Publications by authors named "Kriangsak Ruchusatsawat"

18 Publications

  • Page 1 of 1

Reconstructing unseen transmission events to infer dengue dynamics from viral sequences.

Nat Commun 2021 03 22;12(1):1810. Epub 2021 Mar 22.

Department of Biology, University of Florida, Gainesville, FL, USA.

For most pathogens, transmission is driven by interactions between the behaviours of infectious individuals, the behaviours of the wider population, the local environment, and immunity. Phylogeographic approaches are currently unable to disentangle the relative effects of these competing factors. We develop a spatiotemporally structured phylogenetic framework that addresses these limitations by considering individual transmission events, reconstructed across spatial scales. We apply it to geocoded dengue virus sequences from Thailand (N = 726 over 18 years). We find infected individuals spend 96% of their time in their home community compared to 76% for the susceptible population (mainly children) and 42% for adults. Dynamic pockets of local immunity make transmission more likely in places with high heterotypic immunity and less likely where high homotypic immunity exists. Age-dependent mixing of individuals and vector distributions are not important in determining spread. This approach provides previously unknown insights into one of the most complex disease systems known and will be applicable to other pathogens.
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http://dx.doi.org/10.1038/s41467-021-21888-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985522PMC
March 2021

Identification of GII.14[P7] norovirus and its genomic mutations from a case of long-term infection in a post-symptomatic individual.

Infect Genet Evol 2020 12 1;86:104612. Epub 2020 Nov 1.

Thailand-Japan Research Collaboration Center on Emerging and Re-emerging Infections, Nonthaburi, Thailand. Electronic address:

Norovirus is a leading cause of acute gastroenteritis worldwide. Norovirus shedding typically lasts one week to one month after the onset of diarrhea in immunocompetent hosts. The occurrence of mutations in the genome during infection has contributed to the evolution of norovirus. It has been suggested that genomic mutations in the P2-domain of capsid protein VP1, the major antigenic site for virus clearance, are involved in the evasion of host immunity and prolonged shedding of norovirus. In our previous study, we found a case of long-term shedding of GII.14 norovirus in a post-symptomatic immunocompetent individual that lasted about three months. In this study, we characterized the genomic sequence of the GII.14 strain to gain insight into the context of long-term shedding. By sequencing a 4.8 kb region of the genome corresponding to half of ORF1 and the entire ORF2 and ORF3, which encode several non-structural proteins and the structural proteins VP1 and VP2, the GII.14 strain was found to be classified as recombinant GII.14[P7]. Six point-mutations occurred during the three-month period of infection in a time-dependent manner in the genomic regions encoding RNA-dependent RNA polymerase, VP1, and VP2. Three of the six mutations were sense mutations, but no amino acid substitution was identified in the P2-domain of VP1. These results suggest that there is a mechanism by which long-term shedding of norovirus occurs in immunocompetent individuals independent of P2-domain mutations.
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http://dx.doi.org/10.1016/j.meegid.2020.104612DOI Listing
December 2020

Norovirus transmission mediated by asymptomatic family members in households.

PLoS One 2020 23;15(7):e0236502. Epub 2020 Jul 23.

Thailand-Japan Research Collaboration Center on Emerging and Re-emerging Infections, Nonthaburi, Thailand.

The transmission of human norovirus excreted from infected persons occasionally causes sporadic infections and outbreaks. Both symptomatic patients and asymptomatic carriers have been reported to contribute to norovirus transmission, but little is known about the magnitude of the contribution of asymptomatic carriers. We carried out a 1-year survey of residents of a district of Bangkok, Thailand to determine the percentage of norovirus transmissions originating from asymptomatic individuals. We screened 38 individuals recruited from 16 families from May 2018 to April 2019 for GI and GII genotypes. Norovirus was detected every month, and 101 of 716 stool samples (14.1%) from individuals with no symptoms of acute gastroenteritis were norovirus-positive. The average infection frequency was 2.4 times per person per year. Fourteen genotypes were identified from the positive samples, with GII.4 being detected most frequently. Notably, 89.1% of the norovirus-positive samples were provided by individuals with no diarrhea episode. Similar to cases of symptomatic infections in Thailand, asymptomatic infections were observed most frequently in December. We detected 4 cases of NV infection caused by household transmission, and 3 of the 4 transmissions originated from asymptomatic individuals. We also identified a case in which norovirus derived from an asymptomatic individual caused diarrhea in a family member. These results suggest that asymptomatic individuals play a substantial role in both the maintenance and spreading of norovirus in a community through household transmission.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236502PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377487PMC
September 2020

Anti-Chikungunya Virus Monoclonal Antibody That Inhibits Viral Fusion and Release.

J Virol 2020 09 15;94(19). Epub 2020 Sep 15.

Thailand-Japan Research Collaboration Center on Emerging and Re-emerging Infections (RCC-ERI), Department of Medical Sciences, Ministry of Public Health, Nonthaburi, Thailand

Chikungunya fever, a mosquito-borne disease manifested by fever, rash, myalgia, and arthralgia, is caused by chikungunya virus (CHIKV), which belongs to the genus of the family Anti-CHIKV IgG from convalescent patients is known to directly neutralize CHIKV, and the state of immunity lasts throughout life. Here, we examined the epitope of a neutralizing mouse monoclonal antibody against CHIKV, CHE19, which inhibits viral fusion and release. docking analysis showed that the epitope of CHE19 was localized in the viral E2 envelope and consisted of two separate segments, an N-linker and a β-ribbon connector, and that its bound Fab fragment on E2 overlapped the position that the E3 glycoprotein originally occupied. We showed that CHIKV-E2 is lost during the viral internalization and that CHE19 inhibits the elimination of CHIKV-E2. These findings suggested that CHE19 stabilizes the E2-E1 heterodimer instead of E3 and inhibits the protrusion of the E1 fusion loop and subsequent membrane fusion. In addition, the antigen-bound Fab fragment configuration showed that CHE19 connects to the CHIKV spikes existing on the two individual virions, leading us to conclude that the CHE19-CHIKV complex was responsible for the large virus aggregations. In our subsequent filtration experiments, large viral aggregations by CHE19 were trapped by a 0.45-μm filter. This virion-connecting characteristic of CHE19 could explain the inhibition of viral release from infected cells by the tethering effect of the virion itself. These findings provide clues toward the development of effective prophylactic and therapeutic monoclonal antibodies against the infection. Recent outbreaks of chikungunya fever have increased its clinical importance. Neither a specific antiviral drug nor a commercial vaccine for CHIKV infection are available. Here, we show a detailed model of the docking between the envelope glycoprotein of CHIKV and our unique anti-CHIKV-neutralizing monoclonal antibody (CHE19), which inhibits CHIKV membrane fusion and virion release from CHIKV-infected cells. Homology modeling of the neutralizing antibody CHE19 and protein-protein docking analysis of the CHIKV envelope glycoprotein and CHE19 suggested that CHE19 inhibits the viral membrane fusion by stabilizing the E2-E1 heterodimer and inhibits virion release by facilitating the formation of virus aggregation due to the connecting virions, and these predictions were confirmed by experiments. Sequence information of CHE19 and the CHIKV envelope glycoprotein and their docking model will contribute to future development of an effective prophylactic and therapeutic agent.
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http://dx.doi.org/10.1128/JVI.00252-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495367PMC
September 2020

Down-regulation of miR-155 after treatment with narrow-band UVB and methotrexate associates with apoptosis of keratinocytes in psoriasis.

Asian Pac J Allergy Immunol 2019 Mar 24. Epub 2019 Mar 24.

Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.

Background: Psoriasis is a chronic inflammatory skin disease arising from a complex interaction between genetics, epigenetics, the host's immune system and the environment. Recent accumulated data revealed the dysregulation of various microRNAs (miRNAs) in several diseases including psoriasis.

Objective: We explored the functional role and regulation of hsa-miR-155-5p (miR-155) in an immortalized keratinocyte cell line (HaCaT), in relation to the pathogenesis and treatment of psoriasis.

Methods: miR-155 expression in normal skin and psoriatic skin lesion before and after treatment with methotrexate (MTX) and narrow-band ultraviolet B phototherapy (NB-UVB) were analyzed using quantitative reverse transcription PCR (qRT-PCR). Apoptotic activity, cell cycle and viable cells of miR-155 transfected HaCaT were measured using flow cytometry and MTS assay. Since, caspase-3 (CASP3) gene was predicted as a target gene of miR-155, the expression of CASP3 was detected in transfected HaCaT using western blot.

Results: We discovered that both MTX and NB-UVB significantly down-regulated miR-155 expression in psoriatic skin lesions. We also found that overexpression of miR-155 in HaCaT led to suppression of cell apoptosis and induced cell arrest at G0/G1 phase. Moreover, CASP3 expression was down-regulated in miR-155 transfected HaCaT.

Conclusion: This study demonstrates down-regulation of miR155 after treatment with MTX and NB-UVB in psoriatic skin lesion. miR155 plays significant role in apoptosis on HaCaT via CASP3. This finding provides a better understanding of the pathogenesis of psoriasis and might aid on developing the new monitoring tool or therapy for psoriasis in the future.
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http://dx.doi.org/10.12932/AP-031218-0451DOI Listing
March 2019

Long-term circulation of Zika virus in Thailand: an observational study.

Lancet Infect Dis 2019 04 27;19(4):439-446. Epub 2019 Feb 27.

Mathematical Modelling of Infectious Diseases Unit, Institut Pasteur, UMR2000, CNRS, Paris, France; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address:

Background: Little is known about the historical and current risk of Zika virus infection in southeast Asia, where the mosquito vector is widespread and other arboviruses circulate endemically. Centralised Zika virus surveillance began in Thailand in January, 2016. We assessed the long-term circulation of Zika virus in Thailand.

Methods: In this observational study, we analysed data from individuals with suspected Zika virus infection who presented at hospitals throughout the country and had biological samples (serum, plasma, or urine) tested for confirmation with PCR at the National Institute of Health laboratories in Bangkok. We analysed the spatial and age distribution of cases, and constructed time-resolved phylogenetic trees using genomes from Thailand and elsewhere to estimate when Zika virus was first introduced.

Findings: Of the 3089 samples from 1717 symptomatic individuals tested between January, 2016, and December, 2017, 368 were confirmed to have Zika virus infection. Cases of Zika virus infection were reported throughout the year, and from 29 of the 76 Thai provinces. Individuals had 2·8 times (95% CI 2·3-3·6) the odds of testing positive for Zika virus infection if they came from the same district and were sick within the same year of a person with a confirmed infection relative to the odds of testing positive anywhere, consistent with focal transmission. The probability of cases being younger than 10 years was 0·99 times (0·72-1·30) the probability of being that age in the underlying population. This probability rose to 1·62 (1·33-1·92) among those aged 21-30 years and fell to 0·53 (0·40-0·66) for those older than 50 years. This age distribution is consistent with that observed in the Zika virus epidemic in Colombia. Phylogenetic reconstructions suggest persistent circulation within Thailand since at least 2002.

Interpretation: Our evidence shows that Zika virus has circulated at a low but sustained level for at least 16 years, suggesting that Zika virus can adapt to persistent endemic transmission. Health systems need to adapt to cope with regular occurrences of the severe complications associated with infection.

Funding: European Research Council, National Science Foundation, and National Institutes of Health.
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http://dx.doi.org/10.1016/S1473-3099(18)30718-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511259PMC
April 2019

Characterization of a G10P[14] rotavirus strain from a diarrheic child in Thailand: Evidence for bovine-to-human zoonotic transmission.

Infect Genet Evol 2018 09 15;63:43-57. Epub 2018 May 15.

Department of Virology and Parasitology, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan.

An unusual rotavirus strain, DB2015-066 with the G10P[14] genotype (RVA/Human-wt/THA/DB2015-066/2015/G10P[14]), was detected in a stool sample from a child hospitalized with acute gastroenteritis in Thailand. Here, we sequenced and characterized the full-genome of the strain DB2015-066. On whole genomic analysis, strain DB2015-066 was shown to have a unique genotype constellation: G10-P[14]-I2-R2-C2-M2-A3-N2-T6-E2-H3. The backbone genes of this strain (I2-R2-C2-M2-A3-N2-T6-E2-H3) are commonly found in rotavirus strains from artiodactyls such as cattle. Furthermore, phylogenetic analysis indicated that each of the 11 genes of strain DB2015-066 could be of artiodactyl (likely bovine) origin. Thus, strain DB2015-066 appeared to be derived from through zoonotic transmission of a bovine rotavirus strain. Of note, the VP7 gene of strain DB2015-066 was located in G10 lineage-6 together with ones of bovine and bovine-like rotavirus strains, away from the clusters comprising other G10P[14] strains in G10 lineage-2/4/5/9, suggesting the occurrence of independent bovine-to-human interspecies transmission events. Our observations provide important insights into the origins of rare G10P[14] strains, and into dynamic interactions between artiodactyl and human rotavirus strains.
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http://dx.doi.org/10.1016/j.meegid.2018.05.009DOI Listing
September 2018

The dynamics of norovirus genotypes and genetic analysis of a novel recombinant GII.P12-GII.3 among infants and children in Bangkok, Thailand between 2014 and 2016.

Infect Genet Evol 2018 06 20;60:133-139. Epub 2018 Feb 20.

Thailand-Japan Research Collaboration Center on Emerging and Re-emerging Infections (RCC-ERI), Nonthaburi 11000, Thailand; Research Institute of Microbial Diseases, Osaka University, Suita, Osaka 565-0781, Japan; Osaka Institute of Public Health, Osaka 537-0025, Japan. Electronic address:

Norovirus (NoV) is the leading cause of viral acute gastroenteritis among all age groups in the world. We performed a molecular epidemiological study of the NoVs prevalent in Bangkok between November 2014 and July 2016 to investigate the emergence of new NoV variants in Thailand. A total of 332 stool specimens were collected from hospitalized pediatric patients with acute gastroenteritis in Bangkok, Thailand. NoVs were detected by real-time PCR. The genome of the N-terminal/shell domain was amplified, the nucleotide sequence was determined, and phylogenetic analyses were performed. GII NoV was detected in 58 (17.5%) of the 332 specimens. GII.17, a genotype strain prevalent from 2014 to mid-2015, was hardly detected and replaced by the GII.3 genotype strain. Entire genome sequencing followed by phylogenetic analysis of the GII.3 genotype strains indicated that they are new recombinant viruses, because the genome encoding ORF1 is derived from a GII.12 genotype strain, whereas that encoding ORF2-3 is from a GII.3 genotype strain. The putative recombination breakpoints with the highest statistical significance were located around the border of 3D and ORF2. The change in the prevalent strain of NoV seems to be linked to the emergence of new forms of recombinant viruses. These findings suggested that the swapping of the structural and non-structural proteins of NoV is a common mechanism by which new epidemic variants are generated in nature.
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http://dx.doi.org/10.1016/j.meegid.2018.02.028DOI Listing
June 2018

An Outbreak of Acute Hepatitis Caused by Genotype IB Hepatitis A Viruses Contaminating the Water Supply in Thailand.

Intervirology 2016 17;59(4):197-203. Epub 2017 Feb 17.

National Institute of Health, Ministry of Public Health, Nonthaburi, Thailand.

Background: In 2000, an outbreak of acute hepatitis A was reported in a province adjacent to Bangkok, Thailand.

Aims: To investigate the cause of the 2000 hepatitis A outbreaks in Thailand using molecular epidemiological analysis.

Methods: Serum and stool specimens were collected from patients who were clinically diagnosed with acute viral hepatitis. Water samples from drinking water and deep-drilled wells were also collected. These specimens were subjected to polymerase chain reaction (PCR) amplification and sequencing of the VP1/2A region of the hepatitis A virus (HAV) genome. The entire genome sequence of one of the fecal specimens was determined and phylogenetically analyzed with those of known HAV sequences.

Results And Conclusions: Eleven of 24 fecal specimens collected from acute viral hepatitis patients were positive as determined by semi- nested reverse transcription PCR targeting the VP1/2A region of HAV. The nucleotide sequence of these samples had an identical genotype IB sequence, suggesting that the same causative agent was present. The complete nucleotide sequence derived from one of the samples indicated that the Thai genotype IB strain should be classified in a unique phylogenetic cluster. The analysis using an adjusted odds ratio showed that the consumption of groundwater was the most likely risk factor associated with the disease.
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http://dx.doi.org/10.1159/000455856DOI Listing
April 2017

BCAP 31 expression and promoter demethylation in psoriasis.

Asian Pac J Allergy Immunol 2017 Jun;35(2):86-90

Center of Excellence in Immunology and Immune Mediated Diseases, Division of Immunology, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Background: Psoriasis is the disease of abnormal keratinocyte differentiation and apoptosis. Alterations in DNA methylation leading to keratinocyte hyperproliferation is one of the proposed pathogenic mechanisms of psoriasis. B-cell receptor associated protein (BCAP31) has been reported to be involved in the proliferation and apoptosis of keratinocytes. Up-regulation and changing in BCAP31 promoter methylation has been reported to be associated with some cancers. To date, there has been no study of psoriasis.

Objective: We investigated BCAP31 protein expression and the status of BCAP31 promoter methylation in psoriasis.

Methods: Ten patients with psoriasis and 10 healthy subjects were enrolled. The immunohistochemistry was performed on paraffin-embedded tissue section to detect BCAP31 protein expression and compared between psoriasis and normal skin. The laser capture micro-dissected keratinocyte were analyzed using bisulfite PCR method and cloning and sequencing.

Results: Increased BCAP31 protein expression was observed in psoriatic epidermis compared with normal epidermis. Interestingly the methylation level of the BCAP31 promoter was significantly lower in patients with psoriasis compared with healthy subjects (p < 0.001, % psoriasis vs. normal skin methylation = 14.94 vs. 60.61).

Conclusion: The present study demonstrated increase expression of BCAP31 protein related to BCAP31 DNA demethylation in psoriasis. Future study is needed to indicate the mechanism of BCAP31 promoter demethylation and its potential use as a novel treatment for psoriasis in the future.
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http://dx.doi.org/10.12932/AP0818DOI Listing
June 2017

Patterns and functional roles of LINE-1 and Alu methylation in the keratinocyte from patients with psoriasis vulgaris.

J Hum Genet 2015 Jul 2;60(7):349-55. Epub 2015 Apr 2.

Center of Excellence in Immunology and Immune Mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.

Alterations in LINE-1 methylation are related to many diseases. The levels and patterns of LINE-1 hypomethylation were associated with a higher risk in developing several cancers, having a poorer prognosis and more aggressiveness. To evaluate the LINE-methylated status in psoriasis, LINE-1 methylation in various cells from patients with psoriasis, squamous cell carcinoma and normal controls were assessed by combined bisulfite restriction analysis of LINE-1. The results of the epigenetic changes for intragenic LINE-1 gene expression were also tested on two known expression microarrays. In patients with psoriasis, hypomethylation of LINE-1 and increase in %(u)C(u)C were prominent in the keratinocytes when compared with normal controls (P=0.014 and P=0.020, respectively). Alternatively, %(u)C(m)C was significantly lower in patients with severe psoriasis compared with mild psoriasis (P=0.022). The receiver-operating characteristic curve analysis indicated the high specificity and sensitivity of (u)C(u)C and (u)C(m)C in detecting psoriasis and severity of psoriasis. From expression array analysis, genes with LINE-1 were downregulated more than those genes without LINE-1 (P=3.84 × 10(-27) and P=2.14 × 10(-21), respectively). Modification in LINE-1 methylation may alter the gene expression resulting in a phenotypic change of the psoriatic skin. %(u)C(u)C and %(u)C(m)C may be used as biomarkers for psoriasis.
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http://dx.doi.org/10.1038/jhg.2015.33DOI Listing
July 2015

Alterations in the LINE-1 methylation pattern in patients with lichen simplex chronicus.

Asian Pac J Allergy Immunol 2013 Mar;31(1):51-7

Graduate School Chulalongkorn University, Bangkok, Thailand.

Background: Long interspersed element-1 (LINE-1) and short interspersed element (Alu) retrotransposons have been identified to influence the human genome by modifications in gene expression. Variations in LINE-1 and Alu methylation have been shown to be associated with many diseases, predominantly malignancies and autoimmune diseases. Moreover, the degree and pattern of LINE-1 methylation are related to risk, prognosis and aggressiveness of several cancers. However, a similar study has not been performed in lichen simplex chronicus (LSC).

Objective: To evaluate DNA methylation status of repetitive sequences in LSC.

Results: The %mCmC of LINE-1 was significantly decreased in keratinocytes from patients with LSC (p=0.012). Moreover, the %mCuC was significantly lower in LSC than controls (p=0.029). Conversely, %uCmC was significantly higher LSC than controls (p=0.004). A receiver-operating characteristic (ROC) curve analysis demonstrated that % mCmC, % mCuC and % uCmC were highly sensitive and specific for LSC with an optimal cut-off value. There were no significant differences in Alu methylation in keratinocytes from LSC patients.

Methods: We determined the level and pattern of LINE-1 and Alu methylation in keratinocytes from patients with LSC (n=10) compared to normal controls (n=13), by the improved combined bisulfite restriction analysis of LINE-1 and Alu (COBRA-LINE-1 and Alu). COBRA-LINE-1 classifies LINE-1 loci according to the methylation patterns of two CpG dinucleotides in the 5'UTR into four categories: hypermethylated (mCmC), hypomethylated (uCuC), and two forms of partially methylated loci (uCmC and mCuC).

Conclusion: Changes in the LINE-1 pattern were revealed in the epidermis from patients with LSC. A particular LINE-1 methylation pattern is indicative of LSC and might be used as a diagnostic tool.
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March 2013

Parakeratosis in skin is associated with loss of inhibitor of differentiation 4 via promoter methylation.

Hum Pathol 2011 Dec 12;42(12):1878-87. Epub 2011 Jun 12.

National Institute of Health, Department of Medical Sciences, Nonthaburi 11000, Thailand.

Parakeratosis refers to incomplete maturation of epidermal keratinocytes, resulting in abnormal retention of nuclei in the stratum corneum. It occurs in many diseases of the skin, particularly in psoriasis. Down-regulation of inhibitor of differentiation 4 messenger RNA has been demonstrated in psoriatic skin, but the specificity and mechanism for this finding are unknown. In this study, we addressed specificity by immunohistochemical staining for inhibitor of differentiation 4 protein in skin disorders showing parakeratosis, including: psoriasis (n = 9), chronic eczema (n = 6), and squamous cell carcinoma (n = 7). In these conditions, parakeratotic keratinocytes in the upper layers of the skin lacked inhibitor of differentiation 4 protein expression, whereas keratinocytes in the lower layers were densely stained, in contrast to diffuse expression in normal skin. Because promoter hypermethylation of inhibitor of differentiation 4 has been described in several cancers, we determined the methylation pattern of the inhibitor of differentiation 4 promoter in psoriasis and compared this with squamous cell carcinoma. We found a novel methylation pattern of the inhibitor of differentiation 4 promoter in both conditions. Inhibitor of differentiation 4 promoter methylation was significantly increased in psoriasis (34.8%) and squamous cell carcinoma (21.8%), compared with normal skin (0%). Moreover, cells in the upper and lower parts of psoriatic epidermis were, respectively, hypermethylated and nonmethylated, at the inhibitor of differentiation 4 promoter. Comparable studies in several cell lines confirmed that hypermethylation of the promoter was associated with loss of inhibitor of differentiation 4 messenger RNA and protein expression. Our study demonstrates a previously unreported link between gene-specific promoter hypermethylation and abnormal cellular differentiation in several skin diseases. This mechanism might provide clues for novel therapies for skin disorders characterized by parakeratosis.
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http://dx.doi.org/10.1016/j.humpath.2011.02.005DOI Listing
December 2011

Effect of methotrexate on serum levels of IL-22 in patients with psoriasis.

Eur J Dermatol 2011 Jul-Aug;21(4):501-4

Medicine Department, Chulalongkorn University Medical Faculty, Rama 4 road, Bangkok 10330, Thailand.

Interleukin-22 (IL-22) is the effector molecule of T-helper subset 22 (Th-22) lineage that promotes keratinocyte proliferation and dermal inflammation in psoriasis. Methotrexate is widely used as a first-line treatment in moderate to severe psoriasis. Methotrexate inhibits inflammatory and cytokinetic processes via various mechanisms, but the relevance of these to psoriasis is limited and whether methotrexate is specifically able to down-regulate Th22 cytokines is unknown. To determine if methotrexate reduces IL-22 in cases of psoriasis. Nineteen patients with moderate to severe psoriasis were given methotrexate 15 mg per week for up to 12 weeks. Serum levels of IL-22 were determined by enzyme-linked immunosorbent assay (ELISA) before and after treatment. Eleven of 19 patients (57.8%) achieved a 75% PASI score reduction. IL-22 levels were significantly higher in untreated psoriasis patients (56.63 ± 60.73 pg/mL) than in controls (12.58 ± 12.59 pg/mL). Methotrexate significantly reduced serum levels of IL-22 in psoriasis patients to 5.91 ± 7.97 pg/mL (p<0.001). Moreover, there was a significant positive correlation between IL-22 levels and PASI (r=0.63, p=0.004). Methotrexate significantly reduces serum IL-22 levels in cases of psoriasis. This is a novel mechanism by which methotrexate acts in the treatment of this disease.
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http://dx.doi.org/10.1684/ejd.2011.1335DOI Listing
December 2011

A novel pathway involving melanoma differentiation associated gene-7/interleukin-24 mediates nonsteroidal anti-inflammatory drug-induced apoptosis and growth arrest of cancer cells.

Cancer Res 2006 Dec;66(24):11922-31

BIDMC Genomics Center, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.

Numerous studies show that nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in chemoprevention or treatment of cancer. Nevertheless, the mechanisms underlying these antineoplastic effects remain poorly understood. Here, we report that induction of the cancer-specific proapoptotic cytokine melanoma differentiation associated gene-7/interleukin-24 (MDA-7/IL-24) by several NSAIDs is an essential step for induction of apoptosis and G(2)-M growth arrest in cancer cells in vitro and inhibition of tumor growth in vivo. We also show that MDA-7/IL-24-dependent up-regulation of growth arrest and DNA damage inducible 45 alpha (GADD45alpha) and GADD45gamma gene expression is sufficient for cancer cell apoptosis via c-Jun NH(2)-terminal kinase (JNK) activation and growth arrest induction through inhibition of Cdc2-cyclin B checkpoint kinase. Knockdown of GADD45alpha and GADD45gamma transcription by small interfering RNA abrogates apoptosis and growth arrest induction by the NSAID treatment, blocks JNK activation, and restores Cdc2-cyclin B kinase activity. Our results establish MDA-7/IL-24 and GADD45alpha and GADD45gamma as critical mediators of apoptosis and growth arrest in response to NSAIDs in cancer cells.
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http://dx.doi.org/10.1158/0008-5472.CAN-06-2068DOI Listing
December 2006

SHP-1 promoter 2 methylation in normal epithelial tissues and demethylation in psoriasis.

J Mol Med (Berl) 2006 Feb 31;84(2):175-82. Epub 2005 Dec 31.

Inter-Department of Biomedical Sciences, Graduate School, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.

SHP-1 promoter hypermethylation has been studied in hematopoietic cells and observed only in various types of lymphoma and leukemia. This study reports a contrasting situation in normal epithelial tissues and an association with skin pathogenesis, particularly in psoriasis. We investigated several cell lines, five of them were epithelial and six were hematopoietic, white blood cells from normal, healthy donors, and normal microdissected epithelium of kidney, liver, breast, cervix, lung, prostate, bladder, and skin. Interestingly, promoter 2 hypermethylation was apparent in all epithelial cell lines and tissues. However, distinctive degrees of demethylation were noted in some skin samples. The methylation patterns of each cell line corresponded to their mRNA isoforms, in that isoforms I and II could not be detected with either promoter 1 or 2 hypermethylation, respectively. We further explored whether an enhanced degree of demethylation could be observed in various dermatopathology lesions. While the promoter 2 methylation levels of squamous cell cancers, eczemas, and normal skins were not different, a significant degree of demethylation can be observed in psoriasis (p<0.005). In addition, psoriasis displays a higher level of SHP-1 isoform II than normal skin (p<0.05). In conclusion, this study discovered an unprecedented role of SHP-1 methylation in tissue-specific expression and its alteration in a nonmalignant human disease besides the transcription inhibition in leukemia and lymphoma. Furthermore, the promoter demethylation may play an important role in skin pathogenesis by enhancing SHP-1 isoform II transcription in psoriatic skin lesions.
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http://dx.doi.org/10.1007/s00109-005-0020-6DOI Listing
February 2006

Phylogenetic analysis of hepatitis A virus in Thailand.

J Med Virol 2005 Jan;75(1):1-7

Viral Hepatitis Section, National Institute of Health, Department of Medical Sciences, Ministry of Public Health, Nonthaburi 11000, Thailand.

Human hepatitis A virus (HAV) is a major causative agent of acute hepatitis, and the isolates are categorised into four genotypes: I (GI), II (GII), III (GIII), and VII (GVII). Although viral hepatitis has been detected under a nationwide surveillance system in Thailand, the genetic variation of HAV has not yet been determined. In the present study, serum specimens were collected from acute hepatitis patients in Thailand from 1998-2002. The IgM-class antibody to HAV was detected in 156 out of 394 sera, counting as many as 39.6% of acute viral hepatitis cases. HAV RNA in the serum specimens was amplified by reverse-transcription polymerase chain reaction (RT-PCR), and a phylogenetic analysis of the putative VP1/2A junction of the genome was performed. The isolates were grouped into two genetic groups, GIA and GIB. This is the first report to identify subgenotype IB (GIB) in Thailand. The genetic segregation was closely related to the province where hepatitis A occurred and the serum specimens were collected. In addition, genetically similar strains were identified in both 1998 and 2001-2002 isolates from two close provinces in the southern part of Thailand, suggesting that a strain indigenous to the province or district has been circulating in southern Thailand.
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http://dx.doi.org/10.1002/jmv.20234DOI Listing
January 2005