• Bulletin of the Korean Chemical Society
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• v.29 no.7
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• pp.1303-1310
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• 2008

Inhibitors of farnesyltransferase (FT), a key enzyme in the post-translational modifications of Ras proteins, have been extensively studied as novel anticancer agents in the preclinical stages, some of which are currently in clinical development. Previously, it has been reported that a novel FT inhibitor LB42907 inhibits Ras farnesylation in the nanomolar range in vitro. The aim of this study was to assess the antitumor efficacy of LB42907 in vitro and in vivo. Anchorage-independent growth of various human tumor cell lines was potently inhibited by treatment with LB42907, comparable to other FT inhibitors in clinical development. In the nude mouse, oral administration of LB42907 demonstrated potent antitumor activity in several human tumor xenograft models including bladder, lung and pancreas origin. Interestingly, significant tumor regression in EJ (bladder) and A549 (lung) xenografts was induced by LB42907 treatment. The effectiveness of LB42907 was also investigated in simultaneous combination with paclitaxel, vincristine, cisplatin or gemcitabine against NCI-H460, A549, and HCT116 cells in vitro using median-effect analysis. LB42907 markedly synergized with most anticancer drugs tested in this study in NCI-H460 cell. In contrast, LB42907 displayed antagonism or partial synergism with these drugs in A549 and HCT116 cells, depending on the class of combined drugs and/ or the level of cytotoxicity. Our results demonstrate that LB42907 is an effective antitumor agent in vitro and in vivo and combination of LB42907 with other chemotherapeutic drugs results in synergistic or antagonistic effects mainly in a cell line-dependent manner. Further preclinical study is warranted.

• Childhood Kidney Diseases
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• v.4 no.2
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• pp.127-135
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• 2000

Purpose: Cyclosporine(CsA) is a potent immunosuppressant but the use of CsA is associated with various side effects, especially nephrotoxicity. In tile kidney, salt depletion activates tile renin-angiotensin-aldosteron(RAS) system and accentuates chronic CsA nephropathy. We postulate that angiotensin converting enzyme inhibitors(ACEI) can prevent chronic CsA nephropathy, since ACEI may inhibit this cascades. This study was aimed to assess the effect of ACEI on chronic cyclosporin nephropathy in salt depleted rats. Methods: 36 Fischer-344 rats were divided into 6 goups. Group I received normal salt diet(NSD). Group II received a low salt diet(LSD). Group III received CsA with a NSD. Group IV received CsA with a LSD. Group V received NSD+CsA with ACEI. Group VI received LSD+CsA with ACEI. Rats were sacrificed after six weeks and the glomerular filtration rate(GFR), serum sodium, potassium and whole blood cyclosporine levels were measured. Renal tissues me sampled for the observation of histological changes. Results: No differences in blood CsA level & serum sodium were found between groups during the course of this experiment. Serum potassium in group VI was significantly increased compared with group IV and V (P<0.05). In groups treated with CsA only and in those where CsA was combined with ACEI, GFR was found to be significantly more decreased in LSD than NSD, and GFR in group V was significantly decreased in comparison with group III (P<0.05). Renal histologic lesions associated with CsA which consisted of cortical interstitial fibrosis, tubular atrophy and hyalinization of arterioles were more severe in tile LSD group. But, no differences were observed between tile groups treated with CsA and ACEI, and the groups treated with only CsA. Conclusion: Salt depletion associated with the activation of the RAS system accentuated chronic CsA nephrotoxicity, but, ACEI could not reduce the functional and morphological changes of salt depleted kidneys, in which nephropathy can be exacerbated in spite of the blocking of the angiotensin II pathway. further studies are required to elucidate whether Am ameliorated the effect of salt-depleted CsA nephrotoxicity upon the effective renal blood flow.

• Tuberculosis and Respiratory Diseases
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• v.56 no.3
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• pp.289-296
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• 2004

Background : Mucus hypersecretion in the patients with airway diseases represents poor prognosis as well as discomfort. However, there is no known therapy for its effective control. One important component of mucus is mucin, a glycosylated protein, which endows mucus with viscosity. We studied whether a proteinase has a role in mucin secretion and if so, which. Methods : (1) Inhibition of mucin secretion Group-specific proteinase inhibitors were tested to evaluate whether a proteinase belonging to a group of proteinases plays a role in mucin secretion. Phenylmethylsulfonyl fluoride(PMSF, a serine proteinase inhibitor), E-64(a cysteine proteinase inhibitor), Pepstatin(an aspartic proteinase inhibitor) and 1, 10-Phenanthroline(a metalloproteinase inhibitor) were treated into the Calu-3 cell line for 24 hours. The enzyme linked immunoabsorbant assay(ELISA) for MUC5AC was performed to evaluate the amount of mucin secretion and to compare with a control. (2) Stimulation of mucin secretion Matrix metalloproteinase-9(MMP-9), MMP-12 and TACE(TNF-alpha converting enzyme), which are known to be related with airway diseases, were used to be treated into Calu-3 for 24 hours. ELISA for MUC5AC was performed to evaluate the amount of mucin secretion and to compare with the controls. Results : (1) PMSF($10^{-4}M$), E-64($10^{-4}M$), Pepstatin($10^{-6}M$) and 1, 10-Phenanthroline($10^{-4}M$) reduced the MUC5AC secretion by $1{\pm}4.9%$(mean${\pm}$standard deviation; P=1.0 compared with the control), $-6{\pm}3.9%$(P=0.34), $-13{\pm}9.7%$(P=0.34) and $41{\pm}8.2%$(P=0.03), respectively. (2) The amounts of MUC5AC secretion stimulated by MMP-9(250ng/ml), MMP-12(100ng/ml) and TACE(200ng/ml) were $103{\pm}6%$(P=0.39), $102{\pm}8%$(P=1.0) and $107{\pm}13%$(P=0.39), respectively, compared with the controls. Conclusion : Metalloproteinase(s) is (are) suggested to play a role in mucin secretion. It appears that metalloproteinases, other than MMP-9, MMP-12 or TACE, affect the mucin secretion in this in vitro model.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.31 no.5
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• pp.370-378
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• 2005

The purpose of this study is that evaluate the distribution and biological roles of TNF-a, interleukin-1${\beta}$(IL-1${\beta}$), interleukin-6(IL-6) and tissue inhibitors of metalloproteinase-1(TIMP-1) in the synovial fliud of patients with non-inflammatory chronic temporomandibular joint(TMJ) disorders in relation to pain during joint movements and magnetic resonance imaging(MRI) findings. TMJ synovial fluids aspirates were obtained from 36 patients (36 joints) with chronic TMJ disorders and from 8 controls(8 joints). Patients were divided to four groups. The control group was from healthy volunteers(8 joints), group I(18 joints) was patients with anterior disc displacement with reduction, group II(5 joints) was patients with disc displacement without reduction and group III (5 joints) was osteoarthritis. The TNF-${\alpha}$, IL-1${\beta}$ and IL-6 levels in the aspirates were determined by using an enzyme-linked immunosorbent assay and the TIMP-1 level was measured by an enzyme immunoassay. Following examinations for pain during joint movements and MRI observations, these cytokines' level and frequencies of detection were compared. The level of IL-1${\beta}$was not significant different in all groups. but the level of TNF-${\alpha}$, IL-6 and TIMP-1 were significant different among groups. The level of IL-6 and TIMP-1 were correlated to pain during movement(p<0.01) and the level of TNF-a(p<0.05). Also, the level of IL-6 was correlated to the level of TIMP-1(p<0.01). Especially, The level of the TIMP-1 level was significantly correlated to the pain during movement and showed very high levle of Pearson's correlation coefficient (r=0.833)(p<0.001). The results indicated that the TNF-${\alpha}$, IL-6 and TIMP-1 levels in the TMJ aspirates of patients with chronic TMJ disorders have been raised. Especially, IL-6 and TIMP-1 were very high levels in the patients who were degraded in the TMJ. Also, TNF-${\alpha}$, IL-6 and TIMP-1 showed the significant correlation in the chronic temporomandibular joint disorders. Therefore I suggest that these cytokines were also correlated to the pain during movement in the chronic temporomandibular joint disorders.

• The Korean Journal of Pharmacology
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• v.30 no.3
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• pp.337-342
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• 1994

It is well known that angiotensin converting enzyme inhibitors(ACEIs) increase endothelium-dependent relaxation in aortic strips of spontaneously hypertensive rats(SHR) and this increase in relaxation may be due to altered endothelial nitric oxide breakdown. But there are few studies on the effect of the angiotensin II receptor blocker on the nitric oxide-mediated relaxation. So we attempted to investigate the effect of angiotensin II receptor blocker on the nitric oxide-dependent relaxation in isolated aorta of SHR. Two week-treatment of losartan (30 mg/kg/day) increased the acetylcholine$(10^{-9}\;to\;10^{-5}\;M)$-and histamine$(10^{-8}\;to\;10^{-4}\;M)$-induced relaxation in endothelium intact strips but 90 minutes-treatment of losartan $(10^{-4}\;M)$ showed no increase in relaxation. The phenylephrine $(10^{-7}\;M)$-induced contraction, repeated every 2 hours, was diminished gradually following lipopolysaccharide (LPS)-treatment $(100\;{\mu}g/ml)$ but there was no significant difference in enalapril- and losartan-treated group compared with control group. These results suggest that activity of the endothelial constitutive NO synthase may be changed by chronic treatment of angiotensin II receptor blockers and ACEIs but angiotensin II antagonist and ACEI have no effect on the inducible NO synthase activity in the isolated aorta of SHR

• Journal of Bio-Environment Control
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• v.12 no.4
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• pp.259-265
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• 2003

The physiological changes and antioxidant enzyme activities of plug seedlings irradiated with 4 kJ${\cdot}m^{-2}{\cdot}d^{-1}$ UV-B or sprayed growth inhibitors of 50 ${\cdot}L^{-1}$ diniconazole and 500 mg${\cdot}L^{-1}$ hexaconazole for retarding the overgrowth of cucumber, tomato and hot pepper seedlings in summer season were investigated. Photosynthetic rate just after UV-B irradiation was significantly low but recovered to the level of non-treated seedlings 10 days after IV-B irradiation. And photosynthetic rate of chemical-sprayed seedlings was slightly lower in tomatoes but not different in cucumbers and peppers, compared with non-treated seedlings. Cholrophyll contens in the leaves showed no difference among treatments. Anthocyanin contents in the leaves of UV-B-irradiated seedlings were higher and no difference inchmical-sprayed seedlings, compared with non-treated seedlings. the activites of SOD(superoside dismutase), CAT )catalase), and POD(perosidase) of UV-B-irradated seedlings were higher thatn those of the non-irradiated seedlings just after UV-B irradiation. However. 10 days after UV-B irradiation, the activities were decreased to half of the value just after UV-B irradiation Whereasd the activies of chemical-sprayed seedlings were slightly higher than those of non-treated ones but lower than those of UV-B-irradiated one.

• Journal of the Society of Cosmetic Scientists of Korea
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• v.31 no.3 s.52
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• pp.273-277
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• 2005

This study was performed to develop new cosmeceutical agents with sebosuppressive activity from native plant extracts in Korea. Inhibitory efforts of the extracts on $5{\alpha}-reductase$ (5-AR) were evaluated by enzyme kinetics analysis using UV-spectrophotometric method. Two kinds of enzyme suspensions as 5-AR sources were prepared from rat liver tissue and cultured hSG cells. The sebosuppressive effects were determined by measuring the total lipid quantity produced in cultured hSG cells after incubation with the extracts. As a result, Pinus thunbergii extracts showed the most potent 5-AR inhibitory effects. Its $K_i$ values were 0.0002% and 0.0014% for rat liver 5-AR and human sebaceous gland 5-AR, respectively. Addition of Pinus thunberii extract to hSG cells showed 48% reduction in total lipid production at 0.005% concentration. In conclusion, Pinus thunbergii extracts can be used as a cosmeceutical agent to regulate sebum production and to alleviate the sebum-involved skin diseases, such as acne and seborrheic dermatitis.

• Journal of the Korean Society of Food Science and Nutrition
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• v.37 no.1
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• pp.42-47
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• 2008

Prevention of postprandial hyperglycemia is important, as it is implicated in the development of macro- and microvascular complications associated with diabetes. An inhibitor of ${\alpha}$-amylase which acts in the first step of carbohydrate digestion, is expected to be a suppressor of postprandial hyperglycemia. This study investigated the porcine pancreatic ${\alpha}$-amylase inhibitory activity of the extracts from buckwheat (Fagopyrum esculentum) flower, leaf, stem and grain. Flower, leaf, stem and grain of buckwheat were extracted by water and ethanol (40%, 70%, 100%), respectively. Flower and leaf extracts were more effective ${\alpha}$-amylase inhibitors than stem and grain extracts in all tested solutions. Ethanol extracts were more effective than water extracts or powders on the ${\alpha}$-amylase inhibitory activities. At concentrations of $0.5%{\sim}10%$ (w/w, starch basis), the flower extracts of 40%, 70% and 100% ethanol lowered the enzyme activity by about 90% and the results were similar to the values of acarbose. At the same concentrations, the leaf extracts of 100% ethanol lowered the enzyme activity by about 90%. These results suggest that buckwheat flower and leaf ethanol extracts may delay carbohydrate digestion and lower postprandial hyperglycemia.

• Journal of Life Science
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• v.13 no.6
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• pp.879-888
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• 2003

In order to measure the enzyme activity of 5-epi-aristolochene hydroxylase, one of cytochrome P450 (P450) enzymes in eicitor-treated pepper cell, we used in vivo assay method and demonstrated a dramatic suppression of the activity by P450-inhibitors, ancymidol and ketocornazole. Using RT-PCR method with degenerate primer of the well conserved domains found within most P450-enzymes, and using cDNA library screening method, one distinct cDNA, being designated P450Hy01, was successfully isolated from elicitor-treated pepper cells. P450Hy01 mRNA was all induced in elicitor-treated cells whereas never induced in control cells. Moreover, levels of P450Hy01 expression were highly correlated with the levels of extracellular capsidiol production by different elicitors in cell cultures. P450Hy01 transcript was also induced by several other elicitors such as, cellulase, arachidonic acid, jasmonic acid, yeast extract as well as UV stress. P450Hy01 sequence contained high probability amino acid matches to known Plant P450 genes and ORF with a conserved FxxGxRxCxG heme-binding domain. P450Hy01 cDNA showed 98% of homology in sequence of nucleotide as well as amino acid to 5-epi-aristolochene-1, 3-hydroxylase (5EAl, 3H) which has been isolated in tobacco cells, suggesting that P450Hy01 is prominent candidate gene for P450-enzyme encoding 5EAl, 3H in pepper cell.

• Journal of Life Science
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• v.29 no.3
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• pp.287-294
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• 2019

Calystegia soldanella is distributed in coastal sand dunes and has high environmental adaptability; it is also known to be effective for anti-oxidant, anti-pyretic, anti-septic, and diuretic action. This study investigated the effect of crude extracts and organic solvent fractions of C. soldanella on MMP-2 and MMP-9 expression, MMP activity, and cell mobility in phorbol-12-myristate-13-acetate (PMA)-induced fibrosarcoma HT-1080 cells. C. soldanella was twice extracted, once with methylene chloride (MC) and once with methanol (MeOH). After the MC and MeOH extracts were combined, their suppressive effects on MMP-2 and MMP-9 expression, MMP enzymatic activity, and gene and protein expression were measured by gelatin zymography, enzyme-linked immunosorbent assay, reverse-transcription polymerase chain reaction, and western blot method. Cell mobility for the HT-1080 cells was observed by wound healing assay. The combined crude extracts showed a significant suppressive effects on MMP-2 and MMP-9 expression. To explore active inhibitory elements, the combined extracts were fractionated according to polarity into with n-hexane, 85% aqueous methanol, n-butanol, and water. Across these four solvent fractions, MMP-2 and MMP-9 activity and cell mobility in the HT-1080 cells were all strongly inhibited by the n-hexane fraction. These results suggest that C. soldanella extract and organic solvent fractions could be used as potent MMP inhibitors for effective anti-cancer treatments to suppress cancer invasion and metastasis.