventive treatments.This paper reviews the etiology,pathogenesis,risks,treatments and diets related to T2DM to summarize the types of recently available natural products,from both local and foreign sources,for lowering blood glucose at home and their application in supplementary hypoglycemic foods.The key findings and conclusions suggest that there are various known T2DM-inducing factors,including genetic and environmental factors and three types of hybrid factors.
基金supported by the Science and Technology Development Fund(Macao SAR,China)(No.0007/2020/A1,0020/2022/A1)the State Key Laboratory of Quality Research in Chinese Medicine(University of Macao)(SKL-QRCM(UM)-2020-2022)+9 种基金the University of Macao(China)(MYRG2019-00002-ICMS,MYRG2020-00017-ICMS)2022 Internal Research Grant of SKL-QRCM(University of Macao)(QRCM-IRG2022-011)the National Natural Science Foundation of China,China(No.22077109,21775131)the HKBU SKLEBA Research Grant(SKLP_2223_P03)the National Natural Science Foundation of China(No.82204482)the Guangdong Basic and Applied Basic Research Foundation(China)(No.2021A1515012520)Young Elite Scientists Sponsorship Program by CACM(China)(No.2021-QNRC2-B22)Guangzhou Basic and Applied Basic Research Foundation(China)(No.202102020203)the Fundamental Research Funds for the Central Universities(China)(No.11620355)A part of the research is supported by a trust fund for Yung-Chi Cheng's lab at Yale University.
文摘The protein–protein interaction between menin and mixed lineage leukemia(MLL)plays an important role in the development of human hepatocellular carcinogenesis(HCC)and is associated with poor prognosis of HCC patients.1,2 Hence,interrupting the menin-MLL interaction is an attractive strategy in cancer treatment,particularly for liver cancer.3,4 In this study,we identified complex C1 as the first rhodium(III)-based orally bioavailable selective inhibitor of the menin-MLL interaction for HCC.
基金supported by Hong Kong Baptist University,the Health and Medical Research Fund(HMRF/14150561)the National Natural Science Foundation of China(22077109 and 21775131)+3 种基金the Science and Technology Development Fund,Macao SAR(File no.0007/2020/A),SKL-QRCM(UM)-20202022the University of Macao(MYRG2019-00002-ICMS,China)Foshan Medicine Dengfeng Project of China(2019-2021)2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund(Guangdong-Hong KongMacao Joint Lab,No:2020B1212030006,China)。
文摘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.
基金supported by Hong Kong Baptist University (FRG2/ 16–17/007, FRG2/17–18/003, China)the Health and Medical Research Fund (HMRF/14150561, China)+9 种基金the Research Grants Council (HKBU/12301115, China)the National Natural Science Foundation of China (21575121 and 21775131, China)the Hong Kong Baptist University Century Club Sponsorship Scheme 2018 (China)the Interdisciplinary Research Matching Scheme (RC-IRMS/16–17/03, China)Interdisciplinary Research Clusters Matching Scheme (RC-IRCs/17–18/03, China)Innovation and Technology Fund (ITS/260/16FX, China), Matching Proof of Concept Fund (MPCF-001–2017/18, China)Collaborative Research Fund (C5026-16G, China), SKLEBA and HKBU Strategic Development Fund (SKLP_1718_P04, China)the Science and Technology Development Fund, Macao SAR (0072/ 2018/A2, China)the University of Macao (MYRG2016-00151ICMS-QRCM and MYRG2018-00187-ICMS, China)a Discovery Project Grant (DP160101682, Australia) from the Australian Research Council
文摘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.
基金This work was supported by the Health and Medical Research Fund(No.HMRF/14150561)the National Natural Science Foundation of China(No.201575121 and 21775131)+3 种基金the Hong Kong Baptist University Century Club Sponsorship Scheme 2020,Teaching Development Fund(No.TDG/1920/02)the Science and Technology Development Fund,Macao SAR,China(File no.0072/2018/A2 and 0007/2020/A1)SKLQRCM(UM)-2020-2022the University of Macao,China(MYRG2019e00002eICMS).
文摘Triple-negative breast cancer(TNBC)is a highly aggressive and metastasizing cancer that has the worst prognosis out of all breast cancer subtypes.The epithelial emesenchymal transition(EMT)and cancer stem cells(CSCs)have been proposed as important mechanisms underlying TNBC metastasis.CDK9 is highly expressed in breast cancer,including TNBC,where it promotes EMT and induces cancer cell stemness.In this study,we have identified a tetrahydroisoquinoline derivative(compound 1)as a potent and selective CDK9-cyclin T1 inhibitor via virtual screening.Interestingly,by targeting the ATP binding site,compound 1 not only inhibited CDK9 activity but also disrupted the CDK9-cyclin T1 proteineprotein interaction(PPI).Mechanistically,compound 1 reversed EMT and reduced the ratio of CSCs by blocking the CDK9-cyclin T1 interaction,leading to reduced TNBC cell proliferation and migration.To date,compound 1 is the first reported tetrahydroisoquinoline-based CDK9-cyclin T1 ATP-competitive inhibitor that also interferes with the interaction between CDK9 and cyclin T1.Compound 1 may serve as a promising scaffold for developing more selective and potent anti-TNBC agents.Our work also provides insight into the role of the CDK9-cyclin T1 PPI on EMT and CSCs and highlights the feasibility and significance of targeting CDK9 for the treatment of TNBC.
文摘While the function of DNA in biology is for storage of genetic information,chemists have developed methods to obtain DNA sequences with catalytic and molecular recognition functions.Thus,DNA is a highly attractive molecule for developing biosensors.DNA probes are known for their detection of complementary DNA and RNA.In addition,DNA aptamers allow for the detection of,essentially,any type of molecule.By coupling DNA with biological elements such as CRISPR-Cas12,highly sensitive detection with signal amplification can also be achieved.Overall,using DNA as a sensor component and as a target are hot areas of research for biomedical diagnosis,environmental monitoring,and food safety.