Human Notum(hNotum)inhibitors could be used for treating Wnt signalling-associated diseases including colorectal cancer.Herein,two series of chalcone derivatives were designed and synthesized aiming to find selective ...Human Notum(hNotum)inhibitors could be used for treating Wnt signalling-associated diseases including colorectal cancer.Herein,two series of chalcone derivatives were designed and synthesized aiming to find selective and potent hNotum inhibitors.Structure–activity relationship(SAR)studies showed that 2-methoxyl and 5-bromine substitutions on A-ring significantly enhanced anti-hNotum effect,while 4’-ethoxyl and 3’-alkyl substitutions on B-ring were beneficial for hNotum inhibition.Among all tested chalcones,B11 displayed the most potent anti-Notum effect(IC_(50)=3.6 nmol/L),good selectivity,excellent chemical stability and suitable metabolic stability.Further investigations showed that B11 acted as a competitive inhibitor of hNotum,while this agent(5μmol/L)significantly weaken the migration abilities of colorectal cancer cells.Collectively,this study deciphers the SARs of chalcones as hNotum inhibitors and reports a novel and potent hNotum inhibitor with the anti-migration effect on colorectal cancer cells,which offers a promising lead compound to develop novel anti-cancer agents.展开更多
Background and Objective:Cardiac fibrosis is a pathological reparative process that follows myocardial infarctionand is associated with compromised cardiac systolic and reduced cardiac compliance.The Wnt signaling pat...Background and Objective:Cardiac fibrosis is a pathological reparative process that follows myocardial infarctionand is associated with compromised cardiac systolic and reduced cardiac compliance.The Wnt signaling pathway is closely implicated in organ fibrosis,and Notum,a highly conserved secreted inhibitor,modulates Wnt signaling.The objective of this study was to explore the role and mechanism of Notum in cardiac fibrosis.Methods:A mouse model of cardiac remodeling was established through left coronary artery ligation surgery,with the addition of Notum injection following myocardial infarction surgery.The protective effect of Notum on myocardial infarction was assessed by evaluating cardiac function,including survival rate,echocardiographic assessment,and cardiac contraction analyses.Inflammatory cell necrosis and infiltration were confirmed through H&E and Masson staining.The expression of fibrosis-related genes andβ-catenin pathway markers was detected using Western blot quantificational RT-PCR(qRT-PCR).Additionally,EdU,wound healing,and immunofluorescence staining analyses were performed to detect the effect of Notum's in transforming growth factor beta-1(TGF-β1)induced myofibroblast transformation.Results:The administration of Notum treatment resulted in enhanced survival rates,improved cardiac function,and decreased necrosis and infiltration of inflammatory cells in mice subjected to left coronary artery ligation.Furthermore,Notum effectively impeded the senescence of cardiac fibroblasts and hindered their pathological transformation into cardiac fibroblasts.Additionally,it significantly reduced collagen production and attenuated the activation of the Wnt/β-catenin pathway.Our preliminary investigations successfully demonstrated the therapeutic potential of Notum in both fibroblasts in vitro and in a mouse model of myocardial infarction-induced cardiac fibrosis in vivo.Conclusion:Notum inhibition of the Wnt/β-catenin signaling pathway and cardiac fibroblast senescence ultimately hampers the onset of cardiac fibrosis.Our findings suggest that Notum could represent a new therapeutic strategy for the treatment of cardiac fibrosis.展开更多
Notum,a negative feedback regulator of the Wnt signaling,has emerged as a promising target for treating glucocorticoid-induced osteoporosis(GIOP).This study showcases an efficient strategy for discovering the anti-Not...Notum,a negative feedback regulator of the Wnt signaling,has emerged as a promising target for treating glucocorticoid-induced osteoporosis(GIOP).This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines(HMs)as novel anti-GIOP agents.Firstly,a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs.The results showed that Bu-Gu-Zhi(BGZ),a known anti-osteoporosis herb,potently inhibited Notum in a competitive-inhibition manner.To uncover the key anti-Notum constituents in BGZ,an efficient strategy was adapted via integrating biochemical,phytochemical,computational,and pharmacological assays.Among all identified BGZ constituents,three furanocoumarins were validated as strong Notum inhibitors,while 5-methoxypsoralen(5-MP)showed the most potent anti-Notum activity and favorable safety profiles.Mechanistically,5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum.Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone(DXMS)-challenged MC3T3-E1 osteoblasts.In dexamethasone-induced osteoporotic mice,5-MP strongly elevated bone mineral density(BMD)and improved cancellous and cortical bone thickness.Collectively,this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs,while 5-MP emerges as a promising antiGIOP agent.展开更多
Alzheimer's disease,a significant contributor to dementia,is rapidly becoming a serious healthcare concern in the 21st century.The alarming number of patients with Alzheimer's disease is steadily increasing,wh...Alzheimer's disease,a significant contributor to dementia,is rapidly becoming a serious healthcare concern in the 21st century.The alarming number of patients with Alzheimer's disease is steadily increasing,which is contributed by the dearth of treatment options.The current treatment for Alzheimer's disease is heavily dependent on symptomatic treatment that has failed to cure the disease despite huge investments in the development of drugs.The clinical treatment of Alzheimer's disease with limited drugs is generally targeted towards the inhibition of N-methyl-d-aspartate receptor and acetylcholine esterase,which only elevate cognition levels for a limited period.Beyond the aforementioned molecular targets,β-amyloid was much explored with little success and thus created a feel and palpable growing emphasis on discovering new putative and novel targets for AD.This has inspired medicinal chemists to explore new targets,including microglia,triggering receptors expressed on myeloid cells 2(Trem-2),and notum carboxylesterase,to discover new lead compounds.This review explores the functions,pathophysiological roles,and importance of all AD-related targets that address therapeutic and preventive approaches for the treatment and protection of Alzheimer's disease.展开更多
基金financially supported by the National Natural Science Foundation of China(Nos.82104281,81922070,81973286,81801818 and 82273897)Shanghai Municipal Health Commission’s TCM research project(No.2022CX005)+1 种基金Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-D-202004)Three-year Action Plan for Shanghai TCM Development and Inheritance Program[No.ZY(2021–2023)-0401]。
文摘Human Notum(hNotum)inhibitors could be used for treating Wnt signalling-associated diseases including colorectal cancer.Herein,two series of chalcone derivatives were designed and synthesized aiming to find selective and potent hNotum inhibitors.Structure–activity relationship(SAR)studies showed that 2-methoxyl and 5-bromine substitutions on A-ring significantly enhanced anti-hNotum effect,while 4’-ethoxyl and 3’-alkyl substitutions on B-ring were beneficial for hNotum inhibition.Among all tested chalcones,B11 displayed the most potent anti-Notum effect(IC_(50)=3.6 nmol/L),good selectivity,excellent chemical stability and suitable metabolic stability.Further investigations showed that B11 acted as a competitive inhibitor of hNotum,while this agent(5μmol/L)significantly weaken the migration abilities of colorectal cancer cells.Collectively,this study deciphers the SARs of chalcones as hNotum inhibitors and reports a novel and potent hNotum inhibitor with the anti-migration effect on colorectal cancer cells,which offers a promising lead compound to develop novel anti-cancer agents.
基金This study was supported by the National Natural Science Foundation of China(82330011,82170299,81900225)the Scientific Fund Project of Heilongjiang Province(JQ2022H001)the CAMS Innovation Fund for Medical Sciences(CIFMS,2019-I2M-5-078).
文摘Background and Objective:Cardiac fibrosis is a pathological reparative process that follows myocardial infarctionand is associated with compromised cardiac systolic and reduced cardiac compliance.The Wnt signaling pathway is closely implicated in organ fibrosis,and Notum,a highly conserved secreted inhibitor,modulates Wnt signaling.The objective of this study was to explore the role and mechanism of Notum in cardiac fibrosis.Methods:A mouse model of cardiac remodeling was established through left coronary artery ligation surgery,with the addition of Notum injection following myocardial infarction surgery.The protective effect of Notum on myocardial infarction was assessed by evaluating cardiac function,including survival rate,echocardiographic assessment,and cardiac contraction analyses.Inflammatory cell necrosis and infiltration were confirmed through H&E and Masson staining.The expression of fibrosis-related genes andβ-catenin pathway markers was detected using Western blot quantificational RT-PCR(qRT-PCR).Additionally,EdU,wound healing,and immunofluorescence staining analyses were performed to detect the effect of Notum's in transforming growth factor beta-1(TGF-β1)induced myofibroblast transformation.Results:The administration of Notum treatment resulted in enhanced survival rates,improved cardiac function,and decreased necrosis and infiltration of inflammatory cells in mice subjected to left coronary artery ligation.Furthermore,Notum effectively impeded the senescence of cardiac fibroblasts and hindered their pathological transformation into cardiac fibroblasts.Additionally,it significantly reduced collagen production and attenuated the activation of the Wnt/β-catenin pathway.Our preliminary investigations successfully demonstrated the therapeutic potential of Notum in both fibroblasts in vitro and in a mouse model of myocardial infarction-induced cardiac fibrosis in vivo.Conclusion:Notum inhibition of the Wnt/β-catenin signaling pathway and cardiac fibroblast senescence ultimately hampers the onset of cardiac fibrosis.Our findings suggest that Notum could represent a new therapeutic strategy for the treatment of cardiac fibrosis.
基金supported by the National Natural Science Foundation of China(82273897,U23A20516,82104281,and 32101202)Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine(2023YZZ02,China)+5 种基金Shanghai Municipal Health Commission’s TCM research project(2022CX005,China)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(ZYYCXTDD-202004,China)Three-year Action Plan for Shanghai TCM Development and Inheritance Program(ZY(2021-2023)-0401,China)the Fundamental Research Funds for the Central Universities(G2024KY05106,China)the State Key Laboratory of Fine Chemicals,Dalian University of Technology(KF2202,China)supported by China Postdoctoral Science Foundation(2024M762108,China).
文摘Notum,a negative feedback regulator of the Wnt signaling,has emerged as a promising target for treating glucocorticoid-induced osteoporosis(GIOP).This study showcases an efficient strategy for discovering the anti-Notum constituents from herbal medicines(HMs)as novel anti-GIOP agents.Firstly,a rapid-responding near-infrared fluorogenic substrate for Notum was rationally engineered for high-throughput identifying the anti-Notum HMs.The results showed that Bu-Gu-Zhi(BGZ),a known anti-osteoporosis herb,potently inhibited Notum in a competitive-inhibition manner.To uncover the key anti-Notum constituents in BGZ,an efficient strategy was adapted via integrating biochemical,phytochemical,computational,and pharmacological assays.Among all identified BGZ constituents,three furanocoumarins were validated as strong Notum inhibitors,while 5-methoxypsoralen(5-MP)showed the most potent anti-Notum activity and favorable safety profiles.Mechanistically,5-MP acted as a competitive inhibitor of Notum via creating strong hydrophobic interactions with Trp128 and Phe268 in the catalytic cavity of Notum.Cellular assays showed that 5-MP remarkably promoted osteoblast differentiation and activated Wnt signaling in dexamethasone(DXMS)-challenged MC3T3-E1 osteoblasts.In dexamethasone-induced osteoporotic mice,5-MP strongly elevated bone mineral density(BMD)and improved cancellous and cortical bone thickness.Collectively,this study constructs a high-efficient platform for discovering key anti-Notum constituents from HMs,while 5-MP emerges as a promising antiGIOP agent.
文摘Alzheimer's disease,a significant contributor to dementia,is rapidly becoming a serious healthcare concern in the 21st century.The alarming number of patients with Alzheimer's disease is steadily increasing,which is contributed by the dearth of treatment options.The current treatment for Alzheimer's disease is heavily dependent on symptomatic treatment that has failed to cure the disease despite huge investments in the development of drugs.The clinical treatment of Alzheimer's disease with limited drugs is generally targeted towards the inhibition of N-methyl-d-aspartate receptor and acetylcholine esterase,which only elevate cognition levels for a limited period.Beyond the aforementioned molecular targets,β-amyloid was much explored with little success and thus created a feel and palpable growing emphasis on discovering new putative and novel targets for AD.This has inspired medicinal chemists to explore new targets,including microglia,triggering receptors expressed on myeloid cells 2(Trem-2),and notum carboxylesterase,to discover new lead compounds.This review explores the functions,pathophysiological roles,and importance of all AD-related targets that address therapeutic and preventive approaches for the treatment and protection of Alzheimer's disease.
