Glutathione S-transferases (GSTs) play an important role in the detoxification of polycyclic aromatic hydrocarbons and aromatic amines, the toxic substances contained in cigarettes. GST Omega 1 (GSTO1) not only utiliz...Glutathione S-transferases (GSTs) play an important role in the detoxification of polycyclic aromatic hydrocarbons and aromatic amines, the toxic substances contained in cigarettes. GST Omega 1 (GSTO1) not only utilizes glutathione in conjugation reaction but also contributes to the biotransformation of several xenobiotics. A single nucleotide polymorphism (Ala-140Asp) of GSTO1 gene causing variations in enzyme activity may influence individual susceptibility to bladder cancer (BC). It is hypothesized that genetic polymorphism of GSTO1 gene has an effect on BC risk in particular by interacting with cigarette smoking. A total of histopathologically confirmed 300 BC patients and 300 cancer-free controls were recruited from February 2002 to February 2009. Genotyping of the GSTO1 Ala140Asp polymorphism was determined using a polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) method. The odds ratio (OR) and 95% confidence interval (CI) were calculated as a measure of the combined effect of cigarette smoking and the GSTO1 Ala140Asp polymorphism on BC risk. We found that study subjects with the GSTO1 Ala/Ala genotype have a significantly increased BC risk (OR = 1.5;95% CI = 1.1 - 2.7). A statistically significant increased BC risk was also found in ever smokers with the GSTO1 Ala/Ala genotype (OR = 4.9;95%CI = 2.8 - 9.7). In conclusion, this study provides an epidemiologic evidence of a significantly increased BC risk among ever smokers with the GSTO1 Ala/Ala genotype.展开更多
Covalent bioactive compounds are successfully used in clinic and attracted intense research efforts in the fundamental study as well as drug development.The advantageous effects of covalent compounds compared with non...Covalent bioactive compounds are successfully used in clinic and attracted intense research efforts in the fundamental study as well as drug development.The advantageous effects of covalent compounds compared with non-covalent ones are highly dependent on electrophilic warheads.Hence,electrophilic warheads with tunable reactivity and selectivity are highly demanded in fields of medicinal chemistry and chemical biology.Herein,we report a novel electrophilic warhead,chloromethyl group activated by thiol-substituted 1,2,4-triazole.Interestingly,a pair of regioisomers could be simultaneously occurred in the step of alkylation during the synthesis of this unique motif.This is a rare example that the alkylation could simultaneously generate these two separable regioisomers of 1,2,4-triazole at the nitrogen or sulfur atom.The covalent-working mechanism of this new warhead is confirmed by various chemoproteomics experiments including target identification and binding site mapping.Importantly,the reactivity and selectivity of this new electrophilic warhead could be efficiently tuned by virtue of stereo effect.Interestingly,one pair of regioisomers(19S and 19X)induced distinct modes of cell death.Isomer 19S could induce apoptosis of colon cancer cells while 19X could induce both apoptosis and ferroptosis.Together,this study provides pairs of novel electrophilic warheads that could be useful not only in supporting the design of covalent compounds for drug discovery but also in providing chemical probes for the fundamental biological study.展开更多
文摘Glutathione S-transferases (GSTs) play an important role in the detoxification of polycyclic aromatic hydrocarbons and aromatic amines, the toxic substances contained in cigarettes. GST Omega 1 (GSTO1) not only utilizes glutathione in conjugation reaction but also contributes to the biotransformation of several xenobiotics. A single nucleotide polymorphism (Ala-140Asp) of GSTO1 gene causing variations in enzyme activity may influence individual susceptibility to bladder cancer (BC). It is hypothesized that genetic polymorphism of GSTO1 gene has an effect on BC risk in particular by interacting with cigarette smoking. A total of histopathologically confirmed 300 BC patients and 300 cancer-free controls were recruited from February 2002 to February 2009. Genotyping of the GSTO1 Ala140Asp polymorphism was determined using a polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) method. The odds ratio (OR) and 95% confidence interval (CI) were calculated as a measure of the combined effect of cigarette smoking and the GSTO1 Ala140Asp polymorphism on BC risk. We found that study subjects with the GSTO1 Ala/Ala genotype have a significantly increased BC risk (OR = 1.5;95% CI = 1.1 - 2.7). A statistically significant increased BC risk was also found in ever smokers with the GSTO1 Ala/Ala genotype (OR = 4.9;95%CI = 2.8 - 9.7). In conclusion, this study provides an epidemiologic evidence of a significantly increased BC risk among ever smokers with the GSTO1 Ala/Ala genotype.
基金supported by grants from The National Natural Science Foundation of China(81801548,82071736)the Fundamental Research Funds for the Central Universities(WK9110000149)。
基金The National Natural Science Foundation of China(No.22177136)CAMS Innovation Fund for Medical Sciences(CIFMS,Nos.CIFMS-2021-I2M-1-007,2022-I2M-2-002)。
文摘Covalent bioactive compounds are successfully used in clinic and attracted intense research efforts in the fundamental study as well as drug development.The advantageous effects of covalent compounds compared with non-covalent ones are highly dependent on electrophilic warheads.Hence,electrophilic warheads with tunable reactivity and selectivity are highly demanded in fields of medicinal chemistry and chemical biology.Herein,we report a novel electrophilic warhead,chloromethyl group activated by thiol-substituted 1,2,4-triazole.Interestingly,a pair of regioisomers could be simultaneously occurred in the step of alkylation during the synthesis of this unique motif.This is a rare example that the alkylation could simultaneously generate these two separable regioisomers of 1,2,4-triazole at the nitrogen or sulfur atom.The covalent-working mechanism of this new warhead is confirmed by various chemoproteomics experiments including target identification and binding site mapping.Importantly,the reactivity and selectivity of this new electrophilic warhead could be efficiently tuned by virtue of stereo effect.Interestingly,one pair of regioisomers(19S and 19X)induced distinct modes of cell death.Isomer 19S could induce apoptosis of colon cancer cells while 19X could induce both apoptosis and ferroptosis.Together,this study provides pairs of novel electrophilic warheads that could be useful not only in supporting the design of covalent compounds for drug discovery but also in providing chemical probes for the fundamental biological study.
