• Natural Product Sciences
• /
• v.8 no.1
• /
• pp.1-15
• /
• 2002

An International Cooperative Biodiversity Group (ICBG) program based at the University of Illinois at Chicago initiated its activities in 1998, with the following specific objectives: (a) inventory and conservation of of plants of Cuc Phuong National Park in Vietnam and of medicinal plants of Laos; (b) drug discovery (and development) based on plants of Vietnam and Laos; and (c) economic development of communities participating in the ICBG project both in Vietnam and Laos. Member-institutions and an industrial partner of this ICBG are bound by a Memorandum of Agreement that recognizes property and intellectual property rights, prior informed consent for access to genetic resources and to indigenous knowledge, the sharing of benefits that may arise from the drug discovery effort, and the provision of short-term and long-term benefits to host country institutions and communities. The drug discovery effort is targeted to the search for agents for therapies against malaria (antimalarial assay of plant extracts, using Plasmodium falciparum clones), AIDS (anti-HIV-l activity using HOG.R5 reporter cell line (through transactivation of the green fluorescent protein/GFP gene), cancer (screening of plant extracts in 6 human tumor cell lines - KB, Col-2, LU-l, LNCaP, HUVEC, hTert-RPEl), tuberculosis (screening of extracts in the microplate Alamar Blue assay against Mycobacterium tuberculosis $H_{37}Ra\;and\;H_{37}Rv),$ all performed at UIC, and CNS-related diseases (with special focus on Alzheimer's disease, pain and rheumatoid arthritis, and asthma), peformed at Glaxo Smith Kline (UK). Source plants were selected based on two approaches: biodiversity-based (plants of Cuc Phuong National Park) and ethnobotany-based (medicinal plants of Cuc Phuong National Park in Vietnam and medicinal plants of Laos). At mc, as of July, 2001, active leads had been identified in the anti-HIV, anticancer, antimalarial, and anti- TB assay, after the screening of more than 800 extracts. At least 25 biologically active compounds have been isolated, 13 of which are new with anti-HIV activity, and 3 also new with antimalarial activity. At GSK of 21 plant samples with a history of use to treat CNS-related diseases tested to date, a number showed activity against one or more of the CNS assay targets used, but no new compounds have been isolated. The results of the drug discovery effort to date indicate that tropical plant diversity of Vietnam and Laos unquestionably harbors biologically active chemical entities, which, through further research, may eventually yield candidates for drug development. Although the substantial monetary benefit of the drug discovery process (royalties) is a long way off, the UIC ICBG program provides direct and real-term benefits to host country institutions and communities.

• BMB Reports
• /
• v.36 no.1
• /
• pp.82-94
• /
• 2003

Although debates still exist whether Helicobacter pylori infection is really class I carcinogen or not, H. pylori has been known to provoke precancerous lesions like gastric adenoma and chronic atrophic gastritis with intestinal metaplasia as well as gastric cancer. Chronic persistent, uncontrolled gastric inflammations are possible basis for ensuing gastric carcinogenesis and H. pylori infection increased COX-2 expressions, which might be the one of the mechanisms leading to gastric cancer. To know the implication of long-term treatment of antiinflammatory drugs, rebamipide or nimesulide, on H. pylori-associated gastric carcinogenesis, we infected C57BL/6 mice with H. pylori, especially after MNU administration to promote carcinogenesis and the effects of the long-term administration of rebamipide or nimesulide were evaluated. C57BL/6 mice were sacrificed 50 weeks after H. pylori infection. Colonization rates of H. pylori, degree of gastric inflammation and other pathological changes including atrophic gastritis and metaplasia, serum levels and mRNA transcripts of various mouse cytokines and chemokines, and NF-${\kappa}B$ binding activities, and finally the presence of gastric adenocarcinoma were compared between H. pylori infected group (HP), and H. pylori infected group administered with long-term rebamipide containing pellet diets (HPR) or nimesulide mixed pellets (HPN). Gastric mucosal expressions of ICAM-1, HCAM, MMP, and transcriptional regulations of NF-${\kappa}B$ binding were all significantly decreased in HPR group than in HP group. Multi-probe RNase protection assay showed the significantly decreased mRNA levels of apoptosis related genes and various cytokines genes like IFN-$\gamma$, RANTES, TNF-$\alpha$, TNFR p75, IL-$1{\beta}$ in HPR group. In the experiment designed to provoke gastric cancer through MNU treatment with H. pylori infection, the incidence of gastric carcinoma was not changed between HP and HPR group, but significantly decreased in HPN group, suggesting the chemoprevention of H. pylori-associated gastric carcinogenesis by COX-2 inhibition. Long-term administration of antiinflammatory drugs should be considered in the treatment of H. pylori since they showed the molecular and biologic advantages with possible chemopreventive effect against H. pylori-associated gastric carcinogenesis. If the final concrete proof showing the causal relationship between H. pylori infection and gastric carcinogenesis could be obtained, that will shed new light on chemoprevention of gastric cancer, that is, that gastric/cancer could be prevented through either the eradication of H. pylori or lessening the inflammation provoked by H. pylori infection in high risk group.

• Proceedings of the Ginseng society Conference
• /
• 2007.12a
• /
• pp.57-58
• /
• 2007

Purpose: Ginseng is a well-known medical plant used in traditional Oriental medicine. Korean red ginseng (KRG) has been known to have potent biological activities such as radical scavenging, vasodilating, anti-tumor and anti-diabetic activities. However, the mechanism of the beneficial effects of KRG on diabetes is yet to be elucidated. The present study was designed to investigate the anti-diabetic effect and mechanism of KRG extract in C57BL/KsJ db/db mice. Methods: The db/db mice were randomly divided into six groups: diabetic control group (DC), red ginseng extract low dose group (RGL, 100 mg/kg), red ginseng extract high dose group (RGH, 200 mg/kg), metformin group (MET, 300 mg/kg), glipizide group (GPZ, 15 mg/kg) and pioglitazone group (PIO, 30 mg/kg), and treated with drugs once per day for 10 weeks. During the experiment, body weight and blood glucose levels were measured once every week. At the end of treatment, we measured Hemoglobin A1c (HbA1c), blood glucose, insulin, triglyceride (TG), adiponectin, leptin, non-esterified fatty acid (NEFA). Morphological analyses of liver, pancreas and white adipose tissue were done by histological observation through hematoxylin-eosin staining. Pancreatic islet insulin and glucagon levels were detected by double-immunofluorescence staining. To elucidate an action of mechanism of KRG, DNA microarray analyses were performed, and western blot and RT-PCR were conducted for validation. Results: Compared to the DC group mice, body weight gain of PIO treated group mice showed 15.2% increase, but the other group mice did not showed significant differences. Compared to the DC group, fasting blood glucose levels were decreased by 19.8% in RGL, 18.3% in RGH, 67.7% in MET, 52.3% in GPZ, 56.9% in PIO-treated group. With decreased plasma glucose levels, the insulin resistance index of the RGL-treated group was reduced by 27.7% compared to the DC group. Insulin resistance values for positive drugs were all markedly decreased by 80.8%, 41.1% and 68.9%, compared to that of DC group. HbA1c levels in RGL, RGH, MET, GPZ and PIO-treated groups were also decreased by 11.0%, 6.4%, 18.9%, 16.1% and 27.9% compared to that of DC group, and these figure revealed a similar trend shown in plasma glucose levels. Plasma TG and NEFA levels were decreased by 18.8% and 16.8%, respectively, and plasma adiponectin and leptin levels were increased by 20.6% and 12.1%, respectively, in the RGL-treated group compared to those in DC group. Histological analysis of the liver of mice treated with KRG revealed a significantly decreased number of lipid droplets compared to the DC group. The control mice exhibited definitive loss and degeneration of islet, whereas mice treated with KRG preserved islet architecture. Compared to the DC group mice, KRG resulted in significant reduction of adipocytes. From the pancreatic islet double-immunofluorescence staining, we observed KRG has increased insulin production, but decreased glucagon production. KRG treatment resulted in stimulation of AMP-activated protein kinase (AMPK) phosphorylation in the db/db mice liver. To elucidate mechanism of action of KRG extract, microarray analysis was conducted in the liver tissue of mice treated with KRG extract, and results suggest that red ginseng affects on hepatic expression of genes responsible for glycolysis, gluconeogenesis and fatty acid oxidation. In summary, multiple administration of KRG showed the hypoglycemic activity and improved glucose tolerance. In addition, KRG increased glucose utilization and improved insulin sensitivity through inhibition of lipogenesis and activation of fatty acid $\beta$-oxidation in the liver tissue. In view of our present data, we may suggest that KRG could provide a solid basis for the development of new anti-diabetic drug.

• Journal of Life Science
• /
• v.22 no.9
• /
• pp.1224-1230
• /
• 2012

Cancer chemotherapy drugs command a large share of the market, and the development of new therapeutics with high efficacy and specificity is an active area of study. Recently, the development of cancer therapeutics from natural products targeting angiogenesis has drawn attention due to conventional chemotherapeutics showing serious side effects and resistance in cancer cells. In this study, we investigated the pharmacological efficacy of Gomisin A, an active ingredient of Schizandra chinensis baillon, on tumor growth and metastasis. Administration of Gomisin A at 10 and 100 ${\mu}g/ml$ reduced tumor growth in vivo by $80.5{\pm}8.1%$ and $96.2{\pm}2%$, respectively, compared with positive tumor controls. Treatment of Gomisin A in normal and various tumor cell lines did not exert significant toxicity. Mice treated with Gomisin A at a concentration of 10 and 100 ${\mu}g$/head showed a significant reduction in tumor-induced angiogenesis of $151{\pm}16.9%$ and $98.5{\pm}29.5%$, respectively. Furthermore, tumor metastasis analysis revealed that the administration of Gomisin A at a concentration of 10 and 100 ${\mu}g$/head inhibited tumor metastasis by $13.5{\pm}8.56%$ and $58.3{\pm}9.12%$, respectively. In addition, Gomisin A significantly decreased cell adhesion of the B16BL6 cells to the extracellular matrix. These results demonstrate that Gomisin A inhibits tumor growth via suppression of angiogenesis and tumor metastasis inhibition, without cellular toxicity. The pharmacological efficacy of Gomisin A suggests that it may be a potential candidate for the development of cancer drugs.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.16
• /
• pp.7071-7076
• /
• 2015

Epidermal growth factor receptor (EGFR) is one of the targeted molecular markers in many cancers including lung malignancies. Gefitinib and erlotinib are two available therapeutics that act as specific inhibitors of tyrosine kinase (TK) domains. We performed a case-control study with formalin-fixed paraffin-embedded tissue blocks (FFPE) from tissue biopsies of 167 non-small cell lung carcinoma (NSCLC) patients and 167 healthy controls. The tissue biopsies were studied for mutations in exons 18-21 of the EGFR gene. This study was performed using PCR followed by DNA sequencing. We identified 63 mutations in 33 men and 30 women. Mutations were detected in exon 19 (delE746-A750, delE746-T751, delL747-E749, delL747-P753, delL747-T751) in 32 patients, exon 20 (S786I, T790M) in 16, and exon 21 (L858R) in 15. No mutations were observed in exon 18. The 63 patients with EFGR mutations were considered for upfront therapy with oral tyrosine kinase inhibitor (TKI) drugs and have responded well to therapy over the last 15 months. The control patients had no mutations in any of the exons studied. The advent of EGFR TKI therapy has provided a powerful new treatment modality for patients diagnosed with NSCLC. The study emphasizes the frequency of EGFR mutations in NSCLC patients and its role as an important predictive marker for response to oral TKI in the south Indian population.

• Korean Journal of Acupuncture
• /
• v.25 no.2
• /
• pp.159-177
• /
• 2008

Objectives : Crohn's disease is a severe chronic inflammation that is treated mainly by immunosuppression, which often has serious side effects. There is need to develop new therapeutic methods or drugs that have few side effects in order to treat this disease. Acupuncture with Moxi-tar at Cheonchu (ST25) has anti-inflammatory properties, but the mechanism of its anti-inflammatory actions is unclear. We investigated the protective effects and speculated the mechanisms of acupuncture with Moxi-tar at ST25 on trinitrobenzene sulfonic acid (TNBS) induced colitis in mice which is a well known Crohn's disease animal model. Methods : 5 % TNBS was treated at day 1 and day 7 into rectum of mice. To investigate therapeutic effects of acupuncture with Moxi-tar at ST25, acupuncture was carried out on day 3, and day 6. For the data analysis, we observed macroscopic and microscopic findings of the colon. Weight and width of the colon, degree of damage, changes of body weight, and myeloperoxygenase (MPO) activity were checked. For analysing protein expression, we carried out immunohistochemical staining and Western blot. For analysing mRNA expression, RT-PCR was carried out. Results : TNBS induced damages on the colon of mice, while acupuncture of Moxi-tar at ST25 suppressed TNBS mediated damages similar to those on the colons of mice in the control (not treated with TNBS) group. The average body weight of TNBS treated mice (77.4%) was decreased compared with that of the control mice (105%), and acupuncture with Moxi-tar at ST25 suppressed the loss of body weight caused by TNBS (from 77.4% to 95.3%). TNBS induced infiltration of immune cells in all layers of the colon while acupuncture with Moxi-tar at ST25 suppressed infiltration of immune cells caused by TNBS. Furthermore, acupunctured with Moxi-tar at ST25 suppressed macro-, micro- colonic damages caused by TNBS. Acupunctured with Moxi-tar at ST25 dramatically improved the clinical and histopathological symptoms such as the increase in weight of the distal colon and the MPO activity in TNBS-induced colitis. Acupuncture with Moxi-tar at ST25 down-regulated the nuclear transcription factor kappa B ($NF-{\kappa}B$) activity and suppressed tumor necrosis factor-a (TNF-${\alpha}$), interleukin-$1{\beta}$ (IL-1${\beta}$), and intracellular adhesion molecule-1 (ICAM-1) expressions caused by TNBS. Conclusions : Acupuncture with Moxi-tar at ST25 helps recovery from the TNBS-induced colonic damage by down-regulation of $NF-{\kappa}B$ activity and suppressing of TNF-${\alpha}$, IL-1${\beta}$, and ICAM-1 expressions. This may be an important method for the treatment of Crohn's disease.

• Tuberculosis and Respiratory Diseases
• /
• v.83 no.1
• /
• pp.96-103
• /
• 2020

Background: The aim of this study was to investigate the effectiveness of intravenous isoniazid (H) and ethambutol (E) administered in patients with new sputum positive drug-susceptible pulmonary tuberculosis (TB) with tuberculous meningoencephalitis (TM) and human immunodeficiency virus (HIV) co-infection in the intensive phase of treatment. Methods: Fifty-four patients with TB/TM and HIV co-infection were enrolled for this study. Group 1 comprised of 23 patients treated with E and H intravenously, while rifampicin and pyrazinamide were prescribed orally. Group 2 consisted of 31 patients treated with the first-line anti-TB drugs orally. The concentrations of H and E in blood serum were detected using a chromatographic method. Results: A significant improvement in the clinical symptoms and X-ray signs in patients treated intravenously with H and E was observed and compared to group 2. The sputum Mycobacterium tuberculosis positivity was observed during the second month of the treatment in 25.0% of patients from group 1 and 76.1% of the patients from the control group (p=0.003). In addition, nine patients (39.1%) died up to 6 months when H and E were prescribed intravenously compared with 22 (70.9%) in group 2 (p=0.023). Conclusion: In TB/TM with HIV, the intravenous H and E treatment was more effective than oral H and E treatment at 2 months of intensive treatment in sputum conversion as well as in clinical improvement, accompanied by significantly higher mean serum concentrations. In addition, the mortality rate was lower in intravenous H and E treatment compared to oral treatment.

• Proceedings of the Korean Society of Developmental Biology Conference
• /
• 2001.10a
• /
• pp.37-43
• /
• 2001

1. About fifty thousand of cattle embryos were transferred and 16000 ET-calves were born in 1999. Eighty percents of embryos were collected from Japanese Black beef donors and transferred to dairy Holstein heifers and cows. Since 1985, we have achieved in bovine in vitro fertilization using immature oocytes collected from ovaries of slaughterhouse. Now over 8000 embryos fertilized by Japanese Black bull, as Kitaguni 7~8 or Mitsufuku, famousbulls as high marbling score of progeny tests were sold to dairy farmers and transferred to their dairy cattle every year. 2. Embryo splitting for identical twins is demonstrated an useful tool to supply a bull for semen collection and a steer for beef performance test. According to the data of Dr. Hashiyada(2001), 296 pairs of split-half embryos were transferred to recipients and 98 gave births of 112 calves (23 pairs of identical twins and 66 singletons). 3. A blastomere-nuclear-transferred cloned calf was born in 1990 by a joint research with Drs. Tsunoda, National Institute of Animal Industry (NIAI) and Ushijima, Chiba Prefectural Farm Animal Center. The fruits of this technology were applied to the production of a calf from a cell of long-term-cultured inner cell mass (1988, Itoh et al, ZEN-NOH Central Research Institute for Feed and Livestock) and a cloned calf from three-successive-cloning (1997, Tsunoda et al.). According to the survey of MAFF of Japan, over 500 calves were born until this year and a glaf of them were already brought to the market for beef. 4. After the report of "Dolly", in February 1997, the first somatic cell clone female calves were born in July 1998 as the fruits of the joint research organized by Dr. Tsunoda in Kinki University (Kato et al, 2000). The male calves were born in August and September 1998 by the collaboration with NIAI and Kagoshima Prefecture. Then 244 calves, four pigs and a kid of goat were now born in 36 institutes of Japan. 5. Somatic cell cloning in farm animal production will bring us as effective reproductive method of elite-dairy- cows, super-cows and excellent bulls. The effect of making copy farm animal is also related to the reservation of genetic resources and re-creation of a male bull from a castrated steer of excellent marbling beef. Cloning of genetically modified animals is most promising to making pig organs transplant to people and providing protein drugs in milk of pig, goat and cattle. 6. Farm animal cloning is one of the most dreamful technologies of 21th century. It is necessary to develop this technology more efficient and stable as realistic technology of the farm animal production. We are making researches related to the best condition of donor cells for high productivity of cloning, genetic analysis of cloned animals, growth and performance abilities of clone cattle and pathological and genetical analysis of high rates of abortion and stillbirth of clone calves (about 30% of periparutum mortality). 7. It is requested in the report of Ministry of Health, labor and Welfare to make clear that carbon-copy cattle(somatic cell clone cattle) are safe and heathy for a commercial market since the somatic cell cloning is a completely new technology. Fattened beef steers (well-proved normal growth) and milking cows(shown a good fertility) are now provided for the assessment of food safety.

• Proceedings of the Korean Society of Near Infrared Spectroscopy Conference
• /
• 2001.06a
• /
• pp.1162-1162
• /
• 2001

Whereas NIR spectroscopy has been applied in agriculture for more than 20 years, few studies refer to those plant substances occurring only in smaller amounts. Nevertheless there is a growing interest today to support efficiently activities in the production of high-quality medicinal and spice plants by this fast and non-invasive method. Therefore, it was the aim of this study to develop new NIR methods for the reliable prediction of secondary metabolites found as valuable substances in various plant species. First, sophisticated NIR methods were established to perform fast quality analyses of intact fennel, caraway and dill fruits deriving from single-plants [1]. Later on, a characterization of several leaf drugs and the corresponding fresh material has been successfully performed. In this context robust calibrations have been developed for dried peppermint, rosemary and sage leaves for the determination of their individual essential oil content and composition [2]. A specially adopted NIR method has been developed also for the analysis of carnosic acid in the leaves of numerous rosemary and sage gene bank accessions. Carnosic acid is an antioxidative substance for which several health promoting properties including cancer preservation are assumed. Also some other calibrations have been developed for non-volatile substances such as aspalathin (in unfermented rooibos leaves), catechins (in green tea) and echinacoside (in different Echinacea species) [3]. Some NIR analyses have also been successfully performed on fresh material, too. In spite of the fact that these measurements showed less accuracy in comparison to dried samples, the calibration equations are precise enough to register the individual plant ontogenesis and genetic background. Based on the information received, the farmers and breeders are able to determine the right harvest time (when the valuable components have reached their optimum profile) and to select high-quality genotypes during breeding experiments, respectively. First promising attempts have also been made to introduce mobile diode array spectrometers to collect the spectral data directly on the field or in the individual natural habitats. Since the development of reliable NIRS methods in this special field of application is very time-consuming and needs continuous maintenance of the calibration equations over a longer period, it is convenient to supply the corresponding calibration data to interested user via NIRS network. The present status of all activities, preformed in this context during the last three years, will be presented in detail.

• Journal of fish pathology
• /
• v.14 no.1
• /
• pp.31-36
• /
• 2001

A novel clonidine binding sites were characterized in the intestinal membrane isolated from seawater eels, Anguilla japonica. The specific clonidine binding sites consisted of at least two classes, high affinity ($K_d=1.4{\pm}0.3$ nM n = 5) and low affinity ($K_d=175{\pm}34$ nM n = 5) sites. The specific binding of 2 nM [$^3H$]clonidine was most enhanced at $20^{\circ}C$ and pH 7.5, and reversed by unlabelled clonidine. Such binding was hardly inhibited by adrenaline, yohimbine or rauwolscine, indicating that most binding sites are distinct from $\alpha_2$-adrenoceptor. The specific clonidine binding sites was inhibited by various imidazoline/guanidinium drugs, indicating existence of imidazoline/guanidinium receptive sites (IGRS) or imidazoline receptors in the eel intestine. Competition experiments revealed that rank order to displace 2 nM [$^3H$]clonidine from their binding sites was as follows : guanabenz > cirazoline = naphazoline = UK14,304 = ST587 $\geq$ clonidine $\geq$ idazoxan = RX821002 = tolazoline > ST93 = oxymetazoline = amiloride = ST91 > yohimbine = efaroxan = rauwolscine $\geq$ adrenaline = ST567 = histamine = agmatine. Although physiological role of IGRS is not clear yet even in mammalian cell/tissues, eel intestine may be a good model to elucidate how the IGRS act in the cell and to decide what is the endogenous ligand for the IGRS.