AIM:Phase I/II enzymes metabolize environmental carcinogens and several functional polymorphisms have been reported in their encoding genes. Although their significance with regard to esophageal carcinogenicity has be...AIM:Phase I/II enzymes metabolize environmental carcinogens and several functional polymorphisms have been reported in their encoding genes. Although their significance with regard to esophageal carcinogenicity has been examined epidemiologically, it remains controversial. The present systematic review of the literature was performed to clarify associations. METHODS: Eligible studies were case-control or cohort studies published until September 2004 that were written in any language. From PubMed and a manual review of reference lists in relevant review articles, we obtained 16 studies related to the CYP1A1 Ile-Val substitution in exon 7, CYP1A1 MspI polymorphisms, CYP2E1 Rsal polymorphisms, GSTM1 null type, GSTT1 null type and GSTP1 Ilel04Val. All were of case-control design. Summary statistics were odds ratios (ORs) comparing heterozygous-, homozygous-non-wild type or these two in combination with the homozygous wild type, or the null type with the non-null type for GSTM1 and GSTT1, A random effect model was used to estimate the summary ORs. A meta-regression analysis was applied to explore sources of heterogeneity. RESULTS: Individuals with the Ile-Val substitution in CYP1A1 exon 7 had increased esophageal cancer risk, with ORs (95%CI) compared with lie/lie of 1.37 (1.09-1.71), 2.52 (1.62-3.91) and 1.44 (1.17-1.78) for Ile-Val, Val/Val genotype and the combined group. No significant association was found between esophageal cancer risk and the other genetic parameters. CONCLUSION: A significant association exists between the CYP1A1 Ile-Val polymorphism and risk of esophageal cancer. Polymorphisms that increase the internal exposure to activated carcinogens may increase the risk of esophageal cancer.展开更多
The latest study published in Nature by Andrew R.Burns,Peter J.Roy and co-authors is highlighted in this paper,they investigated a series of novel nematicidal compounds,including Selectivin-A and Selectivin-E,and expl...The latest study published in Nature by Andrew R.Burns,Peter J.Roy and co-authors is highlighted in this paper,they investigated a series of novel nematicidal compounds,including Selectivin-A and Selectivin-E,and explored their mechanism of action.Experiments have displayed that the Selectivin compound is inactive to human cells,fish,fungi,insects and even beneficial nematodes.In the exploration of its mechanism of action,it was found that the mechanism of action of Selectivin is different with those of commercial nematocides:Selectivin needs to be activated by biotin produced by nematodes,after that they can be transformed into compounds with high nematicidal activity.This proves that the family of Selectivin compounds has the advantages of high selectivity and environmental friendliness,and their mechanism of action is completely new,proposing a completely new path for the development of new nematicides.展开更多
Hydroxylation of steroid core is critical to the synthesis of steroid drugs.Direct sp^(3) C-H hydroxylation is challenging through chemical catalysis,alternatively,fungal biotransformation offers a possible solution t...Hydroxylation of steroid core is critical to the synthesis of steroid drugs.Direct sp^(3) C-H hydroxylation is challenging through chemical catalysis,alternatively,fungal biotransformation offers a possible solution to this problem.However,mining and metabolic engineering of cytochrome P450 monooxygenases(CYPs)is usually regarded as a more eco-friendly and efficient strategy.Herein,we report the mining and identification of a new steroid CYP(CYP68BE1)from Beauveria bassiana by transcriptomics,heterologous expression,in vivo and in vitro functional characterization.The catalytic promiscuity of CYP68BE1 was explored,and CYP68BE1 showed promiscuously and catalytically versatile,which is qualified for monohydroxylation on C11α,C1α,C6βand dihydroxylation on C1β,11αand C6β,11αof six steroids,leading to the production of key steroid intermediates required in the industrial synthesis of some indispensable steroid drugs.Molecular dynamics simulations were performed,revealing the molecular basis of different binding orientations of CYP68BE1 with different substrates.The discovery of CYP68BE1 offers a promising biocatalyst for enriching the steroid structural and functional diversity,which also can be applied to biosynthesize valuable steroid drug intermediates.展开更多
Psoraleae Fructus(the dried fruits of Psoralea corylifolia), one of the most frequently used Chinese herbs in Asian countries, has a variety of biological activities. In clinical settings, Psoraleae Fructus or Psorale...Psoraleae Fructus(the dried fruits of Psoralea corylifolia), one of the most frequently used Chinese herbs in Asian countries, has a variety of biological activities. In clinical settings, Psoraleae Fructus or Psoraleae Fructus-related herbal medicines frequently have been used in combination with a number of therapeutic drugs for the treatment of various human diseases, such as leukoderma, rheumatism and dysentery. The use of Psoraleae Fructus in combination with drugs has aroused concern of the potential risks of herb-drug interactions(HDI) or herb-endobiotic interactions(HEI). This article reviews the interactions between human drug-metabolizing enzymes and the constituents of Psoraleae Fructus;the major constituents in Psoraleae Fructus, along with their chemical structures and metabolic pathways are summarized, and the inhibitory and inductive effects of the constituents in Psoraleae Fructus on human drug-metabolizing enzymes(DMEs), including target enzyme(s), its modulatory potency, and mechanisms of action are presented. Collectively, this review summarizes current knowledge of the interactions between the Chinese herb Psoraleae Fructus and therapeutic drugs in an effort to facilitate its rational use in clinical settings, and especially to avoid the potential risks of HDI or HEI through human DMEs.展开更多
文摘AIM:Phase I/II enzymes metabolize environmental carcinogens and several functional polymorphisms have been reported in their encoding genes. Although their significance with regard to esophageal carcinogenicity has been examined epidemiologically, it remains controversial. The present systematic review of the literature was performed to clarify associations. METHODS: Eligible studies were case-control or cohort studies published until September 2004 that were written in any language. From PubMed and a manual review of reference lists in relevant review articles, we obtained 16 studies related to the CYP1A1 Ile-Val substitution in exon 7, CYP1A1 MspI polymorphisms, CYP2E1 Rsal polymorphisms, GSTM1 null type, GSTT1 null type and GSTP1 Ilel04Val. All were of case-control design. Summary statistics were odds ratios (ORs) comparing heterozygous-, homozygous-non-wild type or these two in combination with the homozygous wild type, or the null type with the non-null type for GSTM1 and GSTT1, A random effect model was used to estimate the summary ORs. A meta-regression analysis was applied to explore sources of heterogeneity. RESULTS: Individuals with the Ile-Val substitution in CYP1A1 exon 7 had increased esophageal cancer risk, with ORs (95%CI) compared with lie/lie of 1.37 (1.09-1.71), 2.52 (1.62-3.91) and 1.44 (1.17-1.78) for Ile-Val, Val/Val genotype and the combined group. No significant association was found between esophageal cancer risk and the other genetic parameters. CONCLUSION: A significant association exists between the CYP1A1 Ile-Val polymorphism and risk of esophageal cancer. Polymorphisms that increase the internal exposure to activated carcinogens may increase the risk of esophageal cancer.
基金supported in part by the National Key Research and Development Program of China(2021YFD1700103)the National Natural Science Foundation of China(22177051,32061143045)+1 种基金the Fundamental Research Funds for the Central Universities(KYCYXT2022010)Sichuan Key Research and Development Program(22ZDYF0186,2021YFN0134).
文摘The latest study published in Nature by Andrew R.Burns,Peter J.Roy and co-authors is highlighted in this paper,they investigated a series of novel nematicidal compounds,including Selectivin-A and Selectivin-E,and explored their mechanism of action.Experiments have displayed that the Selectivin compound is inactive to human cells,fish,fungi,insects and even beneficial nematodes.In the exploration of its mechanism of action,it was found that the mechanism of action of Selectivin is different with those of commercial nematocides:Selectivin needs to be activated by biotin produced by nematodes,after that they can be transformed into compounds with high nematicidal activity.This proves that the family of Selectivin compounds has the advantages of high selectivity and environmental friendliness,and their mechanism of action is completely new,proposing a completely new path for the development of new nematicides.
基金supported by the National Key Research and Development Program of China(Nos.2020YFA0908003 and 2018YFA0901900)CAMS Innovation Fund for Medical Sciences(No.CIFMS2021-I2M-1-029).
文摘Hydroxylation of steroid core is critical to the synthesis of steroid drugs.Direct sp^(3) C-H hydroxylation is challenging through chemical catalysis,alternatively,fungal biotransformation offers a possible solution to this problem.However,mining and metabolic engineering of cytochrome P450 monooxygenases(CYPs)is usually regarded as a more eco-friendly and efficient strategy.Herein,we report the mining and identification of a new steroid CYP(CYP68BE1)from Beauveria bassiana by transcriptomics,heterologous expression,in vivo and in vitro functional characterization.The catalytic promiscuity of CYP68BE1 was explored,and CYP68BE1 showed promiscuously and catalytically versatile,which is qualified for monohydroxylation on C11α,C1α,C6βand dihydroxylation on C1β,11αand C6β,11αof six steroids,leading to the production of key steroid intermediates required in the industrial synthesis of some indispensable steroid drugs.Molecular dynamics simulations were performed,revealing the molecular basis of different binding orientations of CYP68BE1 with different substrates.The discovery of CYP68BE1 offers a promising biocatalyst for enriching the steroid structural and functional diversity,which also can be applied to biosynthesize valuable steroid drug intermediates.
基金supported by the NSF of China(Nos.81922070,81973286,81773687)the National Key Research and Development Program of China(No.2017YFC1700200,2017YFC1702000)+3 种基金Program of Shanghai Academic/Technology Research Leader(No.18XD1403600)Shuguang Program(No.18SG40)Program for applied basic research of Qinghai Provincial Science and Technology Department(No.2017-ZJ-713)Program for Innovative Leading Talents of Qinghai Province(2018&2019)
文摘Psoraleae Fructus(the dried fruits of Psoralea corylifolia), one of the most frequently used Chinese herbs in Asian countries, has a variety of biological activities. In clinical settings, Psoraleae Fructus or Psoraleae Fructus-related herbal medicines frequently have been used in combination with a number of therapeutic drugs for the treatment of various human diseases, such as leukoderma, rheumatism and dysentery. The use of Psoraleae Fructus in combination with drugs has aroused concern of the potential risks of herb-drug interactions(HDI) or herb-endobiotic interactions(HEI). This article reviews the interactions between human drug-metabolizing enzymes and the constituents of Psoraleae Fructus;the major constituents in Psoraleae Fructus, along with their chemical structures and metabolic pathways are summarized, and the inhibitory and inductive effects of the constituents in Psoraleae Fructus on human drug-metabolizing enzymes(DMEs), including target enzyme(s), its modulatory potency, and mechanisms of action are presented. Collectively, this review summarizes current knowledge of the interactions between the Chinese herb Psoraleae Fructus and therapeutic drugs in an effort to facilitate its rational use in clinical settings, and especially to avoid the potential risks of HDI or HEI through human DMEs.
