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Publication Open Access Preliminary report: homology modeling of human ryanodine receptor-1(2012) Waraphan Toniti; Pranom Puchadapirom; Aekkapot Chamkasem; Mahidol University. Faculty of Veterinary Science. Department of Pre-clinic and Applied Animal Sciences; Mahidol University. Faculty of Science. Department of Pathobiology; Mahidol University. Faculty of Veterinary ScienceExcitation-contraction (E-C) coupling is the series of events in which an electrical stimulus is converted into a mechanical contraction. Ryanodine receptors (RyRs), the Ca2+ release channels, located at the sarcoplasmic reticulum membranePublication Open Access Preliminary report: Homology modeling of Human Ryanodine Receptor-1(2012) Waraphan Toniti; Pranom Puchadapirom; Aekkapot Chamkasem; Mahidol University. Faculty of Veterinary Science. Department of Pre-clinic and Applied Animal Science; Mahidol University. Faculty of Science. Department of PathobiologyExcitation-contraction (E-C) coupling is the series of events in which an electrical stimulus is converted into a mechanical contraction. Ryanodine receptors (RyRs), the Ca2+ release channels, located at the sarcoplasmic reticulum membranePublication Open Access Genetic diversity and lack of artemisinin selection signature on the Plasmodium falciparum ATP6 in the Greater Mekong Subregion(2013) Miao, Miao; Wang, Zenglei; Yang, Zhaoqing; Yuan, Lili; Parker, Daniel M.; Chaturong Putaporntip; Somchai Jongwutiwes; Xangsayarath, Phonepadith; Pongvongsa, Tiengkham; Moji, Hazuhiko; Tuong, Trinh Dinh; Abe, Tomoko; Nakazawa, Shusuke; Kyaw, Myat Phone; Yan, Guiyun; Jeeraphat Sirichaisinthop; Jetsumon Sattabongkot; เจตสุมน สัตตบงกช; Mu, Jianbing; Su, Xin-zhuan; Kaneko, Osamu; Cui, Liwang; Cui, Liwang; Mahidol University. Faculty of Tropical Medicine./endoplasmic reticulum Ca(2+)-ATPase (PfSERCA or PfATP6) has been speculated to be the target of ARTs and thus a potential marker for ART resistance. Here we amplified and sequenced pfatp6 gene (~3.6 Kb) in 213 samples collected after 2005 from the GreaterPublication Open Access Questions over high frequency of mutant PfATP6 haplotypes in traveller isolates(2012) Woodrow, Charles J; Gardner, Kate B; Bustamante, Leyla Y; Mahidol University. Faculty of Tropical Medicine. Mahidol-Oxford Tropical Medicine Research Unit (MORU)A recent paper in Malaria Journal suggests that a high proportion of Plasmodium falciparum isolates found in travellers returning from a range of African countries carry the PfATP6 A623E S769N haplotype, and that this genotype is associated with artemether resistance. Such a finding would represent a substantial departure from the extensive literature reporting these individual mutations to be very rare, with the double mutation never documented. The number of isolates screened to obtain these double mutants is unstated, but highly relevant, not least because selection of isolates could have introduced significant confounders, such as timing of in vitro testing. An additional concern relates to the location of sequencing primers used to assess these positions. In the absence of clear information on these fundamental questions it would be appropriate to treat the findings with caution.Publication Open Access Voltage dependent anion channel is redistributed during Japanese encephalitis virus infection of insect cells(2014) Chanida Fongsaran; Narumon Phaonakrop; Sittiruk Roytrakul; Chutima Thepparit; Atichat Kuadkitkan; Smith, Duncan R.; Mahidol University. Institute of Molecular Biosciences; Mahidol University. Center for Emerging and Neglected Infectious DiseasesDespite the availability of an effective vaccine, Japanese encephalitis remains a significant cause of morbidity and mortality in many parts of Asia. Japanese encephalitis is caused by the Japanese encephalitis virus (JEV), a mosquito transmitted flavivirus. Many of the details of the virus replication cycle in mosquito cells remain unknown. This study sought to determine whether GRP78, a well-characterized flavivirus E protein interacting protein, interacted with JEV E protein in insect cells, and whether this interaction was mediated at the cell surface. GRP78 was shown to interact with JEV E protein by coimmunoprecipitation, and was additionally shown to interact with voltage dependent anion protein (VDAC) through the same methodology. Antibody inhibition experiments showed that neither GRP78 nor VDAC played a role in JEV internalization to insect cells. Interestingly, VDAC was shown to be significantly relocalized in response to JEV infection, and significant levels of colocalization between VDAC and GRP78 and VDAC and ribosomal L28 protein were seen in JEV infected but not uninfected cells. This is the first report of relocalization of VDAC in response to JEV infection and suggests that this may be a part of the JEV replication strategy in insect cells.Publication Open Access The efficacy of edaravone (radicut), a free radical scavenger, for cardiovascular disease.(2013-07) Kikuchi, Kiyoshi; Salunya Tancharoen; ศรัณยา ตันเจริญ; Takeshige, Nobuyuki; Yoshitomi, Munetake; Morioka, Motohiro; Murai, Yoshinaka; Tanaka, Eiichiro; Mahidol University. Faculty of Dentistry. Department of PharmacologyEdaravone was originally developed as a potent free radical scavenger, and has been widely used to treat acute ischemic stroke in Japan since 2001. Free radicals play an important role in the pathogenesis of a variety of diseases, such as cardiovascular diseases and stroke. Therefore, free radicals may be targets for therapeutic intervention in these diseases. Edaravone shows protective effects on ischemic insults and inflammation in the heart, vessel, and brain in experimental studies. As well as scavenging free radicals, edaravone has anti-apoptotic, anti-necrotic, and anti-cytokine effects in cardiovascular diseases and stroke. Edaravone has preventive effects on myocardial injury following ischemia and reperfusion in patients with acute myocardial infarction. Edaravone may represent a new therapeutic intervention for endothelial dysfunction in the setting of atherosclerosis, heart failure, diabetes, or hypertension, because these diseases result from oxidative stress and/or cytokine-induced apoptosis. This review evaluates the potential of edaravone for treatment of cardiovascular disease, and covers clinical and experimental studies conducted between 1984 and 2013. We propose that edaravone, which scavenges free radicals, may offer a novel option for treatment of cardiovascular diseases. However, additional clinical studies are necessary to verify the efficacy of edaravone.Publication Open Access Bacopa monnieri extract increases rat coronary flow and protects against myocardial ischemia/reperfusion injury(2017) Sirintorn Srimachai; Devaux, Sylvie; Demougeot, Celine; Sarawut Kumphune; Ullrich, Nina D.; Niggli, Ernst; Kornkanok Ingkaninan; Natakorn Kamkaew; Scholfield, Norman; Sompol Tapechum; Krongkarn Chootip; Mahidol University. Faculty of Medicine, Siriraj Hospital, Department of Physiology; Naresuan University. Faculty of Medical Science. Department of Physiology; Naresuan University. Faculty of Allied Health Sciences. Department of Medical Technology; Naresuan University. Faculty of Pharmaceutical Sciences. Department of Pharmaceutical Chemistry and Pharmacognosy; University of Phayao. School of Medical Sciences; Heidelberg University. Department of Physiology and PathophysiologyBackground: This study explored Bacopa monnieri, a medicinal Ayurvedic herb, as a cardioprotectant against ischemia/reperfusion injury using cardiac function and coronary flow as end-points. Methods: In normal isolated rat hearts, coronary flow, left ventricular developed pressure, heart rate, and functional recovery were measured using the Langendorff preparation. Hearts were perfused with either (i) Krebs-Henseleit (normal) solution, (control), or with 30, 100 μg/ml B. monnieri ethanolic extract (30 min), or (ii) with normal solution or extract for 10 min preceding no-perfusion ischemia (30 min) followed by reperfusion (30 min) with normal solution. Infarct volumes were measured by triphenyltetrazolium staining. L-type Ca2+-currents (ICa, L) were measured by whole-cell patching in HL-1 cells, a mouse atrial cardiomyocyte cell line. Cytotoxicity of B. monnieri was assessed in rat isolated ventricular myocytes by trypan blue exclusion. Results: In normally perfused hearts, B. monnieri increased coronary flow by 63 ± 13% (30 μg/ml) and 216 ± 21% (100 μg/ml), compared to control (5 ± 3%) (n = 8–10, p < 0.001). B. monnieri treatment preceding ischemia/reperfusion improved left ventricular developed pressure by 84 ± 10% (30 μg/ml), 82 ± 10% (100 μg/ml) and 52 ± 6% (control) compared to pre- ischemia/reperfusion. Similarly, functional recovery showed a sustained increase. Moreover, B. monnieri (100 μg/ml) reduced the percentage of infarct size from 51 ± 2% (control) to 25 ± 2% (n = 6-8, p < 0.0001). B. monnieri (100 μg/ml) reduced ICa, L by 63 ± 4% in HL-1 cells. Ventricular myocyte survival decreased at higher concentrations (50–1000 μg/ml) B. monnieri. Conclusions: B. monnieri improves myocardial function following ischemia/reperfusion injury through recovery of coronary blood flow, contractile force and decrease in infarct size. Thus this may lead to a novel cardioprotectant strategy.Publication Open Access Protein-based signatures of functional evolution in Plasmodium falciparum(2011-09-14) Gardner, Kate B.; Sinha, Ipsita; Bustamante, Leyla Y.; Day, Nicholas P.J.; White, Nicholas J.; Woodrow, Charles J.; Woodrow, Charles J.; Mahidol University. Faculty of Tropical Medicine. Wellcome Trust Mahidol University-Oxford Tropical Medicine Research Unit (MORU).BACKGROUND: It has been known for over a decade that Plasmodium falciparum proteins are enriched in non-globular domains of unknown function. The potential for these regions of protein sequence to undergo high levels of genetic drift provides a fundamental challenge to attempts to identify the molecular basis of adaptive change in malaria parasites. RESULTS: Evolutionary comparisons were undertaken using a set of forty P. falciparum metabolic enzyme genes, both within the hominid malaria clade (P. reichenowi) and across the genus (P. chabaudi). All genes contained coding elements highly conserved across the genus, but there were also a large number of regions of weakly or non-aligning coding sequence. These displayed remarkable levels of non-synonymous fixed differences within the hominid malaria clade indicating near complete release from purifying selection (dN/dS ratio at residues non-aligning across genus: 0.64, dN/dS ratio at residues identical across genus: 0.03). Regions of low conservation also possessed high levels of hydrophilicity, a marker of non-globularity. The propensity for such regions to act as potent sources of non-synonymous genetic drift within extant P. falciparum isolates was confirmed at chromosomal regions containing genes known to mediate drug resistance in field isolates, where 150 of 153 amino acid variants were located in poorly conserved regions. In contrast, all 22 amino acid variants associated with drug resistance were restricted to highly conserved regions. Additional mutations associated with laboratory-selected drug resistance, such as those in PfATPase4 selected by spiroindolone, were similarly restricted while mutations in another calcium ATPase (PfSERCA, a gene proposed to mediate artemisinin resistance) that reach significant frequencies in field isolates were located exclusively in poorly conserved regions consistent with genetic drift. CONCLUSION: Coding sequences of malaria parasites contain prospectively definable domains subject to neutral or nearly neutral evolution on a scale that appears unrivalled in biology. This distinct evolutionary landscape has potential to confound analytical methods developed for other genera. Against this tide of genetic drift, polymorphisms mediating functional change stand out to such an extent that evolutionary context provides a useful signal for identifying the molecular basis of drug resistance in malaria parasites, a finding that is of relevance to both genome-wide and candidate gene studies in this genus.Publication Open Access Transcriptional regulation of the human manganese superoxide dismutase gene: the role of specificity protein 1 (Sp1) and activating protein-2 (AP-2)(2002) Yong XU; Sureerut Porntadavity; Daret K St ClairManganese superoxide dismutase (MnSOD) plays an important role in regulating cellular redox conditions. Expression of MnSOD has been shown to protect against damage by oxidative stress and to suppress the malignant phenotype of human cancer cells. We have previously cloned the human MnSOD (SOD2) gene and analysed its 5' proximal promoter, which has been characterized by a lack of a TATA or CAAT box and the presence of multiple GC boxes. To define further the molecular mechanisms for the regulation of MnSOD expression, multiple transcription factor-binding motifs containing overlapping specificity protein 1 (Sp1)- and activator protein (AP)-2-binding sites were identified by DNase I footprinting analysis. Functional studies in three cell lines with different levels of Sp1 and AP-2 proteins suggested that the cellular levels of these proteins may differentially regulate transcription via GC-binding motifs in the human SOD2 promoter. Co-transfection of an Sp1 expression vector resulted in an increase in the transcription of the promoter-driven reporter gene. In contrast, co-transfection of the AP-2 expression vector caused a decrease in transcription. Direct mutagenesis analysis of Sp1- and AP-2-binding sites showed that Sp1 is essential for transcription of the human SOD2 gene, whereas AP-2 plays a negative role in the transcription. Immunoprecipitation of Sp1 and AP-2 proteins demonstrated that Sp1 interacts with AP-2 in vivo. Two-hybrid analysis revealed that interaction between Sp1 and AP-2 plays both a positive and negative role in the transcription of the reporter gene in vivo. Taken together, our data indicate that AP-2 down-regulates transcription of the human SOD2 gene via its interaction with Sp1 within the promoter region. These findings, coupled with our previous observation that several cancer cell lines have mutations in the promoter region of the human MnSOD gene, which lead to an increase in an AP-2-binding site and a decrease in the promoter activity, signal the importance of understanding the promoter structure and the regulation of the human SOD2 gene by Sp1 and AP-2.Publication Open Access A review on the functions of the horse back and longissimus dorsi muscle(2015) Pattama Ritruechai; Mahidol University. Faculty of Veterinary Science. Department of Clinical Science and Public HealthThe function of a muscle is to permit movement and maintain posture. Such a key role depends on the interplay between its anatomical structure and the way is used during movement. From a mechanical sense, a muscle changes its length to generate force. If it generates force while shortening (concentric), it will generate mechanical power, and if it generates force whilst it is being stretched (eccentric), it will absorb mechanical power. The longissimus dorsi, the largest muscle of the horse's back, is of considerable importance for its key functions on the athletic ability and performance of the animal. In this review, I summarized the anatomy, functions, biomechanics, and disorders of the horse back. The biomechanics of the horse's back depend on the interaction between the spinal column and the spinal musculature. Especially, longissimus dorsi muscle performs different functions both along its length and different regions across each segment. Several studies have reported muscular disorders in the horse's back such as stiffness and limitation of motion range, as also by electromyography records on the muscle activity (albeit at single recording sites during locomotion). These reports are typically isolated observations and no study has yet integrated muscle activity patterns with the cycles of flexion-extension in any detail, neither a study has linked these factors to the muscle fascicle strains in the longissimus dorsi. Such studies will be fundamental to fully understand the mechanical role of the longissimus dorsi, particularly during locomotion, and will develop new treatment techniques for horse veterinarians. In addition, 3D anatomical measures of the structure in vivo integrated with measures of function back motion and longissimus dorsi muscle activity would be ideal to understand in further detail the function of the horse's back.