Evaluation of the transporter-mediated herb-drug interaction potential of DA-9801, a standardized dioscorea extract for diabetic neuropathy, in human in vitro and rat in vivo

BACKGROUND: Drug transporters play important roles in the absorption, distribution, and elimination of drugs and thereby, modulate drug efficacy and toxicity. With a growing use of poly pharmacy, concurrent administration of herbal extracts that modulate transporter activities with drugs can cause serious adverse reactions. Therefore, prediction and evaluation of drug-drug interaction potential is important in the clinic and in the drug development process. DA-9801, comprising a mixed extract of Dioscoreae rhizoma and Dioscorea nipponica Makino, is a new standardized extract currently being evaluated for diabetic peripheral neuropathy in a phase II clinical study. METHOD: The inhibitory effects of DA-9801 on the transport functions of organic cation transporter (OCT)1, OCT2, organic anion transporter (OAT)1, OAT3, organic anion transporting polypeptide (OATP)1B1, OATP1B3, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) were investigated in HEK293 or LLC-PK1 cells. The effects of DA-9801 on the pharmacokinetics of relevant substrate drugs of these transporters were also examined in vivo in rats. RESULTS: DA-9801 inhibited the in vitro transport activities of OCT1, OCT2, OAT3, and OATP1B1, with IC(50) values of 106, 174, 48.1, and 273 μg/mL, respectively, while the other transporters were not inhibited by 300 μg/mL DA-9801. To investigate whether this inhibitory effect of DA-9801 on OCT1, OCT2, and OAT3 could change the pharmacokinetics of their substrates in vivo, we measured the pharmacokinetics of cimetidine, a substrate for OCT1, OCT2, and OAT3, and of furosemide, a substrate for OAT1 and OAT3, by co-administration of DA-9801 at a single oral dose of 1,000 mg/kg. Pre-dose of DA-9801 5 min or 2 h prior to cimetidine administration decreased the C(max) of cimetidine in rats. However, DA-9801 did not affect the elimination parameters such as half-life, clearance, or amount excreted in the urine, suggesting that it did not inhibit elimination process of cimetidine, which is governed by OCT1, OCT2, and OAT3. Moreover, DA-9801 did not affect the pharmacokinetic characteristics of furosemide, as evidenced by its unchanged pharmacokinetic parameters. CONCLUSION: Inhibitory effects of DA-9801 on OCT1, OCT2, and OAT3 observed in vitro may not necessarily translate into in vivo herb-drug interactions in rats even at its maximum effective dose

Protective effect of genistein on radiation-induced intestinal injury in tumor bearing mice

BACKGROUND: Radiation therapy is the most widely used treatment for cancer, but it causes the side effect of mucositis due to intestinal damage. We examined the protective effect of genistein in tumor-bearing mice after abdominal irradiation by evaluation of apoptosis and intestinal morphological changes. METHODS: Mouse colon cancer CT26 cells were subcutaneously injected at the flank of BALB/c mice to generate tumors. The tumor-bearing mice were treated with abdominal radiation at 5 and 10 Gy, and with genistein at 200 mg/kg body weight per day for 1 d before radiation. The changes in intestinal histology were evaluated 12 h and 3.5 d after irradiation. To assess the effect of the combination treatment on the cancer growth, the tumor volume was determined at sacrifice before tumor overgrowth occurred. RESULTS: Genistein significantly decreased the number of apoptotic nuclei compared with that in the irradiation group 12 h after 5 Gy irradiation. Evaluation of histological changes showed that genistein ameliorated intestinal morphological changes such as decreased crypt survival, villus shortening, and increased length of the basal lamina 3.5 d after 10 Gy irradiation. Moreover, the genistein-treated group exhibited more Ki-67-positive proliferating cells in the jejunum than the irradiated control group, and crypt depths were greater in the genistein-treated group than in the irradiated control group. The mean weight of the CT26 tumors was reduced in the group treated with genistein and radiation compared with the control group. CONCLUSION: Genistein had a protective effect on intestinal damage induced by irradiation and delayed tumor growth. These results suggest that genistein is a useful candidate for preventing radiotherapy-induced intestinal damage in cancer patients

Validation of the ECOS-16 Questionnaire in Koreans with Osteoporosis

Study DesignProspective study.PurposeTo evaluate the reliability and validity of the adapted Korean version of the Quality of Life Questionnaire of the European Foundation for Osteoporosis (ECOS-16).Overview of LiteratureThe validity of the Korean version of ECOS-16 has not been completely demonstrated.MethodsTranslation/retranslation of the English version of ECOS-16, and full cross-cultural adaptation were performed. The Korean version of a visual analog scale measure of pain, and the Korean versions of ECOS-16 and of the previously validated short form-36 (SF-36) were mailed to 158 consecutive patients with osteoporosis. Factor analysis and reliability assessment using kappa statistics of agreement for each item, intraclass correlation coefficient, and Cronbach's α were done. Construct validity was evaluated by comparing responses to ECOS-16 with responses to SF-36 using Pearson's correlation coefficient.ResultsFactor analysis extracted three factors. All items had a kappa statistics of agreement >0.6. The ECOS-16 showed good test/re-test reliability (0.8469) and internal consistency of Cronbach's α (0.897). The Korean version of ECOS-16 showed significant correlation with SF-36 total scores and with single SF-36 domains scores.ConclusionsThe adapted Korean version of the ECOS-16 was successfully translated and showed acceptable measurement properties. It is considered suitable for outcome assessments in Korean patients with osteoporosis

Methionine deprivation suppresses triple-negative breast cancer metastasis in vitro and in vivo

Nutrient deprivation strategies have been proposed as an adjuvant therapy for cancer cells due to their increased metabolic demand. We examined the specific inhibitory effects of amino acid deprivation on the metastatic phenotypes of the human triple-negative breast cancer (TNBC) cell lines MDA-MB-231 and Hs 578T, as well as the orthotopic 4T1 mouse TNBC tumor model. Among the 10 essential amino acids tested, methionine deprivation elicited the strongest inhibitory effects on the migration and invasion of these cancer cells. Methionine deprivation reduced the phosphorylation of focal adhesion kinase, as well as the activity and mRNA expression of matrix metalloproteinases MMP-2 and MMP-9, two major markers of metastasis, while increasing the mRNA expression of tissue inhibitor of metalloproteinase 1 in MDA-MB-231 cells. Furthermore, methionine restriction downregulated the metastasis-related factor urokinase plasminogen activatior and upregulated plasminogen activator inhibitor 1 mRNA expression. Animals on the methionine-deprived diet showed lower lung metastasis rates compared to mice on the control diet. Taken together, these results suggest that methionine restriction could provide a potential nutritional strategy for more effective cancer therapy

NF-κB/STAT3/PI3K signaling crosstalk in iMycEμ B lymphoma

<p>Abstract</p> <p>Background</p> <p>Myc is a well known driver of lymphomagenesis, and Myc-activating chromosomal translocation is the recognized hallmark of Burkitt lymphoma, an aggressive form of non-Hodgkin's lymphoma. We developed a model that mimics this translocation event by inserting a mouse <it>Myc </it>cDNA gene into the immunoglobulin heavy chain locus, just upstream of the intronic Eμ enhancer. These mice, designated iMyc^Eμ, readily develop B-cell lymphoma. To study the mechanism of Myc-induced lymphoma, we analyzed signaling pathways in lymphoblastic B-cell lymphomas (LBLs) from iMyc^Eμmice, and an LBL-derived cell line, iMyc^Eμ-1.</p> <p>Results</p> <p>Nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) were constitutively activated in iMyc^Eμmice, not only in LBLs but also in the splenic B-lymphocytes of young animals months before tumors developed. Moreover, inhibition of either transcription factor in iMyc^Eμ-1 cells suppressed growth and caused apoptosis, and the abrogation of NF-κB activity reduced DNA binding by both STAT3 and Myc, as well as Myc expression. Inhibition of STAT3 signaling eliminated the activity of both NF-κB and Myc, and resulted in a corresponding decrease in the level of Myc. Thus, in iMyc^Eμ-1 cells NF-κB and STAT3 are co-dependent and can both regulate Myc. Consistent with this, NF-κB and phosphorylated STAT3 were physically associated with one another. In addition, LBLs and iMyc^Eμ-1 cells also showed constitutive AKT phosphorylation. Blocking AKT activation by inhibiting PI3K reduced iMyc^Eμ-1 cell proliferation and caused apoptosis, via downregulation of NF-κB and STAT3 activity and a reduction of Myc levels. Co-treatment with NF-κB, STAT3 or/and PI3K inhibitors led to additive inhibition of iMyc^Eμ-1 cell proliferation, suggesting that these signaling pathways converge.</p> <p>Conclusions</p> <p>Our findings support the notion that constitutive activation of NF-κB and STAT3 depends on upstream signaling through PI3K, and that this activation is important for cell survival and proliferation, as well as for maintaining the level of Myc. Together, these data implicate crosstalk among NF-κB, STAT3 and PI3K in the development of iMyc^EμB-cell lymphomas.</p

18F-FDG PET/CT in Primary AL Hepatic Amyloidosis Associated with Multiple Myeloma

We report here on a rare case of primary AL hepatic amyloidosis associated with multiple myeloma in a 64-year-old woman. The patient was referred for evaluating her progressive jaundice and right upper quadrant pain. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) showed diffusely and markedly increased 18F-FDG uptake in the liver. Although there have been several case studies showing positive 18F-FDG uptake in pulmonary amyloidosis, to the best of our knowledge, the 18F-FDG PET/CT findings of hepatic amyloidosis or primary hepatic amyloidosis associated with multiple myeloma have not been reported previously

Tuning orbital-selective phase transitions in a two-dimensional Hund's correlated system

Hund's rule coupling ($\textit{J}$) has attracted much attention recently for its role in the description of the novel quantum phases of multi orbital materials. Depending on the orbital occupancy, $\textit{J}$ can lead to various intriguing phases. However, experimental confirmation of the orbital occupancy dependency has been difficult as controlling the orbital degrees of freedom normally accompanies chemical inhomogeneities. Here, we demonstrate a method to investigate the role of orbital occupancy in $\textit{J}$ related phenomena without inducing inhomogeneities. By growing SrRuO$_3$ monolayers on various substrates with symmetry-preserving interlayers, we gradually tune the crystal field splitting and thus the orbital degeneracy of the Ru \textit{t_2_g$}$ orbitals. It effectively varies the orbital occupancies of two-dimensional (2D) ruthenates. Via in-situ angle-resolved photoemission spectroscopy, we observe a progressive metal-insulator transition (MIT). It is found that the MIT occurs with orbital differentiation: concurrent opening of a band insulating gap in the $\textit{d$_x_y} band and a Mott gap in the \textit{d_x$$_z$$_/$$_y$$_z} bands. Our study provides an effective experimental method for investigation of orbital-selective phenomena in multi-orbital materials