SR-5, the specific ratio of Korean multi-herbal formula: An evaluation of antiulcerogenic effects on experimentally induced gastric ulcers in mice.

PURPOSE: Previously, we demonstrated that the specific ratio of Korean multi-herbal formula (SR-5) exhibits hepatoprotective properties against ethanol-induced hepatic damage in rats. Chronic and excessive alcohol consumption is a major etiological factor involved in gastric disease and ulcer development induced by the inflammatory response and oxidative stress. METHODS: The present study evaluated the gastroprotective effects of SR-5 (100, 150, and 200 mg/kg) against hydrochloride acid/ethanol (HCl/EtOH)-induced and indomethacin/hydrochloride acid (INDO/HCl)-induced gastritis in a mouse model and the mechanisms involved. RESULTS: All the tested doses of SR-5 significantly inhibited gastric lesions in the HCl/EtOH-induced ulcer model mice. Similarly, all the tested doses of SR-5 significantly inhibited gastric lesions in the INDO/HCl-induced ulcer model mice. Furthermore, mice pretreated with SR-5 had significantly increased gastric levels of enzymatic and nonenzymatic antioxidants, namely, catalase (CAT) and glutathione (GSH), with concomitant reductions in malondialdehyde (MDA) and reactive oxygen species (ROS) levels compared with those in the HCl/EtOH or INDO/HCl group. SR-5 suppressed the expression of nuclear factor-kappa B (NF-κB)/p65, inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2) to their normal values. CONCLUSION: These findings are the first to demonstrate the powerful protective effect of SR-5 against gastric injury development and provide hope for clinical application.

Comparison of antiaging, anti-melanogenesis effects, and active components of Raspberry (Rubus occidentalis L.) extracts according to maturity.

In this study, we carried out a comparative evaluation of antiaging and anti-melanogenesis activities of raspberry extracts (Rubus occidentalis L.) according to their stage of ripening (uRo: unripe raspberry, Ro: ripe raspberry), and analyzed the active component (ellagic acid) present in these extracts. Our results showed higher inhibitory effects of the uRo extract in terms of elastase and collagenase activities than Ro extract. In the CCD-986sk cells, uRo extract significantly inhibited MMP-1 activity by 18% and increased the rate of type 1 pro-collagen synthesis by 25%. Besides, treatment with uRo extract significantly inhibited α-melanocyte-stimulating hormone-induced melanin synthesis and tyrosinase activity in B16F10 mouse melanoma cells. Overall, uRo was a more potent mediator of antiaging and anti-melanogenesis effects than Ro extract. Further analysis showed that the functional effects of uRo could be attributed to its 18.5 times higher ellagic acid content than that in Ro extract. PRACTICAL APPLICATIONS: This study reported the differential effect of the raspberry extracts depending on their stage of ripening. To the best of our knowledge, this was the first study to report the antiaging, anti-wrinkle, and anti-pigmentation effects of the uRo extracts. We showed that the extracts from the uRo have an overall better antiaging and skin-whitening effect than ripe ones. The effects were attributed to high ellagic acid content in uRo. We believed that our study makes a significant contribution to the literature because the outcome of the study has both, cosmetic as well as therapeutic implications.

Long-Term Exposure to Urban Particulate Matter on the Ocular Surface and the Incidence of Deleterious Changes in the Cornea, Conjunctiva and Retina in Rats.

We investigated the time-dependent deleterious ocular changes induced by urban particulate matter (UPM) in vitro and in vivo. UPM treatment decreased human corneal epithelial cell migration and survival. Fluorescein scores were consistently increased by UPM application for 16 weeks. One week of rest at 2 or 4 weeks led to a recovery trend, whereas two weeks of rest at 8 weeks induced no change. UPM treatment decreased the tear film break-up time at 2 weeks, which was thereafter maintained until 16 weeks. No changes were found after periods of rest. UPM-treated eyes exhibited greater corneal epithelium thickness than normal eyes at 2 weeks, which recovered to normal at 4 and 8 weeks and was significantly decreased at 16 weeks. Apoptotic cell number in the epithelium was increased at 2 weeks, which remained constant except at 8 weeks. IL-6 expression in the cornea of the right eye continually increased for 16 weeks, and significant recovery was only observed at 8 weeks after 2 weeks of rest. Ocular pressure was significantly increased in the right eye at 12 and 16 weeks. Topical UPM application to the eye induced deleterious changes to various closely related parts of the eye.

Unripe Rubus coreanus Miquel Extract Containing Ellagic Acid Regulates AMPK, SREBP-2, HMGCR, and INSIG-1 Signaling and Cholesterol Metabolism In Vitro and In Vivo.

Our previous study demonstrated that a 5% ethanol extract of unripe Rubus coreanus (5-uRCK) has hypo-cholesterolemic and anti-obesity activity. However, the molecular mechanisms of its effects are poorly characterized. We hypothesized that 5-uRCK and one of its major bioactive compounds, ellagic acid, decrease cellular and plasma cholesterol levels. Thus, we investigated the hypocholesterolemic activity and mechanism of 5-uRCK in both hepatocytes and a high-cholesterol diet (HCD)-induced rat model. Cholesterol in the liver and serum was significantly reduced by 5-uRCK and ellagic acid. The hepatic activities of HMG-CoA and CETP were reduced, and the hepatic activity of LCAT was increased by both 5-uRCK extract and ellagic acid, which also caused histological improvements. The MDA content in the aorta and serum was significantly decreased after oral administration of 5-uRCK or ellagic acid. Further immunoblotting analysis showed that AMPK phosphorylation in the liver was induced by 5-uRCK and ellagic acid, which activated AMPK, inhibiting the activity of HMGCR by inhibitory phosphorylation. In contrast, 5-uRCK and ellagic acid suppressed the nuclear translocation and activation of SREBP-2, which is a key transcription factor in cholesterol biosynthesis. In conclusion, our results suggest that 5-uRCK and its bioactive compound, ellagic acid, are useful alternative therapeutic agents to regulate blood cholesterol.

Neurolytic abdominal wall blocks with alcohol for intractable gastrostomy site pain in a cancer patient -a case report.

BACKGROUND: There have been reports of neurolytic transversus abdominis plane (TAP) block using different agents such as alcohol or phenol for the treatment of chronic abdominal pain caused by malignant abdominal wall invasion. However, to date, there have been no reports on neurolytic abdominal wall blocks for pain with non-cancer-related origin in cancer patients. CASE: We performed subcostal TAP neurolysis using ethanol in a patient with esophageal cancer with constant pain at the site of gastrostomy. After neurolysis, the patient's overall pain decreased, with the exception of pain in the medial part of the gastrostomy site. We performed additional rectus sheath neurolysis using ethanol for the treatment of continuous pain at the medial site, and the effect of neurolysis has persisted for over 4 months. CONCLUSIONS: Alcohol-based TAP neurolysis and rectus sheath neurolysis provide effective pain control in a cancer patient with chronic treatment-related pain involving the abdominal wall.

Amyloid ß1-42 (Aß1-42) Induces the CDK2-Mediated Phosphorylation of Tau through the Activation of the mTORC1 Signaling Pathway While Promoting Neuronal Cell Death.

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by cognitive impairment and memory loss. Amyloid ß1-42 (Aß) and hyper-phosphorylation of microtubule-associated protein tau have been considered as major histological features in AD. However, the mechanism of how Aß induces the hyper-phosphorylation of tau remains to be clarified. In the present study, we investigated the underlying cellular mechanisms of Aß with regard to the cell cycle regulatory protein-mediated phosphorylation of tau in promoting neuronal cell death. The oligomer Aß (5 µM) significantly increased the level of caspase 3 cleavage and has the ability to induce cytotoxicity in human neuroblastoma SK-N-MC cells. Aß induced the degree of extracellular calcium influx via the L-type channel to facilitate the production of reactive oxygen species (ROS). Aß signaling through ROS production is uniquely mediated by the activation of PI3K/Akt, which is in turn required for mammalian target of rapamycin complex 1 (mTORC1) phosphorylation. mTORC1 activated by Aß further increased the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), a binding protein (4E-BP1) and p70S6K1 to stimulate the HIF1α synthesis responsible for the induction of cyclinD1/cyclin-dependent kinase 4 (CDK4) and cyclinE/CDK2, whereas it significantly attenuated the activation of autophagy. Aß distinctively induced the CDK2-mediated phosphorylation of tau, which is responsible for microtubule destabilization in promoting neuronal apoptosis. In mouse hippocampal primary neurons, the apoptotic cell death induced by Aß is highly susceptible to the mTORC1 signaling pathway. These results demonstrate that Aß efficiently stimulates the mTORC1 signaling pathway to facilitate HIF1α synthesis and autophagy inhibition to promote the expression of cell cycle regulatory proteins, during which CDK2 uniquely stimulates tau phosphorylation for microtubule destabilization-mediated neuronal apoptosis.

Aß-Induced Drp1 phosphorylation through Akt activation promotes excessive mitochondrial fission leading to neuronal apoptosis.

Mitochondrial dysfunction is known as one of causative factors in Alzheimer's disease (AD), inducing neuronal cell death. Mitochondria regulate their functions through changing their morphology. The present work was undertaken to investigate whether Amyloid ß (Aß) affects mitochondrial morphology in neuronal cells to induce apoptosis. Aß treatment induced not only the fragmentation of mitochondria but also neuronal apoptosis in association with an increase in caspase-9 and -3 activity. Calcium influx induced by Aß up-regulated the activation of Akt through CaMKII resulting in changes to the phosphorylation level of Drp1 in a time-dependent manner. Translocation of Drp1 from the cytosol to mitochondria was blocked by CB-124005 (an Akt inhibitor). Recruitment of Drp1 to mitochondria led to ROS generation and mitochondrial fission, accompanied by dysfunction of mitochondria such as loss of membrane potential and ATP production. ROS generation and mitochondrial dysfunction by Aß were attenuated when treated with Mdivi-1, a selective Drp1 inhibitor. Furthermore, the sustained Akt activation induced not only the fragmentation of mitochondria but also the activation of mTOR, eventually suppressing autophagy. Inhibition of autophagic clearance of Aß led to increased ROS levels and aggravating mitochondrial defects, which were blocked by Rapamycin (an mTOR inhibitor). In conclusion, sustained phosphorylation of Akt by Aß directly activates Drp1 and inhibits autophagy through the mTOR pathway. Together, these changes elicit abundant mitochondrial fragmentation resulting in ROS-mediated neuronal apoptosis.

Multi-biofunction of antimicrobial peptide-immobilized silk fibroin nanofiber membrane: Implications for wound healing.

UNLABELLED: An antimicrobial peptide motif (Cys-KR12) originating from human cathelicidin peptide (LL37) was immobilized onto electrospun SF nanofiber membranes using EDC/NHS and thiol-maleimide click chemistry to confer the various bioactivities of LL37 onto the membrane for wound care purposes. Surface characterizations revealed that the immobilization density of Cys-KR12 on SF nanofibers could be precisely controlled with a high reaction yield. The Cys-KR12-immobilized SF nanofiber membrane exhibited antimicrobial activity against four pathogenic bacterial strains (Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa) without biofilm formation on the membrane surface. It also facilitated the proliferation of keratinocytes and fibroblasts and promoted the differentiation of keratinocytes with enhanced cell-cell attachment. In addition, immobilized Cys-KR12 significantly suppressed the LPS-induced TNF-α expression of monocytes (Raw264.7) cultured on the membrane. These results suggest that a Cys-KR12-immobilized SF nanofiber membrane, which has multiple biological activities, would be a promising candidate as a wound dressing material. STATEMENT OF SIGNIFICANCE: This research article reports various bioactivities of an antimicrobial peptide on electrospun silk fibroin nanofiber membrane. Recently, human cathelicidin peptide LL37 has been extensively explored as an alternative antibiotic material. It has not only a great antimicrobial activity but also a wide variety of bioactivities which can facilitate wound healing process. Especially, many studies on immobilization of LL37 or its analogues have shown the immobilization technique could improve performance of wound dressing materials or tissue culture matrices. Nevertheless, so far studies have only focused on the bactericidal effect of immobilized peptide on material surface. On the other hand, we tried to evaluate multi-biofunction of immobilized antimicrobial peptide Cys-KR12, which is the shortest peptide motif as an analogue of LL37. We fabricated silk fibroin nanofiber membrane as a model wound dressing by electrospinning and immobilized the antimicrobial peptide. As a result, we confirmed that the immobilized peptide can play multi-role in wound healing process, such as antimicrobial activity, facilitation of cell proliferation and keratinocyte differentiation, and inhibition of inflammatory cytokine expression. These findings have not been reported and can give an inspiration in wound-care application.

Ultraviolet-C efficacy against a norovirus surrogate and hepatitis A virus on a stainless steel surface.

In this study, the effects of 10-300 mWs/cm(2) of ultraviolet radiation (UV-C) at 260 nm were investigated for the inactivation of two foodborne viruses: murine norovirus-1 (MNV-1; a human norovirus [NoV] surrogate) and hepatitis A virus (HAV). We used an experimentally contaminated stainless steel surface, a common food-contact surface, to examine the effects of low doses of UV-C radiation on MNV-1 and HAV titers. The modified Gompertz equation was used to generate non-linear survival curves and calculate dR-values as the UV-C dose of 90% reduction for MNV-1 (R(2)=0.95, RMSE=0.038) and HAV (R(2)=0.97, RMSE=0.016). Total MNV-1 and HAV titers significantly decreased (p<0.05) with higher doses of UV-C. MNV-1 and HAV were reduced to 0.0-4.4 and 0.0-2.6 log10PFU/ml, respectively, on the stainless steel surfaces by low-dose UV-C treatment. The dR-value, 33.3 mWs/cm(2) for MNV-1 was significantly (p<0.05) lower than 55.4 mWs/cm(2) of HAV. Therefore, the present study shows that HAV is more resistant to UV-C radiation than MNV-1. These data suggest that low doses of UV-C light on food contact surfaces could be effective to inactivate human NoV and HAV in restaurant, institutional, and industrial kitchens and facilities.

The effect of combination treatment using palonosetron and dexamethasone for the prevention of postoperative nausea and vomiting versus dexamethasone alone in women receiving intravenous patient-controlled analgesia.

BACKGROUND: The purpose of this study was to evaluate the effect of palonosetron combined with dexamethasone for the prevention of PONV compared to dexamethasone alone in women who received intravenous patient-controlled analgesia (IV-PCA) using fentanyl. METHODS: In this randomized, double-blinded, placebo-controlled study, 204 healthy female patients who were scheduled to undergo elective surgery under general anesthesia followed by IV-PCA for postoperative pain control were enrolled. Patients were divided into two groups: the PD group (palonosetron 0.075 mg and dexamethasone 5 mg IV; n = 102) and the D group (dexamethasone 5 mg IV; n = 102). The treatments were given after the induction of anesthesia. The incidence of nausea, vomiting, severity of nausea, and the use of rescue anti-emetics during the first 48 hours after surgery were evaluated. RESULTS: The incidence of PONV was significantly lower in the PD group compared with the D group during the 0-24 hours (43 vs. 59%) and 0-48 hours after surgery (45 vs. 63%) (P < 0.05). The severity of nausea during the 6-24 hours after surgery was significantly less in the PD group compared with the D group (P < 0.05). The incidence of rescue antiemetic used was significantly lower in the PD group than in the D group during the 0-6 hours after surgery (13.1 vs. 24.5%) (P < 0.05). CONCLUSIONS: Palonosetron combined with dexamethasone was more effective in preventing PONV compared to dexamethasone alone in women receiving IV-PCA using fentanyl.

Impact of serum C-reactive protein level on the prognosis of patients with hepatocellular carcinoma undergoing TACE.

BACKGROUND/AIMS: The aim of this study was to determine the relationship between serum CRP levels and the prognosis of hepatocellular carcinoma (HCC) patients. METHODS: HCC patients who underwent the first session of transcatheter arterial chemoembolization (TACE) between January 2005 and December 2009 (n=211) were analyzed retrospectively. The patients were divided into two groups: high C-reactive protein (CRP; ≥1 mg/dL, n=51) and low CRP (<1 mg/dL, n=160). They were followed for a mean of 22.44 months and their clinicoradiological variables and overall survival were compared. RESULTS: There were significant differences between the two groups in regard to tumor type, tumor-progression-free survival, 10-month mortality, white blood cell (WBC) count, tumor size, and TNM stage. Multivariate analysis revealed that a high serum CRP level was independently associated with tumor size and tumor type. Subgroup analysis of CRP groups according to tumor size demonstrated that a high serum level of CRP was significantly associated with poorly defined (diffuse) tumor type in the tumor size <5 cm group [hazard ratio (HR)=4.81, P=0.018]. A Lipiodol dose exceeding 7 mL (HR=5.55, P=0.046) and the 10-month mortality (HR=7.693, P=0.004) were significantly associated with high serum CRP level in the group of patients with a tumor size of ≥5 cm. In addition, subgroup analysis of matched CRP according to TNM stage revealed that elevated serum CRP was independently associated with tumor type, WBC count, and tumorprogression-free survival. CONCLUSIONS: A high serum CRP level is associated with large tumors and a poorly defined tumor type, and is significantly associated with 10-month mortality in patients with large HCC (size ≥5 cm) who undergo TACE.

Gene expression profiling of KBH-A42, a novel histone deacetylase inhibitor, in human leukemia and bladder cancer cell lines.

The aim of this study was to investigate the anti-tumor activity of KBH-A42, a novel synthetic histone deacetylase (HDAC) inhibitor. KBH-A42 was shown to significantly suppress the proliferation of all 14 human cancer cell lines tested. Among these cell lines, the human leukemia cell line K562 was the most sensitive, whereas the UM-UC-3 bladder cancer cells were the least sensitive. Additionally, in a human tumor xenograft model using Balb/c nude mice, KBH-A42 was shown to significantly inhibit the growth of K562 tumors, although it only slightly inhibited the growth of UM-UC-3 tumors. The results of flow cytometry analysis and caspase 3/7 activation assays showed that the growth inhibition of K562 cells by KBH-A42 was mediated, at least in part, by the induction of apoptosis, but its growth inhibitory effects on UM-UC-3 cells were not mediated by apoptotic induction. In an effort to gain insight into the mechanism by which KBH-A42 inhibits the growth of cancer cells, a microarray analysis was conducted. Four genes were selected from the genes that were down-regulated or up-regulated by KBH-A42 and confirmed via reverse transcription-polymerase chain reaction as follows: Harakiri (HRK), tumor necrosis factor receptor superfamily, member 10b (TNFRSF10B), PYD and CARD domain containing protein gene (PYCARD) and tumor necrosis factor receptor superfamily, member 8 (TNFRSF8). Collectively, the in vitro and in vivo results suggested that KBH-A42 exhibits anti-cancer activity, but various types of cells may be regulated differentially by KBH-A42.

Widdrol induces apoptosis via activation of AMP-activated protein kinase in colon cancer cells.

Widdrol, a natural sesquiterpene present in Juniperus sp., has been shown to exert anticancer and antifungal effects. Emerging evidence has suggested that AMP-activated protein kinase (AMPK), which functions as a cellular energy sensor, is a potential therapeutic target for human cancers. In this study, we found that AMPK mediates the anticancer effects of widdrol through induction of apoptosis in HT-29 colon cancer cells. We showed that widdrol induced the phosphorylation of AMPK in a dose- and time-dependent manner. The selective AMPK inhibitor compound C abrogated the inhibitory effect of widdrol on HT-29 cell growth. In addition, we demonstrated that widdrol induced apoptosis and this was associated with the activation of caspases, including caspase­3/7 and caspase-9, in HT-29 cells. We also demonstrated that transfection of HT-29 cells with AMPK siRNAs significantly suppressed the widdrol-mediated apoptosis and the activation of caspases. However, cell cycle arrest induced by widdrol was not affected by transfection of HT-29 cells with AMPK siRNAs. Furthermore, widdrol inhibited HT-29 tumor growth in a human tumor xenograft model. Taken together, our results suggest that the anticancer effect of widdrol may be mediated, at least in part, by induction of apoptosis via AMPK activation.

DBM1285 suppresses tumor necrosis factor alpha production by blocking p38 mitogen-activated protein kinase/mitogen-activated protein kinase-activated protein kinase 2 signaling pathway.

Tumor necrosis factor alpha (TNF-alpha) is a major inflammatory cytokine that plays an important role in the development of various inflammatory diseases. TNF-alpha has been considered as a potential therapeutic target for the treatment of chronic inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. In this study, we report that cyclopropyl-{4-[4-(4-fluorophenyl)-2-piperidin-4-yl-thiazol-5-yl]pyrimidin-2-yl}amine (DBM1285) is a novel inhibitor of TNF-alpha production. DBM1285 concentration-dependently inhibited lipopolysaccharide (LPS)-induced TNF-alpha secretion in various cells of macrophage/monocyte lineage, including mouse bone marrow macrophages, THP-1 cells, and RAW 264.7 cells. However, LPS-induced mRNA expression of TNF-alpha was not affected by DBM1285 in these cells. Further studies demonstrated that the inhibitory effect of DBM1285 on TNF-alpha production might be mediated by post-transcriptional regulation through the modulation of the p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein kinase 2 (MK2) signaling pathway. We also confirmed that DBM1285 directly inhibits p38 MAPK enzymatic activity. In vivo administration of DBM1285 inhibited LPS-induced increase in the plasma level of TNF-alpha in mice. Whole-blood in vivo target inhibition assay also revealed that DBM1285 attenuates p38 MAPK activity after oral administration in mice. Moreover, DBM1285 suppressed zymosan-induced inflammation and adjuvant-induced arthritis in murine models. Collectively, these results suggest that DBM1285 inhibits TNF-alpha production, at least in part, by blocking the p38 MAPK/MK2 pathway. Furthermore, in vivo results suggest that DBM1285 might be a possible therapeutic candidate for the treatment of TNF-alpha-related chronic inflammatory diseases.

A lipid-soluble red ginseng extract inhibits the growth of human lung tumor xenografts in nude mice.

Lipid-soluble ginseng extract was prepared by n-hexane extraction of red ginseng. BALB/c-nu mice were inoculated with human lung cancer (NCI-H460) cells to establish a human tumor xenograft model in nude mice, and the lipid-soluble ginseng extract was orally administered. The tumor inhibitory rates of the lipid-soluble ginseng extract at doses of 0.1, 0.3, and 1.0 g/kg/day were 18.9% (P < .05), 60.0% (P < .001), and 67.5% (P < .001), respectively. The oral administration of the lipid-soluble extract of red ginseng showed a potent anticancer effect in nude mice bearing human lung cancer cells in a dose-dependent manner without any apparent toxicity. This lipid-soluble ginseng extract is a potential nontoxic anticancer supplement for the prevention and intervention of lung tumor growth through an oral administration route.

KBH-A42, a histone deacetylase inhibitor, inhibits the growth of doxorubicin-resistant leukemia cells expressing P-glycoprotein.

Multidrug resistance mediated by the drug efflux protein, P-glycoprotein (P-gp), is one of the principal mechanisms by which tumor cells escape the cell death induced by chemotherapeutic agents. In our previous study, we demonstrated that KBH-A42 [N-hydroxy-3-(2-oxo-1-(3-phenylpropyl)-1,2,5,6-tetrahydropyridin-3-yl)propanamide], a synthetic histone deacetylase inhibitor, effectively inhibited the growth of several human cancer cell lines. In this study, we attempted to determine whether KBH-A42 was also capable of inhibiting the growth of multidrug-resistant cells. Doxorubicin dose-dependently inhibited the growth of P-gp-negative K562 human leukemia cells, but did not show substantial inhibition on the growth of P-gp-positive K562/ADR cells even at 10 microM, the highest concentration of KBH-A42 used, which increased the acetylation of histones in these leukemia cells, dose-dependently and effectively inhibited the cell growth, regardless of the presence of P-gp in the cells. KBH-A42 mediated G0/G1 cell cycle arrest, probably as the result of the down-regulation of CDK2, CDK4 and CDK6 and the up-regulation of p21WAF1. When the expression of p21WAF1 was ablated by a specific siRNA, the inhibition of cell growth by KBH-A42 was partly reduced in both cell lines. In addition to the cell cycle arrest, KBH-A42 also induced apoptosis in these cells, which was accompanied by the activation of caspases, including caspase-9, caspase-8 and caspase-3. The pan-caspase inhibitor, Z-VAD-fmk, partially blocked the cell death induced by KBH-A42. These results indicate that KBH-A42 induces cell cycle arrest and apoptosis via the up-regulation of p21WAF1 and caspase activation, respectively, regardless of the presence of P-gp in the leukemia cells.

Glabridin inhibits lipopolysaccharide-induced activation of a microglial cell line, BV-2, by blocking NF-kappaB and AP-1.

Glabridin, a flavonoid present in licorice root, is known to have antiinflammatory and cardiovascular protective activities. The present study reports an inhibitory effect of glabridin on microglial activation. Glabridin dose-dependently attenuated lipopolysaccharide (LPS)-induced production of inflammatory mediators, including nitric oxide, tumor necrosis factor-alpha and interleukin-1beta, in BV-2 cells, a murine microglia cell line. Moreover, mRNA expression of these inflammatory mediators was also suppressed by glabridin in LPS-stimulated BV-2 cells. Further study demonstrated that glabridin inhibited LPS-induced DNA binding activity of NF-kappaB and AP-1 in BV-2 cells. Collectively, the results presented in this report demonstrate that glabridin inhibits the production of inflammatory mediators in BV-2 cells and this is mediated, at least in part, by blocking NF-kappaB and AP-1 activation. The results suggest that glabridin might be a potential therapeutic agent for the treatment of neuroinflammatory and neurodegenerative diseases.

A novel delta-lactam-based histone deacetylase inhibitor, KBH-A42, induces cell cycle arrest and apoptosis in colon cancer cells.

In this study, we investigated the anti-tumor activity of KBH-A42 [N-hydroxy-3-(2-oxo-1-(3-phenylpropyl)-1,2,5,6-tetrahydropyridin-3-yl)propanamide], a novel synthetic histone deacetylase (HDAC) inhibitor. KBH-A42 inhibited a variety of HDAC isoforms in enzyme assays and suppressed growth of various cancer cell lines. Among the cell lines examined, colon cancer cells, including SW620, SW480 and HCT-15, were the cell types most sensitive to KBH-A42. KBH-A42 inhibition of cancer cell growth was comparable to or stronger than that of suberoylanilide hydroxamic acid (SAHA), a well-known HDAC inhibitor approved by the FDA to treat cutaneous T cell lymphomas. In SW620 cells, KBH-A42 increased the acetylation of histones, mediated cell cycle arrest (G1 arrest at low doses and G2 arrest at high doses), and induced apoptosis. The cell cycle arrest and apoptosis induced by KBH-A42 might be mediated through up-regulation of p21(Waf1) and activation of caspases, respectively. In addition, KBH-A42 inhibited SW620 tumor growth in a human tumor xenograft model. Taken together, our results indicate that KBH-A42 exerts an anti-tumor activity in vitro and in vivo and is a promising therapeutic candidate to treat human cancers.

Low dose estrogen supplementation reduces mortality of mice in estrogen-dependent human tumor xenograft model.

Breast cancer is one of the most frequent female cancers in the Western world. Perturbation of estrogen levels by hormone replacement therapy or pregnancy is associated with a variety of diseases, including breast cancer. Estrogen supplementation is required to establish appropriate animal models for estrogen-related diseases. In this report, we demonstrated that supplementation with high doses of 17beta-estradiol results in deaths in estrogen-dependent MCF-7 tumor xenograft model. Renal damage and bladder stone formation was implicated as a major cause of death. The mortality rate was significantly reduced when mice received a low dose of 17beta-estradiol. We also confirmed that low dose of 17beta-estradiol supplementation can support the growth of tumors in MCF-7 tumor xenograft model. These results suggest that low dose estrogen supplementation may be more appropriate in estrogen-dependent tumor xenograft models.

Comparative clinical trial of S-adenosylmethionine versus nabumetone for the treatment of knee osteoarthritis: an 8-week, multicenter, randomized, double-blind, double-dummy, Phase IV study in Korean patients.

BACKGROUND: S-adenosylmethionine (SAMe) has antiinflammatory and analgesic effects and has been reported to ameliorate the pain and dysfunction of osteoarthritis (OA). The metabolism of SAMe can be affected by geographic or ethnic factors. However, its efficacy and tolerability versus NSAIDs have not been reported in an Asian population. OBJECTIVE: This study compared the efficacy and tolerability of SAMe 1200 mg/d and nabumetone 1000 mg/d in Korean patients with knee OA. METHODS: This study was an 8-week, multicenter, randomized, double-blind, double-dummy, Phase IV clinical trial. Eligible patients were aged >18 years and had knee OA according to the clinical and radiologic criteria of the American College of Rheumatology, with a symptom duration of > or =3 months and with a baseline pain rating of >40 mm on a visual analog scale (VAS) or a pain rating on the VAS that was increased by >10 mm or 20% during the washout period compared with the screening visit. After a washout period of 2 weeks, patients with OA were randomly assigned to receive SAMe 1200 mg/d (400 mg TID) or nabumetone 1000 mg once a day in the evening for 8 weeks. The primary end point was the patient's assessment of pain intensity using a VAS at week 8, and the secondary end points were functional class, patient's global assessment of disease status, physician's global assessment of response to therapy, and the Western Ontario and McMaster Universities (WOMAC) index. Adverse events were assessed based on spontaneous reports by patients during interviews and by laboratory tests. RESULTS: One hundred thirty-four patients, all Asians, were randomly allocated to 1 of 2 treatment groups: 67 patients (56 women, 11 men; mean [SD] age, 63.9 [8.2] years) received SAMe 400 mg TID, and 67 patients (60 women, 7 men; mean age, 62.1 [8.4] years) received nabumetone 1000 mg once daily for 8 weeks. An analysis of changes in pain intensity between weeks 0 and 8 found that both SAMe and nabumetone effectively reduced pain intensity from baseline in each group (mean [SD] change: SAMe, -13.0 [20.8] mm, P < 0.001; nabumetone, -15.7 [20.9] mm, P < 0.001), and the degree of decrease in pain intensity was not significantly different between groups. Secondary end points showed significant improvements from baseline to 8 weeks in both groups. The patient's global assessment of disease status, physician's global assessment of response to therapy, and WOMAC index scores were not significantly different between the groups. Use of acetaminophen as rescue medication did not differ significantly between the groups during weeks 0 to 4 (SAMe, 88.5% [54/61]; nabumetone, 81.3% [52/64]) or weeks 4 to 8 (SAMe, 79.5% [35/44]; nabumetone, 68.5% [37/54]). No significant differences were observed between the treatments in the proportions of patients with all adverse events (SAMe, 35.8% [24/67]; nabumetone, 31.3% [21/67]), drugrelated clinical or laboratory-determined adverse events (SAMe, 22.4% [15/67]; nabumetone, 25.4% [17/67]), or discontinuations due to any adverse events (SAMe, 13.4% [9/67]; nabumetone, 10.4% [7/67]). CONCLUSION: This study found no significant differences in pain relief or tolerability between treatment with SAMe or nabumetone over 8 weeks in Korean patients with knee OA.