Publications by authors named "Kesara Na-Bangchang"

185 Publications

Association between ABCB1 Polymorphisms and Artesunate-Mefloquine Treatment Responses of Patients with Falciparum Malaria on the Thailand-Myanmar Border.

Am J Trop Med Hyg 2021 May 3. Epub 2021 May 3.

1Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathum Thani, Thailand.

A decrease in the clinical efficacy of a 3-day artesunate-mefloquine combination treatment was reported in the areas of multidrug-resistant Plasmodium falciparum along the Thailand-Myanmar border. The current study investigated the possible contribution of genetic polymorphisms of the three major genes encoding drug efflux transporters, ABCB1, ABCG2, and ABCC1, to responses to the aforementioned treatment in 91 patients with acute uncomplicated falciparum malaria residing along the Thailand-Myanmar border. Patients carrying homozygous mutant genotype ABCB1 c.1236C>T (TT) were found to have a three-times higher chance of successful treatment with this combination compared with other genotypes (CC and CT). Furthermore, whole blood mefloquine concentrations in these patients with the TT genotype were significantly lower than those of patients carrying the CC genotype. Patients with heterozygous mutant genotype (CT), however, were three-times more likely to experience treatment failure. No significant association was found with the ABCG2 and ABCC1 gene polymorphisms. The results suggest that ABCB1 c.1236CT polymorphisms could be useful genetic markers for predicting responses to the 3-day artesunate-mefloquine treatment; however, studies using larger sample sizes in different malaria-endemic areas are necessary to confirm this finding. This study highlights the impact of pharmacogenetic factors on antimalarial treatment responses and the basis for the application of control policies in various malaria-endemic areas.
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http://dx.doi.org/10.4269/ajtmh.21-0047DOI Listing
May 2021

Atractylodin inhibited the migration and induced autophagy in cholangiocarcinoma cells via PI3K/AKT/mTOR and p38MAPK signalling pathways.

J Pharm Pharmacol 2021 Apr 22. Epub 2021 Apr 22.

Chulabhorn International College of Medicine, Thammasat University, Rangsit Center, Klong Luang, Pathum Thani, Thailand.

Objectives: The effects of atractylodin (ATD), the bioactive compound from Atractylodes lancea, on migration and autophagy status of cholangiocarcinoma cell line were investigated.

Methods: Cytotoxic activity and effects on cell migration and invasion were evaluated by MTT and trans-well assay, respectively. Autophagy and underlying molecular mechanisms were investigated using flow cytometry and western blot analysis.

Key Findings: ATD regulated the activity of PI3K/AKT/mTOR and p38MAPK signalling pathways which contributed to autophagy induction. HuCCT-1 cell growth was inhibited by ATD in a time- and dose-dependent manner. ATD inhibited the migration and invasion of HuCCT1 cells in a concentration-dependent manner. It also induced autophagy in HuCCT1 cells in a time- and dose-dependent manner. The SB202190 (autophagy inducer) and 3-MA (autophagy inhibitor) significantly increased and decreased the rate of ATD-induced autophagy, respectively. The 24 h exposure of ATD inhibited the phosphorylation of phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (p38MAPK) and increased Beclin-1 expression and LC3 conversion. It also reduced p-AKT/AKT, p-mTOR/mTOR and p-p38MAPK/p38MAPK.

Conclusions: ATD inhibits the proliferation and induces CCA cell autophagy via regulating PI3K/AKT/mTOR and p38MAPK signalling pathways.
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http://dx.doi.org/10.1093/jpp/rgab036DOI Listing
April 2021

The Proteomics and Metabolomics Analysis for Screening the Molecular Targets of Action of β-Eudesmol in Cholangiocarcinoma.

Asian Pac J Cancer Prev 2021 Mar 1;22(3):909-918. Epub 2021 Mar 1.

Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Paholyothin Road, Klonglung, Pathumthani Thailand.

Objective: β-eudesmol is the active compound isolated from Atractylodes lancea (Thunb) D.C. The actions of this compound against cholangiocarcinoma (CCA) cells include anti-angiogenesis and anti-cell proliferation and growth. For more understanding of the molecular targets of action of β-eudesmol, the CCA cells (CL-6) were exposed to β-eudesmol for 24 and 48 hours.

Methods: Proteins and metabolites from the intra- and extra-cellular components of the CL-6 cells were extracted and identified by LC-MS/MS.  Protein analysis was performed using the Venn diagram (protein grouping), PANTHER (gene ontology), and STITCH software (protein-protein interaction). Metabolite analysis including their interactions with proteins, was performed using MetaboAnalyst software.

Results: The analysis showed that the actions of β-eudesmol were associated with various biological processes particularly apoptosis and cell cycle. These included blood coagulation, wound healing, DNA repair, PI3K-Akt signaling pathway, immune system process, MAPK cascade, urea cycle, purine metabolism, ammonia recycling, and methionine metabolism.

Conclusion: Possible molecular targets of action of β-eudesmol against CL-6 for cell apoptosis induction were TNFRSf6, cytochrome C, BAX3, DHCR24, CD29, and ATP.  On the other hand, possible targets for cell cycle arrest induction were CDKN2B, MLF1, TFDP2, CDK11-p110, and nicotinamide.
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http://dx.doi.org/10.31557/APJCP.2021.22.3.909DOI Listing
March 2021

A randomized placebo-controlled phase I clinical trial to evaluate the immunomodulatory activities of Atractylodes lancea (Thunb) DC. in healthy Thai subjects.

BMC Complement Med Ther 2021 Feb 12;21(1):61. Epub 2021 Feb 12.

Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathumthani, 12121, Thailand.

Background: Atractylodes lancea (Thunb) DC. (AL) and bioactive compounds β-eudesmol and atractylodin have been demonstrated in the in vitro and in vivo studies for their potential clinical use in cholangiocarcinoma. The study was a randomized, double-blinded, placebo-controlled phase I clinical trial to evaluate the immunomodulatory effect of AL in human subjects.

Methods: The modulatory effects of AL and β-eudesmol and atractylodin on TNFα and IL6 expression in PBMCs were measured using real-time PCR. Blood samples were collected from forty-eight healthy subjects following oral administration of a single or multiple dosing of capsule formulation of the standardized AL extract or placebo. Serum cytokine profiles, lymphocyte subpopulations (B lymphocytes, CD8 cytotoxic T lymphocytes, CD4 T-helper lymphocytes, and NK cells), and cytotoxic activity of PBMCs against the cholangiocarcinoma cell line CL-6 were evaluated using cytometric bead array (CBA) with flow cytometry analysis.

Results: AL extract at almost all concentrations significantly inhibited both TNFα and IL6 expression in Con A-mediated inflammation in PBMCs. β-Eudesmol at all concentrations significantly inhibited only IL6 expression. Atractylodin at the lowest concentration significantly inhibited the expression of both cytokines, while the highest concentration significantly inhibited only IL6 expression. The administration of AL at a single oral dose of 1000 mg appeared to decrease IFNγ and IL10 and increase B cell, while significantly increase NK and CD4 and CD8 cells. A trend of increasing (compared with placebo) in the cytotoxic activity of PBMCs at 24 h of dosing was observed. AL at multiple dosing of 1000 mg for 21 days tended to decrease the production of all cytokines, while significantly inhibited IL17A production at 24 h of dosing. In addition, a significant increase in CD4 and CD8 cells was observed. A trend of increase in the cytotoxic activity of PBMCs was observed at 24 h but terminated at 48 h of dosing.

Conclusions: The results confirm the immunomodulatory activity of AL in humans. This activity, in complementary with the direct action of AL on inducing cholangiocarcinoma cell apoptosis, suggests its potential role for CCA control.

Trial Registration: Retrospectively registered on 17 October 2020 [Thai Clinical Trials Registry (TCTR: www.clinical trials.in.th ) Number TCTR20201020001 #].
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http://dx.doi.org/10.1186/s12906-020-03199-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879636PMC
February 2021

Anticancer Activity of Fucoidan via Apoptosis and Cell Cycle Arrest on Cholangiocarcinoma Cell.

Asian Pac J Cancer Prev 2021 Jan 1;22(1):209-217. Epub 2021 Jan 1.

Center of Excellence in Molecular Biology and Pharmacology of Malaria and Cholangiocarcinoma, Thammasat University, Pathumthani, 12120, Thailand.

Objective: Many previous studies reported that fucoidan has antitumor activities. The objective of the present study was to determine the cytotoxic effects and related mechanisms of cell death induced by fucoidan extracted from Fucus vesiculosus on CL-6 cholangiocarcinoma cell.

Methods: CL-6 and OUMS cells were treated with 0, 100, 200, and 300 μg/mL of fucoidan. MTT assay was used to determine cytotoxicity. Flow cytometry-based assay was used to examine the distribution of apoptosis and cell cycle. The changes in nuclear morphology were determined using Hoechst 33,342 staining. Mitochondrial membrane potential (ΔΨm) was evaluated using the JC-1 kit. The apoptotic, anti-apoptotic, and cell cycle-related proteins study were examined by Western blot analysis.

Results: The relative viable cell number of treated CL-6 cells was decreased but no effect was observed in OUMS normal cells. Furthermore, treated cells were arrested in the G0/G1 phase with down-regulation of cyclin D1 and CDK4. Annexin V/PI staining with flow cytometry analysis suggested that fucoidan could induce apoptosis in CL-6 cells. Western blot study revealed the up-regulation of apoptotic markers including Bax, cleaved PARP, cleaved caspase-3, but down-regulation of anti-apoptotic markers,  cl-2. Moreover, fucoidan could induce nuclear fragmentation and chromatin condensation with alteration of ΔΨm.  Conclusion: Fucoidan exerts antitumor properties against CL-6 cholangiocarcinoma cells illustrated by the induction of apoptosis and cell cycle arrest.
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http://dx.doi.org/10.31557/APJCP.2021.22.1.209DOI Listing
January 2021

Anti-angiogenic effects of beta-eudesmol and atractylodin in developing zebrafish embryos.

Comp Biochem Physiol C Toxicol Pharmacol 2021 May 22;243:108980. Epub 2021 Jan 22.

Graduate Studies, Chulabhorn International College of Medicine, Thammasat University, Paholyothin Road, Klong Luang, Pathumthani 12120, Thailand; Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Paholyothin Road, Klong Luang, Pathumthani 12120, Thailand; Drug Discovery and Development Center, Thammasat University, Paholyothin Road, Klong Luang, Pathumthani 12120, Thailand. Electronic address:

Angiogenesis is the process of formation of new blood vessels which plays an essential role in the normal physiological development of the organs and systems. Several factors contribute to and regulate this process. Unregulated angiogenesis, however, is harmful and is usually found in tumors and cancerous cells. β-Eudesmol and atractylodin are sesquiterpenoid contents extracted from the rhizome of Atractylodes lancea (AL). Reports suggest potential anti-angiogenic activities of both compounds. In this study, the anti-angiogenic activities of both compounds were investigated using the well-established zebrafish in vivo model. Zebrafish embryos were treated with a series of concentrations (6.3, 12.5, 25, and 50 μM) of β-eudesmol and (6.3, 12.5, and 25 μM) of atractylodin up to 72 h post-fertilization. Assessment of the effects on phenotypic blood vessel development (sub-intestinal vessel intersection count) revealed that both the compounds inhibited vessel development, particularly at higher concentrations. At the genetic levels, only β-eudesmol significantly downregulated the expression of the Vegfaa gene and also its receptor Vegfr2. β-Eudesmol also affected the expression of Vegfaa protein in a concentration-dependent manner. Results indicate that β-eudesmol exerts anti-angiogenic property through inhibition of Vegfaa at both the gene and protein levels. However, atractylodin does not possess this property.
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http://dx.doi.org/10.1016/j.cbpc.2021.108980DOI Listing
May 2021

Therapeutic potential and pharmacological activities of β-eudesmol.

Chem Biol Drug Des 2021 Apr 7;97(4):984-996. Epub 2021 Feb 7.

Chulabhorn International College of Medicine, Thammasat University, Rangsit Center, Klong Luang, Pathum Thani, Thailand.

Herbal medicines are attracting the attention of researchers worldwide. β-Eudesmol is one of the most studied and major bioactive sesquiterpenes, mainly extracted from Atractylodes lancea (Thunb) DC. rhizomes. It has potential anti-tumor and anti-angiogenic activities and is an inhibitor of tumor growth by inhibiting angiogenesis by suppressing CREB activation of the growth factor signaling pathway. It also stimulates neurite outgrowth in rat pheochromocytoma cells with activation of mitogen-activated protein kinases. It may be a promising lead compound for enhancing neural function, and it may help to explain the underlying mechanisms of neural differentiation. In this review, we summarized the currently available clinical and preclinical studies describing the therapeutic applications of β-eudesmol.
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http://dx.doi.org/10.1111/cbdd.13823DOI Listing
April 2021

Enhanced oral bioavailability and biodistribution of atractylodin encapsulated in PLGA nanoparticle in cholangiocarcinoma.

Clin Exp Pharmacol Physiol 2021 Mar 15;48(3):318-328. Epub 2020 Dec 15.

Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Bangkok, Thailand.

Atractylodes lancea (Thunb) DC. and its bioactive compound atractylodin (ATD), have been shown to exert promising anticancer activity against cholangiocarcinoma (CCA) both in vitro and in vivo. However, the clinical development of ATD could be hindered due to hydrophobicity and poor pharmacokinetic properties, and thus, the requirement of high dose administration and the risk of toxicity. In the present study, ATD-loaded in PLGA nanoparticles (ATD-PLGA) and that coated with chitosan (ATD-PLGA-CS) were developed using nanoprecipitation and single emulsification methods, respectively. The optimized ATD-PLGA formulation provided superior physical and pharmaceutical properties over ATD-PLGA-CS. The antiproliferative activity of ATD-PLGA against the two CCA cell lines, HuCCT1 and CL6, and the normal cell line (OUMS-36T-1F) was evaluated using MTT assay. Results showed that normal epithelial cell was less sensitive to ATD-PLGA compared to both CCA cell lines. In mice, the radiolabelled Tc-ATD-PLGA showed superior pharmacokinetic profile over free Tc-ATD, as evidenced by a 2.7-fold increase of area under plasma concentration-time curve (AUC ), maximum plasma concentration (C ), time to C (t ), and mean residence time (MRT). Higher accumulation of Tc-ATD-PLGA was observed in vital organs/tissues such as blood, liver, heart, and kidney, compared with free Tc-ATD-PLGA. Altogether, the results suggest that PLGA NPs could be a suitable drug delivery carrier for ATD in CCA.
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http://dx.doi.org/10.1111/1440-1681.13433DOI Listing
March 2021

Embryotoxicity evaluation of atractylodin and β-eudesmol using the zebrafish model.

Comp Biochem Physiol C Toxicol Pharmacol 2021 Jan 14;239:108869. Epub 2020 Aug 14.

Nano Environmental and Health Safety Research Team, National Nanotechnology Center (NANOTEC), National Science and Technology Development Agency (NSTDA), Pathum Thani 12120, Thailand. Electronic address:

Atractylodin and β-eudesmol are the major active ingredients of Atractylodes lancea (Thunb) DC. (AL). Both compounds exhibit various pharmacological activities, including anticancer activity against cholangiocarcinoma. Despite the widespread use of this plant in traditional medicine in China, Japan, Korea, and Thailand, studies of their toxicological profiles are limited. The present study aimed to evaluate the embryotoxicity of atractylodin and β-eudesmol using the zebrafish model. Zebrafish embryos were exposed to a series of concentrations (6.3, 12.5, 25, 50, and 100 μM) of each compound up to 72 h post-fertilization (hpf). The results showed that atractylodin and β-eudesmol induced mortality of zebrafish embryos with the 50% lethal concentration (LC) of 36.8 and 53.0 μM, respectively. Both compounds also caused embryonic deformities, including pericardial edema, malformed head, yolk sac edema, and truncated body. Only β-eudesmol decreased the hatching rates, while atractylodin reduced the heart rates of the zebrafish embryos. Additionally, both compounds increased reactive oxygen species (ROS) production and altered the transcriptional expression levels of superoxide dismutase 1 (sod1), catalase (cat), and glutathione S-transferase pi 2 (gstp2) genes. In conclusion, atractylodin and β-eudesmol induce mortality, developmental toxicity, and oxidative stress in zebrafish embryos. These findings may imply similar toxicity of both compounds in humans.
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http://dx.doi.org/10.1016/j.cbpc.2020.108869DOI Listing
January 2021

Prevalence of Glucose 6-Phosphate Dehydrogenase Variants in Malaria-Endemic Areas of South Central Timor, Eastern Indonesia.

Am J Trop Med Hyg 2020 08 25;103(2):760-766. Epub 2020 Jun 25.

Chulabhorn International College of Medicine (CICM), Thammasat University (Rangsit Campus), Patum Thani, Thailand.

Primaquine is an effective anti-hypnozoite drug for and However, it can trigger erythrocyte hemolysis in people with glucose 6-phosphate dehydrogenase (G6PD) deficiency. In a previous report from South Central Timor (SCT), Indonesia, we described the prevalence of Vanua Lava, Chatham, and Viangchan variants; in this study, other G6PD variants (Kaiping, Coimbra, Gaohe, Canton, and Mahidol) were subsequently analyzed. For clarity, all of these results are described together. The 381 DNA samples from the previous study during 2013-2014 were analyzed for G6PD variants by using PCR-restriction fragment length polymorphism (RFLP). The prevalence of G6PD deficiency in SCT was 6.3% (24/381 cases), including 4.2% (16/381 cases), 0.5% (2/381 cases), and 1.6% (6/381 cases) for Coimbra, Kaiping, and Vanua Lava variants, respectively. No other variants were found in this population. A significant association was found between ethnicity and the distribution of G6PD Kaiping in female subjects. A positive association was shown between G6PD activity and heterozygous females carrying Coimbra genotype, hemizygous males carrying Vanua Lava, infection in female subjects, and infection in male subjects. Further molecular analysis of heterozygous females, particularly in malaria-endemic areas, is needed for mapping distribution of G6PD deficiency status in Indonesia.
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http://dx.doi.org/10.4269/ajtmh.19-0780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410420PMC
August 2020

In vitro cytotoxic and toxicological activities of ethanolic extract of Kaempferia galanga Linn. and its active component, ethyl-p-methoxycinnamate, against cholangiocarcinoma.

J Integr Med 2020 Jul 22;18(4):326-333. Epub 2020 Apr 22.

Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Pathum Thani 12120, Thailand; Center of Excellence in Molecular Biology and Pharmacology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Pathum Thani 12120, Thailand; Drug Discovery and Development Center, Office of Advanced Science and Technology, Thammasat University, Pathum Thani 12120, Thailand. Electronic address:

Objective: To evaluate the cytotoxic, apoptotic, mutagenic and immunomodulatory activities of Kaempferia galanga Linn. (KG) extract and ethyl-p-methoxycinnamate (EPMC) in vitro.

Methods: The present study investigated the cytotoxic [using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide test], apoptotic (using a mitochondrial membrane potential assay), mutagenic (using a micronucleus test) and immunomodulatory (using flow cytometry) activities of the ethanolic extract of KG and its bioactive component, EPMC, against two cholangiocarcinoma (CCA) cell lines, CL-6 and HuCCT1, and one normal human cell line, OUMS-36T-1F.

Results: Both KG extract and EPMC exhibited moderate cytotoxic activity against both CCA cells. The cytotoxic activity was supported by their concentration-dependent induction of apoptosis. CL-6 was most sensitive (3-4 fold) and selective to 5-fluorouracil (5-FU), compared with KG extract and EPMC [median half inhibiting concentration (IC) and selectivity index (SI) were 23.01 μg/mL and 17.32; 78.41 μg/mL and 4.44; 100.76 μg/mL and 2.20, respectively for 5-FU vs. KG extract vs. EPMC]. HuCCT1 was relatively more sensitive and selective to 5-FU and EPMC than KG extract [median IC and SI were 66.03 μg/mL and 6.04; 60.90 μg/mL and 3.65; 156.60 μg/mL and 2.23, respectively for 5-FU vs. EPMC vs. KG extract]. EPMC produced relatively potent cytotoxic activity against polymorphonuclear cells (IC = 92.20 μg/mL). KG extract and EPMC exhibited concentration-dependent mutagenic activity, as well as inhibition of tumor necrosis factor-α and interleukin-6.

Conclusion: Considering cytotoxic, apoptotic, immunomodulatory and mutagenic activities, further development of KG as a drug candidate is likely to focus on the oral pharmaceutical formulation of a standardized KG extract rather than isolated compounds.
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http://dx.doi.org/10.1016/j.joim.2020.04.002DOI Listing
July 2020

The Potential of Atractylodin-Loaded PLGA Nanoparticles as Chemotherapeutic for Cholangiocarcinoma.

Asian Pac J Cancer Prev 2020 Apr 1;21(4):935-941. Epub 2020 Apr 1.

Chulabhorn International College of Medicine,Thammasat University, Pathum Thani, Thailand.

Backgrounds: The anti-cholangiocarcinoma (CCA) activity of atractylodin isolated from Atractylodes lacea (Thunb.) DC. has previously been demonstrated both in vitro and in vivo. However, the compound is insoluble in water and must be dissolved in organic solvent which might be harmful to human body. The aim of the study was to develop atractylodin-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) (ALNPs) and to investigate its cytotoxic activity against CCA.

Methods: The ALNPs were prepared using PLGA MW 12,000 and 48,000 by solvent displacement methods. Particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency (%EE) and loading efficiency (%LE) as well as drug releasing profile of ALNPs were characterized. The selected ALNPs formulation was then investigated cytotoxic activity against CCA cell lines, CL-6 and HuCC-T1.

Results: The ALNPs preparation was achieved using PLGA MW 12,000 (ALNPs-1) with mean (±SD) values of particle diameter, PDI and zeta potential of 158.13±0.21 nm, 0.076±0.003, and (-) 23.80± (-) 0.75 mV, respectively. The transmission electron microscopy (TEM) showed spherical morphology of NPs. The %EE and %LE were 50.16±1.77% and 2.22±0.08%, respectively. The release of atractylodin from ALNPs-1 in PBS was up to 88% in 72 h. The potency of ALNPs-1 cytotoxic activity including selectivity against CCA cell line, CL-6, were about twice of the unformulated atractylodin after 24 h of exposure (IC50: 29.28 vs 56.36 µg/mL, selectivity index 2.99 vs 1.50).

Conclusion: ALNPs were successfully prepared by solvent displacement method using PLGA MW 12,000 (ALNPs-1) with suitable pharmaceutical properties and cytotoxic activity against CCA. However, nano-formulation with improved pharmaceutical properties (higher %EE and %LE) and cytotoxic activity (improved selectivity to CCA) should be further developed for potential used as drug delivery systems for the treatment of CCA.
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http://dx.doi.org/10.31557/APJCP.2020.21.4.935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445967PMC
April 2020

Cytotoxicity, Cell Cycle Arrest, and Apoptosis Induction Activity of Ethyl-p-methoxycinnamate in Cholangiocarcinoma Cell.

Asian Pac J Cancer Prev 2020 Apr 1;21(4):927-934. Epub 2020 Apr 1.

Drug Discovery and Development Center, Office of Advanced Science and Technology, Thammasat University, Pathumthani, Thailand.

Objective: To investigate cytotoxic activity of ethyl-p-methoxycinnamate (EPMC) including its effect on p-glycoprotein (multidrug resistance-1: mdr-1 gene) in human cholangiocarcinoma cell.

Methods: Cytotoxic activity of EPMC against human cholangiocarcinoma (CL-6), fibroblast (OUMS-36T-1F), and colon cancer (Caco-2) cell lines were assessed using MTT assay. Selectivity index (SI) was determined as the ratio of IC50 (concentration that inhibits cell growth by 50%) of EPMC in OUMS-36T-1F and that in CL-6 cell. Cell cycle arrest and apoptosis in CL-6 cells were investigated by flow cytometry and fluorescent microscopy. Effect of EPMC on mdr-1 gene expression in CL-6 and Caco-2 was determined by real-time PCR.

Results: The median (95% CI) IC50 values of EPMC in CL-6, OUMS-36T-1F, and Caco-2 were 245.5 (243.1-266.7), 899.60 (855.8-966.3) and 347.0 (340.3-356.9) µg/ml, respectively. The SI value of the compound for the CL-6 cell was 3.70. EPMC at IC50 inhibited CL-6 cell division and induced apoptosis compared to untreated control. EPMC exposure did not induce mdr-1 gene expression in both CL-6 and Caco-2 cells.

Conclusion: The results suggest the potential role of EPMC in cholangiocarcinoma with a low possibility of drug resistance induction.
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http://dx.doi.org/10.31557/APJCP.2020.21.4.927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445962PMC
April 2020

Metabolite Profiling in Anticancer Drug Development: A Systematic Review.

Drug Des Devel Ther 2020 9;14:1401-1444. Epub 2020 Apr 9.

Chulabhorn International College of Medicine, Thammasat University, Pathum Thani 12120, Thailand.

Drug metabolism is one of the most important pharmacokinetic processes and plays an important role during the stage of drug development. The metabolite profile investigation is important as the metabolites generated could be beneficial for therapy or leading to serious toxicity. This systematic review aims to summarize the research articles relating to the metabolite profile investigation of conventional drugs and herb-derived compounds for cancer chemotherapy, to examine factors influencing metabolite profiling of these drugs/compounds, and to determine the relationship between therapeutic efficacy and toxicity of their metabolites. The literature search was performed through PubMed and ScienceDirect databases up to January 2019. Out of 830 published articles, 78 articles were included in the analysis based on pre-defined inclusion and exclusion criteria. Both phase I and II enzymes metabolize the anticancer agents/herb-derived compounds . The major phase I reactions include oxidation/hydroxylation and hydrolysis, while the major phase II reactions are glucuronidation, methylation, and sulfation. Four main factors were found to influence metabolite formation, including species, gender, and route and dose of drug administration. Some metabolites were identified as active or toxic metabolites. This information is critical for cancer chemotherapy and anticancer drug development.
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http://dx.doi.org/10.2147/DDDT.S221518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154001PMC
January 2021

Proteomics Analysis for Identification of Potential Cell Signaling Pathways and Protein Targets of Actions of Atractylodin and β-Eudesmol Against Cholangiocarcinoma.

Asian Pac J Cancer Prev 2020 Mar 1;21(3):621-628. Epub 2020 Mar 1.

Chulabhorn International College of Medicine, Thammasat University, Paholyothin Road, Klonglung, Pathumthani Thailand.

Objective: The study aimed to identify potential cell signaling pathways and protein targets of actions of atractylodin and β-eudesmol in cholangiocarcinoma, the two active compounds isolated from Atracylodes lancea using proteomics approach.

Method: The cholangiocarcinoma cell line, CL-6, was treated with each compound for 3 and 6 hours, and the proteins from both intra- and extracellular components were extracted. LC-MS/MS was applied following the separation of the extract proteins by SDS-PAGE and digestion with trypsin. Signaling pathways and protein expression were analyzed by MASCOT and STITCH software.

Results: A total of 4,323 and 4,318 proteins were identified from intra- and extracellular components, respectively. Six and 4 intracellular proteins were linked with the signaling pathways (apoptosis, cell cycle control, and PI3K-AKT) of atractylodin and β-eudesmol, respectively. Four and 3 extracellular proteins were linked with the signaling pathways (NF-κB and PI3K-AKT) of atractylodin and β-eudesmol, respectively.

Conclusion: In conclusion, a total of 17 proteins associated with four cell signaling pathways that could be potential molecular targets of anticholangiocarcinoma action of atractylodin and β-eudesmol were identified through the application of proteomics approach.
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http://dx.doi.org/10.31557/APJCP.2020.21.3.621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437331PMC
March 2020

The Role of Clinical Pharmacology in Chemotherapy of Multidrug-Resistant Plasmodium falciparum.

J Clin Pharmacol 2020 07 27;60(7):830-847. Epub 2020 Feb 27.

Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathumthani, Thailand.

Malaria remains one of the major global public health problems due to the emergence and spread of multidrug-resistant Plasmodium falciparum. In recent years, clinical pharmacology has significantly contributed to the optimal dosing regimens of antimalarial drugs. The application of pharmacometric modeling and simulation has assisted in the accurate characterization of pharmacokinetic-pharmacodynamic relationships and the optimization of the dosage regimens of existing antimalarial drugs, including new antimalarial candidates for multidrug-resistant P falciparum in different populations.
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http://dx.doi.org/10.1002/jcph.1589DOI Listing
July 2020

Systematic Analysis of the Application and Inappropriate Use/Misuse of Statistics in Cholangiocarcinoma Research in Southeast Asia.

Asian Pac J Cancer Prev 2020 Feb 1;21(2):275-280. Epub 2020 Feb 1.

Chulabhorn International College of Medicine, Thammasat University, Paholyothin Road, Klongluang, Pathumthani Thailand.

Objective: The aim of the study was to perform a systematic review of research articles related to cholangiocarcinoma (CCA), the bile duct cancer in Southeast Asian (SEA) countries published during 2010-2015 including analysis of inappropriate use/misuse of statistics.

Methods: Research articles were retrieved from the PubMed database using different 'keywords' for seven research disciplines/categories in biomedical sciences (medicine/physiology, epidemiology, immunology, pharmacology and toxicology, diagnosis/diagnostics, drug resistance, and biochemistry).

Results: A total of 353 articles were finally included in the analysis based on the pre-defined eligibility criteria. Most were articles of which the studies were conducted in Thailand (335 articles, 94.90%). Disease diagnosis/diagnostics (n=266, 75.35%), biochemistry (n =223, 63.17%), and pharmacology and toxicology (n =218, 61.76%) were the three main research disciplines/categories for CAA conducted in SEA countries during 2010-2015. Thailand was the country which most published CCA-related research articles in all disciplines/categories. Drug resistance was the research category that most applied both descriptive and inferential statistics (100%). The student's t-test was the most applied test (35.13%). Inappropriate use/misuse of statistics in all types was highest in diagnosis/diagnostics (73.59%) and pharmacology and toxicology (73.06%) research disciplines/categories and was lowest in medicine/pathophysiology (0.26%). Inappropriate use/misuse in almost all types (seven types) was found in the diagnosis/diagnostics category.

Conclusion: Results of the systematic analysis of CCA-related research articles published from the ten SEA countries during 2010-2015 reveal high rates of inappropriate use/misuse of statistics. The readers should be aware of the reliability of the articles and the possibility of wrong interpretation and conclusion of these articles.
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http://dx.doi.org/10.31557/APJCP.2020.21.2.275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332113PMC
February 2020

β-Eudesmol induces the expression of apoptosis pathway proteins in cholangiocarcinoma cell lines.

J Res Med Sci 2020 20;25. Epub 2020 Jan 20.

Department of Clinical Product Development, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.

Background: Cholangiocarcinoma (CCA) is a neglected disease prevalent in developing countries with high burden and mortality rate, and there is no effective treatment. We aimed to investigate β-eudesmol molecular target of action in human CCA cell lines using the selected key molecules of apoptotic pathways.

Materials And Methods: Two CCA cell lines (HuH28 and HuCCT1) were assessed at different time points after β-eudesmol treatment for mRNA and protein expression profiles of , and by real-time polymerase chain reaction and western blot, respectively.

Results: β-eudesmol induced expressions of p21 and p53 in mRNA/protein level in HuH28 and HuCCT1 cells. These CCA cells also expressed caspase-3, -8, -9 and bax (mRNA and/or protein level) among others after β-eudesmol treatment indicating its role in both intrinsic and extrinsic caspase-dependent apoptotic pathways.

Conclusion: The study demonstrated that β-eudesmol induced the expression of apoptosis pathway proteins, suggesting its potential role in promoting the caspase-dependent apoptotic pathway, and induction of the cell cycle arrest in CCA cell lines. β-eudesmol can be considered as a potential compound for further investigation as an anti-CCA agent.
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http://dx.doi.org/10.4103/jrms.JRMS_291_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003544PMC
January 2020

Pharmacogenetic relevant polymorphisms of CYP2C9, CYP2C19, CYP2D6, and CYP3A5 in Bhutanese population.

Drug Metab Pers Ther 2019 12;34(4)

Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Thammasat University, Thailand.

Background Marked differences among genotype frequencies (Caucasians, Asians, and Africans) have been observed in cytochrome P450 (CYP) genes. Data on the frequency of pharmacogenetic relevant polymorphisms in Bhutanese population is absent. This study aimed to investigate the frequencies of pharmacogenetic relevant polymorphisms of CYP2C9 (*2 and *3), CYP2C19 (*2 and *3), CYP2D6 (*10), and CYP3A5 (*3) in Bhutanese population. Methods Genotyping was performed in 443 DNA samples using polymerase chain reaction-restriction fragment length polymorphism. Results For CYP2C9, allele frequencies of *2 and *3 variants were 0.339% and 0%, respectively. For CYP2C19, frequencies of *2 and *3 variants were 30.135% and 15.689%, respectively. Allele frequencies of CYP2D6*10 and CYP3A5*3 were 21.332% and 77.314%, respectively. Allele frequencies of CYP2C9*2 are similar to most Asians while CYP2C9*3 was absent. CYP2C19*2 showed a close resemblance to Japanese and Burmese, while CYP2C19*3 is near to Japanese and Korean. CYP2D6*10 is noticeably lower than other Asians. CYP3A5*3 is similar to East Asians (Chinese, Japanese, and Korean). Conclusions The Bhutanese population is polymorphic for these CYP genes, except for CYP2C9*3. Similar to other populations, genetic testing for these genes may, therefore, be helpful to obtain the benefit from pharmacological treatments and prevent adverse drug reactions.
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http://dx.doi.org/10.1515/dmpt-2019-0020DOI Listing
December 2019

Preclinical Toxicology and Anticholangiocarcinoma Activity of Oral Formulation of Standardized Extract of Zingiber Officinale.

Planta Med 2020 Jan 27;86(2):104-112. Epub 2019 Nov 27.

Center of Excellence in Molecular Biology and Pharmacology of Malaria and Cholangiocarcinoma, Chulabhor International College of Medicine, Thammasat University, Pathum Thani, Thailand.

Cholangiocarcinoma (CCA) remains a significant public health problem in Thailand. New effective and safe drugs are urgently needed. Roscoe (ZO) is a widely used medicinal plant for the treatment of several ailments, and the animal study suggests a potential anti-CCA activity. The present study aimed to develop the oral formulation of standardized extract of ZO and investigate toxicological profiles (acute, repeated dose, and chronic toxicity), including anti-CCA activity of the ZO formulation. The oral pharmaceutical formulation of the standardized ZO extract was successfully developed with an acceptable level of contamination and physicochemical and pharmaceutical properties. Acute, subacute, and chronic toxicity tests were conducted in healthy Sprague Dawley rats according to the OECD guidelines. The results showed no evidence of toxicity and death in the acute and subacute toxicity testing with the maximum tolerated dose (MTD) of 5000 and 2000 mg/kg body weight, respectively. Chronic toxicity revealed MTD and No-Observed-Adverse-Effect level (NOAEL) of 1000 mg/kg body weight. The anti-CCA activity was evaluated in CCA-xenografted mouse model. The formulated ZO powder was fed to animals daily for 30 days. Significant anti-CCA activity on tumor growth inhibition and prolongation of survival time were demonstrated at the high (2000 mg/kg body weight) and moderate (1000 mg/kg body weight) dose levels. Further investigation to elucidate molecular targets of action of ZO against CCA cells is encouraged.
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http://dx.doi.org/10.1055/a-1037-4081DOI Listing
January 2020

Physiologically-Based Pharmacokinetic Modeling for Optimal Dosage Prediction of Quinine Coadministered With Ritonavir-Boosted Lopinavir.

Clin Pharmacol Ther 2020 05 12;107(5):1209-1220. Epub 2020 Jan 12.

Department of Clinical Product Development, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.

The coformulated lopinavir/ritonavir significantly reduces quinine concentration in healthy volunteers due to potential drug-drug interactions (DDIs). However, DDI information in malaria and HIV coinfected patients are lacking. The objective of the study was to apply physiologically-based pharmacokinetic (PBPK) modeling to predict optimal dosage regimens of quinine when coadministered with lopinavir/ritonavir in malaria and HIV coinfected patients with different conditions. The developed model was validated against literature. Model verification was evaluated using the accepted method. The verified PBPK models successfully predicted unbound quinine disposition when coadministered with lopinavir/ritonavir in coinfected patients with different conditions. Suitable dose adjustments to counteract with the DDIs have identified in patients with various situations (i.e., a 7-day course at 1,800 mg t.i.d. in patients with malaria with HIV infection, 648 mg b.i.d. in chronic renal failure, 648 mg t.i.d. in hepatic insufficiency except for severe hepatic insufficiency (324 mg b.i.d.), and 648 mg t.i.d. in CYP3A4 polymorphism).
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http://dx.doi.org/10.1002/cpt.1721DOI Listing
May 2020

Herbal Medicine Development: Methodologies, Challenges, and Issues.

Evid Based Complement Alternat Med 2019 9;2019:4935786. Epub 2019 Oct 9.

Institute of Herbal Medicine, National Institutes of Health, University of the Philippines, Manila, Philippines.

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http://dx.doi.org/10.1155/2019/4935786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811782PMC
October 2019

Screening of Molecular Targets of Action of Atractylodin in Cholangiocarcinoma by Applying Proteomic and Metabolomic Approaches.

Metabolites 2019 Nov 1;9(11). Epub 2019 Nov 1.

Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Paholyothin Road, Klonglung, Pathumthani 12120, Thailand.

Cholangiocarcinoma (CCA) is cancer of the bile duct and the highest incidence of CCA in the world is reported in Thailand. Our previous in vitro and in vivo studies identified (Thunb) D.C. as a promising candidate for CCA treatment. The present study aimed to examine the molecular targets of action of atractylodin, the bioactive compound isolated from , in CCA cell line by applying proteomic and metabolomic approaches. Intra- and extracellular proteins and metabolites were identified by LC-MS/MS following exposure of CL-6, the CCA cell line, to atractylodin for 24 and 48 h. Analysis of the protein functions and pathways involved was performed using a Venn diagram, PANTHER, and STITCH software. Analysis of the metabolite functions and pathways involved, including the correlation between proteins and metabolites identified was performed using MetaboAnalyst software. Results suggested the involvement of atractylodin in various cell biology processes. These include the cell cycle, apoptosis, DNA repair, immune response regulation, wound healing, blood vessel development, pyrimidine metabolism, the citrate cycle, purine metabolism, arginine and proline metabolism, glyoxylate and dicarboxylate metabolism, the pentose phosphate pathway, and fatty acid biosynthesis. Therefore, it was proposed that the action of atractylodin may involve the destruction of the DNA of cancer cells, leading to cell cycle arrest and cell apoptosis.
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http://dx.doi.org/10.3390/metabo9110260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918361PMC
November 2019

A Systematic Review of Drug Metabolism Studies of Plants With Anticancer Properties: Approaches Applied and Limitations.

Eur J Drug Metab Pharmacokinet 2020 Apr;45(2):173-225

Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Klong Luang, Pathum Thani, 12120, Thailand.

Background And Objectives: Hepatic drug metabolism is a key influence on the efficacy and safety of medicines from both chemical and natural product sources. Studies of the metabolism of synthetic compounds, herbal medicines/supplements, and herb-derived bioactive compounds are therefore challenging. The aim of the present review is to provide a summary of the approaches/techniques that are currently being employed to investigate different aspects of the metabolism of herbs and herb-derived compounds (reaction phenotyping, metabolite profiling, metabolic clearance prediction, metabolic/pharmacokinetic drug interactions, and metabolism-related pharmacokinetic studies), including their limitations.

Methods: A thorough search of the PubMed database was performed using the terms 'Cancer' AND 'Cytochrome P450 (CYP)' OR 'Phase I metabolism' OR 'Phase II metabolism' AND 'Natural product' OR 'Herbal medicine' OR 'Herbal product' OR 'Herb-derived compound.'

Results: Most of the studies (84 studies, 83.2%) retrieved during the search investigated metabolic/pharmacokinetic drug interactions. Three (3.0%), 7 (6.9%), 6 (5.9%), and 1 (1.0%) study involved metabolism-related pharmacokinetic studies, reaction phenotyping, metabolite profiling, and prediction of metabolic clearance, respectively.

Conclusions: Various studies reported conflicting results, with the results depending on the nature of the herb investigated (extracts or active constituents) and the biochemical tool (subcellular fractions, cells, or recombinant enzymes) and study system (in vitro/in vivo/ex vivo/clinical) applied. Each approach/system has its own advantages and disadvantages. Selecting the most appropriate approaches/systems allows us to extract the most meaningful and clinically relevant information on the metabolic pathways (the metabolites generated and the enzymes involved) and the potential drug interactions of herb-derived compounds for cancer therapy and prevention. Human primary hepatocytes are the best model that can be applied in any metabolic study. Human liver microsomes (HLMs) are a useful biochemical tool for preliminary drug metabolism studies. Recombinant microsomes that express specific enzymes and CYP-isoform-specific monoclonal antibodies are useful tools for enzyme inhibition studies.
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http://dx.doi.org/10.1007/s13318-019-00582-8DOI Listing
April 2020

Pharmacokinetic studies of nanoparticles as a delivery system for conventional drugs and herb-derived compounds for cancer therapy: a systematic review.

Int J Nanomedicine 2019 23;14:5659-5677. Epub 2019 Jul 23.

Graduate Studies, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, Thailand.

The poor pharmacokinetic characteristics of most anticancer drugs have limited their clinical effectiveness. The application of nanoparticles as a novel drug delivery system has provided opportunities to tackle the current challenges facing conventional drug delivery systems such as poor pharmacokinetics, lack of specificity to tumor cells, multidrug resistance, and toxicity. This systematic review aims to examine the application of pharmacokinetic studies of nanoparticles loaded in conventional drugs and herb-derived compounds for cancer therapy. The pharmacokinetic parameters of several herbal medicines and chemotherapeutic drugs loaded into nanoparticles were reported. This included area under the curve (AUC) of plasma concentration-time profile, maximum plasma concentration (C), time to maximum plasma concentration (T), volume of distribution (V or V), elimination half-life (t), and clearance (CL). The systematic review was conducted using information available in the PubMed and Science Direct databases up to February 2019. The search terms employed were: pharmacokinetics, pharmacokinetic study, nanoparticles, anticancer, traditional medicine, herbal medicine, herb-derived compounds, natural products, and chemotherapy. Overall, nanoparticle carriers not only significantly improved pharmacokinetics but also further enhanced permeability, solubility, stability, specificity, and selectivity of the carried anticancer drugs/herb-derived compounds to target tumor cells. Additionally, they also limited hepatic first-pass metabolism and P-glycoprotein (P-gp) efflux of the carried anticancer drugs/herb-derived compounds. Based on this systematic review, polymeric nanoparticles were the most commonly used nanocarrier to improve the pharmacokinetic parameters. The use of nanoparticles as a novel drug delivery system has the potential to improve both pharmacokinetics and cytotoxicity activity of the loaded drugs/herb-derived compounds for cancer therapy.
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http://dx.doi.org/10.2147/IJN.S213229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781664PMC
December 2019

IL-17A, a possible biomarker for the evaluation of treatment response in Trypanosoma cruzi infected children: A 12-months follow-up study in Bolivia.

PLoS Negl Trop Dis 2019 09 25;13(9):e0007715. Epub 2019 Sep 25.

Department of Immunogenetics, Institute of Tropical Medicine (NEKKEN), School of Tropical Medicine and Global Health, Nagasaki University, Sakamoto, Nagasaki, Japan.

Background: The National Program for Chagas disease was implemented in Bolivia in 2006, and it greatly decreased the number of infections through vector control. Subsequently, a treatment regimen of benznidazole (BNZ) was started in seropositive school-age children living in certified vector control areas.

Methods And Findings: We conducted a 12-month follow-up study and seven blood samples were taken during and after the treatment. Serology, conventional diagnostic PCR (cPCR) and quantitative Real-time PCR (qPCR) were performed. Plasma Th1/Th2/Th17 cytokines levels were also determined. Approximately 73 of 103 seropositive children complied with BNZ, with three interruptions due to side effects. To evaluate each individual's treatment efficacy, the cPCR and qPCR values during the final 6 months of the follow-up period were observed. Among 57 children who completed follow-up, 6 individuals (11%) showed both cPCR(+) and qPCR(+) (non reactive), 24 (42%) cPCR(-) but qPCR(+) (ambiguous) and 27 (47%) cPCR(-) and qPCR(-) (reactive). Within 14 Th1/Th2/Th17 cytokines, IL-17A showed significantly higher levels in seropositive children before the treatment compared to age-matched seronegative children and significantly decreased to the normal level one-year after. Moreover, throughout the follow-up study, IL-17A levels were positively co-related to parasite counts detected by qPCR. At the 12 months' time point, IL-17A levels of non-reactive subjects were significantly higher than either those of reactive or ambiguous subjects suggesting that IL-17A might be useful to determine the reactivity to BNZ treatment.

Conclusions: Plasma levels of IL-17A might be a bio-marker for detecting persistent infection of T. cruzi and its chronic inflammation.
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http://dx.doi.org/10.1371/journal.pntd.0007715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760767PMC
September 2019

Malaria elimination in Bhutan: asymptomatic malaria cases in the Bhutanese population living in malaria-risk areas and in migrant workers from India.

Rev Inst Med Trop Sao Paulo 2019 Sep 12;61:e52. Epub 2019 Sep 12.

Thammasat University, Cholangiocarcinoma, Chulabhorn International College of Medicine, Center of Excellence in Pharmacology and Molecular Biology of Malaria, Pathumthani, Thailand.

In 2018, Bhutan reported 54 cases of malaria, of which six were indigenous, 14 introduced and 34 imported. Considering the continuous reduction in the number of indigenous cases, Bhutan plans to eliminate malaria by 2025 under the Bhutan Malaria Elimination Strategy. The study was conducted to assess the presence of asymptomatic plasmodial infection in both, Bhutanese population living in malaria-risk areas and in migrant workers to guide the elimination strategies. A cross-sectional study was conducted from April to May 2016 in 750 Bhutanese people and 473 migrant workers. Plasmodium falciparum and Plasmodium vivax infections were investigated by using a rapid diagnostic test (RDT) and the polymerase chain reaction (PCR). Prevalence of asymptomatic plasmodial infection based on PCR was 0.27% (95% CI: 0.05-1.07%) among Bhutanese people with a mean age of 43 years old. The proportions of males and females were 45% and 55%, respectively. Among migrant workers, the prevalence of asymptomatic plasmodial infection was 0.42% (95% CI: 0.07-1.69%) with a mean age of 30 years old. The majority of migrant workers were from the neighboring Indian State of West Bengal (57.51%), followed by Assam (12.26%). RDT in both study groups did not detect any plasmodial infection. The presence of a low prevalence of asymptomatic plasmodial infection indicates that the current elimination strategies and interventions are effective.
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http://dx.doi.org/10.1590/S1678-9946201961052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746194PMC
September 2019

Polymorphisms of genes encoding drug transporters or cytochrome P450 enzymes and association with clinical response in cancer patients: a systematic review.

Cancer Chemother Pharmacol 2019 Nov 4;84(5):959-975. Epub 2019 Sep 4.

Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University (Rangsit Campus), Pathumtani, 12121, Thailand.

Purpose: Not all patients respond well to cancer chemotherapy. One of the most important factors contributing to treatment response (efficacy and toxicity) is genetic determinant. The current systematic review aims to provide current status of the information on the genetic contribution of genes encoding drug transport proteins and drug metabolizing enzyme, cytochrome P450 (CYP), and relationship with clinical outcomes of cancer chemotherapy.

Methods: The literature search was performed through PubMed and ScienceDirect databases. One hundred and four research articles that fulfilled the inclusion criteria and had none of the exclusion criteria were included in the analysis.

Results: Various studies reported conflicting results for the polymorphisms of the major genes and association with treatment outcomes in patients with various types of cancer. Nevertheless, among the investigated gene polymorphisms, it appears that the 1236C>T, 3435C>T and 2677 G>T/A SNPs of the drug transporter gene ABCB1 were the most promising determinants of clinical outcomes. Although both 1236C>T and 3435C>T polymorphism are synonymous SNPs, several studies have demonstrated that not all synonymous SNPs are silent. Therefore, using the haplotype (1236C>T, 2677G>T, and 3435C>T) analysis rather than a single SNP may be a more useful approach for phenotype prediction. Some of the patients with variants of CYP genes were associated with unsatisfactory treatment response (efficacy and toxicity), suggesting that these variants may be associated with either reduction or absence of CYP enzyme activity.

Conclusions: The controversial results may be due to several factors including difference in populations studied, sample size, tumor sites and stages, chemotherapeutic drug regimens, and evaluation parameters for efficacy and/or toxicity. Before the information can be successfully applied to individualized cancer chemotherapy, further studies should be focused on these promising genetic markers and their association with clinical outcomes using standardized protocols.
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http://dx.doi.org/10.1007/s00280-019-03932-0DOI Listing
November 2019

Chronic exposure to cadmium is associated with a marked reduction in glomerular filtration rate.

Clin Kidney J 2019 Aug 21;12(4):468-475. Epub 2018 Nov 21.

Centre for Kidney Disease Research, Faculty of Medicine, Translational Research Institute, University of Queensland, Brisbane, Australia.

Background: Urinary 20-hydroxyeicosatetraenoic acid (20-HETE) has been associated with hypertension in women with elevated urinary cadmium (Cd) excretion rates. The present study investigates the urinary Cd and 20-HETE levels in relation to the estimated glomerular filtration rate (eGFR) and albumin excretion in men and women.

Methods: A population-based, cross-sectional study, which included 225 women and 84 men aged 33-55 years, was conducted in a rural area known to be polluted with Cd.

Results: In all subjects, lower eGFR values were associated with higher urinary Cd excretion (P = 0.030), and tubulopathy markers -acetyl-β-d-glucosaminidase (P < 0.001) and β2-microglobulin (β2-MG) (P < 0.001). On average, the hypertensive subjects with the highest quartile of urinary Cd had eGFR values of 12 and 17 mL/min/1.73 m lower than that in the hypertensive (P = 0.009) and normotensive subjects (P < 0.001) with the lowest quartile of urinary Cd, respectively. In men, urinary albumin was inversely associated with 20-HETE (β = -0.384, P < 0.001), while showing a moderately positive association with systolic blood pressure (SBP) (β = 0.302, P = 0.037). In women, urinary albumin was not associated with 20-HETE (P = 0.776), but was associated with tubulopathy, reflected by elevated urinary excretion of β2-MG (β = 0.231, P = 0.002).

Conclusions: Tubulopathy is a determinant of albumin excretion in women, while 20-HETE and SBP are determinants of urinary albumin excretion in men. Associations of chronic exposure to Cd with marked eGFR decline and renal tubular injury seen in both Cd-exposed men and women add to mounting research data that links Cd to the risk of developing chronic kidney disease.
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http://dx.doi.org/10.1093/ckj/sfy113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6671389PMC
August 2019

Ethical approval and informed consent reporting in ASEAN journals: a systematic review.

Curr Med Res Opin 2019 12 13;35(12):2179-2186. Epub 2019 Sep 13.

Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Chulabhorn International College of Medicine, Thammasat University, Pathumthani, Thailand.

Scientific publication is a way to disseminate knowledge to the scientific community. However, an article usually has very little information on how and why ethical approval (EA) and informed consent (IC) was obtained, which can make it very difficult for a reader to evaluate the ethical validity of the study. While many internationally recognized journals and publishers have already adopted a high EA/IC reporting standard, many journals still fail to do so. The aim of this study was to explore the EA/IC reporting standards, as well as their implementation, of the Association of Southeastern Asian Nation (ASEAN) member journals. A literature search was performed in PubMed for articles that were published in journals from ASEAN member states in 2016. The articles were then reviewed, categorized into study types, and given two scores-one for their EA statement and one for their IC statement-ranging from 0-4. A list of journals was compiled from the articles retrieved and their instructions to authors regarding EA/IC statements were scored on a scale of 0-2. The data was statistically analyzed using Chi-square test (2-sided) with SPSS (version 21) with -value < .05 being considered statistically significant. While a high proportion of articles adequately reported EA, many failed to report IC. Journals with better EA and IC instruction scores had a higher percentage of articles that adequately reported EA/IC. There were significant relationships between EA/IC statement scores and journals' instructions scores (EA:  = .002; IC:  = .019). There may be a need for journals to play key roles in advocating the importance of reporting EA and IC by strictly enforcing high EA/IC reporting standards and refusing the publication of articles that fail to comply.
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http://dx.doi.org/10.1080/03007995.2019.1647505DOI Listing
December 2019