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REFERENCE LINKING PLATFORM OF KOREA S&T JOURNALS
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Biomolecules and Therapeutics
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Journal DOI :
The Korean Society of Applied Pharmacology
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Volume & Issues
Volume 18, Issue 4 - Oct 2010
Volume 18, Issue 3 - Jul 2010
Volume 18, Issue 2 - Apr 2010
Volume 18, Issue 1 - Jan 2010
Selecting the target year
DNA Vaccines against Infectious Diseases and Cancer
Han, Duk-Jae ; Weiner, David B. ; Sin, Jeong-Im ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 1~15
DOI : 10.4062/biomolther.2010.18.1.001
Progress in the development of DNA vaccines and their delivery strategies has been made since their initial concept as a next generation vaccine. Since DNA vaccine includes non-infectious DNA parts of pathogens, it can`t cause disease yet it closely mimic the natural process of infection and immune responses. Despite their early promising results of controlling infectious diseases and cancer in small animal models, DNA vaccines failed to display a level of immunogenicity required for combating these diseases in humans, possibly due to their lower protein expression levels. However, increasing evidence has shown that DNA vaccines are clinically well-tolerated and safe. Furthermore, one notable advantage of DNA vaccines includes convenient utilities of plasmid DNAs coding for antigens. For instance, any emerging pathogens could be prevented easily and timely by allowing the simple exchange of antigen-encoding genes. In this review, newly developed DNA vaccine strategies, including electroporation, which has emerged as a potent method for DNA delivery, targeting infectious diseases and cancer will be discussed with a focus on any on-going DNA vaccine trials or progress made pre-clinically and in clinics.
15-Hydroxyprostaglandin Dehydrogenase Is Associated with the Troglitazone-Induced Promotion of Adipocyte Differentiation in Human Bone Marrow Mesenchymal Stem Cells
Noh, Min-Soo ; Lee, Soo-Hwan ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 16~23
DOI : 10.4062/biomolther.2010.18.1.016
Adipocyte differentiation in human bone marrow mesenchymal stem cells (hBM-MSCs) is not as efficient as that in murine pre-adipocytes when induced by adipogenic agents including insulin, dexamethasone, and 3-isobutyl-1-methylxanthine (IDX condition). Therefore, the promotion of adipocyte differentiation in hBM-MSCs has been used as a cell culture model to evaluate insulin sensitivity for anti-diabetic drugs. In hBM-MSCs,
agonists or sulfonylurea anti-diabetic drugs have been added to IDX conditions to promote adipocyte differentiation. Here we show that troglitazone, a peroxisome proliferator-activated receptor-gamma (
) agonist, significantly reduced the levels of anti-adipogenic
in IDX-conditioned hBM-MSC culture supernatants when compared to
levels in the absence of
agonist. However, there was no difference in the mRNA levels of cyclooxygenases (COXs) and the activities of COXs and prostaglandin synthases during adipocyte differentiation in hBM-MSCs with or without troglitazone. In hBM-MSCs, troglitazone significantly increased the mRNA level of 15-hydroxyprostaglandin dehydrogenase (HPGD) which can act to decrease
levels in culture. These results suggest that the role of
activation in promoting adipocyte differentiation in hBM-MSCs is to reduce anti-adipogenic
levels through the up-regulation of HPGD expression.
Neuroprotective Effect of Taurine against Oxidative Stress-Induced Damages in Neuronal Cells
Yeon, Jeong-Ah ; Kim, Sung-Jin ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 24~31
DOI : 10.4062/biomolther.2010.18.1.024
Taurine, 2-aminoethanesulfonic acid, is an abundant free amino acid present in brain cells and exerts many important biological functions such as anti-convulsant, modulation of neuronal excitability, regulation of learning and memory, anti-aggressiveness and anti-alcoholic effects. In the present study, we investigated to explore whether taurine has any protective actions against oxidative stress-induced damages in neuronal cells. ERK I/II regulates signaling pathways involved in nitric oxide (NO) and reactive oxygen species (ROS) production and plays a role in the regulation of cell growth, and apoptosis. We have found that taurine significantly inhibited AMPA induced cortical depolarization in the Grease Gap assays using rat cortical slices. Taurine also inhibited AMPA-induced neuronal cell damage in MTT assays in the differentiated SH-SY5Y cells. When the neuronal cells were treated with
, levels of NO were increased; however, taurine pretreatment decreased the NO production induced by
to approximately normal levels. Interestingly, taurine treatment stimulated ERK I/II activity in the presence of AMPA or
, suggesting the potential role of ERK I/II in the neuroprotection of taurine. Taken together, taurine has significant neuroprotective actions against AMPA or
induced damages in neuronal cells, possibly via activation of ERK I/II.
Influence of Environmental Conditions on c-Jun N-terminal Kinase Mediated Apoptosis of HL60 Cells by Anti-Cancer Drugs
Hur, Eun-Hye ; Kang, Mun-Jung ; Kim, Sung-Doo ; Lim, Sung-Nam ; Kim, Dae-Young ; Lee, Jung-Hee ; Lee, Kyoo-Hyung ; Lee, Je-Hwan ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 32~38
DOI : 10.4062/biomolther.2010.18.1.032
Activation of JNK has long been associated with the apoptotic response induced by various anti-cancer drugs including doxorubicin, vinblastine, and etoposide. In this study, we examined and compared patterns of apoptosis and JNK activation according to three different anti-cancer drugs (daunorubicin, vinblastine, and etoposide) and two different sources of HL60 cells (Jackson Laboratory and ATCC). HL60 cells from Jackson Laboratory (HL60/RPMI) were maintained in RPMI 1640 containing 5% fetal bovine serum and those from ATCC (HL60/IMDM) in IMDM containing 20% fetal bovine serum as to each manufacture`s guideline. In general, HL60/RPMI cells were more sensitive to anti-cancer drugs compared to HL60/IMDM cells, demonstrated by the XTT and flow cytometric analyses. Apoptotic pathways after treatment with anti-cancer drugs seemed to be different between HL60/RPMI (daunorubicin and etoposide, caspase 3 dependent, but caspase 8 or 9 independent; vinblastine, caspase 3 independent) and HL60/IMDM (caspase 3 and caspase 9 dependent). The expression of apoptotic protein, BID, was consistent with caspase 3 activation. Immunoblotting of phospho-JNK and JNK kinase assay showed JNK activation by all three anti-cancer drugs in HL60/RPMI, while JNK activation was observed only in vinblastine-treated cells in HL60/IMDM. Our study results suggest that in vitro environmental conditions have a significant influence on JNK mediated apoptosis of HL60 cells by anti-cancer drugs and in vitro culture conditions are important factors in JNK or possibly other MAPK related studies.
Synergistic Increase of BDNF Release from Rat Primary Cortical Neuron by Combination of Several Medicinal Plant-Derived Compounds
Jeon, Se-Jin ; Bak, Hae-Rang ; Seo, Jung-Eun ; Kwon, Kyung-Ja ; Kang, Young-Sun ; Kim, Hee-Jin ; Cheong, Jae-Hoon ; Ryu, Jong-Hoon ; Ko, Kwang-Ho ; Shin, Chan-Young ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 39~47
DOI : 10.4062/biomolther.2010.18.1.039
Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor involved in neuronal differentiation, plasticity, survival and regeneration. BDNF draws massive attention mainly due to the potential as a therapeutic target in neurological diseases such as depression and Alzheimer`s disease. In a primary screening for the natural compounds enhancing BDNF release from cultured rat primary cortical neuron, we found that compounds such as baicalein, tanshinone IIa, cinnamic acid, epiberberine, genistein and wogonin among many others increased BDNF release. All the compounds at
of concentration barely showed stimulatory effect on BDNF induction, however, their combination (mixture 1; baicalein, tanshinone IIa and cinnamic acid, mixture 2; epiberberine, genistein and wogonin) showed synergistic increase in BDNF release as well as mRNA and protein expression. The level of BDNF expression was comparable to the maximum BDNF stimulation attainable by a positive control oroxylin A (
) without cell toxicity as determined by MTT analysis. Both mixtures synergistically increased the phosphorylation of extracellular signal-regulated kinase (ERK) as well as cAMP response element binding protein (CREB), an immediate and essential regulator of BDNF expression. Similar to these results, mixture of these compounds synergistically inhibited the up-regulation of inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide treatments in rat primary astrocytes. These results suggest that the combinatorial treatment of natural compounds in lower concentration might be a useful strategy to obtain sufficient BDNF stimulation in neurological disease condition such as depression, while minimizing potential side effects and toxicity of higher concentration of a single compound.
Inhibitory Effects of Phylligenin on the Proliferation of Cultured Rat Neural Progenitor Cells
Lee, Sung-Hoon ; Go, Hyo-Sang ; Choi, Chang-Soon ; Cheong, Jae-Hoon ; Han, Sun-Young ; Bae, Ki-Hwan ; Ko, Kwang-Ho ; Park, Seung-Hwa ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 48~55
DOI : 10.4062/biomolther.2010.18.1.048
Neural progenitor cells (NPCs) differentiate into astrocytes, neurons and oligodendrocytes, which is controlled by various factors in brain. Recent evidences suggest that small molecules modulating the proliferation and differentiation of NPCs may have therapeutic value as well as the potential use as chemical probes. Phylligenin is a lignan with anti-inflammatory activity that is isolated from the fruits of Forsythia koreana. We investigated effects of phylligenin on proliferation and differentiation of NPCs. Treatment of phylligenin decreased the number of proliferating NPCs in culture without effects on the differentiation and survival of neural cells such as neurons and astrocytes. To examine the mechanism of the decreased NPCs number, we performed cell cycle analysis. Proliferation of NPCs was decreased via G1-S transition block by phylligenin treatment, and it was mediated by the increase of p21 level. However, phylligenin did not induce apoptosis of NPCs as determined by TUNEL assay and PARP cleavage. We also found that viability of glioma cell lines such as C6 and U87MG glioma cells, but not that of primary neuron and astrocyte, was inhibited by phylligenin. These results suggest that phylligenin selectively inhibits proliferation of rapidly growing cells such as neural stem cells and glioma cells. Given that the possible role of brain tumor stem cells in the pathology of brain cancers, the inhibitory effects of phylligenin might be useful in the development of new therapeutic agents against brain cancers.
Pentoxifylline Induces Lipolysis and Apoptosis of Human Preadipocytes, Keratinocytes and Fibroblasts In Vitro
Lee, Il-Kyu ; Choi, Yun-Jung ; Shim, In-Sop ; Kim, Kyung-Soo ; Choi, Chang-Jin ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 56~64
DOI : 10.4062/biomolther.2010.18.1.056
Pentoxifylline (PTX) has been used for the local reduction of fat tissue in the clinical setting. However, its safety and efficacy have not been proven. The aim of this study was to evaluate the effects of PTX on cell lines established from fat tissue. Newly cultured human preadipocytes and adipocytes from subcutaneous abdominal fat in addition to purchased human lung fibroblasts and keratinocytes were treated with PTX at different concentrations. Cell viability was determined using the Cell counting kit (CCK)-8 assay and lipolysis was evaluated using an Elisa kit. DNA fragmentation, Western blot analysis, Hoechst and Propidium Iodide (PI) staining and fluorescence activated cell scanning analysis were performed to confirm apoptosis. The viability of adipocytes, preadipocytes, keratinocytes and fibroblasts was markedly decreased at concentrations of PTX above 20 mM. Apoptosis was induced at concentrations of PTX over 40 mM in all cell lines. Lipolysis was increased by 60% at concentrations of PTX of 20 mM compared to the control. In conclusion, the results of this study showed that 20 mM of PTX induced lipolysis. At concentrations over 20 mM, PTX reduced the viability of all cells studied including: adipocytes, preadipocytes, fibroblasts and keratinocytes, in a non-specific manner.
The Inhibitory Effect of Rivastigmine and Galantamine on Choline Transport in Brain Capillary Endothelial Cells
Lee, Na-Young ; Kang, Young-Sook ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 65~70
DOI : 10.4062/biomolther.2010.18.1.065
The blood-brain barrier (BBB) transport of acetylcholinesterase (AChE) inhibitors, donepezil and tacrine suggested to be mediated by choline transport system in our previous study. Therefore, in the present study, we investigated the interaction of other AChE inhibitors, rivastigmine and galantamine with choline transporter at the BBB. The effects of rivastigmine and galantamine on the transport of choline by conditionally immortalized rat brain capillary endothelial cell lines (TR-BBB cells) were characterized by cellular uptake study using radiolabeled choline. The uptake of [
]choline was inhibited by rivastigmine and galantamine, with
values (i.e. concentration necessary for 50% inhibition) for 1.13 and 1.15 mM, respectively. Rivastigmine inhibited the uptake of [
]choline competitively with
of 1.01 mM, but galantamine inhibited noncompetitively. In addition, the efflux of [
]choline was significantly inhibited by rivastigmine and galantamine. Our results indicated that the BBB choline transporter may be involved in a part of the influx and efflux transport of rivastigmine across the BBB. These findings should be therapeutically relevant to the treatment of Alzheimer`s disease (AD) with AChE inhibitors, and, more generally, to the BBB transport of CNS-acting cationic drugs via choline transporter.
Ethacrynic Acid and Citral Suppressed the All Trans Retinoid-Induced Monocyte Chemoattractant Protein-1 Production in Human Dermal Fibroblasts
Kim, Kwang-Mi ; Noh, Min-Soo ; Kim, Soo-Hyun ; Park, Mi-Kyung ; Lee, Hye-Ja ; Kim, Soo-Youl ; Lee, Chang-Hoon ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 71~76
DOI : 10.4062/biomolther.2010.18.1.071
Skin irritation caused by retinol and retinoic acid results in mild erythema called as retinoid dermatitis. To develop compounds modulating the retinoid dermatitis, we tried to establish the screening method for retinoid dermatitis. At first we examined the inflammatory cytokine profile in neonatal human dermal fibroblasts which are known to be one of main site of retinoid action. As a result, interleukin-8 (IL-8) and monocytes chemoattractant protein-1 (MCP-1) were significantly produced by all trans retinoic acid (ATRA) and all trans retinol (ATROL) in dermal fibroblasts. Especially the production of MCP-1 was more than that of IL-8. The production of MCP-1 by retinoid was dose-dependently increased, continuing up to 24 hrs. After then using ethacrynic acid (ECA) known to reduce mouse ear edema induced by ATRA, we checked whether ECA suppressed the production of MCP-1. As a result, ECA effectively suppressed the production of MCP-1 in the ATRA- or ATROL-treated-fibroblasts. These results suggested that screening method effectively reflects the in vivo anti-inflammatory activity of ECA. It was reported that citral inhibited the enzyme involved in the conversion of ATROL to ATRA. We showed that citral suppressed the production of MCP-1 in ATROL-treated fibroblasts. We expect these finding might be helpful to find useful compounds modulating the side effects of retinoid or retinoid dermatitis.
A Novel PPARγ Agonist, SP1818, Shows Different Coactivator Profile with Rosiglitazone
Park, Yun-Sun ; Choi, Ji-Won ; Kim, Kun-Yong ; Lim, Jong-Seok ; Yoon, Suk-Joon ; Yang, Young ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 77~82
DOI : 10.4062/biomolther.2010.18.1.077
Peroxisome proliferator-activated receptor
) is a ligand-activated transcription factor that is used as a target for anti-diabetic drug development. In a search for novel PPAR
-carboxyethyl-rhodanine derivative SP1818 was identified. We report here the characteristics of SP1818 as a selective PPAR
agonist. In transactivation assays, SP1818 selectively activated PPAR
, but the degree of PPAR
stimulation was less than with
rosiglitazone. SP1818 also stimulated glucose uptake in a concentration-dependent manner. The adipocyte differentiation markers adiponectin, scavenger receptor CD36 and aP2 were weakly induced by treatment with SP1818, and TRAP220 subunit was specifically recruited into PPAR
activated by rosiglitazone but not PPAR
activated by SP1818.
Therapeutic Effect of Whole Bear Bile and Its Components against Croton Oil-Induced Rectal Inflammation in Rats
Park, Jeong-Sook ; Yoo, Dong-Ho ; Lee, In-Jeong ; Roh, Eun-Mi-Ri ; Kim, Young-Soo ; Han, Kun ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 83~91
DOI : 10.4062/biomolther.2010.18.1.083
Bear bile has been used as a therapeutic for cerebral and coronary thrombosis, convulsion, hepatitis, jaundice, and abscess in traditional oriental medicine. In recent decades, the effects of bile acids on cancer, cholestasis, and liver injury have been investigated in many studies. In this study, we investigated the anti-inflammatory effects of whole bear bile (WBB) and its two major components, chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA), on rectal inflammation in rats. Bile acids in WBB were quantitatively analyzed by HPLC. Rectal inflammation was induced in male Sprague-Dawley rats by insertion of croton oil-saturated cotton tips. WBB, UDCA or CDCA solution was orally administered to rats one hour after induction of rectal inflammation. Rats were sacrificed 4 or 24 hours after induction of rectal inflammation. The evaluation included measurement of weight and thickness of rectum and histopathologic examination of rectal tissue. Furthermore, we examined the inhibitory effect of WBB, UDCA or CDCA against NO production in LPS-stimulated RAW 264.7 cells. The contents of UDCA and CDCA in WBB were
, respectively. WBB treatment significantly reduced the weight and thickness of rectum compared with UDCA or CDCA treatment. The inhibition of NO production by WBB, UDCA and CDCA in LPS-stimulated RAW 264.7 cells was much higher than that by the control. And, WBB treatment suppressed the induction of NO synthase in rectum homogenates. These results suggest that the anti-inflammatory effect of WBB is related to the suppression of NO synthase induction and the inhibition of NO production by UDCA, CDCA and other bile acids of WBB.
Lycopene Inhibits Proliferation, Invasion and Migration of Human Breast Cancer Cells
Koh, Min-Soo ; Hwang, Jin-Sun ; Moon, A-Ree ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 92~98
DOI : 10.4062/biomolther.2010.18.1.092
Breast cancer has been estimated as one of the most common causes of cancer death among women. The major cause of death from breast cancer is the metastatic spread of the disease from the primary tumor to distant sites in the body. Lycopene is one of the major carotenoids in fruits and vegetables including tomatoes. Epidemiological studies have shown that the dietary intake of lycopene is associated with decreased risk of cancer. Although mounting evidence shows the chemopreventive effect of lycopene, the role of lycopene in the prevention of metastatic potential of breast cancer has not been determined yet. In the present study, we investigated the inhibitory effect of lycopene on invasive and migratory phenotypes of two highly aggressive breast cancer cell lines, H-Ras-transformed MCF10A human breast epithelial cells (H-Ras MCF10A) and MDA-MB-231 human breast cancer cells. Here, we report that lycopene significantly inhibits invasion and migration as well as proliferation of H-Ras MCF10A and MDA-MB-231 cells. This study suggested an in vitro anti-cancer and anti-metastatic potential of lycopene. We also showed that activations of ERKs and Akt were inhibited by lycopene in H-Ras MCF10A cells, suggesting that the ERKs and Akt signaling pathways may be involved in lycopene-induced anti-proliferative and/or anti-invasive/migratory effects in these cells. Taken in conjunction with the fact that breast cancer metastasis is one of the most lethal malignancies in women, our findings may provide useful information for the application of lycopene in establishing strategy to prevent the metastatic breast cancer.
Relative Bioavailability of Coenzyme Q10 in Emulsion and Liposome Formulations
Choi, Chee-Ho ; Kim, Si-Hun ; Shanmugam, Srinivasan ; Baskaran, Rengarajan ; Park, Jeong-Sook ; Yong, Chul-Soon ; Choi, Han-Gon ; Yoo, Bong-Kyu ; Han, Kun ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 99~105
DOI : 10.4062/biomolther.2010.18.1.099
The purpose of this study was to evaluate relative bioavailability of the coenzyme Q10 (CoQ10) in emulsion and three liposome formulations after a single oral administration (60 mg/kg) into rats. Emulsion formulation of CoQ10 was prepared by conventional method using Phospholipon 85G as an emulsifier, and three liposome formulations (neutral, anionic, and cationic) of CoQ10 were prepared by traditional lipid film hydration technique using Phospholipon 85G, cholesterol, and charge carrier lipids (1,2-dioleoyl-3-trimethylammonium-propane chloride salt for cationic liposome and 1,2-dimyristoyl-sn-glycero-3-phosphate monosodium salt for anionic liposome). Mean particle size of all CoQ10-loaded liposome was less than a micron, and size distribution of the liposome population was homogeneous. Bioavailability of CoQ10 in emulsion was 1.5 to 2.6-fold greater than liposome formulations in terms of
was 3 h when administered as emulsion while it was greater than 6 h in liposome formulations. Notably, it was approximately 8 h in cationic liposome.
was highest in emulsion and was significantly decreased when administered as liposome. Charged liposome showed even lower
than neutral liposome, especially in cationic liposome. In conclusion, therefore, it is suggested that clinicians and patients consider bioavailability issue a primary concern when choosing a CoQ10 product, especially when very high plasma level is required such as in the treatment of heart failure and Parkinson`s disease.
Enhanced Bioavailability of Ambroxol by Transdermal Administration of the EVA Matrix Containing Penetration Enhancer in Rats
Choi, Jun-Shik ; Shin, Sang-Chul ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 106~110
DOI : 10.4062/biomolther.2010.18.1.106
The pharmacokinetics and bioavailability of ambroxol, an expectoration improver and mucolytic agent, were studied to determine the feasibility of enhanced transdermal delivery of ambroxol from the ethylene-vinyl acetate (EVA) matrix system containing polyoxyethylene-2-oleyl ether as an enhancer in rats. The ambroxol-010 matrix system (15 mg/kg) was applied to abdominal skin of rats. Blood samples were collected via the femoral artery for 28 hrs and the plasma concentrations of ambroxol were determined by HPLC. Pharmacokinetic parameters were calculated using Lagran method computer program. The area under the curve (AUC) was significantly higher in the enhancer group (
) than that in the control group
), that is treated transdermally without enhancer, showing about 151% increased bioavailability (p<0.05). The average
was increased in the enhancer group (
/ml) compared with the control group (
/ml). The absolute bioavailability was 13.9% in the transdermal control group, 21.1% in the transdermal enhancer group and 18.1% in the oral administration group compared with the IV group. The
, MRT and
of ambroxol in transdermal enhancer group were increased significantly (p<0.01) compared to those of oral administration. As the ambroxol-EVA matrix containing polyoxyethylene-2-oleyl ether and tributyl citrate was administered to rats via the transdermal routes, the relative bioavailability increased about 1.51-fold compared to the control group, showing a relatively constant, sustained blood concentration. The results of this study show that ambroxol-EVA matrix could be developed as a transdermal delivery system providing sustained plasma concentration.
14 Days Repeat Oral Dose Toxicity of Low Molecular Weight Fucoidan in Rats
Yoon, Hyun-Soo ; Shin, Yong-Kyu ; Lee, Seon-Ha ; Lee, Dong-Sub ; Jung, Young-Mi ; Lee, Hyeung-Sik ; Ku, Sae-Kwang ;
Biomolecules and Therapeutics, volume 18, issue 1, 2010, Pages 111~121
DOI : 10.4062/biomolther.2010.18.1.111
In order to investigate the preliminary repeat oral dose toxicity and to determine the highest dosage for further 4-week repeated dose toxicity test, Low Molecular Weight Fucoidan (LMF) has been showed various pharmacological effects, was orally administered to female and male rats, once a day for 14 days at dose levels of 2,000, 1,000, 500 and 0 (vehicle control) mg/kg (body weights) in a volume of 10 ml/kg. The mortality and changes on the body weights, clinical signs, hematology, serum biochemistry and gross observations were monitored with organ weight and histopathology of principle organs. As the results of 14-day repeated oral treatment of LMF, no LMF treatment related mortalities were detected up to 2,000 mg/kg in both male and female rats, respectively. In addition, no noticeable changes on the body weight and clinical signs were detected except for significant decreases on the body weights and gains restricted to male 2,000 mg/kg treated groups as compared with male vehicle control. No meaningful changes on the organ weights, hematological, serum biochemistrical, gross and histopathological findings were observed. Therefore the highest dosage in the 4-week repeated dose toxicity test is suggested as 2,000 mg/kg in both female and male rats, respectively.