BACKGROUND Coronary heart disease(CHD)is a prominent cause of mortality and disability worldwide.Like most complex diseases,the risk of CHD in individuals is regulated by the interaction between genetic factors and li...BACKGROUND Coronary heart disease(CHD)is a prominent cause of mortality and disability worldwide.Like most complex diseases,the risk of CHD in individuals is regulated by the interaction between genetic factors and lifestyle.APOE and SLCO1B1 genetic polymorphisms and LPA KIV-2 copy number variation may influence the development and progression of CHD.Clarifying gene polymor-phisms can guide clinical precision and prevention,thereby improving treatment outcomes.AIM To investigate the influence of APOE and SLCO1B1 gene polymorphisms,as well as LPA KIV-2 copy number variation on CHD in the Teochew population.METHODS A total of 324 patients with CHD and 143 control participants were involved in this study.Single nucleotide polymorphisms rs429358 and rs7412 in the APOE gene,and rs2306283 and rs4149056 in the SLCO1B1 gene were analyzed via high-resolution melting curve analysis.Additionally,PCR was performed to detect KIV-2 copy number variations.Clinical risk factors and potential effects on CHD patients were subsequently assessed.RESULTS In the CHD group,the frequencies of APOE alleleε2,ε3,ε4 were 8.02%,82.97%,and 9.10%,respectively.Compared to the control groups(13.29%,79.37%,and 7.34%,respectively),theε2 allele frequency showed a significant difference(8.02%vs 13.29%,P=0.012).SLCO1B1 allele frequencies in the CHD group were not significantly different from those in the control group(*1a:26.69%vs 25.52%,*1b:61.17%vs 65.38%,*5:0.15%vs 0.35%,*15:11.83%vs 8.74%).The number of copies of the KIV-2 gene was significantly lower in the CHD group when compared to controls(23.35±8.78 vs 27.21±9.48;P<0.01).Logistic regression analysis revealed that sex,age,hypertension,diabetes,smoking,theε2 allele and KIV-2 copy number were factors influencing the presence of CHD.CONCLUSION In the Teochew population,the APOEε2 allele and a higher KIV-2 copy number were associated with a reduced risk of CHD.In contrast,the APOEε4 allele and SLCO1B1 gene were not associated with CHD.展开更多
Human cytochrome P4501B1(h CYP1B1),an extrahepatic heme-dependent monooxygenase,has been validated as a key target for overcoming chemotherapy resistance and tumorigenesis.Herein,to discover novel efficacious h CYP1B1...Human cytochrome P4501B1(h CYP1B1),an extrahepatic heme-dependent monooxygenase,has been validated as a key target for overcoming chemotherapy resistance and tumorigenesis.Herein,to discover novel efficacious h CYP1B1 inhibitors,a suite of 1,8-naphthalimide derivatives was designed,synthesized,and biologically evaluated,via integrating structure-based drug design(SBDD)and biochemical assays.After two rounds of structural modifications and structure-activity relationship(SAR)studies,the results suggested that introducing a benzene ring at the north part and a halogen atom at the C-4 site significantly enhanced the anti-h CYP1B1 effects of naphthalimides.Among all tested 1,8-naphthalimides,NB-10showed the most potent anti-h CYP1B1 effect(half maximal inhibitory concentration(IC_(50))=0.41 nmol/L)and excellent specificity,while this agent did not activate Ah R transcription activity in living cells.Further cellular assays and in vivo tests in paclitaxel(PTX)-resistance xenograft mice showed that NB-10could significantly potentiate the anti-cancer effects of PTX both in vitro and in vivo,while this agent also showed high safety profiles in mice.Mechanistically,NB-10 potently inhibited h CYP1B1-catalyzed 7-ethoxyresorufin O-deethylation in a competitive manner,with an estimated Kivalue of 0.15 nmol/L.Docking simulations showed that NB-10 could be well-fitted in the catalytic pocket of h CYP1B1 to form a stable conformation with a high binding affinity.Collectively,several potent 4-halogenated naphthalimides were developed as novel h CYP1B1 inhibitors,while NB-10 showed high safety profiles and impressive efficacy for overcoming h CYP1B1-associated PTX resistance both in vitro and in vivo.展开更多
基金Supported by Special Research Plan 2023 of Chaozhou,No.202303GY05。
文摘BACKGROUND Coronary heart disease(CHD)is a prominent cause of mortality and disability worldwide.Like most complex diseases,the risk of CHD in individuals is regulated by the interaction between genetic factors and lifestyle.APOE and SLCO1B1 genetic polymorphisms and LPA KIV-2 copy number variation may influence the development and progression of CHD.Clarifying gene polymor-phisms can guide clinical precision and prevention,thereby improving treatment outcomes.AIM To investigate the influence of APOE and SLCO1B1 gene polymorphisms,as well as LPA KIV-2 copy number variation on CHD in the Teochew population.METHODS A total of 324 patients with CHD and 143 control participants were involved in this study.Single nucleotide polymorphisms rs429358 and rs7412 in the APOE gene,and rs2306283 and rs4149056 in the SLCO1B1 gene were analyzed via high-resolution melting curve analysis.Additionally,PCR was performed to detect KIV-2 copy number variations.Clinical risk factors and potential effects on CHD patients were subsequently assessed.RESULTS In the CHD group,the frequencies of APOE alleleε2,ε3,ε4 were 8.02%,82.97%,and 9.10%,respectively.Compared to the control groups(13.29%,79.37%,and 7.34%,respectively),theε2 allele frequency showed a significant difference(8.02%vs 13.29%,P=0.012).SLCO1B1 allele frequencies in the CHD group were not significantly different from those in the control group(*1a:26.69%vs 25.52%,*1b:61.17%vs 65.38%,*5:0.15%vs 0.35%,*15:11.83%vs 8.74%).The number of copies of the KIV-2 gene was significantly lower in the CHD group when compared to controls(23.35±8.78 vs 27.21±9.48;P<0.01).Logistic regression analysis revealed that sex,age,hypertension,diabetes,smoking,theε2 allele and KIV-2 copy number were factors influencing the presence of CHD.CONCLUSION In the Teochew population,the APOEε2 allele and a higher KIV-2 copy number were associated with a reduced risk of CHD.In contrast,the APOEε4 allele and SLCO1B1 gene were not associated with CHD.
基金supported by the National Natural Science Foundation of China(Nos.82273897,U23A20516,32101202)Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine(No.2023YZZ02)+5 种基金Shanghai Municipal Health Commission’s TCM research project(No.2022CX005)Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTDD-202004)Pudong Institute of Clinical Chinese Medicine(No.YC-2023-0603)The“Fourteenth Five-Year Plan”Traditional Chinese Medicine Specialty Project for the Construction of Andrology Departments in TCM(No.ZYTSZK1-4)the State Key Laboratory of Fine Chemicals,Dalian University of Technology(No.KF2202)the Fundamental Research Funds for the Central Universities(No.G2024KY05106)。
文摘Human cytochrome P4501B1(h CYP1B1),an extrahepatic heme-dependent monooxygenase,has been validated as a key target for overcoming chemotherapy resistance and tumorigenesis.Herein,to discover novel efficacious h CYP1B1 inhibitors,a suite of 1,8-naphthalimide derivatives was designed,synthesized,and biologically evaluated,via integrating structure-based drug design(SBDD)and biochemical assays.After two rounds of structural modifications and structure-activity relationship(SAR)studies,the results suggested that introducing a benzene ring at the north part and a halogen atom at the C-4 site significantly enhanced the anti-h CYP1B1 effects of naphthalimides.Among all tested 1,8-naphthalimides,NB-10showed the most potent anti-h CYP1B1 effect(half maximal inhibitory concentration(IC_(50))=0.41 nmol/L)and excellent specificity,while this agent did not activate Ah R transcription activity in living cells.Further cellular assays and in vivo tests in paclitaxel(PTX)-resistance xenograft mice showed that NB-10could significantly potentiate the anti-cancer effects of PTX both in vitro and in vivo,while this agent also showed high safety profiles in mice.Mechanistically,NB-10 potently inhibited h CYP1B1-catalyzed 7-ethoxyresorufin O-deethylation in a competitive manner,with an estimated Kivalue of 0.15 nmol/L.Docking simulations showed that NB-10 could be well-fitted in the catalytic pocket of h CYP1B1 to form a stable conformation with a high binding affinity.Collectively,several potent 4-halogenated naphthalimides were developed as novel h CYP1B1 inhibitors,while NB-10 showed high safety profiles and impressive efficacy for overcoming h CYP1B1-associated PTX resistance both in vitro and in vivo.
