Effects of maternal cigarette smoke exposure on the progression of nonalcoholic steatohepatitis in offspring mice.

Cigarette smoke (CS) is a dominant carcinogenic agent in a variety of human cancers. CS exposure during pregnancy can adversely affect the fetus. Non-alcoholic fatty liver disease (NAFLD) is considered as a hepatic manifestation of a metabolic disorder, and ranges from simple steatosis to cirrhosis leading to hepatocellular carcinoma. Non-alcoholic steatohepatitis (NASH) is a more severe phase of NAFLD. Recently, there is increasing apprehension about the CS-related chronic liver diseases. Therefore, we examined whether maternal CS exposure could affect the pathogenesis of NASH in offspring. Mainstream CS (MSCS) was exposed to pregnant C57BL/6 mice via nose-only inhalation for 2 h/day, 5 days/week for 2 weeks from day 6 to 17 of gestation at 0, 300, or 600 µg/L. Three-week-old male offspring mice were fed methionine and choline-supplemented (MCS) diet or methionine and choline-deficient including high-fat (MCDHF) diet for 6 weeks to induce NASH. Maternal MSCS exposure increased the severity of NASH by increasing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic total cholesterol (TC) and triglyceride (TG) levels, pro-inflammation, fibrosis, and steatosis in offspring mice. Especially, maternal MSCS exposure significantly downregulated the phosphorylation of AMP-activated protein kinase (AMPK) in MCDHF diet-fed offspring mice. Subsequently, the protein levels of sterol regulatory element-binding protein (SREBP)-1c and stearoyl-CoA desaturase-1 (SCD1) were upregulated by maternal MSCS exposure. In conclusion, maternal MSCS exposure exacerbates the progression of NASH by modulating lipogenesis on offspring mice. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-022-00153-1.

Mental health symptoms among dependent contractors in Korea: a cross-sectional study based on the Fifth Korean Working Condition Survey.

Background: Recently, there has been a call to improve the holistic welfare of dependent contractors (DCs). Thus, our study examined the relationship between DCs and mental health symptoms and how this relationship was modified by age, sex, and income status of workers. Methods: A total of 27,980 workers from the Fifth Korean Working Conditions Survey are included in our study. The participants who reported having depression or anxiety over the last 12 months are defined those who had mental health symptoms. We performed exact matching for age group and sex, followed by conditional logistic regression with survey weights. Finally, stratified analyses by age, sex and income level were conducted. Results: DCs were found to be at increased risk of depression/anxiety compared to other workers. The odds ratio (OR) is 1.52 (95% confidence interval [CI]: 1.06-2.17). In the stratified analyses, vulnerable groups were middle-aged (OR [95% CI]: 1.68 [1.10-2.54]), female (OR [95% CI]: 1.85 [1.20-2.84]), and low-income (OR [95% CI]: 3.18 [1.77-5.73]) workers. Conclusions: Our study's results reinforce those of other studies that show that DCs are at greater risk of experiencing mental health issues than other workers and that and this risk is greater for middle-aged, female, and low-income workers. These results suggest that appropriate policy efforts should be made to improve the psychological well-being of DCs.

Anti-fibrotic effect of pycnogenol® in a polyhexamethylene guanidine-treated mouse model.

Pulmonary fibrosis (PF) is a respiratory disease that causes serious respiratory problems. The effects of French marine pine bark extract (Pycnogenol®), with antioxidant and anti-inflammatory properties, were investigated on lung fibrosis in polyhexamethylene guanidine (PHMG)-treated mice. Mice were separated into four groups (n = 6): vehicle control (VC, saline 50 µl); PHMG (1.1 mg/kg); PHMG + Pycnogenol® (0.3 mg/kg/day); and PHMG + Pycnogenol® (1 mg/kg/day). PF was induced via intratracheal instillation of PHMG. Treatment with PHMG decreased body weight and increased lung weight, both of which were improved by treatment with PHMG + Pycnogenol® (1 mg/kg). Enzyme-linked immunosorbent assay, western blotting, and PCR revealed that Pycnogenol® attenuated PHMG-induced increase in inflammatory cytokines and fibrosis-related factors in a dose-dependent manner. Finally, histopathological analysis revealed reduced inflammation/fibrosis in the PHMG + Pycnogenol® (1 mg/kg) group. Collectively, the results indicate that Pycnogenol® can be used to treat PF as it hinders fibrosis progression by inhibiting inflammatory responses in the lungs of PHMG-treated mice.

Epigallocatechin-3-Gallate as a Novel Vaccine Adjuvant.

Vaccine adjuvants from natural resources have been utilized for enhancing vaccine efficacy against infectious diseases. This study examined the potential use of catechins, polyphenolic materials derived from green tea, as adjuvants for subunit and inactivated vaccines. Previously, catechins have been documented to have irreversible virucidal function, with the possible applicability in the inactivated viral vaccine platform. In a mouse model, the coadministration of epigallocatechin-3-gallate (EGCG) with influenza hemagglutinin (HA) antigens induced high levels of neutralizing antibodies, comparable to that induced by alum, providing complete protection against the lethal challenge. Adjuvant effects were observed for all types of HA antigens, including recombinant full-length HA and HA1 globular domain, and egg-derived inactivated split influenza vaccines. The combination of alum and EGCG further increased neutralizing (NT) antibody titers with the corresponding hemagglutination inhibition (HI) titers, demonstrating a dose-sparing effect. Remarkably, EGCG induced immunoglobulin isotype switching from IgG1 to IgG2a (approximately >64-700 fold increase), exerting a more balanced TH1/TH2 response compared to alum. The upregulation of IgG2a correlated with significant enhancement of antibody-dependent cellular cytotoxicity (ADCC) function (approximately 14 fold increase), providing a potent effector-mediated protection in addition to NT and HI. As the first report on a novel class of vaccine adjuvants with built-in virucidal activities, the results of this study will help improve the efficacy and safety of vaccines for pandemic preparedness.

Laser and anti-vascular endothelial growth factor treatment for drusenoid pigment epithelial detachment in age-related macular degeneration.

This study aims to report the 12 months results of efficacy and safety of laser photocoagulation and anti-vascular endothelial growth factor (VEGF) injections for drusenoid pigment epithelial detachment (dPED). In this prospective study, patients with treatment naïve bilateral intermediate age-related macular degeneration, featuring dPED, with visual acuity ≤ 83 letters were enrolled. The study group received PASCAL laser (532 nm) along the periphery of the dPED, and the fellow eye served as a control group. To prevent complications of choroidal neovascularization, intravitreal anti-VEGF injections to laser treated eye were performed on a 3-month interval up to 1 year. Primary outcomes-drusen area, PED height-and secondary outcomes-best-corrected visual acuity (BCVA), contrast sensitivity, degree of metamorphopsia, NEI-VFQ 25, and fundus autofluorescence-were analyzed. Among 21 patients, a total of 20 patients satisfied the 12 months follow-up. Drusen area and PED height decreased significantly in the laser group, while no significant change appeared in the control group (74.1% vs. - 3.5%, P < 0.001; 76.6% vs. 0.1%, P < 0.001). Mean BCVA improved 4.6 letters in the laser group (vs. 1.1 letters in the control group, P = 0.019). As for safety, one study eye developed retinal pigment epithelial tear, and one control eye developed retinal angiomatous proliferation. Low energy laser photocoagulation and anti-VEGF injection in eyes with dPED showed some improvement in visual acuity. dPED regressed without developing center involving GA in the study eye, but a longer term follow-up is necessary to reveal the efficacy and safety of these treatments. The 2-year results of this study will be followed to reveal long term efficacy and safety of the treatment for dPED.

4-Hydroxycinnamic acid suppresses airway inflammation and mucus hypersecretion in allergic asthma induced by ovalbumin challenge.

In this study, we investigated whether 4-hydroxycinnamic acid (HA) has a palliative effect on asthmatic inflammatory responses using a mouse model of ovalbumin (OVA)-induced allergic asthma. The mice were divided into five groups, each consisting of seven females (normal control phosphate-buffered saline); OVA (OVA sensitization/challenge); dexamethasone (DEX, OVA sensitization/challenge + dexamethasone 3 mg/kg); HA-10 and HA-20 OVA sensitization/challenge + HA 10 and 20 mg/kg, respectively). Mice treated with HA showed a reduction in airway hyperresponsiveness and in the number of inflammatory cells in bronchoalveolar lavage fluid (BALF) compared with asthmatic control. HA treatment also reduced the levels of interleukin (IL)-5 and IL-13 in BALF and of OVA-specific immunoglobulin E in the serum compared with asthmatic control. HA treatment relieved airway inflammation and mucus overproduction caused by OVA exposure. Additionally, HA inhibited the increases in levels of nuclear factor kappa B, inducible nitric oxide synthase, and cyclooxygenase-2 that normally occur after OVA exposure. HA treatment also reduced the activity and protein level of matrix metalloproteinase-9. Taken together, HA effectively suppressed asthmatic airway inflammation and mucus production caused by OVA exposure. These findings indicate that HA has the potential to be used as a therapeutic agent for asthma.

Severe Cardiomyopathy Due to Arthroprosthetic Cobaltism: Report of Two Cases with Different Outcomes.

Cobalt-induced cardiomyopathy is a well-known but uncommon disease, and the physician must maintain a high index of suspicion in order to make a timely diagnosis. We report two patients with cobalt-induced cardiomyopathy. Both patients developed progressively worsening symptoms of cobalt toxicity following revision of a fractured ceramic-on-ceramic total hip replacement to a metal-on-polyethylene bearing. In both patients, echocardiography showed LV hypertrophy, biventricular systolic dysfunction, and a large amount of pericardial effusion. Due to decompensated heart failure, both patients were initially considered candidates for heart transplantation. One patient was diagnosed with cobalt-induced cardiomyopathy before transplantation. He received cobalt chelation therapy and revision surgery, which led to complete recovery of heart function. In the other patient, the diagnosis was not made until the time of heart transplantation. The gross examination of the explanted heart revealed typical features of cobalt cardiotoxicity, which was then diagnosed as cobalt-induced cardiomyopathy. These cases emphasise the importance of early diagnosis and prompt treatment of cobalt intoxication.

The effectiveness of 1,064-nm long-pulsed Nd:YAG laser in the treatment of severe onychomycosis.

INTRODUCTION: Severe onychomycosis in the elderly is a common condition and generally difficult to treat. Long-pulsed Nd:YAG (LPNY) laser has been found to be useful in the treatment of onychomycosis. We sought to evaluate the effectiveness of 1,064-nm LPNY laser in the treatment of severe onychomycosis. MATERIALS AND METHODS: Forty nails in 13 patients with severe onychomycosis were divided into two groups. Each group received eight treatment sessions at one-week intervals with 1,064-nm LPNY laser. Parameters for group A were 0.3 ms pulse duration, 5 mm spot size, 16 J/cm(2) fluence, and 10 Hz frequency, and those for group B were 0.6 ms, 2 mm, 225 J/cm(2), and 5 Hz. Clinical and mycological clearance were evaluated at 12 and 24 weeks after initial treatment. RESULTS: Clinical improvements at 12 and 24 weeks presented 47.6 and 57.1% in group A, and 26.3 and 36.8% in group B. In the treated nails with clinical improvement, mycological positive rates at 24 weeks were approximately 40% in both groups. DISCUSSION: The treatment of onychomycosis using 1,064-nm LPNY laser were incomplete in clinical and mycological improvement, and it could imply a lot of potential recurrence. We suggest that 1,064-nm LPNY laser for severe onychomycosis should need additional or combined therapy with other therapeutic options.

Effect of excimer laser treatment on vitiliginous areas with leukotrichia after confirmation by dermoscopy.

BACKGROUND: Leukotrichia is clinically common in patients with vitiligo, and dermoscopy is useful for finding white vellus hair. The use of phototherapy in the repigmentation of vitiliginous areas with leukotrichia is usually difficult because of a deficient melanocyte reservoir. OBJECTIVES: We sought to evaluate the effect of leukotrichia on the clinical outcomes of excimer laser treatment. METHODS: We treated 77 patients with vitiligo using excimer laser therapy. Vitiligo is classified into two types: segmental vitiligo (SV) and nonsegmental vitiligo (NSV). Before starting the treatment, we confirmed the leukotrichia of vitiliginous lesions by dermoscopy and then treated the areas once weekly for 24 weeks. At the beginning and 24 weeks later, we took clinical pictures and graded the repigmentation from 1 to 4. Grades 1 and 2 were defined as a poor response and grades 3 and 4 as a good response. RESULTS: Thirty-one of 77 patients with vitiligo had SV. Among those with SV, 24 (77.4%) had leukotrichia, and these patients showed a poor response compared to those without leukotrichia (P = 0.272). Three of 24 patients with SV and leukotrichia showed a good response. Among the 46 patients with NSV, 18 (39.1%) had leukotrichia and showed a poor response. Twenty-eight (60.9%) of the 46 patients with NSV without leukotrichia showed a good response in contrast to those with leukotrichia (P < 0.01). Comparison of the response to the excimer laser treatment, regardless of vitiligo type, showed that leukotrichia was a significant negative factor in the repigmentation of vitiliginous areas (P < 0.01). CONCLUSION: Excimer laser therapy was satisfactory in patients with vitiligo, including SV. Confirming the presence of leukotrichia in patients with vitiligo before excimer laser treatment would be helpful in predicting the response to treatment.

Toxicity of colloidal silica nanoparticles administered orally for 90 days in rats.

This study was undertaken to investigate the potential toxicity and establish the no observed adverse effect level (NOAEL) and target organ(s) of negatively charged colloidal silica particles of different sizes, ie, SiO2 (EN20(-)) (20 nm) or SiO2 (EN100(-)) 2(100 nm), administered by gavage in Sprague-Dawley rats. After verification of the physicochemical properties of the SiO2 particles to be tested, a preliminary dose range-finding study and 90-day repeated dose study were conducted according to the Organisation for Economic Cooperation and Development test guideline. Based on the results of the 14-day dose range-finding study, a high dose was determined to be 2,000 mg/kg, and middle and low doses were set at 1,000 and 500 mg/kg, respectively. In the 90-day toxicity study, there were no animal deaths in relation to administration of SiO2 particles of either size. In addition, no treatment-related clinical changes or histopathological findings were observed in any of the experimental groups. Moreover, no difference in toxic effects from chronic exposure to SiO2 (EN20(-))(20 nm) or SiO2 (EN100(-)) (100 nm) was observed. The results of this study indicate that the NOAEL for SiO2 (EN20(-)) and SiO2 (EN100(-)) would most likely be 2,000 mg/kg, and no target organ was identified in rats of either sex.

Toxicity of 100 nm zinc oxide nanoparticles: a report of 90-day repeated oral administration in Sprague Dawley rats.

Nanoparticles (NPs) are used commercially in health and fitness fields, but information about the toxicity and mechanisms underlying the toxic effects of NPs is still very limited. The aim of this study is to investigate the toxic effect(s) of 100 nm negatively (ZnO(AE100[-])) or positively (ZnO(AE100[+])) charged zinc oxide (ZnO) NPs administered by gavage in Sprague Dawley rats, to establish a no observed adverse effect level, and to identify target organ(s). After verification of the primary particle size, morphology, hydrodynamic size, and zeta potential of each test article, we performed a 90-day study according to Organisation for Economic Co-operation and Development test guideline 408. For the 90-day study, the high dose was set at 500 mg/kg and the middle and low doses were set at 125 mg/kg and 31.25 mg/kg, respectively. Both ZnO NPs had significant changes in hematological and blood biochemical analysis, which could correlate with anemia-related parameters, in the 500 mg/kg groups of both sexes. Histopathological examination showed significant adverse effects (by both test articles) in the stomach, pancreas, eye, and prostate gland tissues, but the particle charge did not affect the tendency or the degree of the lesions. We speculate that this inflammatory damage might result from continuous irritation caused by both test articles. Therefore, the target organs for both ZnO(AE100(-)) and ZnO(AE100(+)) are considered to be the stomach, pancreas, eye, and prostate gland. Also, the no observed adverse effect level for both test articles was identified as 31.25 mg/kg for both sexes, because the adverse effects were observed at all doses greater than 125 mg/kg.

Effect of zinc oxide nanoparticles on dams and embryo-fetal development in rats.

This study investigated the potential adverse effects of zinc oxide nanoparticles (ZnO(SM20[-]) NPs; negatively charged, 20 nm) on pregnant dams and embryo-fetal development after maternal exposure over the period of gestational days 5-19 with Sprague Dawley rats. ZnO(SM20(-)) NPs were administered to pregnant rats by gavage at 0 mg/kg/day, 100 mg/kg/day, 200 mg/kg/day, and 400 mg/kg/day. All dams were subjected to caesarean section on gestational day 20, and all the fetuses were examined for external, visceral, and skeletal alterations. Toxicity in the dams manifested as significantly decreased body weight at 400 mg/kg/day and decreased liver weight, and increased adrenal glands weight at 200 mg/kg/day and 400 mg/kg/day. However, no treatment-related difference in the number of corpora lutea, the number of implantation sites, the implantation rate (%), resorption, dead fetuses, litter size, fetal deaths, fetal and placental weights, and sex ratio were observed between the groups. Morphological examinations of the fetuses demonstrated no significant difference in the incidences of abnormalities between the groups. No significant difference was found in the Zn content of fetal tissue between the control and high-dose groups. These results showed that a 15-day repeated oral dose of ZnO(SM20(-)) was minimally maternotoxic at dose of 200 mg/kg/day and 400 mg/kg/day.

Prenatal development toxicity study of zinc oxide nanoparticles in rats.

This study investigated the potential adverse effects of zinc oxide nanoparticles ([ZnO(SM20(+)) NPs] zinc oxide nanoparticles, positively charged, 20 nm) on pregnant dams and embryo-fetal development after maternal exposure over the period of gestational days 5-19 with Sprague-Dawley rats. ZnO(SM20(+)) NPs were administered to pregnant rats by gavage at 0, 100, 200, and 400 mg/kg/day. All dams were subjected to a cesarean section on gestational day 20, and all of the fetuses were examined for external, visceral, and skeletal alterations. Toxicity in the dams manifested as significantly decreased body weight after administration of 400 mg/kg/day NPs; reduced food consumption after administration of 200 and 400 mg/kg/day NPs; and decreased liver weight and increased adrenal glands weight after administration of 400 mg/kg/day NPs. However, no treatment-related difference in: number of corpora lutea; number of implantation sites; implantation rate (%); resorption; dead fetuses; litter size; fetal deaths and placental weights; and sex ratio were observed between the groups. On the other hand, significant decreases between treatment groups and controls were seen for fetal weights after administration of 400 mg/kg/day NPs. Morphological examinations of the fetuses demonstrated significant differences in incidences of abnormalities in the group administered 400mg/kg/day. Meanwhile, no significant difference was found in the Zn content of fetal tissue between the control and high-dose groups. These results showed that oral doses for the study with 15-days repeated of ZnO(SM20(+)) NPs were maternotoxic in the 200 mg/kg/day group, and embryotoxic in the 400 mg/kg/day group.

The genome-wide expression profile of 1,2,3,4,6-penta-O-galloyl-ß-D-glucose-treated MDA-MB-231 breast cancer cells: molecular target on cancer metabolism.

1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG), a polyphenolic compound isolated from Rhus chinensis Mill. PGG has been known to have anti-tumor, anti-angiogenic and anti-diabetic activities. The present study revealed another underlying molecular target of PGG in MDA-MB-231 breast cancer cells by using Illumina Human Ref-8 expression BeadChip assay. Through the Beadstudio v3 micro assay program to compare the identified genes expressed in PGG-treated MDA-MB-231 cells with untreated control, we found several unique genes that are closely associated with pyruvate metabolism, glycolysis/gluconeogenesis and tyrosine metabolism, including PC, ACSS2, ACACA, ACYP2, ALDH3B1, FBP1, PRMT2 and COMT. Consistent with microarray data, real-time RT-PCR confirmed the significant down-regulation of these genes at mRNA level in PGG-treated MDA-MB-231 cells. Our findings suggest the potential of PGG as anticancer agent for breast cancer cells by targeting cancer metabolism genes.

Panacagrimonas perspica gen. nov., sp. nov., a novel member of Gammaproteobacteria isolated from soil of a ginseng field.

A taxonomic study was carried out on Gsoil 142(T), a bacterial strain isolated from the soil collected in a ginseng field in Pocheon province, South Korea. Comparative 16S rRNA gene sequence studies showed a clear affiliation of this bacterium to the Gammaproteobacteria, and it was most closely related to Hydrocarboniphaga effusa ATCC BAA 332(T) (94.4%, 16S rRNA gene sequence similarity), Nevskia ramosa DSM 11499(T) (94.1%) and Alkanibacter difficilis MN154.3(T) (92.0%). Strain Gsoil 142(T) was a gram-negative, strictly aerobic, motile, and rod-shaped bacterium. The G+C content of the genomic DNA was 69.9% and predominant ubiquinone was Q-8. Major fatty acids were summed feature 8 (C(18:1) omega7c and/or omega6c, 36.3%), summed feature 3 (iso-C(15:0) 2-OH and/or C(16:1) omega7c, 20.6%) and C(16:0) (17.4%). The major polar lipids detected in strain Gsoil 142(T) were phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, and an unknown glycolipid. On the basis of polyphasic evidence, it is proposed that strain Gsoil 142(T) should be placed in a novel genus and species, for which the name Panacagrimonas perspica gen. nov., sp. nov. is proposed. The type strain is Gsoil 142(T) (= KCTC 12982(T) = LMG 23239(T)).

MS-1020 is a novel small molecule that selectively inhibits JAK3 activity.

In order to identify Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling inhibitors, a cell-based high throughput screening was performed using a plant extract library that identified Nb-(alpha-hydroxynaphthoyl)serotonin called MS-1020 as a novel JAK3 inhibitor. MS-1020 potently inhibited persistently-active STAT3 in a cell type-specific manner. Further examination showed that MS-1020 selectively blocked constitutively-active JAK3 and consistently suppressed interleukin-2-induced JAK3/STAT5 signalling but not prolactin-induced JAK2/STAT5 signalling. Furthermore, MS-1020 affected cell viability only in cancer cells harbouring persistently-active JAK3/STATs, and in vitro kinase assays showed MS-1020 binds directly with JAK3, blocking its catalytic activity. Therefore, the present study suggested that this reagent selectively inhibits JAK3 and subsequently leads to a block in STAT signalling. Finally, MS-1020 decreased cell survival by inducing apoptosis via down-regulation of anti-apoptotic gene expression. These results suggest that MS-1020 may have therapeutic potential in the treatment of cancers harbouring aberrant JAK3 signalling.

Potent antiandrogen and androgen receptor activities of an Angelica gigas-containing herbal formulation: identification of decursin as a novel and active compound with implications for prevention and treatment of prostate cancer.

Androgen and androgen receptor (AR)-mediated signaling are crucial for the development of prostate cancer. Identification of novel and naturally occurring phytochemicals that target androgen and AR signaling from Oriental medicinal herbs holds exciting promises for the chemoprevention of this disease. In this article, we report the discovery of strong and long-lasting antiandrogen and AR activities of the ethanol extract of a herbal formula (termed KMKKT) containing Korean Angelica gigas Nakai (AGN) root and nine other Oriental herbs in the androgen-dependent LNCaP human prostate cancer cell model. The functional biomarkers evaluated included a suppression of the expression of prostate-specific antigen (PSA) mRNA and protein (IC50, approximately 7 microg/mL, 48-hour exposure) and an inhibition of androgen-induced cell proliferation through G1 arrest and of the ability of androgen to suppress neuroendocrine differentiation at exposure concentrations that did not cause apoptosis. Through activity-guided fractionation, we identified decursin from AGN as a novel antiandrogen and AR compound with an IC50 of approximately 0.4 microg/mL (1.3 micromol/L, 48-hour exposure) for suppressing PSA expression. Decursin also recapitulated the neuroendocrine differentiation induction and G1 arrest actions of the AGN and KMKKT extracts. Mechanistically, decursin in its neat form or as a component of AGN or KMKKT extracts inhibited androgen-stimulated AR translocation to the nucleus and down-regulated AR protein abundance without affecting the AR mRNA level. The novel antiandrogen and AR activities of decursin and decursin-containing herbal extracts have significant implications for the chemoprevention and treatment of prostate cancer and other androgen-dependent diseases.

Penta-O-galloyl-beta-D-glucose suppresses tumor growth via inhibition of angiogenesis and stimulation of apoptosis: roles of cyclooxygenase-2 and mitogen-activated protein kinase pathways.

Recent studies have revealed that 1,2,3,4,6-penta-O-galloyl-beta-d-glucose (PGG) has anti-tumorigenic activity in vitro. In the present work, we evaluated the in vitro and in vivo antiangiogenic and antitumor activities of PGG and examined its molecular mechanisms. PGG significantly inhibited the proliferation and tube formation in basic fibroblast growth factor (bFGF)-treated human umbilical vein endothelial cells (HUVECs) at non-cytotoxic concentrations. PGG effectively disrupted the bFGF-induced neo-vascularization in chick chorioallantoic membrane (CAM) and in Matrigel plugs in the mice. When mice were intraperitoneally injected, PGG also significantly inhibited tumor angiogenesis induced by Lewis lung carcinoma (LLC) and the growth of LLC by 57 and 91% of control tumor weight at 4 and 20 mg/kg, respectively. Immunohistochemical analysis revealed decreased microvessel density, decreased expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF), reduced tumor cell proliferation and increased tumor cell apoptosis. Similarly, PGG significantly attenuated the expression of COX-2 and VEGF and reduced the secretion of VEGF and prostaglandin E2 in bFGF-treated HUVECs. Furthermore, the COX-2 inhibitor NS398 significantly inhibited tube formation and neo-vascularization in CAM, supporting the role of COX-2 in PGG inhibition of angiogenesis. PGG diminished the phosphorylation of extracellular signal regulated kinase 1/2, Jun NH2-terminal kinase and activated phospho-p38 mitogen-activated protein kinase (MAPK) in a dose-dependent manner in bFGF-treated HUVECs. In addition, p38 inhibitor SB203580 abolished the downregulation of COX-2, VEGF and the antiproliferative activity by PGG. Taken together, our data demonstrate that PGG exerts antitumor activity primarily via inhibition of angiogenesis through COX-2 and MAPK- dependent pathways.