In vivo functional neurochemistry of human cortical cholinergic function during visuospatial attention

Cortical acetylcholine is involved in key cognitive processes such as visuospatial attention. Dysfunction in the cholinergic system has been described in a number of neuropsychiatric disorders. Levels of brain acetylcholine can be pharmacologically manipulated, but it is not possible to directly measure it in vivo in humans. However, key parts of its biochemical cascade in neural tissue, such as choline, can be measured using magnetic resonance spectroscopy (MRS). There is evidence that levels of choline may be an indirect but proportional measure of acetylcholine availability in brain tissue. In this study, we measured relative choline levels in the parietal cortex using functional (event-related) MRS (fMRS) during performance of a visuospatial attention task, with a modelling approach verified using simulated data. We describe a task-driven interaction effect on choline concentration, specifically driven by contralateral attention shifts. Our results suggest that choline MRS has the potential to serve as a proxy of brain acetylcholine function in humans

Practical internal and external cooling methods do not influence rapid recovery from simulated taekwondo performance

10.1016/j.jesf.2023.05.003Journal of Exercise Science and Fitness213286-29

Association of CYP3A4/5, ABCB1 and ABCC2 polymorphisms and clinical outcomes of Thai breast cancer patients treated with tamoxifen

Insee Sensorn,1 Ekaphop Sirachainan,2 Montri Chamnanphon,3 Ekawat Pasomsub,4 Narumol Trachu,5 Porntip Supavilai,1 Chonlaphat Sukasem,3 Darawan Pinthong11Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand; 2Division of Medical Oncology, Department of Medicine, 3Division for Pharmacogenomics and Personalized Medicine, 4Division for Virology, Department of Pathology, 5Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, ThailandBackground: Pharmacogenetic study of cytochrome P450 (CYP) gene CYP2D6 and tamoxifen outcomes remain controversial. Apart from CYP2D6, other drug-metabolizing enzymes and transporters also play a role in tamoxifen metabolic pathways. The aim of this study is to investigate the impact of CYP3A4/5, ABCB1, and ABCC2 polymorphisms on the risk of recurrence in Thai patients who received tamoxifen adjuvant therapy.Methods: Patients with early-stage breast cancer who received tamoxifen adjuvant therapy were recruited in this study. All six single-nucleotide polymorphisms (SNPs), including CYP3A4*1B (-392 A>G)/*18(878 T>C), CYP3A5*3(6986 G>A), ABCB1 3435 C>T, ABCC2*1C (-24 C>T), and ABCC2 68231 A>G, were genotyped using real-time polymerase chain reaction assays. The impacts of genetic variants on disease-free survival (DFS) were analyzed using the Kaplan–Meier method and Cox regression analysis.Results: The ABCB1 3435 C>T was found to have the highest allele frequency among other variants; however, CYP3A4*1B/*18 could not be found in this study. Patients with heterozygous ABCB1 3435 CT genotype showed significantly shorter DFS than those with homozygous 3435 CC genotype (P = 0.041). In contrast, patients who carried homozygous 3435 TT genotype showed no difference in DFS from wild-type 3435 CC patients. Cox regression analysis showed that the relative risk of recurrence was increased by five times (P = 0.043; hazard ratio = 5.11; 95% confidence interval: 1.05–24.74) in those patients carrying ABCB1 3435 CT genotype compared to those with ABCB1 3435 CC.Conclusion: ABCB1 3435 C>T is likely to have a clinically significant impact on recurrence risk in Thai patients with breast cancer who receive tamoxifen adjuvant therapy.Keywords: breast cancer, CYP3A4/5, drug transporters, pharmacogenetics, disease-free survival, tamoxife

ABCB1 and ABCC2 and the risk of distant metastasis in Thai breast cancer patients treated with tamoxifen

Insee Sensorn,1,* Chonlaphat Sukasem,2,* Ekaphop Sirachainan,3 Montri Chamnanphon,2 Ekawat Pasomsub,4 Narumol Trachu,5 Porntip Supavilai,1 Darawan Pinthong,1 Sansanee Wongwaisayawan6 1Department of Pharmacology, Faculty of Science, Mahidol University, 2Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 3Division of Medical Oncology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 4Division of Virology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 5Research Center, Faculty of Medicine, Ramathibodi Hospital, 6Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand *These authors contributed equally to this work Background: Genetic polymorphisms of drug-metabolizing enzymes and transporters have been extensively studied with regard to tamoxifen treatment outcomes. However, the results are inconclusive. Analysis of organ-specific metastasis may reveal the association of these pharmacogenetic factors. The aim of this study is to investigate the impact of CYP3A5, CYP2D6, ABCB1, and ABCC2 polymorphisms on the risk of all distant and organ-specific metastases in Thai patients who received tamoxifen adjuvant therapy. Methods: Genomic DNA was extracted from blood samples of 73 patients with breast cancer who received tamoxifen adjuvant therapy. CYP3A5 (6986A>G), CYP2D6 (100C>T), ABCB1 (3435C>T), and ABCC2 (-24C>T) were genotyped using allelic discrimination real-time polymerase chain reaction assays. The impacts of prognostic clinical factors and genetic variants on disease-free survival were analyzed using the Kaplan–Meier method and Cox regression analysis. Results: In the univariate analysis, primary tumor size >5 cm was significantly associated with increased risk of distant metastasis (P=0.004; hazard ratio [HR] =3.05; 95% confidence interval [CI], 1.44–6.47). In the multivariate analysis, tumor size >5 cm remained predictive of distant metastasis (P<0.001; HR=5.49; 95% CI, 2.30–13.10). ABCC2 -24CC were shown to be associated with increased risk of distant metastasis (P=0.040; adjusted HR=2.34; 95% CI, 1.04–5.27). The combined genotype of ABCC2 -24CC – ABCB1 3435 CT+TT was associated with increased risk of distant and bone metastasis (P=0.020; adjusted HR=2.46; 95% CI, 1.15–5.26 and P=0.040; adjusted HR=3.70; 95% CI, 1.06–12.89, respectively). Conclusion: This study indicates that polymorphisms of ABCC2 and ABCB1 are independently associated with bone metastasis. Further prospective studies with larger sample sizes are needed to verify this finding. Keywords: breast cancer, tamoxifen, ABCB1, ABCC2, pharmacogenetics, distant metastasi

Clinically relevant genetic variants of drug-metabolizing enzyme and transporter genes detected in Thai children and adolescents with autism spectrum disorder

Sadeep Medhasi,1–3 Ekawat Pasomsub,4 Natchaya Vanwong,1,2 Nattawat Ngamsamut,5 Apichaya Puangpetch,1,2 Montri Chamnanphon,1,2 Yaowaluck Hongkaew,1,2 Penkhae Limsila,5 Darawan Pinthong,3 Chonlaphat Sukasem1,2 1Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 2Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 3Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand; 4Division of Virology, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 5Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Department of Mental Health Services, Ministry of Public Health, Samut Prakarn, Thailand Abstract: Single-nucleotide polymorphisms (SNPs) among drug-metabolizing enzymes and transporters (DMETs) influence the pharmacokinetic profile of drugs and exhibit intra- and interethnic variations in drug response in terms of efficacy and safety profile. The main objective of this study was to assess the frequency of allelic variants of drug absorption, distribution, metabolism, and elimination-related genes in Thai children and adolescents with autism spectrum disorder. Blood samples were drawn from 119 patients, and DNA was extracted. Genotyping was performed using the DMET Plus microarray platform. The allele frequencies of the DMET markers were generated using the DMET Console software. Thereafter, the genetic variations of significant DMET genes were assessed. The frequencies of SNPs across the genes coding for DMETs were determined. After filtering the SNPs, 489 of the 1,931 SNPs passed quality control. Many clinically relevant SNPs, including CYP2C19*2, CYP2D6*10, CYP3A5*3, and SLCO1B1*5, were found to have frequencies similar to those in the Chinese population. These data are important for further research to investigate the interpatient variability in pharmacokinetics and pharmacodynamics of drugs in clinical practice. Keywords: Thai population, ADME, pharmacokinetics, autism spectrum disorder, microarray, pharmacogenetic

Karyotype diversity and evolutionary trends in the Asian swamp eel Monopterus albus (Synbranchiformes, Synbranchidae): a case of chromosomal speciation?

Abstract Background Synbranchidae or swamp eels are fishes belonging to the order Synbranchiformes that occur in both freshwater and occasionally in brackish. They are worldwide distributed in tropical and subtropical rivers of four different continents. A large degree of chromosomal variation has been found in this family, mainly through the use of conventional cytogenetic investigations. Inside this group, a still almost unexplored species under the cytogenetic point of view is the Asian swamp eel Monopterus albus, a widely distributed species throughout Asia. Here, we tested the hypothesis of chromosomal speciation, where a case of sympatric speciation may occur as the primary consequence of chromosomal rearrangements. We performed a comparative chromosomal analysis of M. albus from 22 different localities in Thailand, using distinct staining methods (C-banding, Ag-NO3, and Chromomycin A3), and FISH with repetitive DNA probes (5S rDNA, 18S rDNA, Rex1 element and microsatellite repeats). Results This approach evidenced two contrasting karyotypes (named karyomorphs A and B) that varied concerning their 2n and repetitive DNAs distribution, where chromosomal fusions and pericentric inversions were involved in such differentiation. While the karyomorph A has 2n = 24 chromosomes, the karyomorph B has only 2n = 18, both with NF = 24. In addition, karyomorph A contains only acrocentric chromosomes, while karyomorph B contains three unique metacentric pairs. These features highlight that M. albus has already gone through a significant genomic divergence, and may include at least two cryptic species. Conclusions This marked chromosomal differentiation, likely linked to the lifestyle of these fishes, point to the occurrence of a chromosomal speciation scenario, in which fusions and inversions had a prominent role. This highlights the biodiversity of M. albus and justifies its taxonomic revision, since this nominal species may constitute a species complex

Targeting the Ubiquinol-Reduction (Qi) Site of the Mitochondrial Cytochrome bc1 Complex for the Development of Next Generation Quinolone Antimalarials

Antimalarials targeting the ubiquinol-oxidation (Qo) site of the Plasmodium falciparum bc1 complex, such as atovaquone, have become less effective due to the rapid emergence of resistance linked to point mutations in the Qo site. Recent findings showed a series of 2-aryl quinolones mediate inhibitions of this complex by binding to the ubiquinone-reduction (Qi) site, which offers a potential advantage in circumventing drug resistance. Since it is essential to understand how 2-aryl quinolone lead compounds bind within the Qi site, here we describe the co-crystallization and structure elucidation of the bovine cytochrome bc1 complex with three different antimalarial 4(1H)-quinolone sub-types, including two 2-aryl quinolone derivatives and a 3-aryl quinolone analogue for comparison. Currently, no structural information is available for Plasmodial cytochrome bc1. Our crystallographic studies have enabled comparison of an in-silico homology docking model of P. falciparum with the mammalian’s equivalent, enabling an examination of how binding compares for the 2- versus 3-aryl analogues. Based on crystallographic and computational modeling, key differences in human and P. falciparum Qi sites have been mapped that provide new insights that can be exploited for the development of next-generation antimalarials with greater selective inhibitory activity against the parasite bc1 with improved antimalarial properties