Impact of warm saline irrigation, hyperthermic intraperitoneal chemotherapy on postoperative pain in primary ovarian cancer from the KOV-HIPEC-01 randomized trial.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a treatment option at the time of cytoreductive surgery after neoadjuvant chemotherapy. The effect of active warming of HIPEC on postoperative pain needs to be investigated. This study aimed to investigate whether HIPEC reduces postoperative pain. METHODS: From the KOV-HIPEC-01 trial, a randomized controlled trial of HIPEC for advanced primary ovarian cancer, 184 patients with a residual tumor size <1 cm were randomly assigned to the HIPEC and control groups at a 1:1 ratio. The consumption of analgesics and pain scales were analyzed. Hyperthermic intraperitoneal chemotherapy was administered after cytoreductive surgery. The primary objective was to compare the consumption of opioids measured in morphine milligram equivalents and non-opioids measured as the maximum daily dose between the HIPEC and control groups. The secondary objective was to compare the minimum and maximum pain intensities on numeric rating scales between the two groups using a linear mixed model. RESULTS: Lesser consumption of non-opioids, with a lower mean maximum daily dose on postoperative days 1 and 2, was observed. The HIPEC group also experienced lower maximum pain intensities on postoperative day 1. No overall differences in the minimum or maximum pain intensities were observed on postoperative day 7. CONCLUSION: The addition of HIPEC to cytoreductive surgery did not lead to increased postoperative pain, as demonstrated by a reduction in the use of analgesics and lower scores on postoperative pain scales during the early postoperative period.

Uncontrolled high blood pressure under total intravenous anesthesia with propofol and remifentanil: A case report.

BACKGROUND: Although propofol generally reduces blood pressure, rarely, it causes hypertension. However, the mechanism by which propofol increases blood pressure has not been established, and so far, there are only a few reported cases. CASE SUMMARY: A 46-year-old woman, diagnosed with thyroid cancer, was administered general anesthesia with propofol and remifentanil for a thyroid lobectomy. An increase in the concentrations of intravenous anesthetics further increased her blood pressure. The blood pressure remained stable when anesthesia was maintained with sevoflurane and remifentanil after the interruption of propofol administration. CONCLUSION: We concluded that propofol administration was the cause of increased blood pressure.

Anti-Osteoarthritic Mechanisms of Chrysanthemum zawadskii var. latilobum in MIA-Induced Osteoarthritic Rats and Interleukin-1ß-Induced SW1353 Human Chondrocytes.

Background and objectives: Chrysanthemum zawadskii var. latilobum (CZ), which has traditionally been used as a oriental tea in Asia, is known to have anti-inflammatory effects in osteoarthritis (OA). But the mechanism of these effects has not been made clear and it needs to be elucidated specifically for the clinical use of CZE in OA. Materials and Methods: To reveal this mechanism, we first identified which biomarkers were expressed in the joints of rats in which OA had been induced with monosodium iodoacetate and determined whether CZ extract (CZE) could normalize these biomarkers in the progression of OA. The anti-osteoarthritis effect of CZE was evaluated for its capability to inhibit levels of extracellular matrix (ECM)-degrading enzymes and enhance ECM synthesis. We also sought to identify whether the marker compound of CZE, linarin, has anti-osteoarthritic effects in the human chondrosarcoma cell line SW1353. Results: The changes in matrix metalloproteinases (MMPs) were remarkable: among them, MMP-1, MMP-3, MMP-9 and MMP-13 were most strongly induced, whereas their expressions were inhibited by CZE dose dependently. The expressions of the ECM synthetic genes, COL2A1 and ACAN, and the transcription factor SOX9 of these genes were reduced by OA induction and significantly normalized by CZE dose dependently. SOX9 is also a repressor of ECM-degrading aggrecanases, ADAMTS-4 and ADAMTS-5, and CZE significantly reduced the levels of these enzymes dose dependently. Similar results were obtained using the human chondrosarcoma cell line SW1353 with linarin, the biologically active compound of CZE. Conclusions: These anti-osteoarthritic effects suggest that CZE has mechanisms for activating ECM synthesis with SOX9 as well as inhibiting articular ECM-degrading enzymes.

Lactic Acid Bacteria Ameliorate Diesel Exhaust Particulate Matter-Exacerbated Allergic Inflammation in a Murine Model of Asthma.

Several air pollution components such as sulfur dioxide, ozone, nitrogen dioxide, and diesel exhaust particulate matter (DEPM) have been linked to the development of asthma. In this study, we investigated the therapeutic potential of three lactic acid bacteria species, Lactobacillus plantarum GREEN CROSS Wellbeing (GCWB)1001, Pediococcus acidilactici GCWB1085, and Lactobacillus rhamnosus GCWB1156, in preventing DEPM-exacerbated asthma in mice. BALB/c mice were first sensitized with ovalbumin (OVA) and were either challenged with OVA or DEPM (DEPM-exacerbated asthma model) by intranasal instillation. All three strains showed no hemolytic activity, suggesting a good safety profile. Oral administration of lactic acid bacteria reduced OVA + DEPM-induced inflammatory infiltration, goblet cell hyperplasia, airway remodeling, and the levels of proinflammatory cytokines and chemokines in bronchoalveolar lavage fluid (BALF). The probiotics also attenuated OVA + DEPM-induced immunoglobulin E (IgE) levels in serum and in BALF, and significantly reduced caspase-3 activity, total collagen level, and matrix metalloproteinase (MMP)-9 activity. In conclusion, lactic acid bacteria such as L. plantarum GCWB1001, P. acidilactici GCWB1085, and L. rhamnosus treatment in mice with asthma showed significant efficacy in preventing lung inflammation exacerbated by DEPM administration.

Immunomodulatory Activity of Lactococcus lactis GCWB1176 in Cyclophosphamide-Induced Immunosuppression Model.

Recently, Lactococcus lactis subsp. lactis has been reported to have immunostimulating properties in an immunosuppressed-animal model. However, the immunological activities of Lactococcus lactis and the molecular mechanisms remain unclear. In this report, we evaluated the immunostimulating activity and associated mechanisms of Lactococcus lactis subsp. lactis GCWB1176 (GCWB1176) in macrophages and cyclophosphamide (CTX)-induced immunosuppressed mice. In a series of safety tests, GCWB1176 was found to have a negative response to hemolysis, as well as susceptibility to antibiotics. Administration of GCWB1176 elevated natural killer (NK) cell activities; concanavalin A-induced T cell proliferation; and serum levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-4, IL-10 and IL-12 in CTX-induced immunosuppressed mice. In RAW264.7 macrophages, treatment with GCWB1176 induced phagocytic activity and increased the production of nitric oxide (NO) and expression of inducible NO synthase. Simultaneously, GCWB1176 increased the production of TNF-α, IFN-γ, IL-1ß, IL-10 and IL-12 from mouse splenocytes and RAW264.7 cells. In addition, GCWB1176 significantly increased the transcriptional activities of NF-κB and iNOS. Taken together, GCWB1176 improved immune function through the activation of macrophages and NK cells. These findings suggest that dietary supplementation of GCWB1176 may be used to enhance immunity.

Effects of Human Placenta Extract (Laennec) on Ligament Healing in a Rodent Model.

Rich in bioactive substances such as amino acids and peptides, Laennec (human placenta hydrolysate) has been widely used to control various types of musculoskeletal pain. However, the effects of Laennec on tendon and ligament injuries are not clearly understood. In the present study, Laennec was tested to identify its in vivo effects on ligament injury in an animal model and its in vitro effects on tendon-derived fibrocytes. A total of 99 Sprague Dawley rats were divided into the negative control (normal) group (n = 11) and the ligament injury group (n = 88). The ligament injury group was subdivided into normal saline-treated group, Laennec-treated group, polydeoxyribonucleotide-treated group, and 20% dextrose-treated group. Ligaments were collected at 1 week and 4 weeks after treatment. Histologic and biomechanical properties were analyzed. In vitro effects of Laennec and polydeoxyribonucleotide on fibrocytes were also analyzed. Although all other treatment groups showed increased inflammatory cells, the Laennec-treated group maintained cell counts and activated macrophage levels that were similar to the normal group. Unlike the saline-treated group and dextrose-treated group, the Laennec-treated group had low levels of degenerative changes at 4 weeks after treatment. Supportively, in vitro results showed that the Laennec-treated group had increased collagen type I, scleraxis (Scx) and tenomodulin (Tnmd) expression (p < 0.05). Our study demonstrates that Laennec treatment enhances wound healing of damaged ligament by suppressing immune responses and reducing degenerative changes of damaged ligament. In addition, we found that Laennec induces the gene expression of type I collagen, Scx and Tnmd in fibrocytes, suggesting that Laennec may facilitate regeneration of damaged ligaments. Therefore, we expect that Laennec can be a useful drug to treat injured ligament.

BST-104, a Water Extract of Lonicera japonica, Has a Gastroprotective Effect via Antioxidant and Anti-Inflammatory Activities.

The gastroprotective effects of BST-104 (a water extract of Lonicera japonica) and the mechanisms involved were investigated in murine models of gastritis and peptic ulcer. The gastroprotective effects of BST-104 and its active components were evaluated in rat models of HCl/ethanol-induced gastritis and acetic acid-induced gastric ulcer. After orally administering BST-104, chlorogenic acid, rebamipide (positive control), or vehicle to each animal model, gastric lesion sizes, gastric mucus statuses, proinflammatory cytokine levels, and oxidative stress were measured. Superoxide dismutase (SOD), catalase, and malondialdehyde (MDA) levels and oxidized/reduced glutathione (GSH) ratios in gastric mucosal tissues were measured to evaluate oxidative stress. To clarify the action mechanism of BST-104, we investigated nuclear factor (NF)-κB pathway involvement by real-time polymerase chain reaction (PCR). In the acetic acid-induced ulcer model, oral administration of BST-104 at 50, 100, or 200 mg/kg significantly reduced gastric lesions by 38%, 43%, and 55%, respectively, compared with vehicle controls. BST-104 significantly increased gastric mucus contents and this was accompanied by higher levels of hexosamine, sialic acid, and prostaglandin E2 in gastric mucus. Furthermore, BST-104 treatment increased antioxidant activities, as evidenced by higher levels of catalase, SOD, and oxidized/reduced GSH and lower MDA levels. In addition, BST-104 significantly suppressed proinflammatory cytokine (tumor necrosis factor-α, interleukin [IL]-6, and IL-1ß) increases, and real-time PCR showed that BST-104 significantly downregulated NF-κB expression. In summary, BST-104 and its active component, chlorogenic acid, were found to have gastroprotective effects by virtue of their antioxidant and anti-inflammatory properties through downregulation of NF-κB expression.

BST106 Protects against Cartilage Damage by Inhibition of Apoptosis and Enhancement of Autophagy in Osteoarthritic Rats.

Chrysanthemum zawadskii var. latilobum (CZ) has been used as a traditional medicine in Asian countries for the treatment of inflammatory diseases. Recently, CZ extract was shown to inhibit differentiation of osteoclasts and provide protection against rheumatoid arthritis. The aim of this study was to investigate the molecular mechanisms of BST106, the ethanol extract of CZ, for cartilage protection in monosodium iodoacetate (MIA)-induced osteoarthritis (OA), particularly focusing on apoptosis and autophagy. BST106 (50, 100, and 200 mg/kg) was orally administered once daily to MIA-induced OA rats. Swelling, limping, roentgenography, and histomorphological changes were assessed 28 d after MIA injection. Biochemical parameters for matrix metalloproteinase (MMP), apoptosis, and autophagy were also assessed. BST106 ameliorated the severity of swelling and limping after MIA injection. Roentgenographic and histomorphological examinations revealed that BST106 reduced MIA-induced cartilage damage. BST106 decreased MIA-induced increases in MMP-2 and MMP-13 mRNA levels. Increased levels of serum cartilage oligomeric matrix protein and glycosaminoglycan release were attenuated by BST106. Furthermore, BST106 suppressed the protein expression of proapoptotic molecules and increased the protein expression of autophagosome- and autolysosome-related molecules. These findings indicate that BST106 protects against OA-induced cartilage damage by inhibition of the apoptotic pathway and restoration of impaired autophagic flux.

Codon optimization of Saccharomyces cerevisiae mating factor alpha prepro-leader to improve recombinant protein production in Pichia pastoris.

OBJECTIVES: To evaluate different codon optimization parameters on the Saccharomyces cerevisiae-derived mating factor α prepro-leader sequence (MFLS) to improve Candida antarctica lipase B (CAL-B) secretory production in Pichia pastoris. RESULTS: Codon optimization based on the individual codon usage (ICU) and codon context (CC) design parameters enhanced secretory production of CAL-B to 7 U/ml and 12 U/ml, respectively. Only 3 U/ml was obtained with the wild type sequence while the sequence optimized using both ICU and CC objectives showed intermediate performance of 10 U/ml. These results clearly show that CC is the most relevant parameter for the codon optimization of MFLS in P. pastoris, and there is no synergistic effect achieved by considering both ICU and CC together. CONCLUSION: The CC optimized MFLS increased secretory protein production of CAL-B in P. pastoris by fourfold.

Pharmacokinetics and tissue distribution of ginsenoside Rh2 and Rg3 epimers after oral administration of BST204, a purified ginseng dry extract, in rats.

1. BST204, a purified ginseng dry extract containing a high concentration of racemic Rh2 and Rg3 mixtures, is being developed for supportive care use in cancer patients in Korea. This study investigates the pharmacokinetics and tissue distribution of BST204 in rats. 2. After oral administration of BST204, only the S epimers, S-Rh2 and S-Rg3, could be determined in rat plasma. The poor absorption of the R-epimers, R-Rh2 and R-Rg3, may be attributed to lower membrane permeability and extensive intestinal oxygenation and/or deglycosylation into metabolites. The AUC and Cmax values of both S-Rh2 and S-Rg3 after BST204 oral administration were proportional to the administered BST204 doses ranged from 400 mg/kg to 2000 mg/kg, which suggested linear pharmacokinetic properties. 3. There were no statistically significant differences in the pharmacokinetics of S-Rh2 and S-Rg3 after oral administration of pure S-Rh2 (31.5 mg/kg) and S-Rg3 (68 mg/kg) compared with oral administration of BST204, 1000 mg/kg. These indicated that the presence of other components of BST204 extract did not influence the pharmacokinetic behavior of S-Rh2 and S-Rg3. 4. After oral dosing of BST204, S-Rh2 and S-Rg3 were distributed mainly to the liver and gastrointestinal tract in rats. 5. Our finding may help to understand pharmacokinetic characteristics of S-Rh2, R-Rh2, S-Rg3, and R-Rg3, comprehensively, and provide useful information in clinical application of BST204.

Evaluation of the in vitro/in vivo drug interaction potential of BST204, a purified dry extract of ginseng, and its four bioactive ginsenosides through cytochrome P450 inhibition/induction and UDP-glucuronosyltransferase inhibition.

We evaluated the potential of BST204, a purified dry extract of ginseng, to inhibit or induce human liver cytochrome P450 enzymes (CYPs) and UDP-glucuronosyltransferases (UGTs) in vitro to assess its safety. In vitro drug interactions of four bioactive ginsenosides of BST204, S-Rg3, R-Rg3, S-Rh2, and R-Rh2, were also evaluated. We demonstrated that BST204 slightly inhibited CYP2C8, CYP2D6, CYP2C9, and CYP2B6 activities with IC50 values of 17.4, 26.8, 31.5, and 49.7µg/mL, respectively. BST204 also weakly inhibited UGT1A1, UGT1A9, and UGT2B7 activities with IC50 values of 14.5, 26.6, and 31.5µg/mL, respectively. The potential inhibition by BST204 of the three UGT activities might be attributable to S-Rg3, at least in part, as its inhibitory pattern was similar to that of BST204. However, BST204 showed no time-dependent inactivation of the nine CYPs studied. In addition, BST204 did not induce CYP1A2, 2B6, or 3A4/5. On the basis of an in vivo interaction studies, our data strongly suggest that BST204 is unlikely to cause clinically significant drug-drug interactions mediated via inhibition or induction of most CYPs or UGTs involved in drug metabolism in vivo. Our findings offer a clearer understanding and possibility to predict drug-drug interactions for the safe use of BST204 in clinical practice.

Stereoselective determination of ginsenosides Rg3 and Rh2 epimers in rat plasma by LC-MS/MS: application to a pharmacokinetic study.

We developed and validated an accurate and sensitive LC-MS/MS method for the simultaneous quantitation of ginsenoside Rg3 and Rh2 epimers (R-Rg3, S-Rg3, R-Rh2, and S-Rh2) in rat plasma. Analytes were extracted from 0.1 mL aliquots of rat plasma by liquid-liquid extraction, using 2 mL of ethyl acetate. In this assay, dioscin (500 ng/mL) was used as an internal standard. Chromatographic separation was conducted using an Acclaim RSLC C18 column (150 × 2.1 mm, 2.2 µm) at 40°C, with a gradient mobile phase consisting of 0.1% formic acid in distilled water and in acetonitrile, a flow rate of 0.35 mL/min, and a total run time of 20 min. Detection and quantification were performed using a mass spectrometer in selected reaction-monitoring mode with negative electrospray ionization at m/z 783.4 → 161.1 for R-Rg3 and S-Rg3, m/z 621.3 → 161.1 for R-Rh2 and S-Rh2, and m/z 867.2 → 761.5 for the internal standard. For R-Rg3 and S-Rg3, the lower limit of quantification was 5 ng/mL, with a linear range up to 500 ng/mL; for R-Rh2 and S-Rh2, the lower limit of quantification was 150 ng/mL, with a linear range up to 6000 ng/mL. The coefficient of variation for assay precision was less than 10.5%, with an accuracy of 86.4-112%. No relevant cross-talk or matrix effect was observed. The method was successfully applied to a pharmacokinetic study after oral administration of 400 mg/kg and 2000 mg/kg of BST204, a fermented ginseng extract, to rats. We found that the S epimers exhibited significantly higher plasma concentrations and area under curve values for both Rg3 and Rh2. This is the first report on the separation and simultaneous quantification of R-Rg3, S-Rg3, R-Rh2, and S-Rh2 in rat plasma by LC-MS/MS. The method should be useful in the clinical use of ginseng or its derivatives.

Breast cancer metastasis suppressor 1 (BRMS1) is destabilized by the Cul3-SPOP E3 ubiquitin ligase complex.

Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis without affecting primary tumorigenesis. The regulatory mechanism of BRMS1 at the protein level has not been revealed until recently. Here, we found that cullin 3 (Cul3), a component of E3 ubiquitin ligase, is a new binding partner of BRMS1 and the interaction between BRMS1 and Cul3 is mediated by the SPOP adaptor protein. Intriguingly, BRMS1 turns out to be a potent substrate that is ubiquitinated by the Cul3-SPOP complex. Knockdown of SPOP increases the level of BRMS1 protein and represses the expression of BRMS1 repressive target genes such as OPN and uPA in breast cancer cells. These results suggest that the novel regulatory mechanism of BRMS1 by Cul3-SPOP complex is important for breast cancer progression.

Different antiulcer activities of pantoprazole in stress, alcohol and pylorus ligation-induced ulcer models.

Antiulcer effects of pantoprazole, a proton-pump inhibitor, on water-immersion restraint stress (WIRS)-, alcohol (ethanol)- and pylorus ligation-induced gastric ulcers were investigated in male rats. Rats were orally administered with pantoprazole 30 min prior to exposure to various types of ulcer inducers. In stress-induced ulcer model, rats were subjected to WIRS at 22℃ for 4 hours, and the degree of ulcer (in mm) was evaluated. In alcohol-induced ulcer model, rats were orally administered with pure (100%) ethanol (1 mL/kg), and the ulcer lesions were measured 1 hour after ethanol challenge. In pylorus ligation-induced ulcer model, rats were subjected to pylorus ligation, and the degree of erosions and ulcers was scored 17 hours after the operation. Pantoprazole attenuated the ulcer lesions induced by WIRS in a dose-dependent manner, exhibiting a median effective dose (ED(50)) value of 0.78 mg/kg. By comparison, pantoprazole was effective at relatively-high doses for the improvement of ethanol-induced ulcers, showing an ED(50) value of 20.5 mg/kg. Notably, pantoprazole was practically ineffective (ED(50)>50.0) in pylorus ligation model. Taken together, it was confirmed that pantoprazole showed inhibitory activity on gastric ulcers induced by stress and alcohol, but was ineffective on pylorus ligation-induced ulcer. Therefore, the results indicate that proton-pump inhibitors including pantoprazole might reveal highly-different effects according to the type of ulcer inducers, and that the prescription of antiulcer agents should be carefully selected.

Highly selectively monitoring heavy and transition metal ions by a fluorescent sensor based on dipeptide.

Fluorescent sensor (DMH) based on dipeptide was efficiently synthesized in solid phase synthesis. The dipeptide sensor shows sensitive response to Ag(I), Hg(II), and Cu(II) among 14 metal ions in 100% aqueous solution. The fluorescent sensor differentiates three heavy metal ions by response type; turn on response to Ag(I), ratiometric response to Hg(II), and turn off detection of Cu(II). The detection limits of the sensor for Ag(I) and Cu(II) were much lower than the EPA's drinking water maximum contaminant levels (MCL). Specially, DMH penetrated live cells and detected intracellular Ag(+) by turn on response. We described the fluorescent change, binding affinity, detection limit for the metal ions. The study of a heavy metal-responsive sensor based on dipeptide demonstrates its potential utility in the environment field.

UCH-L1 promotes cancer metastasis in prostate cancer cells through EMT induction.

Ubiquitin C-terminal hydrolse-L1 (UCH-L1) is a deubiquitinating enzyme (DUB) that cleaves the ubiquitin (ub) moiety from ub precursors or protein substrates. The correlation between UCH-L1 and cancer has been reported in various tissues, but the role of UCH-L1 in prostate cancer has not been thoroughly researched. Here we found that UCH-L1 is specifically highly expressed in the metastatic DU145 prostate cancer cell line, but not in the benign or weakly metastatic prostate cancer cells. To determine the role of UCH-L1 in prostate cancer metastasis, we constructed UCH-L1-knockdown DU145 and UCH-L1 or the active site mutant form of UCH-L1 (UCH-L1 C90S) expressing RWPE1 stable cells. Notably, the expression of UCH-L1 in RWPE1 cells promotes epithelial-to-mesenchymal transition (EMT), and this is an important process for cancer cell invasion and metastasis. On the contrary, knockdown of UCH-L1 in DU145 cells induces MET, the reverse program of EMT. Furthermore, the change of EMT status caused by altering the UCH-L1 level affects the migration and invasiveness of prostate cancer cells. Our results indicate that UCH-L1 promotes prostate cancer metastasis through EMT induction and UCH-L1 could be a novel diagnostic and therapeutic target for prostate cancer treatment.

Anti-inflammatory effects of a Houttuynia cordata supercritical extract.

Anti-inflammatory effects of Houttuynia cordata supercritical extract (HSE) were investigated in a carrageenan-air pouch model. HSE (200 mg/kg, oral) suppressed exudation and albumin leakage, as well as inflammatory cell infiltration. Dexamethasone (2 mg/kg, i.p.) only decreased exudation and cell infiltration, while indomethacin (2 mg/kg, i.p.) reduced exudate volume and albumin content. HSE lowered tumor-necrosis factor (TNF)-alpha and nitric oxide (NO), as well as prostaglandin E(2) (PGE(2)). Dexamethasone only reduced TNF-alpha and NO, while indomethacin decreased TNF-alpha and PGE(2). The suppressive activity of HSE on NO and PGE(2) production was confirmed in RAW 264.7. These results demonstrate that HSE exerts anti-inflammatory effects by inhibiting both TNF-alpha-NO and cyclooxygenase II-PGE(2) pathways.

Comparative antihypertensive activities of losartan and HM70186 in rats with hepatic dysfunction.

HM70186, a medoxomil ester of EXP3174 which is an active metabolite of angiotensin II receptor blocker losartan, was synthesized, and its antihypertensive efficacy was evaluated in rats with hepatic dysfunction. Male Wistar rats were intraperitoneally injected with 0.5 mL/kg of carbon tetrachloride to cause hepatic injury, and implanted with an osmotic minipump containing angiotensin II (0.4 mg/kg/day) to induce hypertension. After confirmation of both hepatic damage and hypertension, the rats were orally administered losartan or HM70186, and then blood pressure and heart rate were monitored for 24 h. In normal animals, angiotensin II-induced hypertension was lowered by losartan, resulting in an ED(-30 mmHg) of 9.05 mg/kg. HM70186 also immediately decreased the blood pressure in a dose-dependent manner, exhibiting an ED(-30 mmHg) of 0.89 ng/kg (10,000 times the potency observed with losartan). Moreover, HM70186 (3 ng/kg) exerted a strong antihypertensive effect even in rats with hepatic injury, while losartan (10 microg/kg) was ineffective. These results suggest that HM70186 could be a promising candidate for the treatment of hypertension accompanied by hepatic dysfunction.

Green tea extract increases cyclophosphamide-induced teratogenesis by modulating the expression of cytochrome P-450 mRNA.

The effects of green tea extract (GTE) on the fetal development and external, visceral and skeletal abnormalities induced by cyclophosphamide were investigated in rats. Pregnant rats were daily administered GTE (100mg/kg) by gavage for 7 d, from the 6th to 12th day of gestation, and intraperitoneally administered with cyclophosphamide (11mg/kg) 1h after the final treatment. On the 20th day of gestation, maternal and fetal abnormalities were determined by Cesarian section. Cyclophosphamide was found to reduce fetal and placental weights without increasing resorption or death. In addition, it induced malformations in live fetuses; 94.6%, 41.5% and 100% of the external (skull and limb defects), visceral (cleft palate and ureteric dilatation) and skeletal (acrania, vertebral/costal malformations and delayed ossification) abnormalities. When pre-treated with GTE, cyclophosphamide-induced body weight loss and abnormalities of fetuses were remarkably aggravated. Moreover, repeated treatment with GTE greatly increased mRNA expression and activity of hepatic cytochrome P-450 (CYP) 2B, which metabolizes cyclophosphamide into teratogenic acrolein and cytotoxic phosphoramide mustard, while reducing CYP3A expression (a detoxifying enzyme). The results suggest that repeated intake of GTE may aggravate cyclophosphamide-induced body weight loss and malformations of fetuses by modulating CYP2B and CYP3A.

trans-Resveratrol relaxes the corpus cavernosum ex vivo and enhances testosterone levels and sperm quality in vivo.

We examined the effects of trans-resveratrol on male reproductive functions; ex-vivo penile erection and in-vivo sperm counts and quality. For the ex-vivo study, the relaxation effects of resveratrol on isolated New Zealand white rabbit corpus cavernosum, precontracted by phenylephrine (5x10(-5) M) were measured. The in-vivo study measured reproductive organ weights, blood testosterone levels, testicular histopathology, sperm counts, as well as the epididymal sperm motility and deformity of male ICR mice given an oral dose of resveratrol (50 mg/ kg) for 28 days. Resveratrol elicited a concentration-dependent relaxing effect on corpus cavernosum, leading to a median effective concentration (EC50) of 0.29 mg/mL. Repeated treatment with resveratrol (50 mg/kg) did not cause an increase in body weight, reproductive organ weight or testicular microscopic findings; however, resveratrol did elicit an increase in blood testosterone concentration, testicular sperm counts and epididymal sperm motility by 51.6%, 15.8% and 23.3%, respectively, without influence on sperm deformity. In conclusion, we propose that resveratrol has a positive effect on male reproductive function by triggering a penile erection, as well as enhancing blood testosterone levels, testicular sperm counts, and epididymal sperm motility.