Background: Human organic cationic transporter1 (Hoct1) is a plasma membrane transporter responsible for the main influx of Imatinib into chronic myeloid leukemia (CML) cells. Single nucleotide polymorphisms (SNPs) in...Background: Human organic cationic transporter1 (Hoct1) is a plasma membrane transporter responsible for the main influx of Imatinib into chronic myeloid leukemia (CML) cells. Single nucleotide polymorphisms (SNPs) in the gene coding for hOCT1 are important factors causing Imatinib resistance. We investigated the frequency of hOCT1 SNP C480G among Egyptian CML patients and its relation to early molecular response as an indicator of treatment outcome. Materials and Methods: Two groups of CML patients were included in this study. Group I consisted of 25 patients responding to Imatinib treatment (Imatinib responsive) and group II consisted of 25 patients resistant to Imatinib (Imatinib resistant). Response criteria were assessed according to the NCCN (National Comprehensive Cancer Network) guidelines 2017. Twenty healthy controls of matched age and sex were also included (group III). For all patients, we studied hOCT1 C480G at initial presentation using Taqman drug metabolism genotyping as well as BCR-ABL percent at diagnosis and after 3 months interval. Results: hOCT1 C480G was present in 32% of studied CML patients. CC (wild) was detected in 68% of group I and 64% of group II. CG (mutant heterozygous) was present in 28% of group I and 36% of group II while GG (mutant homozygous) was detected in only one case in group I. CG was also detected in 15% of control subjects There was no significant difference between hOCT1 C480G polymorphism and Early Molecular Response (χ2 = 0.089, p = 0.765). Conclusions: hOCT1 C480G polymorphism has no association with Imatinib resistance in Egyptian population. However, further studies on a larger number of patients are still needed to confirm this finding.展开更多
AIM： To investigate the single nucleotide polymorphism （SNPs） distribution of NOD2/CARD15 （R702W, G908R）, OCTN1 1672CFT and OCTN2-207G/C in Chinese patients with inflammatory bowel disease （IBD）. METHODS： A to...AIM： To investigate the single nucleotide polymorphism （SNPs） distribution of NOD2/CARD15 （R702W, G908R）, OCTN1 1672CFT and OCTN2-207G/C in Chinese patients with inflammatory bowel disease （IBD）. METHODS： A total of 61 patients with Crohn＇s disease （CD）, 151 patients with ulcerative colitis （UC）, and 200 unrelated healthy controls were genotyped. Genotyping was performed by sequence specific primer polymerase chain reaction （PCR-SSP） or by restriction fragment length polymorphism （PCR-RFLP） analysis. RESULTS： Among the subjects in our study groups, including patients with CD, UC and healthy controls, none had OCTN and CARD15 variants and very rare IBD family history was found in our patients with the percentage of 0 （0/61 with CD） and 1.3% （2/151 with UC）. CONCLUSION： Our results indicate that although OCTN or CARD15 variation is associated with susceptibility to IBD in Western populations, these might be rare and may not be associated with susceptibility to IBD in Chinese patients.展开更多
Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to faci...Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery.In particular,intestinal carnitine/organic cation transporter 2(OCTN2)and mono-carboxylate transporter protein 1(MCT1)possess high transport capacities and complementary distributions.Therefore,we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review.First,basic information of the two transporters is reviewed,including their topological structures,characteristics and functions,expression and key features of their substrates.Furthermore,progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed,including improvements in the oral absorption of anti-inflammatory drugs,antiepileptic drugs and anticancer drugs.Finally,the potential of a dual transporter-targeting strategy is discussed.展开更多
AIM: To investigate the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in disease predispo- sition and phenotypes in a large Italian cohort of pediatric patients with inflammatory bowel diseases (IBD). MET...AIM: To investigate the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in disease predispo- sition and phenotypes in a large Italian cohort of pediatric patients with inflammatory bowel diseases (IBD). METHODS: Two hundred patients with Crohn’s disease (CD), 186 ulcerative colitis (UC) patients, 434 par- ents (217 trios), and 347 healthy controls (HC) were studied. Polymorphisms of the three major variants of CARD15, 1672C/T and -207G/C SNPs for OCTN genes, IGR2096a_1 and IGR2198a_1 SNPs for the IBD5 locus, and 113G/A variant of the DLG5 gene were evaluated. Potential correlations with clinical sub-phenotypes were investigated. RESULTS: Polymorphisms of CARD15 were significantly associated with CD, and at least one variant was found in 38% of patients (15% in HC, OR = 2.7, P < 0.001). Homozygosis for both OCTN1/2 variants was more com- mon in CD patients (1672TT 24%, -207CC 29%) than in HC (16% and 21%, respectively; P = 0.03), with an in- creased frequency of the TC haplotype (44.8% vs 38.3% in HC, P = 0.04). No association with the DLG5 variant was found. CD carriers of OCTN1/2 and DLG5 variants more frequently had penetrating disease (P = 0.04 and P = 0.01), while carriers of CARD15 more frequently had ileal localization (P = 0.03). No gene-gene interaction was found. In UC patients, the TC haplotype was morefrequent (45.4%, P = 0.03), but no genotype/phenotype correlation was observed. CONCLUSION: Polymorphisms of CARD15 and OCTN genes, but not DLG5 are associated with pediatric on- set of CD. Polymorphisms of CARD15, OCTN, and DLG5 genes exert a weak influence on CD phenotype.展开更多
Objective To determine the effects of genetic variation in the organic cation transporter 1(OCT1)on the short-term responses of the antidiabetic drug,metformin.Method A total of 22 patients recruited with type 2 diabe...Objective To determine the effects of genetic variation in the organic cation transporter 1(OCT1)on the short-term responses of the antidiabetic drug,metformin.Method A total of 22 patients recruited with type 2 diabetes or IFG were treated with metformin(2 000 mg/day)for 1 week.The patients were screened from Second Jikun hospital and Kashidonglu community medicine service,Urumqi,China and their surrounding districts.To examine the effects of metformin on plasma glucose,total cholesterol,low-density lipoprotein-cholesterol,high-density lipoprotein-cholesterol and triglyceride in relation with R61C,G465R and 420 del variants of OCT1(gene encoding organic cation transporter 1,mainly locating in liver,which is metformin's major target)in subjects.In all,R61C,G465R and 420del of OCT1 gene were examined using DNA extracted from whole blood and PCR-RFLP.Data concerning with gene and metformin treatment were handled by t-test.Result After metformin treatment,there were increases both in FPG and LDL(P=0.011and P=0.013 respectively).To divide all participants into mutant and wild groups,according to the polymorphisms of R61C,G465R and 420 del respectively,as well as carriers with one of the mutant genotypes at least and carriers with none of the mutant sites.Analysis was made to compared FPG,Chol,TG,and LDL and HDL between carriers of wild genotypes and carriers of other genotypes showed no statistic significance both before the metformin treatment and after the treatment.The same is the case with changes of FPG,Chol,TG,and LDL and HDL of wild genotype carriers and variant genotype carriers,except of LDL changes(P=0.05)in patients grouped by G465R polymorphisms and TG changes(P=0.03)in subjects differed by 420del genotypes.Conclusion In this study,it is suggested that OCT1 gene polymorphisms have little contribution to the clinical efficacy of blood glucose control by metformin among Uygur people with type 2 diabetes or IFG,but it may have possible relationship with the clinical efficacy on fat metabolism by metformin.展开更多
The intestinal epithelium is the main barrier to the oral delivery of poorly water-soluble drugs. Based on the specific transporters expressed on the apical membrane of the intestinal epithelium, novel polymer micelle...The intestinal epithelium is the main barrier to the oral delivery of poorly water-soluble drugs. Based on the specific transporters expressed on the apical membrane of the intestinal epithelium, novel polymer micelles targeting to the organic cation transporter 2（OCTN2） were constructed by combining carnitine conjugated poly（2-ethyl-2-oxazoline）-poly（D,L-lactide）（Car-PEOz-PLA） with monomethoxy poly（ethylene glycol）-poly（D,L-lactide）（mP EG-PLA）. The structure of the synthesized Car-PEOz-PLA was confirmed by -1H NMR, TLC and ammonium reineckate precipitation reaction, and the number-average molecular weight determined by GPC was 7260 g/mol with a low PDI of 1.44. Coumarin 6-loaded carnitine modified polymeric micelles prepared by film hydration method were characterized to have a nano-scaled size of about 31 nm in diameter, uniform spherical morphology, high drug loading content of 0.098%±0.03% and encapsulation efficiency of 92.67%±2.80%. Moreover, the carnitine-modified micelles exhibited the similar in vitro release behavior in SGF and SIF, and evidently enhanced intestinal absorption of poorly water-soluble agent. Therefore, the designed OCTN2-targeted micelles might have a promising potential for oral delivery of poorly water-soluble drugs.展开更多
A novel selenium-containing compound,selenoneine,has been isolated as the major form of organic selenium in the blood and tissues of tuna.Selenoneine harbors a selenium atom in the imidazole ring,2-selenylNα,Nα,Nα-...A novel selenium-containing compound,selenoneine,has been isolated as the major form of organic selenium in the blood and tissues of tuna.Selenoneine harbors a selenium atom in the imidazole ring,2-selenylNα,Nα,Nα-trimethyl-L-histidine,and is a selenium analog of ergothioneine.This selenium compound has strong antioxidant capacity and binds to heme proteins,such as hemoglobin and myoglobin,to protect them from iron auto-oxidation,and it reacts with radicals and methylmercury(MeHg) .The organic cations/carnitine transporter OCTN1 transports selenoneine and MeHg,regulates Se-enhanced antioxidant activity,and decreases MeHg toxicity.Thus,the dietary intake of selenoneine,by consuming fish,might decrease the formation of reactive oxygen radicals that could oxidize nucleotides in DNA,and thereby inhibit carcinogenesis,chronic diseases,and aging.展开更多
文摘Background: Human organic cationic transporter1 (Hoct1) is a plasma membrane transporter responsible for the main influx of Imatinib into chronic myeloid leukemia (CML) cells. Single nucleotide polymorphisms (SNPs) in the gene coding for hOCT1 are important factors causing Imatinib resistance. We investigated the frequency of hOCT1 SNP C480G among Egyptian CML patients and its relation to early molecular response as an indicator of treatment outcome. Materials and Methods: Two groups of CML patients were included in this study. Group I consisted of 25 patients responding to Imatinib treatment (Imatinib responsive) and group II consisted of 25 patients resistant to Imatinib (Imatinib resistant). Response criteria were assessed according to the NCCN (National Comprehensive Cancer Network) guidelines 2017. Twenty healthy controls of matched age and sex were also included (group III). For all patients, we studied hOCT1 C480G at initial presentation using Taqman drug metabolism genotyping as well as BCR-ABL percent at diagnosis and after 3 months interval. Results: hOCT1 C480G was present in 32% of studied CML patients. CC (wild) was detected in 68% of group I and 64% of group II. CG (mutant heterozygous) was present in 28% of group I and 36% of group II while GG (mutant homozygous) was detected in only one case in group I. CG was also detected in 15% of control subjects There was no significant difference between hOCT1 C480G polymorphism and Early Molecular Response (χ2 = 0.089, p = 0.765). Conclusions: hOCT1 C480G polymorphism has no association with Imatinib resistance in Egyptian population. However, further studies on a larger number of patients are still needed to confirm this finding.
基金Doctoral Natural Science Fund of Guangdong Province, China, No. 04300361
文摘AIM： To investigate the single nucleotide polymorphism （SNPs） distribution of NOD2/CARD15 （R702W, G908R）, OCTN1 1672CFT and OCTN2-207G/C in Chinese patients with inflammatory bowel disease （IBD）. METHODS： A total of 61 patients with Crohn＇s disease （CD）, 151 patients with ulcerative colitis （UC）, and 200 unrelated healthy controls were genotyped. Genotyping was performed by sequence specific primer polymerase chain reaction （PCR-SSP） or by restriction fragment length polymorphism （PCR-RFLP） analysis. RESULTS： Among the subjects in our study groups, including patients with CD, UC and healthy controls, none had OCTN and CARD15 variants and very rare IBD family history was found in our patients with the percentage of 0 （0/61 with CD） and 1.3% （2/151 with UC）. CONCLUSION： Our results indicate that although OCTN or CARD15 variation is associated with susceptibility to IBD in Western populations, these might be rare and may not be associated with susceptibility to IBD in Chinese patients.
基金This work was financially supported by the Natural Science Foundation of Guangxi Province(Nos.2018JJB140325,2018JJB140377)Guangxi Scientific and Technology Base and Talents of Project(Nos.2018AD19035)+2 种基金Talents Project for Cultivating High-level Talent Teams in the Qi Huang Project of Guangxi University of Chinese Medicine(2018002)the specific subject of the dominant discipline construction of Chinese Pharmacy of Guangxi University of Chinese Medicine,Guang Xi Key Laboratory of Translational Medicine for Treating High-incidence Infectious Diseases with Integrative Medicine and School research projects(no.B170021,2018MS003)Scientific Research Projects of Guangxi University of Chinese Medicine(B170021,2018MS003).
文摘Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery.In particular,intestinal carnitine/organic cation transporter 2(OCTN2)and mono-carboxylate transporter protein 1(MCT1)possess high transport capacities and complementary distributions.Therefore,we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review.First,basic information of the two transporters is reviewed,including their topological structures,characteristics and functions,expression and key features of their substrates.Furthermore,progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed,including improvements in the oral absorption of anti-inflammatory drugs,antiepileptic drugs and anticancer drugs.Finally,the potential of a dual transporter-targeting strategy is discussed.
文摘AIM: To investigate the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in disease predispo- sition and phenotypes in a large Italian cohort of pediatric patients with inflammatory bowel diseases (IBD). METHODS: Two hundred patients with Crohn’s disease (CD), 186 ulcerative colitis (UC) patients, 434 par- ents (217 trios), and 347 healthy controls (HC) were studied. Polymorphisms of the three major variants of CARD15, 1672C/T and -207G/C SNPs for OCTN genes, IGR2096a_1 and IGR2198a_1 SNPs for the IBD5 locus, and 113G/A variant of the DLG5 gene were evaluated. Potential correlations with clinical sub-phenotypes were investigated. RESULTS: Polymorphisms of CARD15 were significantly associated with CD, and at least one variant was found in 38% of patients (15% in HC, OR = 2.7, P < 0.001). Homozygosis for both OCTN1/2 variants was more com- mon in CD patients (1672TT 24%, -207CC 29%) than in HC (16% and 21%, respectively; P = 0.03), with an in- creased frequency of the TC haplotype (44.8% vs 38.3% in HC, P = 0.04). No association with the DLG5 variant was found. CD carriers of OCTN1/2 and DLG5 variants more frequently had penetrating disease (P = 0.04 and P = 0.01), while carriers of CARD15 more frequently had ileal localization (P = 0.03). No gene-gene interaction was found. In UC patients, the TC haplotype was morefrequent (45.4%, P = 0.03), but no genotype/phenotype correlation was observed. CONCLUSION: Polymorphisms of CARD15 and OCTN genes, but not DLG5 are associated with pediatric on- set of CD. Polymorphisms of CARD15, OCTN, and DLG5 genes exert a weak influence on CD phenotype.
基金The National Natural Science Foundation of China(30760288)Xinjiang Uygur Autonomic Tackle Key Problems Plans(200633129)Science and Technology Program of Urumqi(G07231001)
文摘Objective To determine the effects of genetic variation in the organic cation transporter 1(OCT1)on the short-term responses of the antidiabetic drug,metformin.Method A total of 22 patients recruited with type 2 diabetes or IFG were treated with metformin(2 000 mg/day)for 1 week.The patients were screened from Second Jikun hospital and Kashidonglu community medicine service,Urumqi,China and their surrounding districts.To examine the effects of metformin on plasma glucose,total cholesterol,low-density lipoprotein-cholesterol,high-density lipoprotein-cholesterol and triglyceride in relation with R61C,G465R and 420 del variants of OCT1(gene encoding organic cation transporter 1,mainly locating in liver,which is metformin's major target)in subjects.In all,R61C,G465R and 420del of OCT1 gene were examined using DNA extracted from whole blood and PCR-RFLP.Data concerning with gene and metformin treatment were handled by t-test.Result After metformin treatment,there were increases both in FPG and LDL(P=0.011and P=0.013 respectively).To divide all participants into mutant and wild groups,according to the polymorphisms of R61C,G465R and 420 del respectively,as well as carriers with one of the mutant genotypes at least and carriers with none of the mutant sites.Analysis was made to compared FPG,Chol,TG,and LDL and HDL between carriers of wild genotypes and carriers of other genotypes showed no statistic significance both before the metformin treatment and after the treatment.The same is the case with changes of FPG,Chol,TG,and LDL and HDL of wild genotype carriers and variant genotype carriers,except of LDL changes(P=0.05)in patients grouped by G465R polymorphisms and TG changes(P=0.03)in subjects differed by 420del genotypes.Conclusion In this study,it is suggested that OCT1 gene polymorphisms have little contribution to the clinical efficacy of blood glucose control by metformin among Uygur people with type 2 diabetes or IFG,but it may have possible relationship with the clinical efficacy on fat metabolism by metformin.
基金The National Natural Science Foundation of China(Grant No.81673366)the National Key Science Research Program of China(973 Program,Grant No.2015CB932100)
文摘The intestinal epithelium is the main barrier to the oral delivery of poorly water-soluble drugs. Based on the specific transporters expressed on the apical membrane of the intestinal epithelium, novel polymer micelles targeting to the organic cation transporter 2（OCTN2） were constructed by combining carnitine conjugated poly（2-ethyl-2-oxazoline）-poly（D,L-lactide）（Car-PEOz-PLA） with monomethoxy poly（ethylene glycol）-poly（D,L-lactide）（mP EG-PLA）. The structure of the synthesized Car-PEOz-PLA was confirmed by -1H NMR, TLC and ammonium reineckate precipitation reaction, and the number-average molecular weight determined by GPC was 7260 g/mol with a low PDI of 1.44. Coumarin 6-loaded carnitine modified polymeric micelles prepared by film hydration method were characterized to have a nano-scaled size of about 31 nm in diameter, uniform spherical morphology, high drug loading content of 0.098%±0.03% and encapsulation efficiency of 92.67%±2.80%. Moreover, the carnitine-modified micelles exhibited the similar in vitro release behavior in SGF and SIF, and evidently enhanced intestinal absorption of poorly water-soluble agent. Therefore, the designed OCTN2-targeted micelles might have a promising potential for oral delivery of poorly water-soluble drugs.
基金Supported by In part grants from the Ministry of Agriculture,Forestry,and Fisheries of Japan(Rural Biomass Research Project,BM-D2300)and Fisheries Research Agency
文摘A novel selenium-containing compound,selenoneine,has been isolated as the major form of organic selenium in the blood and tissues of tuna.Selenoneine harbors a selenium atom in the imidazole ring,2-selenylNα,Nα,Nα-trimethyl-L-histidine,and is a selenium analog of ergothioneine.This selenium compound has strong antioxidant capacity and binds to heme proteins,such as hemoglobin and myoglobin,to protect them from iron auto-oxidation,and it reacts with radicals and methylmercury(MeHg) .The organic cations/carnitine transporter OCTN1 transports selenoneine and MeHg,regulates Se-enhanced antioxidant activity,and decreases MeHg toxicity.Thus,the dietary intake of selenoneine,by consuming fish,might decrease the formation of reactive oxygen radicals that could oxidize nucleotides in DNA,and thereby inhibit carcinogenesis,chronic diseases,and aging.
