• 약학회지
• /
• 제52권5호
• /
• pp.331-344
• /
• 2008

Recently, the FDA (Food and Drug Administration) of the United States and many advanced countries remark biomarkers and surrogate endpoints as a critical path tool on model based drug development. Economic, technical and social profit on model based drug development like a reduction of the length of research and development have been achieved. Therefore we summarize previous studies about biomarkers and surrogate endpoints and suggest a development direction of therapeutic agents. In diabetes mellitus (DM) and osteoporosis, there are remarkable increases in number of patients and most of patients take medicine during their whole lifetime. For this reason, many patients with DM and osteoporosis have a tolerance on their medicine. We expect that research and development on biomarkers and surrogate endpoints will contribute to new drug development on DM and osteoporosis. Biomarkers for DM are blood levels of glucose, insulin, ${HbA}_{1c}$, CRP, alpha-glucosidase, adiponectin and DPP-4. Among these, validated surrogate endpoints for DM are blood levels of glucose, insulin and ${HbA}_{1c}$ Biomarkers for osteoporosis are BMD, BMC, trabecular volume, ICTP, DPD, osteocalcin, the activity of osteoclast and production of osteoblast. The validated surrogate endpoints for osteoporosis are BMD only. This review summarizes all suggested biomarkers and surrogate endpoints in DM and osteoporosis. The biomarkers are classified by drugs, and the method of validation for surrogate endpoints is suggested. This information would contribute to suggest a direction of DM and osteoporosis therapeutic agent development.

• Mass Spectrometry Letters
• /
• 제6권4호
• /
• pp.116-119
• /
• 2015

Globotriaosylsphingosine (lyso-Gb3) is considered as one of the biological marker for Fabry disease. To date, a reliable biomarker that reflects disease severity and progression has not been discovered to guide the management of Fabry disease. A new method included a simple protein precipitation with acetonitrile in 100 μL of plasma following analyte separation on an Phenomenex Kintex- C18 column using a gradient elution (0.1% formic acid in 5-90% acetonitrile). Total run time was within 12 min including sample preparation and MS/MS analysis. The limit of detection and limit of quantitation were 1 ng/mL and 2 ng/mL, respectively. The calibration curve was linear over the concentration range of 2.0-200.0 ng/mL (r² = 0.9999). Inter-day accuracy and precision at 7 level were 93.4-100.7% with RSD of 0.55-5.97%. Absolute recovery was 97.6-98.6%. The method was applied to human and mice plasma, proved the suitability for quantification of lyso-Gb3 for screening, diagnosis and therapeutic monitoring of Fabry disease patients.

• 한국전문물리치료학회지
• /
• 제22권3호
• /
• pp.98-105
• /
• 2015

Muscular dystrophy is a hereditary musculoskeletal disorder caused by a mutation in the dystrophin gene. Duchenne muscular dystrophy (DMD) is one of the most common, and progresses relatively faster than other muscular dystrophies. It is characterized by progressive myofiber degeneration, muscle weakness and ultimately ambulatory loss. Since it is an X-linked recessive inheritance, DMD is mostly expressed in males and rarely expressed or less severe in females. The most effective measurement tool for DMD is magnetic resonance imaging (MRI), which allows non-invasive examination of longitudinal measurement. It can detect progressive decline of skeletal muscle size by measuring a maximal cross-sectional area of skeletal muscle. Additionally, other techniques in MRI, like $T_2$-weighted imaging, assess muscle damage, including inflammation, by detecting changes in $T_2$ relaxation time. Current MRI techniques even allow quantification of metabolic differences between affected and non-affected muscles in DMD. There is no current cure, but physical therapist can improve their quality of life by maintaining muscle strength and function, especially if treatment (and other forms of medical intervention) begins in the early stages of the disease.

• Molecular & Cellular Toxicology
• /
• 제4권4호
• /
• pp.293-299
• /
• 2008

To screen the differentially expressed genes in cadmuim-exposed marine medaka fish (Oryzias javanicus), a candidate marine test fish for ecological toxicity, the differential display polymerase chain reaction (DD-PCR) was carried out, since the genome-wide gene expression data are not available in this fish species yet. A total of 35 clones were isolated from cadmium-exposed fish and their nucleotide sequences were analyzed. The differentially expressed gene candidates were categorized to response to stimulus (3); ion binding (3); DNA binding (1); protein binding (6); carbohydrate binding (1); metabolic process (4); biological regulation (3); cellular process (2); protein synthesis (2); catalytic activity (2); sense of sight (1); immune (1); neurohormone (1); signaling activity (1); electron carrier activity (1) and others (3). For real-time quantitative RT-PCR, we selected catalase, glucose-6-phosphate dehydrogenase, heat shock protein 70, and metallothionein and confirmed that cadmium exposure enhanced induction of these four genes.

• Toxicological Research
• /
• 제27권4호
• /
• pp.191-203
• /
• 2011

There has been growing concern about the toxicity of phthalate esters. Phthalate esters are being used widely for the production of perfume, nail varnish, hairsprays and other personal/cosmetic uses. Recently, exposure to phthalates has been assessed by analyzing urine for their metabolites. The parent phthalate is rapidly metabolized to its monoester (the active metabolite) and also glucuronidated, then excreted. The objective of this study is to evaluate the toxicity of phthalic acid (PA), which is the final common metabolic form of phthalic acid esters (PAEs). The individual PA isomers are extensively employed in the synthesis of synthetic agents, for example isophthalic acid (IPA), and terephthalic acid (TPA), which have very broad applications in the preparation of phthalate ester plasticizers and components of polyester fiber, film and fabricated items. There is a broad potential for exposure by industrial workers during the manufacturing process and by the general public (via vehicle exhausts, consumer products, etc). This review suggests that PA shows in vitro and in vivo toxicity (mutagenicity, developmental toxicity, reproductive toxicity, etc.). In addition, PA seems to be a useful biomarker for multiple exposure to PAEs in humans.

• Journal of Nutrition and Health
• /
• 제52권2호
• /
• pp.206-216
• /
• 2019

본 연구는 당뇨병 환자들의 소득수준에 따라 대사위험지표 관리수준을 비교하고, 최근 관리 추이를 관찰하여 궁극적으로 당뇨병 환자들의 합병증 예방 관련 전략을 마련할 수 있는 기초자료를 마련하기 위하여 1998 ~ 2014년 국민건강영양조사 자료를 분석하였다. 국민건강영양조사에 참여한 조사대상자 중 당뇨병 환자이면서 본인의 질환을 인지하고 있는 대상자들을 추출하였고, 가구소득정보를 이용하여 세 그룹으로 분류하여 분석하였다. 당뇨병 환자들의 기본정보, 생활습관정보, 영양소 섭취 정보, 혈액지표 등은 건강설문조사, 영양조사, 검진조사를 통해 수집되었다. 자료 분석은 변수 특성에 따라 카이검정, 일원분산분석 등을 실시하였고, 다중선형회귀분석을 이용하여 혈압 및 혈액지표의 보정평균을 산출하였다. 당뇨환자들의 공복혈당, HbA1c 및 혈중지질 농도의 평균은 소득수준에 따라 유의적인 차이를 보이지 않았다. 조사기간인 1998년부터 2014년간의 16년 동안 대사위험지표 변화 추이를 살펴본 결과, 모든 그룹에서 혈압의 유의미한 감소 추세를 보였다 (p < 0.001). 소득이 가장 높은 그룹에서는 공복혈당 (p = 0.004), 총 콜레스테롤 (p < 0.001), LDL-콜레스테롤 농도 (p = 0.01)가 유의하게 감소하는 추이를 보였고, HDL-콜레스테롤 농도 (p < 0.001)는 유의하게 증가하는 추이를 보였다. 저소득층에서는 공복혈당 (p = 0.02), 총 콜레스테롤 (p < 0.001), 중성지방 농도 (p = 0.003)가 시간 경과에 따라 유의적으로 감소하는 경향을 보였다. 그러나 중간소득층에서는 혈압을 제외한 모든 대사 위험 인자에 유의적인 변화 추이가 발견되지 않았다. 결론적으로 당뇨병 환자의 소득수준에 따른 대사 위험 인자의 관리수준에는 차이가 없었다. 최근 16년의 관찰 기간 동안 소득이 가장 높은 그룹과 가장 낮은 그룹은 대사 위험 인자의 유의미한 개선 추이를 보였으나, 중간소득 그룹은 변화가 관찰되지 않았다. 본 연구는 당뇨병 환자들의 지표 관리에 대한 전략 마련과 효과적인 보건대책을 위한 기초자료로서 중요한 의미가 있다고 사료된다.

• 한국식품위생안전성학회지
• /
• 제29권2호
• /
• pp.85-91
• /
• 2014

Deoxynivalenol (DON) and related trichothecene mycotoxins are extensively distributed in the cereal-based food and feed stuffs worldwide. Recent climate changes and global grain trade increased chance of exposure to more DON and related toxic metabolites in poorly managed production systems. Monitoring the biological and environmental exposures to the toxins are crucial in protecting human and animals from toxicities of the hazardous contaminants in food or feeds. Exposure biomarkers including urine DON itself are prone to shift to less harmful metabolites by intestinal microbiota and liver metabolic enzymes. De-epoxyfication of DON by gut microbes such as Eubacterium strain BBSH 797 and Eubacterium sp. DSM 11798 leads to more fecal secretion of DOM-1. By contrast, most of plant-derived DON-glucoside is also easily catabolized to free DON by gut microbes, which produces more burden to body. Phase 2 hepatic metabolism also contributes to the glucuronidation of DON, which can be useful urine biomarkers. However, chemical modification could be very typical depending on the anthropologic or genetic background, luminal bacteria, and hepatic metabolic enzyme susceptibility to the toxins in the diet. After toxin exposure, effect biomarkers are also important in estimating the linkage and mechanisms of foodborne diseases in human and animal population. Most prominent adverse effects are demonstrated in the DON-induced immunological and behavioral disorders. For instance, acutely elevated interleukin-8 from insulted gut exposed to dietaty DON is a dominant clinical biomarker in human and animals. Moreover, subchronic exposure to the toxins is associated with high levels of serum IgA, a biological mediator of IgA nephritis. In particular, anorexia monitoring using mouse models are recently developed to monitor the biological activities of DON-induced feed refusal. It is also mechanistically linked to alteration of serotoin and peptide YY, which are promising biomarkers of neurological disorders by the toxins. As animal-alternative biomonitoring, huamn enterocyte-based assay has been developed and more realistic gut mimetic models would be useful in monitoring the effect biomarkers in resposne to toxic contaminants in the future investigations.

• 농업과학연구
• /
• 제45권3호
• /
• pp.447-454
• /
• 2018

Zearalenone (ZEN), a mycotoxin produced by Fusarium in food and feed, causes serious damage to the health of humans and livestock. Therefore, we compared the metabolomic profiles in the liver, serum, and urine of piglets fed a ZEN-contaminated diet using proton nuclear magnetic resonance ($^1H-NMR$) spectroscopy. The spectra from the three different samples, treated with ZEN concentrations of 0.8 mg/kg for 4 weeks, were aligned and identified using MATLAB. The aligned data were subjected to discriminating analysis using multivariate statistical analysis and a web server for metabolite set enrichment analysis. The ZEN-exposed groups were almost separated in the three different samples. Metabolic analysis showed that 28, 29, and 20 metabolites were profiled in the liver, serum, and urine, respectively. The discriminating analysis showed that the alanine, arginine, choline, and glucose concentrations were increased in the liver. Phenylalanine and tyrosine metabolites showed high concentrations in serum, whereas valine showed a low concentration. In addition, the formate levels were increased in the ZEN-treated urine. For the integrated analysis, glucose, lactate, taurine, glycine, alanine, glutamate, glutamine, and creatine from orthogonal partial least squares discriminant analysis (OPLS-DA) were potential compounds for the discriminating analysis. In conclusion, our findings suggest that potential biomarker compounds can provide a better understanding on how ZEN contaminated feed in swine affects the liver, serum, and urine.

• 한국연초학회지
• /
• 제37권1호
• /
• pp.18-24
• /
• 2015

Urinary mutagenicity is widely recognized as a useful biomarker for the assessment of mutagen exposure level in human. In this study, we optimized the several parameters affecting the activity of Urinary mutagenicity using highly sensitive mutation test(microsuspension assay) instead of the conventional Ames test. First of all, we chose YG1024 as a highly sensitive strain from three str ains of Salmonella typhimurium(TA98, TA100, YG1024) using r epr esentative mutation substances, such as Benzo[a]pyrene, 2-Aminonaphthalene, 2-amino-3-methyl-9H-pyrido[2,3-b]indole($MeA{\alpha}C$) and cigarette total particulate matter(TPM). And we established the several kinds of test conditions such as number of bacter ia, concentr ation of metabolic activation system and incubation time for the most sensitive reaction. Also, we optimized efficient pre-treatment method using commercial C18 column. As a r esults, this method was shown a aver age of 94 % recovery value and 13 % relative standard deviation. When we compared the Urinary mutagenicity between several participants, we confirmed that compar ative measurements were possible for different levels of urine mutagenicity. In conclusion, the optimized highly sensitive mutation test to measure the Urinary mutagenicity may be useful in biological monitoring of mutagen exposure level.

• Asian Pacific Journal of Cancer Prevention
• /
• 제17권3호
• /
• pp.1163-1168
• /
• 2016

Cholangiocarcinoma (CCA) is the bile duct cancer which constitutes one of the important public health problems in Thailand with high mortality rate, especially in the Opisthorchis viverrini (a parasite risk factor for CCA) endemic area of the northeastern region of the country. This study aimed to identify potential biomarkers from the plasma peptidome by CCA patients. Peptides were isolated using 10 kDa cut-off filter column and the flow-through was then used as a peptidome for LC-MS/MS analysis. A total of 209 peptides were obtained. Among these, 15 peptides were concerned with signaling pathways and 12 related to metabolic, regulatory, and biosynthesis of secondary metabolite pathways. Five exclusive peptides were identified as potential biomarkers, i.e. ETS domain-containing transcription factor ERF (P50548), KIAA0220 (Q92617), phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform 1 (P42338), LP2209 (Q6XYC0), and casein kinase II subunit alpha (P19784). Three of these biomarkers are signaling related molecules. A combination of these biomarkers for CCA diagnosis is proposed.