Effects of high fat diets and supplemental tart cherry and fish oil on obesity and type 2 diabetes in male and female C57BL/6J and TALLYHO/Jng mice.

Obesogenic and diabetogenic high fat (HF) diets can influence genetic factors in disease development with sexual dimorphic responses. We investigated potential protective effects of tart cherry (TC), fish oil (FO) and TC+FO supplementation in TALLYHO/Jng (TH) and C57BL/6J (B6) mice fed HF diets. Male and female TH and B6 mice were weaned onto five different diets; low fat (LF), HF, and HF supplemented with TC, FO, or TC+FO and maintained. For both males and females on LF, TH mice were heavier and fatter than B6, which was accentuated by HF in males, but not in females. TH males, but not others, developed severe glucose intolerance and hyperglycemia on HF, with reduced mRNA levels of Adipoq and Esr1 in adipose tissue. Considering energy balance, locomotor activity was lower in TH mice than B6 for both sexes without diet effects, except B6 females where HF decreased it. Compared to LF, HF decreased energy expenditure, RER, and food intake (in grams) for both sexes without strain differences. In all mice, but B6 males, HF increased plasma IL6 levels compared to LF. No preventive effects of TC, FO or TC+FO were noted for HF-induced obesity or energy imbalance, but FO alleviated glucose intolerance in TH males. Further, TC and FO decreased plasma IL6 levels, especially in females, without additive or synergistic effects of these two. Collectively, obesogenic and diabetogenic impacts of HF diets differed depending on the genetic predisposition. Moreover, sexually dimorphic effects of dietary supplementation were observed for glucose metabolism and inflammatory markers.

Multifunctional Two-Dimensional PtSe2-Layer Kirigami Conductors with 2000% Stretchability and Metallic-to-Semiconducting Tunability.

Two-dimensional transition-metal dichalcogenide (2D TMD) layers are highly attractive for emerging stretchable and foldable electronics owing to their extremely small thickness coupled with extraordinary electrical and optical properties. Although intrinsically large strain limits are projected in them (i.e., several times greater than silicon), integrating 2D TMDs in their pristine forms does not realize superior mechanical tolerance greatly demanded in high-end stretchable and foldable devices of unconventional form factors. In this article, we report a versatile and rational strategy to convert 2D TMDs of limited mechanical tolerance to tailored 3D structures with extremely large mechanical stretchability accompanying well-preserved electrical integrity and modulated transport properties. We employed a concept of strain engineering inspired by an ancient paper-cutting art, known as kirigami patterning, and developed 2D TMD-based kirigami electrical conductors. Specifically, we directly integrated 2D platinum diselenide (2D PtSe2) layers of controlled carrier transport characteristics on mechanically flexible polyimide (PI) substrates by taking advantage of their low synthesis temperature. The metallic 2D PtSe2/PI kirigami patterns of optimized dimensions exhibit an extremely large stretchability of ∼2000% without compromising their intrinsic electrical conductance. They also present strain-tunable and reversible photoresponsiveness when interfaced with semiconducting carbon nanotubes (CNTs), benefiting from the formation of 2D PtSe2/CNT Schottky junctions. Moreover, kirigami field-effect transistors (FETs) employing semiconducting 2D PtSe2 layers exhibit tunable gate responses coupled with mechanical stretching upon electrolyte gating. The exclusive role of the kirigami pattern parameters in the resulting mechanoelectrical responses was also verified by a finite-element modeling (FEM) simulation. These multifunctional 2D materials in unconventional yet tailored 3D forms are believed to offer vast opportunities for emerging electronics and optoelectronics.

Three dimensionally-ordered 2D MoS2 vertical layers integrated on flexible substrates with stretch-tunable functionality and improved sensing capability.

The intrinsically anisotropic crystallinity of two-dimensional (2D) transition metal dichalcogenide (2D TMD) layers enables a variety of intriguing material properties which strongly depend on the physical orientation of constituent 2D layers. For instance, 2D TMDs with vertically-aligned layers exhibit numerous dangling bonds on their 2D layer edge sites predominantly exposed on the surface, projecting significantly improved physical and/or chemical adsorption capability compared to their horizontally-oriented 2D layer counterparts. Such property advantages can be further promoted as far as the material can be integrated onto unconventional substrates of tailored geometry/functionality, offering vast opportunities for a wide range of applications which demand enhanced surface area/reactivity and mechanical flexibility. Herein, we report a new form of 2D TMDs, i.e., three-dimensionally ordered 2D molybdenum disulfide (2D MoS2) with vertically-aligned layers integrated on elastomeric substrates and explore their tunable multi-functionalities and technological promise. We grew large-scale (>2 cm2) vertically-aligned 2D MoS2 layers using a three-dimensionally patterned silicon dioxide (SiO2) template and directly transferred/integrated them onto flexible polydimethylsiloxane (PDMS) substrates by taking advantage of the distinguishable water-wettability of 2D MoS2vs. SiO2. The excellent structural integrity of the integrated vertical 2D MoS2 layers was confirmed by extensive spectroscopy/microscopy characterization. In addition, the stretch-driven unique tunability of their optical and surface properties was also examined. Moreover, we applied this material for flexible humidity sensing and identified significantly improved (>10 times) sensitivity over conventionally-designed horizontal 2D MoS2 layers, further confirming their high potential for unconventional flexible technologies.

The Effects of Kaempferol-Inhibited Autophagy on Osteoclast Formation.

Kaempferol, a flavonoid compound, is derived from the rhizome of Kaempferia galanga L., which is used in traditional medicine in Asia. Autophagy has pleiotropic functions that are involved in cell growth, survival, nutrient supply under starvation, defense against pathogens, and antigen presentation. There are many studies dealing with the inhibitory effects of natural flavonoids in bone resorption. However, no studies have explained the relationship between the autophagic and inhibitory processes of osteoclastogenesis by natural flavonoids. The present study was undertaken to investigate the inhibitory effects of osteoclastogenesis through the autophagy inhibition process stimulated by kaempferol in murin macrophage (RAW 264.7) cells. The cytotoxic effect of Kaempferol was investigated by MTT assay. The osteoclast differentiation and autophagic process were confirmed via tartrate-resistant acid phosphatase (TRAP) staining, pit formation assay, western blot, and real-time PCR. Kaempferol controlled the expression of autophagy-related factors and in particular, it strongly inhibited the expression of p62/SQSTM1. In the western blot and real time-PCR analysis, when autophagy was suppressed with the application of 3-Methyladenine (3-MA) only, osteoclast and apoptosis related factors were not significantly affected. However, we found that after cells were treated with kaempferol, these factors inhibited autophagy and activated apoptosis. Therefore, we presume that kaempferol-inhibited autophagy activated apoptosis by degradation of p62/SQSTM1. Further study of the p62/SQSTM1 gene as a target in the autophagy mechanism, may help to delineate the potential role of kaempferol in the treatment of bone metabolism disorders.

Centimeter-Scale 2D van der Waals Vertical Heterostructures Integrated on Deformable Substrates Enabled by Gold Sacrificial Layer-Assisted Growth.

Two-dimensional (2D) transition metal dichalcogenides (TMDs) such as molybdenum or tungsten disulfides (MoS2 or WS2) exhibit extremely large in-plane strain limits and unusual optical/electrical properties, offering unprecedented opportunities for flexible electronics/optoelectronics in new form factors. In order for them to be technologically viable building-blocks for such emerging technologies, it is critically demanded to grow/integrate them onto flexible or arbitrary-shaped substrates on a large wafer-scale compatible with the prevailing microelectronics processes. However, conventional approaches to assemble them on such unconventional substrates via mechanical exfoliations or coevaporation chemical growths have been limited to small-area transfers of 2D TMD layers with uncontrolled spatial homogeneity. Moreover, additional processes involving a prolonged exposure to strong chemical etchants have been required for the separation of as-grown 2D layers, which is detrimental to their material properties. Herein, we report a viable strategy to universally combine the centimeter-scale growth of various 2D TMD layers and their direct assemblies on mechanically deformable substrates. By exploring the water-assisted debonding of gold (Au) interfaced with silicon dioxide (SiO2), we demonstrate the direct growth, transfer, and integration of 2D TMD layers and heterostructures such as 2D MoS2 and 2D MoS2/WS2 vertical stacks on centimeter-scale plastic and metal foil substrates. We identify the dual function of the Au layer as a growth substrate as well as a sacrificial layer which facilitates 2D layer transfer. Furthermore, we demonstrate the versatility of this integration approach by fabricating centimeter-scale 2D MoS2/single walled carbon nanotube (SWNT) vertical heterojunctions which exhibit current rectification and photoresponse. This study opens a pathway to explore large-scale 2D TMD van der Waals layers as device building blocks for emerging mechanically deformable electronics/optoelectronics.

Patterns of Initial Recurrence in Completely Resected Papillary Thyroid Carcinoma.

BACKGROUND: Despite improvements in the surgical and medical treatment of papillary thyroid carcinoma (PTC), subsets of patients suffer from structural recurrence after initial treatment. This study evaluated the timing and patterns of recurrence in completely resected PTC patients. METHODS: A retrospective review of a prospectively maintained thyroid cancer database was performed. The timing and patterns of recurrence were reviewed in 2250 patients with PTC >1 cm who achieved complete remission after total thyroidectomy and/or radioactive iodine treatment. Univariate and multivariate analyses were performed to identify factors predictive of recurrence patterns. RESULTS: During 8.1 years of mean follow-up, 68 (3.0%) patients developed structural recurrences: 53 lymph node recurrences (LNR), 11 local soft tissue recurrences (LR), and four distant recurrences (DR). Two patients died of DR. Younger patients had a higher proportion of LNR, and older patients had a tendency toward LR/DR. LNR showed a peak incidence between one and three years after remission, but LR/DR showed a delayed peak incidence between two and four years. The factors that significantly increased the risk of LNR were multifocal tumor and lymph node metastasis (central/lateral). The factors that increased the risk of LR/DR were old age, large tumor size (>2 cm), and lateral lymph node metastasis. In addition, central neck dissection significantly reduced subsequent LR/DR. CONCLUSION: Patterns of recurrence after complete PTC resection are variable and associated with specific clinicopathologic factors. Understanding the timing and patterns of recurrence may lead to more effective adjuvant treatment and improved long-term follow-up strategies.

Preserving Parathyroid Gland Vasculature to Reduce Post-thyroidectomy Hypocalcemia.

BACKGROUND: The failure to preserve parathyroid function in patients who have undergone total thyroidectomy is of major concern, because hypocalcemia is difficult to prevent and remains a common postoperative complication. Here, we describe procedures designed to preserve the vasculature supplying the parathyroid glands and examine both recent outcomes and retrospective reports of results obtained prior to the application of these preservation techniques. METHODS: Our technique for preserving parathyroid function during thyroidectomy was adopted in 2009 and involves separating a relatively long segment of a vessel distally from the thyroid gland. We reviewed the medical records of 1,411 patients who underwent total thyroidectomy, with or without lateral neck dissection, at the Samsung Medical Center from January 2006 through June 2014 to determine outcomes. Patients were divided into three groups according to the time period during which the surgery took place: Group A, 2006-2008 (before the vasculature-preserving technique was applied); Group B, 2009-2011 (the time when the technique was first adopted); and Group C, 2012-2014 (more recent results of the technique). We analyzed the incidence of hypoparathyroidism in the three groups, as well as risk factors that influenced its development. RESULTS: The rates of transient and permanent hypoparathyroidism in Group A were 25.4 and 4.3 %, respectively. However, the incidence of hypoparathyroidism decreased significantly over time after the vasculature-preserving procedure was adopted. Transient hypoparathyroidism developed in 4.8 % of Group C patients, and only four (0.7 %) of the 565 patients in this group required calcium supplementation, despite the fact that a greater number of patients were included who underwent total thyroidectomy combined with lateral neck dissection. Although female sex and lateral neck dissection tended to increase the rate of transient hypoparathyroidism, multivariate analysis showed that the vasculature-preserving procedure was the only significant risk factor related to postoperative hypoparathyroidism. CONCLUSION: The blood flow of the final branch to the parathyroid gland is mostly in the lateral-to-medial direction; therefore, mobilization and preservation of the vessels lateral to the gland is essential to prevent devascularization of the parathyroid gland.

Radioactive iodine ablation may not decrease the risk of recurrence in intermediate-risk papillary thyroid carcinoma.

The use of radioactive iodine (RAI) ablation in patients with intermediate-risk papillary thyroid carcinoma (PTC) who show microscopic extrathyroidal extension (ETE), regional lymph node (LN) metastasis, tumors with aggressive histology, or vascular invasion has been debated due to the lack of data regarding long-term prognosis in this risk group. Therefore, the purpose of this study was to resolve the controversy surrounding the prognostic benefit of RAI ablation, especially in intermediate-risk PTC patients. We retrospectively reviewed the medical records of 8297 intermediate-risk PTC patients who underwent primary total thyroidectomy with or without neck dissection at the Thyroid Cancer Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea, between January 1997 and June 2015. Of these 8297 patients, 7483 (90.2%) received RAI ablation. After adjusting for clinicopathological characteristics, RAI ablation did not significantly decrease the risk of loco-regional recurrence (LRR) (adjusted hazard ratio (HR) 0.852, P 0.413). Moreover, RAI ablation did not decrease the risk of LRR even in intermediate-risk PTC patients with aggressive features such as BRAF positivity (adjusted HR 0.729, P 0.137), tumor size >1 cm (adjusted HR 0.762, P 0.228), multifocality (adjusted HR 1.032, P 0.926), ETE (adjusted HR 0.870, P 0.541), and regional LN metastasis (adjusted HR 0.804, P 0.349). Furthermore, high-dose RAI ablation (>100 mCi) did not significantly decrease the risk of LRR (adjusted HR 0.942, P 0.843). Therefore, RAI ablation in intermediate-risk PTC patients should be considered on the basis of tailored risk restratification.

Efficacy of the mineral oil and hyaluronic acid mixture eye drops in murine dry eye.

PURPOSE: To investigate the therapeutic effects of mineral oil (MO) and hyaluronic acid (HA) mixture eye drops on the tear film and ocular surface in a mouse model of experimental dry eye (EDE). METHODS: Eye drops consisting of 0.1% HA alone or mixed with 0.1%, 0.5%, or 5.0% MO were applied to desiccating stress-induced murine dry eyes. Tear volume, corneal irregularity score, tear film break-up time (TBUT), and corneal fluorescein staining scores were measured at 5 and 10 days after treatment. Ten days after treatment, goblet cells in the conjunctiva were counted after Periodic acid-Schiff staining. RESULTS: There was no significant difference in the tear volume between desiccating stress-induced groups. The corneal irregularity score was lower in the 0.5% MO group compared with the EDE and HA groups. The 0.5% and 5.0% MO groups showed a significant improvement in TBUT compared with the EDE group. Mice treated with 0.1% and 0.5% MO mixture eye drops showed a significant improvement in fluorescein staining scores compared with the EDE group and the HA group. The conjunctival goblet cell count was higher in the 0.5% MO group compared with the EDE group and HA group. CONCLUSIONS: The MO and HA mixture eye drops had a beneficial effect on the tear films and ocular surface of murine dry eye. The application of 0.5% MO and 0.1% HA mixture eye drops could improve corneal irregularity, the corneal fluorescein staining score, and conjunctival goblet cell count compared with 0.1% HA eye drops in the treatment of EDE.

Distant, solitary skeletal muscle metastasis in recurrent papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid cancer (PTC) is the most common differentiated thyroid carcinoma. Metastases usually occur in regional lymph nodes or to lungs. Distant metastases to skeletal muscle are rare. Here, we report a patient with a solitary metastasis to skeletal muscle. PATIENT FINDINGS: A 31-year-old woman was found on routine physical examination to have a 1-cm nodule in the right thyroid lobe. The patient underwent endoscopic total thyroidectomy with central cervical lymph node dissection in April 2008. Pathological analysis showed a 1.5 × 0.9 cm PTC in the right thyroid lobe with extension into perithyroidal soft tissue and lymph node involvement (all six central lymph nodes examined were positive). After surgery, she received 100 mCi of radioactive iodine. Subsequently, the patient was found to have a lateral neck recurrence and, therefore, underwent right unilateral modified radical neck dissection followed by additional radioactive iodine ablation. In February 2010, her serum thyroglobulin was 19.4 ng/mL, but the neck ultrasound was negative. However, a fluorodeoxyglucose (FDG) positron emission tomography scan showed focal FDG uptake in the vastus medialis muscle of the right distal femur. A 0.9 × 0.5 cm, well-defined, whitish mass in the vastus medialis muscle was confirmed on histopathology to be metastatic PTC. SUMMARY: Here, we report an adult woman who presented with a thyroid nodule that was noted to be PTC on histopathology after total thyroidectomy. Almost 2 years later, she was noted to have had focal FDG uptake consistent in the region of the right femur. A solitary metastasis of PTC in the right vastus medialis muscle was resected. A MEDLINE (Medical Literature Analysis and Retrieval System Online) search showed that this is only the third report of PTC with a distant, solitary skeletal muscle metastasis. CONCLUSIONS: Distant skeletal metastasis in PTC is very rare. Until the availability of FDG to detect skeletal metastasis of PTC, they may have been more difficult to discern.

Comparison of calcitriol versus cholecalciferol therapy in addition to oral calcium after total thyroidectomy with central neck lymph node dissection: a prospective randomized study.

BACKGROUND: The purpose of this study was to determine the effectiveness of oral calcium plus vitamin D supplementation and to compare the effects of cholecalciferol versus calcitriol treatments on postoperative hypocalcemia. METHODS: After total thyroidectomy with central neck dissection, 306 patients were divided into 4 groups according to "routine use versus on-demand use" and "cholecalciferol versus calcitriol." RESULTS: Hypocalcemic symptoms developed in 101 patients (33.0%). Hypocalcemia developed less frequently in patients receiving routine supplementation regardless of vitamin D type. However, routine supplementation did not prevent severe hypocalcemia. In patients receiving on-demand supplements, calcitriol was more effective and faster acting than was cholecalciferol. CONCLUSION: Routine oral calcium and vitamin D supplements are beneficial after total thyroidectomy with central neck lymph node dissection with no difference between cholecalciferol and calcitriol. If taken after the onset of hypocalcemia, however, calcitriol along with calcium carbonate seems to be more effective than is cholecalciferol with calcium carbonate.

12-O-Tetradecanoyl phorbol-13-acetate (TPA)-induced growth arrest is increased by silibinin by the down-regulation of cyclin B1 and cdc2 and the up-regulation of p21 expression in MDA-MB231 human breast cancer cells.

TPA is a potent regulator of cell growth, including cell proliferation and differentiation. In this study, we determined the effect of silibinin on TPA-induced growth arrest in breast cancer cells. Silibinin increased growth arrest of the G2/M phase in a dose-dependent fashion. Silibinin decreased the basal level of cyclin B1 and cdc2 expression, which is involved in S phase and G2/M transition. In addition, TPA-induced G2/M phase arrest was increased by silibinin. Under the same conditions, TPA-induced down-regulation of cyclin B1 and cdc2 was decreased by silibinin. In contrast, TPA-induced p21 expression was further increased by silibinin. To determine the regulatory mechanism of TPA-induced growth arrest, we pretreated cells with various inhibitors, such as UO126, SB203580, and LY294002. Interestingly, TPA-induced growth arrest was significantly increased by LY294002, but not by UO126 and SB203580. In addition, TPA-induced down-regulation of cyclin B1 was inhibited by LY294002; however, the basal level of p21 was increased by TPA and TPA-induced p21 expression was further increased by LY294002. Finally, adenoviral constitutively active-Akt (Ad-CA-Akt) overexpression regulated the up-regulation of cyclin B1 and the down-regulation of p21. Therefore, we have demonstrated that silibinin has an additive effect on TPA-induced growth arrest through the PI-3-kinase/Akt-dependent pathway.

A phase II study of pemetrexed and carboplatin as a salvage therapy for platinum-pretreated patients with non-small cell lung cancer.

BACKGROUND: Although platinum-based doublet chemotherapy is considered as standard of care for patients with advanced non-small cell lung cancer (NSCLC), most of them are eventually supposed to experience disease progression. Pemetrexed, docetaxel, erlotinib, and gefitinib have been shown to be active as monotherapy for pretreated patients. In this study, the efficacy of pemetrexed and carboplatin as a salvage therapy for patients with advanced NSCLC is evaluated. PATIENTS AND METHODS: From March 2007 to February 2009, 32 patients who were diagnosed with inoperable NSCLC and treated with one or more prior cisplatin-based chemotherapies were enrolled. Treatment consisted of pemetrexed 500 mg/m(2) over a 10-min intravenous infusion and carboplatin at an AUC 5 mg/mL/min over a 30-min intravenous infusion on Day 1 of a 21-day cycle. All patients were supplemented with folic acid and vitamin B12 to reduce the hematological toxicity of pemetrexed. RESULTS: There were one (3.1%) complete response and five partial (15.6%) responses. The overall response rate was 18.8% and the median response duration was 4.4 months. Among the responders, four patients had adenocarcinoma and two had squamous cell carcinoma. Nine patients had stable disease, and the disease control rate was 46.9%. With a median follow up duration of 9.4 months, the median time to progression was 2.3 months and the median OS was 9.4 months. Seven patients (21.9%) experienced grade 3 and 4 hematologic toxicities; one anemia (3.1%), six neutropenia (18.8%), and six thrombocytopenia (18.8%). Two patients experienced grade 4 febrile neutropenia with infection. Four patients (12.5%) experienced grade 3 non-hematologic toxicities; four asthenia (12.5%), two anorexia (6.3%), and one stomatitis (3.1%). Grade 1-2 peripheral neuropathy developed in 13 patients (40.6%). CONCLUSION: The combination of pemetrexed and carboplatin showed favorable toxicity profiles and activity in the pretreated patients with advanced NSCLC. It is suggested that this regimen can be a good chemotherapeutic option as a salvage therapy for patients with NSCLC.

Silibinin prevents TPA-induced MMP-9 expression by down-regulation of COX-2 in human breast cancer cells.

ETHNOPHARMACOLOGICAL RELEVANCE: The expression of matrix metalloproteinase-9 (MMP-9) and cyclooxygenase-2 (COX-2) are pivotal steps in breast cancer pathogenesis. In a previous study, we reported that silibinin suppresses TPA-induced MMP-9 expression through the Raf/MEK/ERK pathway. AIMS OF THE STUDY: Herein we determined the co-relationship between MMP-9 and COX-2, as well as the effect of silibinin on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 and COX-2 expression in the human breast cancer cells, MCF-7 and MDA-MB231. METHODS: The toxicity of silibinin was evaluated by Quick Cell Proliferation Assay Kit II. MMP-9 and COX-2 expression were analyzed by Zymography and Western blotting, respectively. Adenoviral constitutively active (CA)-MEK was used to activate MEK/ERK pathway. RESULTS: The expression of MMP-9 and COX-2 in response to TPA was increased, whereas TPA-induced MMP-9 and COX-2 expression was decreased by silibinin. Our results showed that TPA-induced MMP-9 expression was inhibited by celecoxib in a dose-dependent fashion, but not MMP-1-expression. Both MMP-9 and COX-2 expression were significantly increased by CA-MEK overexpression. In contrast, TPA-induced MMP-9 and COX-2 expression was decreased by UO126 (MEK 1/2 inhibitor). CONCLUSION: Silibinin down-regulates TPA-induced MMP-9 expression through inhibition of COX-2 expression in breast cancer cells.

Silibinin prevents TPA-induced MMP-9 expression and VEGF secretion by inactivation of the Raf/MEK/ERK pathway in MCF-7 human breast cancer cells.

Matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression are pivotal steps in cancer metastasis. Herein, we investigated the effect of silibinin, a major constituent (flavanolignan) of the fruits of Silybum marianum, on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 and VEGF expression in MCF-7 human breast cancer cells. The expression of MMP-9 and VEGF in response to TPA was increased, whereas TPA-induced MMP-9 and VEGF expression was decreased by silibinin. To investigate the regulatory mechanism of silibinin on TPA-induced MMP-9 and VEGF expression, we pretreated cells with various inhibitors, such as UO126 (MEK1/2 inhibitor), SP600125 (JNK inhibitor), and SB203580 (p38 inhibitor). Interestingly, TPA-induced MMP-9 expression was significantly inhibited by UO126, but not by SP600125 and SB203580. In addition, we pretreated cells with 100 microM silibinin prior to TPA treatment. TPA-induced MEK and ERK phosphorylation was significantly decreased by silibinin in MCF7 cells. TPA-induced VEGF expression was also suppressed by UO126. On the other hand, we found that adenoviral constitutive active-MEK (Ad-CA-MEK) significantly increased MMP-9 and VEGF expression. Taken together, we suggest that the inhibition of TPA-induced MMP-9 and VEGF expression by silibinin is mediated by the suppression of the Raf/MEK/ERK pathway in MCF-7 breast cancer cells.

Inhibitory effects of active compounds isolated from safflower (Carthamus tinctorius L.) seeds for melanogenesis.

In order to develop a new skin whitening agent, safflower (Carthamus tinctorius L.) seeds were evaluated for melanogenesis inhibitory activity and its active principles were identified following activity-guided isolation. The 80% aqueous methanol extract and ethyl acetate fraction from safflower seeds showed a significant inhibition for mushroom tyrosinase. Three active compounds, N-feruloylserotonin, N-(p-coumaroyl)serotonin, and acacetin, were isolated from the ethyl acetate fraction as the active principles. Compared with arbutin (IC50=0.223 mM), the IC50 values of these compounds were 0.023, 0.074, and 0.779 mM for N-feruloylserotonin, N-(p-coumaroyl)serotonin, and acacetin, respectively. It was also found that N-feruloylserotonin and N-(p-coumaroyl)serotonin strongly inhibited the melanin production of Streptomyces bikiniensis and B16 melanoma cells in comparison with a known melanogenesis inhibitor, arbutin.

Antimicrobial activity of 3-O-acyl-(-)-epicatechin and 3-O-acyl-(+)-catechin derivatives.

As an exploratory investigation of antimicrobial promoting compounds, 3- O-acyl-(-)-epicatechins and 3- O-acyl-(+)-catechins possessing various aromatic groups and aliphatic chains of varying length from C4 to C16 for increasing lipophilicity were synthesized and tested for antimicrobial activities against Gram-positive, Gram-negative bacteria and fungi. The (-)-epicatechin and (+)-catechin derivatives comprised of aromatic groups increased activity and derivatives with acyl chain groups of carbon atoms in the close vicinity of C8 to C10 showed strong antimicrobial activity (MIC = 2 - 8 microg/ml) against Gram-positive bacteria and weak activity against fungi. However, the activity decreased when the carbon chain length of the substituents was too short (C4 to C6) or too long (C16). These results suggest that the presence of lipophilic substituents with moderate sizes might be crucial for the optimal antimicrobial activity.

Antimicrobial activity of 9-O-acyl- and 9-O-alkylberberrubine derivatives.

For the structure-activity relationship study on berberrubine derivatives, a series of compounds bearing 9-O-acyl- and 9-O-alkyl-substituents were synthesized and tested for antimicrobial activity against Gram-positive, Gram-negative bacteria and fungi. Octanoyl, decanoyl, lauroyl derivatives among the acyl analogs and hexyl, heptyl, octyl, nonyl, decyl, undecyl derivatives among the alkyl analogs showed strong antimicrobial activity against Gram-positive bacteria and fungi. As a whole, alkyl analogs were more active than acyl analogs for antimicrobial activity. Synthesized derivatives had no activity on Gram-negative bacteria. Too short or too long substituents decreased activity. These results suggest that the presence of lipophilic substituents with moderate sizes might be crucial for the optimal antimicrobial activity.