Publications by authors named "Phoukham Phothirath"

10 Publications

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Genotoxicity, acute and subchronic toxicity evaluation of savory food ingredients.

Regul Toxicol Pharmacol 2017 Jul 6;87:71-87. Epub 2017 May 6.

Intertek Scientific & Regulatory Consultancy, Room 1036, Building A8, Cody Technology Park, Ively Road, Farnborough, Hampshire, GU14 0LX, UK.

The potential toxicity of two savory food ingredients produced by fermentation of enzymatically hydrolyzed corn starch (Savory Base 100 and Savory Base 200) was evaluated individually in a bacterial reverse mutation assay, an in vitro mammalian cell gene mutation assay, an acute oral study and as a mixture in a 90-day dietary study. In the bacterial reverse mutation and in vitro mammalian cell gene mutation assays, neither ingredient was mutagenic at concentrations up to 5000 μg/plate and 5000 μg/mL, respectively in the presence and absence of metabolic activation. In the acute study, the no-observed-adverse-effect level (NOAEL) for each Savory Base 100 and Savory Base 200 in male and female rats was 2000 mg/kg body weight. In the 90-day study, the hematology and clinical chemistry findings and histopathological changes noted in the liver, heart and kidneys were deemed to be of no toxicological significance, as the mean values were within the historical control range, were not dose-dependent, occurred at a similar frequency in control groups, or only occurred in the control group. Considering these findings, the NOAEL for Savory Base 100 and Savory Base 200 was 2333 and 1167 mg/kg body weight, respectively, the highest dose tested in each case.
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http://dx.doi.org/10.1016/j.yrtph.2017.05.006DOI Listing
July 2017

Safety evaluation of the human-identical milk monosaccharide sialic acid (N-acetyl-d-neuraminic acid) in Sprague-Dawley rats.

Regul Toxicol Pharmacol 2014 Nov 8;70(2):482-91. Epub 2014 Aug 8.

Glycom A/S, Diplomvej 373, DK-2800 Kongens Lyngby, Denmark.

N-Acetyl-d-neuraminic acid (Neu5Ac) is the predominant form of sialic acid (Sia) in humans, while other mammals express Sia as a mixture with N-glycolyl-d-neuraminic acid (Neu5Gc). Neu5Ac occurs in highest levels in the brain and in breast milk, and is therefore, coined a human-specific milk monosaccharide, and is thought to play an important nutritional role in the developing infant. Synthesized human-identical milk monosaccharide (HiMM) Neu5Ac is proposed for use in infant formulas to better simulate the free saccharides present in human breast milk. As part of the safety evaluation of HiMM Neu5Ac, a subchronic dietary toxicity study preceded by an in utero phase was conducted in Sprague-Dawley rats. Neu5Ac was without maternal toxicity or compound-related adverse effects on female reproduction and on the general growth and development of offspring at a maternal dietary level of up to 2%, equivalent to a dose of 1895mg/kg body weight (bw)/day. During the subchronic phase, no compound-related adverse effects were observed in first generation rats at dietary levels of up to 2% (highest level tested), corresponding to doses of 974 and 1246mg/kgbw/day in males and females, respectively. Neu5Ac also was non-genotoxic in a series of in vitro genotoxicity/mutagenicity tests. These results support the safe use of Neu5Ac both in infant formula and as a food ingredient at levels equivalent to those found naturally in human breast milk.
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http://dx.doi.org/10.1016/j.yrtph.2014.08.003DOI Listing
November 2014

Pre-clinical safety evaluation of the synthetic human milk, nature-identical, oligosaccharide 2'-O-Fucosyllactose (2'FL).

Regul Toxicol Pharmacol 2014 Feb 18;68(1):59-69. Epub 2013 Nov 18.

Nestlé Research Center, Vers-chez-les-Blanc, PO Box 44, 1000 Lausanne 26, Switzerland.

In order to match the composition of human breast milk more closely, it is now possible to supplement commercial infant formula (IF) with synthesised oligosaccharides that are chemically identical to human milk oligosaccharides. The safety data generated on a new human-identical milk oligosaccharide (HiMO), 2'-O-Fucosyllactose (2'FL), are presented. Standard in vitro genotoxicity tests were performed. To investigate the toxicological profile in a model representative of the intended target population, 2'FL was administered via gavage in a juvenile adapted sub-chronic rat study at dose levels of 0, 2000, 5000 and 6000 mg/kgbw/day. Fructooligosaccharide (FOS), currently acknowledged as safe and approved for use in IF, was used as a reference high-dose control at 6000 mg/kgbw/day. 2'FL was non-mutagenic in the in vitro assays. Oral administration up to 5000 mg/kgbw/day to rats over 90 days was not associated with any adverse effects based on clinical observations, body weight gain, food consumption, ophthalmoscopy, clinical pathology, organ weights and histopathology findings. Based on this 90-day study, a No Observed Adverse Effect Level (NOAEL) of 5000 mg/kgbw/day for both male and female rats was established for 2'FL. These findings support the safety of synthetic 2'FL for possible use in infant food.
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http://dx.doi.org/10.1016/j.yrtph.2013.11.005DOI Listing
February 2014

Pre-clinical safety assessment of the synthetic human milk, nature-identical, oligosaccharide Lacto-N-neotetraose (LNnT).

Food Chem Toxicol 2013 Dec 24;62:528-37. Epub 2013 Sep 24.

Nestlé Research Center, Vers-chez-les-Blanc, PO Box 44, 1000 Lausanne 26, Switzerland. Electronic address:

Lacto-N-neotetraose (LNnT) is a tetrasaccharide naturally occurring in human breast milk, but not in cow's milk. The safety data generated on a potential new LNnT ingredient produced by chemical synthesis is presented. Standard in vitro genotoxicity tests were performed. LNnT was also administered via gavage in 14-, 28- and 90-day studies at levels corresponding to 0 (control), 1000, 2500 and 5000 mg/kg bw/day in juvenile rats. Fructooligosaccharide (FOS) currently approved for use in infant formulae was used as a reference control at one dose level of 5000 mg/kg bw/day. LNnT was non-mutagenic in in vitro assays. Oral administration up to 5000 mg/kg bw/day to rats over 90 days was not associated with any adverse effects, based on clinical observations, body weight gain, feed consumption, clinical pathology, organ weights and histopathology findings. Regarding gastrointestinal effects, LNnT was better tolerated than FOS during the first 2 weeks of treatment. A No Observed Adverse Effect Level (NOAEL) of 5000 mg/kg bw/day for both male and female rats was identified for LNnT when administered by gavage for 90 days. These findings in the juvenile rat support the safety of LNnT for possible use in infant foods and allow further investigation in clinical studies.
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http://dx.doi.org/10.1016/j.fct.2013.09.018DOI Listing
December 2013

Monitoring immune modulation by nutrition in the general population: identifying and substantiating effects on human health.

Br J Nutr 2013 Aug;110 Suppl 2:S1-30

Unilever R&D, 3130 AC, Vlaardingen, The Netherlands.

Optimal functioning of the immune system is crucial to human health, and nutrition is one of the major exogenous factors modulating different aspects of immune function. Currently, no single marker is available to predict the effect of a dietary intervention on different aspects of immune function. To provide further guidance on the assessment and interpretation of the modulation of immune functions due to nutrition in the general population, International Life Sciences Institute Europe commissioned a group of experts from academia, government and the food industry to prepare a guidance document. A draft of this paper was refined at a workshop involving additional experts. First, the expert group defined criteria to evaluate the usefulness of immune function markers. Over seventy-five markers were scored within the context of three distinct immune system functions: defence against pathogens; avoidance or mitigation of allergy; control of low-grade (metabolic) inflammation. The most useful markers were subsequently classified depending on whether they by themselves signify clinical relevance and/or involvement of immune function. Next, five theoretical scenarios were drafted describing potential changes in the values of markers compared with a relevant reference range. Finally, all elements were combined, providing a framework to aid the design and interpretation of studies assessing the effects of nutrition on immune function. This stepwise approach offers a clear rationale for selecting markers for future trials and provides a framework for the interpretation of outcomes. A similar stepwise approach may also be useful to rationalise the selection and interpretation of markers for other physiological processes critical to the maintenance of health and well-being.
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http://dx.doi.org/10.1017/S0007114513001505DOI Listing
August 2013

1,25-Dihydroxyvitamin D3-glycoside of herbal origin exhibits delayed release pharmacokinetics when compared to its synthetic counterpart.

J Steroid Biochem Mol Biol 2013 Jul 26;136:333-6. Epub 2012 Sep 26.

Herbonis AG, Gellertstrasse 33, CH-4001 Basel, Switzerland.

Vitamin D requires two metabolic steps to become biologically active. In a first step 25-hydroxyvitamin D3 is formed, which acts as storage form. After a tightly controlled step in kidney the active metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is formed. Because kidney is the relevant metabolic organ for this conversion, 1,25(OH)2D3 needs to be supplemented in patients with kidney malfunction or kidney failure. Synthetic 1,25(OH)2D3 (calcitriol) has been available as a drug for decades. Due to its high potency and its kinetic profile (fast absorption and rapid elimination) its therapeutic windows has proven to be relatively narrow. A natural form of the active metabolite was identified in a few plants, such as Solanum glaucophyllum (SG) and suggested as alternative for animal and human health. An extract of a SG variety bred for high and uniform level of glycosylated 1,25(OH)2D3 was chemically characterized. Among the typical pharmaceutically inactive plant components (carbohydrates 54.3%, protein 24.9%, minerals 17.1% and water 4.1%) high levels of 1,25(OH)2D3 and a unique flavonoid content was found (1.11mg total quercetin/g extract) consisting exclusively of the quercetin glycosides hyperoside, isoquercetin, rutin and apinosylrutin. The molecular distribution of glycosyl moieties in 1,25(OH)2D3 extracted from SG as determined by gel permeation chromatography was found to be 1-10 hexose units per aglycone. 1,25(OH)2D3-1-β-glucopyranoside was identified in the SG extract, while a di- and triglycoside have been identified in SG by other groups. The pharmacokinetic properties of synthetic 1,25(OH)2D3 and glycosylated 1,25(OH)2D3 extracted from SG were compared in male rats. When compared to synthetic 1,25(OH)2D3, SG-derived 1,25(OH)2D3 exhibited delayed absorption and elimination characteristics, resulting in delayed Tmax (6-12h vs. 1h) and increased T½ (approximately 30h vs. 23h). This putative modified release pattern may be attributed to the glycosylation of herbal 1,25(OH)2D3 because de-glycosylation by ubiquitous intestinal enzymes prior to intestinal uptake of the aglycone appears to be the rate limiting step. In effect, 1,25(OH)2D3 of herbal origin behaves like a precursor of calcitriol, resulting in a wider therapeutic window and thus better pharmacological tolerance. This article is part of a Special Issue entitled 'Vitamin D Workshop.'.
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http://dx.doi.org/10.1016/j.jsbmb.2012.09.016DOI Listing
July 2013

Safety assessment of probiotics for human use.

Gut Microbes 2010 May-Jun;1(3):164-85. Epub 2010 Mar 4.

Dairy and Food Culture Technologies, Centennial, CO, USA.

The safety of probiotics is tied to their intended use, which includes consideration of potential vulnerability of the consumer or patient, dose and duration of consumption, and both the manner and frequency of administration. Unique to probiotics is that they are alive when administered, and unlike other food or drug ingredients, possess the potential for infectivity or in situ toxin production. Since numerous types of microbes are used as probiotics, safety is also intricately tied to the nature of the specific microbe being used. The presence of transferable antibiotic resistance genes, which comprises a theoretical risk of transfer to a less innocuous member of the gut microbial community, must also be considered. Genetic stability of the probiotic over time, deleterious metabolic activities, and the potential for pathogenicity or toxicogenicity must be assessed depending on the characteristics of the genus and species of the microbe being used. Immunological effects must be considered, especially in certain vulnerable populations, including infants with undeveloped immune function. A few reports about negative probiotic effects have surfaced, the significance of which would be better understood with more complete understanding of the mechanisms of probiotic interaction with the host and colonizing microbes. Use of readily available and low cost genomic sequencing technologies to assure the absence of genes of concern is advisable for candidate probiotic strains. The field of probiotic safety is characterized by the scarcity of studies specifically designed to assess safety contrasted with the long history of safe use of many of these microbes in foods.
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http://dx.doi.org/10.4161/gmic.1.3.12127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3023597PMC
September 2011

Evaluation of elutriation and magnetic microbead purification of canine monocytes.

Vet Immunol Immunopathol 2004 Oct;101(3-4):171-8

Immunology Department, Etablissement Français du Sang de Lyon, 1-3 Rue du Vercors, 69007 Lyon, France.

An elutriation technique was developed to obtain large quantities of pure canine monocytes. Firstly, peripheral blood mononuclear cells (PBMC) were isolated from whole blood by Ficoll gradient. Then, the PBMC were separated by an elutriation procedure. We demonstrated that these techniques allow the isolation of canine peripheral blood monocytes with a purity of 64% +/- 7.9 when labelled with anti-CD14 antibody. This purity increased to 83% +/- 2.2 after separation by magnetic anti-CD14 microbeads. The cell viability was more than 95% and apoptotic cells were less than 10%. The monocytes purified by these methods were functionally active in a mixed leukocyte reaction (MLR). A lymphocyte fraction was obtained directly only by elutriation with an average of 79.9% +/- 10.7 of CD5+, 7.9% +/- 3.5 of CD21+ and 1.78% +/- 2.53 of CD14+. Our results indicate that this elutriation procedure is a safe method to purify monocytes as well as lymphocytes, useful in MLR.
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http://dx.doi.org/10.1016/j.vetimm.2004.04.012DOI Listing
October 2004

Upstream open reading frames regulate translation of Mona/Gads adapter mRNA in the megakaryocytic lineage.

Platelets 2002 Dec;13(8):459-64

Centre de Génétique Moléculaire et Cellulaire, UMR CNRS 5534, Université Claude Bernard Lyon-1, Villeurbanne, France.

Mona, also called Gads, is a molecular adapter that plays a key role in T-cell and platelet signalling by linking the adaptors Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (Slp-76) and linker for activation of T cells (LAT) upon T-cell receptor and collagen receptor activation. Platelets express a specific form of Mona mRNA, called 1B, which is transcribed from a megakaryocyte-specific promoter. Mona 1B mRNA differ from 1A transcripts found in T cells and some myeloid cells only by the 5'UTR. We report here that 1B mRNA expressing cells do not express detectable amounts of Mona protein, in contrast to 1A expressing cells, and we show that 1B 5'UTR contains upstream open reading frames (uORFs). Mutating the corresponding uAUG restored efficient Mona translation, or that of an unrelated ORF. This suggested that Mona protein expression in 1B mRNA expressing cells is tightly controlled at the translational level. Accordingly, Mona protein was not detected in resting platelets. Strikingly, platelet activation by thrombin resulted in the rapid induction of Mona protein expression, suggesting that translation inhibition of 1B mRNA may be relieved in activated platelets.
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http://dx.doi.org/10.1080/0953710021000059431DOI Listing
December 2002

Generation of monocyte-derived dendritic cells in patients with hereditary hemochromatosis.

Clin Immunol 2002 Oct;105(1):93-103

Laboratoire d'Immunologie Cellulaire, Etablissement Français du Sang Rhône-Alpes, 69007 Lyon, France.

Hereditary hemochromatosis (HH) is a common genetic disease with autosomal recessive transmission and is characterized by a dysregulation of iron metabolism, leading to serum iron overload and its progressive accumulation in most body tissues. The effects of HH on the immune system include altered lymphocytosis and functions of monocytes. Moreover, monocytes can differentiate into dendritic cells (DCs), which play crucial roles in the immune response (capture, processing, and presentation of antigen to effector T cells) and this process was shown to be impaired in several pathologies. The aim of this study was to determine whether the monocytes from HH patients still displayed the ability to differentiate into DCs. To that purpose, purified monocytes from healthy donors and HH patients were cultured in the appropriate medium. The results showed no phenotypic and functional differences, at both the immature and the mature stages. Furthermore, our work reports altered lymphocytosis with expanded CD8+CD28- T cell subset. These monocyte-derived DCs could therefore be a solid vector for DC-based immunotherapy and a powerful tool for investigating the immune regulatory loops and especially the biological relevance of the expanded CD8+CD28- T cells since this population has also been described as suppressor T cells.
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http://dx.doi.org/10.1006/clim.2002.5276DOI Listing
October 2002