• Parasites, Hosts and Diseases
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• v.60 no.2
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• pp.109-116
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• 2022

Drug resistance is an important problem hindering malaria elimination in tropical areas. Point mutations in Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes confer resistance to antifolate drug, sulfadoxine-pyrimethamine (SP) while P. falciparum chloroquine-resistant transporter (Pfcrt) genes caused resistance to chloroquine (CQ). Decline in Pfdhfr/Pfdhps and Pfcrt mutations after withdrawal of SP and CQ has been reported. The aim of present study was to investigate the prevalence of Pfdhfr, Pfdhps, and Pfcrt mutation from 2 endemic areas of Thailand. All of 200 blood samples collected from western area (Thai-Myanmar) and southern area (Thai-Malaysian) contained multiple mutations in Pfdhfr and Pfdhps genes. The most prevalent haplotypes for Pfdhfr and Pfdhps were quadruple and double mutations, respectively. The quadruple and triple mutations of Pfdhfr and Pfdhps were common in western samples, whereas low frequency of triple and double mutations was found in southern samples, respectively. The Pfcrt 76T mutation was present in all samples examined. Malaria isolated from 2 different endemic regions of Thailand had high mutation rates in the Pfdhfr, Pfdhps, and Pfcrt genes. These findings highlighted the fixation of mutant alleles causing resistance of SP and CQ in this area. It is necessary to monitor the re-emergence of SP and CQ sensitive parasites in this area.

• Molecules and Cells
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• v.43 no.1
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• pp.48-57
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• 2020

The microalga Chlamydomonas reinhardtii accumulates triacylglycerols (TAGs) in lipid droplets under stress conditions, such as nitrogen starvation. TAG biosynthesis occurs mainly at the endoplasmic reticulum (ER) and requires fatty acid (FA) substrates supplied from chloroplasts. How FAs are transferred from chloroplast to ER in microalgae was unknown. We previously reported that an Arabidopsis thaliana ATP-binding cassette (ABC) transporter, AtABCA9, facilitates FA transport at the ER during seed development. Here we identified a gene homologous to AtABCA9 in the C. reinhardtii genome, which we named CrABCA2. Under nitrogen deprivation conditions, CrABCA2 expression was upregulated, and the CrABCA2 protein level also increased. CrABCA2 knockdown lines accumulated less TAGs and CrABCA2 overexpression lines accumulated more TAGs than their untransformed parental lines. Transmission electron microscopy showed that CrABCA2 was localized in swollen ER. These results suggest that CrABCA2 transports substrates for TAG biosynthesis to the ER during nitrogen starvation. Our study provides a potential tool for increasing lipid production in microalgae.

• BMB Reports
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• v.56 no.11
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• pp.600-605
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• 2023

Intrahepatic cholangiocarcinoma (ICC) is a bile duct cancer and a rare malignant tumor with a poor prognosis owing to the lack of an early diagnosis and resistance to conventional chemotherapy. A combination of gemcitabine and cisplatin is the typically attempted first-line treatment approach. However, the underlying mechanism of resistance to chemotherapy is poorly understood. We addressed this by studying dynamics in the human ICC SCK cell line. Here, we report that the regulation of glucose and glutamine metabolism was a key factor in overcoming cisplatin resistance in SCK cells. RNA sequencing analysis revealed a high enrichment cell cycle-related gene set score in cisplatin-resistant SCK (SCK-R) cells compared to parental SCK (SCK WT) cells. Cell cycle progression correlates with increased nutrient requirement and cancer proliferation or metastasis. Commonly, cancer cells are dependent upon glucose and glutamine availability for survival and proliferation. Indeed, we observed the increased expression of GLUT (glucose transporter), ASCT2 (glutamine transporter), and cancer progression markers in SCK-R cells. Thus, we inhibited enhanced metabolic reprogramming in SCK-R cells through nutrient starvation. SCK-R cells were sensitized to cisplatin, especially under glucose starvation. Glutaminase-1 (GLS1), which is a mitochondrial enzyme involved in tumorigenesis and progression in cancer cells, was upregulated in SCK-R cells. Targeting GLS1 with the GLS1 inhibitor CB-839 (telaglenastat) effectively reduced the expression of cancer progression markers. Taken together, our study results suggest that a combination of GLUT inhibition, which mimics glucose starvation, and GLS1 inhibition could be a therapeutic strategy to increase the chemosensitivity of ICC.

• BMB Reports
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• v.50 no.3
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• pp.132-137
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• 2017

Elevated glucose levels in cancer cells can be attributed to increased levels of glucose transporter (GLUT) proteins. Glut1 expression is increased in human malignant cells. To investigate alternative roles of Glut1 in breast cancer, we silenced Glut1 in triple-negative breast-cancer cell lines using a short hairpin RNA (shRNA) system. Glut1 silencing was verified by Western blotting and qRT-PCR. Knockdown of Glut1 resulted in decreased cell proliferation, glucose uptake, migration, and invasion through modulation of the EGFR/MAPK signaling pathway and integrin ${\beta}1$/Src/FAK signaling pathways. These results suggest that Glut1 not only plays a role as a glucose transporter, but also acts as a regulator of signaling cascades in the tumorigenesis of breast cancer.

• Journal of Integrative Natural Science
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• v.5 no.2
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• pp.72-78
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• 2012

Multidrug resistance is a major obstacle in cancer chemotherapy. Cancer cells efflux chemotherapeutic drug out of cell by means of transporter and reduce the active concentration of it inside cell. Such transporters are member of the ATP binding cassettes (ABC) protein. It includes P-gp, multiple resistant protein (MRP), and breast cancer resistant protein (BCRP). These proteins are widely distributed in the human cells such as kidney, lung, endothelial cells of blood brain barrier etc. However, there are number of drugs developed for it, but most of them are getting transported by it. So, still there is necessity of a good modulator, which could effectively combat the transport of chemotherapeutic agents. Natural products origin modulators were found to be effective against transporter such as flavonoids, which belongs to third generation modulators. They have advantage over synthetic inhibitor in the sense that they have simple structure and abundant in nature. This review focuses on the P-gp structure its architecture, efflux mechanism, herbal inhibitors and their mechanism of action.

• BMB Reports
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• v.38 no.3
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• pp.314-319
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• 2005

Adenosine, as a ubiquitous metabolite, mediates many physiological functions via activation of plasma membrane receptors. Mechanisms of most of its physiological roles have been studied extensively, but research on adenosine-induced apoptosis (AIA) has only started recently. In this study we demonstrate that adenosine dose-dependently triggered apoptosis of cultured baby hamster kidney (BHK) cells. Adenosine-induced apoptotic cell death was characterized by DNA laddering, changes in nuclear chromatin morphology and phosphatidylserine staining. Apoptosis was also quantified by flow cytometry. Results suggest the involvement of adenosine $A_1$ and $A_3$ receptors as well as equilibrative nucleoside transporters in apoptosis induced by adenosine. These results indicate a receptor-transporter co-signaling mechanism in AIA in BHK cells. The involvement of $A_1$ and $A_3$ receptors also implies a possible apoptotic pathway mediated by G protein-coupled receptors.

• Korean Journal of Biological Psychiatry
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• v.17 no.2
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• pp.65-69
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• 2010

Gene-environment interactions are important in pathogenesis of suicide or suicidal behavior. Twin and adoption studies and family studies show that genetic factors play a critical role in suicide or suicidal behavior. Given the strong association between serotonergic neurotransmission and suicide, recent molecular genetic studies have focused on polymorphisms of serotonin genes, especially on serotonin transporter and tryptophan hydroxylase genes. Some studies have revealed a significant interaction between s allele of the serotonin transporter gene and the risk of suicide attempt associated with childhood trauma. In addition, the polymorphism of brain-derived neurotrophic factor gene also may influence the effect of childhood trauma in relation to the risk of attempting suicide. Future studies should explore genetic and environmental factors in suicide or suicidal behavior and examine for gene and environment interaction.

• The Korean Journal of Physiology and Pharmacology
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• v.6 no.3
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• pp.131-138
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• 2002

Thanks to recent progress in availability of molecular and functional techniques it became possible to search for the basic molecular and cellular processes that mediate and control $HCO_3{^-}$ and fluid secretion by the pancreatic duct. The coordinated action of various transporters on the luminal and basolateral membranes of polarized epithelial cells mediates the transepithelial $HCO_3{^-}$ transport, which involves $HCO_3{^-}$ absorption in the resting state and $HCO_3{^-}$ secretion in the stimulated state. The overall process of HCO3 secretion can be divided into two steps. First, $HCO_3{^-}$ in the blood enters the ductal epithelial cells across the basolateral membrane either by simple diffusion in the forms of $CO_2$ and $H_2O$ or by the action of an $Na^+-coupled$ transporter, a $Na^+-HCO_3$ cotranporter (NBC) identified as pNBC1. Subsequently, the cells secrete $HCO_3{^-}$ to the luminal space using at least two $HCO_3{^-}$ exit mechanisms at the luminal membrane. One of the critical transporters needed for all forms of $HCO_3{^-}$ secretion across the luminal membrane is the cystic fibrosis transmembrane conductance regulator (CFTR). In the resting state the pancreatic duct, and probably other $HCO_3{^-}$ secretory epithelia, absorb $HCO_3{^-}.$ Interestingly, CFTR also control this mechanism. In this review, we discuss recent progress in understanding epithelial $HCO_3{^-}$ transport, in particular the nature of the luminal transporters and their regulation by CFTR.

• Reproductive and Developmental Biology
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• v.33 no.4
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• pp.211-216
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• 2009

A cell frequently utilizes glucose as a fuel of energy and a major substrate of lipid and protein syntheses. A regulation of glucose movement into and out of the cells is precisely controlled by cooperative works of passive and sodium-dependent active processes. At least 13 glucose cotransporter (Slc2a, GLUT) isoforms involve in passive movement of glucose in cells. The efferent ductules (EDs) play in a number of important functions for maintenance of male fertility. In the present study, using real-time PCR analysis, we determined gene expression of five Slc2a isoforms in the EDs. In addition, we compared expression levels of these Slc2a isoforms according to postnatal development ages, 1 week, 2 weeks, 1 month, and 3 months. Results from the current study showed that expression of Slc2a1, Slc2a3, and Slc2a5 mRNAs reached the highest levels at 1 month of age, followed by a transient decrease at 3 months of age. In addition, the level of Slc2a4 mRNA reminded at steady until 1 month of age and was significantly reduced at 3 months of age, whereas the highest level of Slc2a 8 mRNA was detected at 2 weeks of age. Data from the present study indicate a differential expression of various Slc2a isoforms in the ED according to postnatal ages. Thus, it is believed that glucose movement through the epithelial cells in the ED would be regulated by the coordinated manner among Slc2a isoforms expressed at a given age.

• Molecules and Cells
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• v.43 no.4
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• pp.323-330
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• 2020

Epigenetic events like DNA methylation and histone modification can alter heritable phenotypes. Zinc is required for the activity of various epigenetic enzymes, such as DNA methyltransferases (DNMTs), histone acetyltransferases (HATs), histone deacetylases (HDACs), and histone demethylases, which possess several zinc binding sites. Thus, the dysregulation of zinc homeostasis can lead to epigenetic alterations. Zinc homeostasis is regulated by Zinc Transporters (ZnTs), Zrt- and Irt-like proteins (ZIPs), and the zinc storage protein metallothionein (MT). Recent advances revealed that ZIPs modulate epigenetics. ZIP10 deficiency was found to result in reduced HATs, confirming its involvement in histone acetylation for rigid skin barrier formation. ZIP13 deficiency, which is associated with Spondylocheirodysplastic Ehlers-Danlos syndrome (SCD-EDS), increases DNMT activity, leading to dysgenesis of dermis via improper gene expressions. However, the precise molecular mechanisms remain to be elucidated. Future molecular studies investigating the involvement of zinc and its transporters in epigenetics are warranted.