Xuemeng Liang

Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.Metformin, the most widely prescribed antidiabetic drug, requires transporters to enter tissues involved in its pharmacologic action, including liver, kidney, and peripheral tissues. Organic cation transporter 3, expressed ubiquitously, transports metformin, but its in vivo role in metformin response is not known. Using Oct3 knockout mice, the role of the transporter in metformin pharmacokinetics and pharmacodynamics was determined. After an intravenous dose of metformin, a 2-fold decrease in the apparent volume of distribution and clearance was observed in knockout compared with wild-type mice, indicating an important role of OCT3 in tissue distribution and elimination of the drug. After oral doses, a significantly lower bioavailability was observed in knockout compared with wild-type mice. Importantly, metformin's effect on the plasma glucose concentration-time curve was reduced in knockout compared with wild-type mice along with its accumulation in skeletal muscle and adipose tissue. Furthermore, the effect of metformin on phosphorylation of AMP activated protein kinase, and expression of glucose transporter type 4 was absent in the adipose tissue of Oct3-/- mice. Additional analysis revealed that an OCT3 3′ untranslated region variant was associated with reduced activity in luciferase assays and reduced response to metformin in 57 healthy volunteers. These findings suggest that OCT3 plays an important role in the absorption and elimination of metformin and that the transporter is a critical determinant of metformin bioavailability, clearance, and pharmacologic action.

© 2015 Baum et al.; licensee BioMed Central. Background: Malaria is a public health problem in parts of Thailand, where Plasmodium falciparum and Plasmodium vivax are the main causes of infection. In the northwestern border province of Tak parasite prevalence is now estimated to be less than 1% by microscopy. Nonetheless, microscopy is insensitive at low-level parasitaemia. The objective of this study was to assess the current epidemiology of falciparum and vivax malaria in Tak using molecular methods to detect exposure to and infection with parasites; in particular, the prevalence of asymptomatic infections and infections with submicroscopic parasite levels. Methods: Three-hundred microlitres of whole blood from finger-prick were collected into capillary tubes from residents of a sentinel village and from patients at a malaria clinic. Pelleted cellular fractions were screened by quantitative PCR to determine parasite prevalence, while plasma was probed on a protein microarray displaying hundreds of P. falciparum and P. vivax proteins to obtain antibody response profiles in those individuals. Results: Of 219 samples from the village, qPCR detected 25 Plasmodium sp. infections, of which 92% were asymptomatic and 100% were submicroscopic. Of 61 samples from the clinic patients, 27 were positive by qPCR, of which 25.9% had submicroscopic parasite levels. Cryptic mixed infections, misdiagnosed as single-species infections by microscopy, were found in 7 malaria patients. All sample donors, parasitaemic and non-parasitaemic alike, had serological evidence of parasite exposure, with 100% seropositivity to at least 54 antigens. Antigens significantly associated with asymptomatic infections were P. falciparum MSP2, DnaJ protein, putative E1E2 ATPase, and three others. Conclusion: These findings suggest that parasite prevalence is higher than currently estimated by local authorities based on the standard light microscopy. As transmission levels drop in Thailand, it may be necessary to employ higher throughput and sensitivity methods for parasite detection in the phase of malaria elimination.

© 2015 American Chemical Society.The biguanide metformin is widely used as first-line therapy for the treatment of type 2 diabetes. Predominately a cation at physiological pH's, metformin is transported by membrane transporters, which play major roles in its absorption and disposition. Recently, our laboratory demonstrated that organic cation transporter 1, OCT1, the major hepatic uptake transporter for metformin, was also the primary hepatic uptake transporter for thiamine, vitamin B1. In this study, we tested the reverse, i.e., that metformin is a substrate of thiamine transporters. Our study demonstrated that human THTR-2, SLC19A3, which is highly expressed in the small intestine, but not hTHTR-1, transports metformin and other cationic compounds. The uptake mechanism for hTHTR-2 was pH and electrochemical gradient sensitive. Furthermore, metformin as well as other drugs including phenformin, chloroquine, verapamil, famotidine, and amprolium inhibited hTHTR-2 mediated uptake of both thiamine and metformin. Species differences in the substrate specificity of THTR-2 between human and mouse orthologues were observed. Taken together, our data suggest that hTHTR-2 may play a role in the intestinal absorption and tissue distribution of metformin and other organic cations and that the transporter may be a target for drug-drug and drug-nutrient interactions.

A positive connection has been established between personality traits and suicidal ideation. However, the possible mediation of resilience within this association has never been thoroughly discussed. In this study, we aimed to investigate this topic by using population-based cross-sectional survey data of 4,489 Chinese children and adolescents. A self-administered questionnaire was used to collect information from the participants. Univariate and multivariate logistic regression models were adopted to measure the crude and adjusted associations between personality traits, SI, and resilience. Path analysis was performed to evaluate the mediation of resilience in the association between personality traits and SI. For 4,489 study subjects, the mean age was 13.4 years, ethnic minorities accounted for 71.8%, and over a half were middle school students. The reported prevalence rates for 1-week, 1-year, and lifetime SI were 27.6%, 35.5%, and 56.7%, respectively. Girls reported a significantly higher prevalence of SI than boys. Path analysis results revealed a prominent mediation of resilience; moreover, for different dimensions of personality traits, the proportion of mediation by resilience varied. Our major findings suggest that resilience-based intervention measures could be considered in preventing personality traits related to suicidal risk among youngsters. For children and adolescents, the measuring of personality dimensions may also be helpful in targeting key subpopulations of intervention priority.