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Dong P.,University of Massachusetts Amherst | Qiu P.,University of Massachusetts Amherst | Qiu P.,Ocean University of China | Zhu Y.,University of Massachusetts Amherst | And 5 more authors.
Journal of Chromatography A | Year: 2010

Accumulating evidence has suggested the potential health-promoting effects of 5-hydroxy polymethoxyflavones (5-OH-PMFs) naturally existing in citrus genus. However, research efforts are hampered by the lack of reliable and sensitive methods for their determination in plant materials and biological samples. Using reversed-phase high performance liquid chromatography (HPLC) equipped with electrochemical (EC) detection, we have developed a fast and highly sensitive method for quantification of four 5-OH-PMFs, namely 5-hydroxy-6,7,8,3′,4′-pentamethoxyflavone, 5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone, 5-hydroxy-6,7,4′-trimethoxyflavone, and 5-hydroxy-6,7,8,4′-tetramethoxyflavone. The method was fully validated in terms of linearity, accuracy and precision. The limit of detection (LOD) was determined as being between 0.65 and 1.8 ng/mL (ppb), demonstrating an over 160 times higher sensitivity in comparison with the previously reported method using UV detection. The recovery rate of the method was between 96.17% and 110.82%, and the precision for the retention times and peak areas was all below 13%. The method was successfully used to quantify 5-OH-PMFs with a wide range of abundance in the citrus products and preparations, such as orange juice, citrus peel, and dried tangerine peel. The quantification method for 5-OH-PMFs developed herein could be useful for the nutritional and pharmacological studies of these compounds in future. © 2009 Elsevier B.V. All rights reserved.

Bryant B.,Monell Chemical Senses Center | Xu J.,Monell Chemical Senses Center | Audige V.,University of Pennsylvania | Lischka F.W.,Monell Chemical Senses Center | Rawson N.E.,Wellgen Inc.
ACS Chemical Neuroscience | Year: 2010

Smokers regulate their smoking behavior on the basis of sensory stimuli independently of the pharmacological effects of nicotine (Rose, J. E., et al. (1993) Pharmacol., Biochem. Behav. 44 (4), 891 -900). A better understanding of sensory mechanisms underlying smoking behavior may help to develop more effective smoking alternatives. Olfactory stimulation by nicotine makes up a considerable part of the flavor of tobacco smoke, yet our understanding of the cellular mechanisms responsible for olfactory detection of nicotine remains incomplete. We used biophysical methods to characterize the nicotine sensitivity and response mechanisms of neurons from olfactory epithelium. In view of substantial differences in the olfactory receptor repertoire between rodent and human (Mombaerts, P. (1999) Annu. Rev. Neurosci. 22, 487-509), we studied biopsied human olfactory sensory neurons (OSNs), cultured human olfactory cells (Gomez, G., et al. (2000) J. Neurosci. Res. 62 (5), 737-749), and rat olfactory neurons. Rat and human OSNs responded to S(-)-nicotine with a concentration dependent influx of calcium and activation of adenylate cyclase. Some rat OSNs displayed some stereoselectivity, with neurons responding to either enantiomer alone or to both. Freshly biopsied and primary cultured human olfactory neurons were less stereoselective. Nicotinic cholinergic antagonists had no effect on the responses of rat or human OSNs to nicotine. Patch clamp recording of rat OSNs revealed a nicotine-activated, calcium-sensitive nonspecific cation channel. These results indicate that nicotine activates a canonical olfactory receptor pathway rather than nicotinic cholinergic receptors on OSNs. Further, because the nicotine-sensitive mechanisms of rodents appear generally similar to those of humans, this animal model is an appropriate one for studies of nicotine sensation. © 2010 American Chemical Society.

Qiu P.,Ocean University of China | Qiu P.,University of Massachusetts Amherst | Dong P.,University of Massachusetts Amherst | Guan H.,Ocean University of China | And 5 more authors.
Molecular Nutrition and Food Research | Year: 2010

Hydroxylated polymethoxyflavones (PMFs) are a class of novel flavonoid compounds mainly found in citrus plants. We studied the effects of three major 5-hydroxy PMFs, namely: 5-hydroxy-6,7,8,3′,4′-pentamethoxyflavone, 5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone, and 5-hydroxy-6,7,8,4′-tetramethoxyflavone, on human colon cancer HCT116 and HT29 cells. Their effects were compared with those produced by their permethoxylated counterparts, namely: nobiletin, 3,5,6,7,8,3′,4′-heptamethoxylflavone, and tangeretin. 5-Hydroxy PMFs showed much stronger inhibitory effects on the growth of the colon cancer cells in comparison with their permethoxylated counterparts, suggesting the pivotal role of hydroxyl group at 5-position in the enhanced inhibitory activity by 5-hydroxy PMFs. Flow cytometry analysis demonstrated that three 5-hydroxy PMFs produced different effects on the cell cycle and apoptosis, which may suggest that three 5-hydroxy PMFs act through different mechanisms. For example, 5-hydroxy-6,7,8,3′,4′-pentamethoxyflavone caused cell cycle arrest at G2/M phase in HT29 cells, while 5-hydroxy-3,6,7,8,3′,4′-hexamethoxyflavone led to significant G0/G1 phase arrest. In contrast, 5-hydroxy-6,7,8,4′-tetramethoxyflavone increased sub-G0/G1 cell population, which has been confirmed to be due to enhanced apoptosis. Our results further demonstrated that the inhibitory effects of 5-hydroxy PMFs were associated with their ability in modulating key signaling proteins related to cell proliferation and apoptosis, such as p21 Cip1/Waf1, CDK-2, CDK-4, phosphor-Rb, Mcl-1, caspases 3 and 8, and poly ADP ribose polymerase (PARP). Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Qiu P.,Ocean University of China | Qiu P.,University of Massachusetts Amherst | Guan H.,Ocean University of China | Dong P.,University of Massachusetts Amherst | And 5 more authors.
Molecular Nutrition and Food Research | Year: 2011

Scope: Previously, we reported that 5-hydroxy polymethoxyflavones (5OH-PMFs) isolated from orange, namely 5-hydroxy-6,7,8,3',4'-pentamethoxyflavone, 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5HHMF) and 5-hydroxy-6,7,8,4'-tetramethoxyflavone (5HTMF), potently induced apoptosis and cell-cycle arrest in multiple human colon cancer cells. Herein, using isogenic variants of HCT116 human colon cancer cells, we investigated the effects of p53, Bax and p21 on the apoptosis and cell-cycle arrest induced by different 5OH-PMFs. Methods and results: Annexin V/PI co-staining assay demonstrated that 5HHMF and 5HTMF significantly induced apoptosis in HCT116 (p53+/+) cells but not in HCT116 (p53-/-) cells. Furthermore, 5HHMF and 5HTMF significantly induced apoptosis in HCT116 (Bax+/-) cells, whereas their pro-apoptotic effects on HCT116 (Bax-/-) cells were marginal. All three 5OH-PMFs increased G0/G1 cell population of HCT116 (p53+/+) cells, and these effects were abolished in HCT116 (p53-/-) and HCT116 (p21-/-) cells. Immunoblotting analysis showed that 5HHMF and 5HTMF increased the levels of cleaved caspase-3, cleaved PARP in both HCT116 (p53+/+) and HCT116 (Bax+/-) cells and these effects were much weaker in HCT116 (p53-/-) and HCT116 (Bax-/-) cells. Conclusion: Our results demonstrated that 5OH-PMFs, especially 5HHMF and 5HTMF, induce apoptosis and cell-cycle arrest by p53-, Bax- and p21-dependent mechanism. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Gosslau A.,Wellgen Inc. | Gosslau A.,Rutgers University | En Jao D.L.,Rutgers University | Huang M.-T.,Rutgers University | And 4 more authors.
Molecular Nutrition and Food Research | Year: 2011

Scope: Theaflavin-2 (TF-2), a major component of black tea extract, induces apoptosis of human colon cancer cells and suppresses serum-induced cyclooxygenase-2 (COX-2) expression 1. Here, we explored the mechanisms for activation of apoptosis, evaluated the impact on inflammatory genes in a broader panel of cells and tested whether topical anti-inflammatory effects could be observed in vivo. Methods and results: TF-2 triggered apoptosis in five other transformed cancer cell lines, inducing cell shrinkage, membrane blebbing, and mitochondrial clustering within 3h of treatment. Among a set of pro-apoptotic genes, TF-2 quickly induced the up-regulation of P53 and BAX, suggesting mitochondria as the primary target. Using a cell model for inflammatory response, we showed that TF-2 suppressed the 12-O-tetradecanoylphorbol-13-acetate-induced COX-2 gene expression, and also down-regulated TNF-α, iNOS, ICAM-1, and NFκB. A reporter gene assay showed that TF-2 down-regulated COX-2 at the transcriptional level. We also demonstrated that TF-2 exhibited anti-inflammatory activity in two mouse models of inflammation. Topical application with TF-2 significantly reduced ear edema and produced a pattern of gene down-regulation similar to that observed in the cell model. Conclusion: These results suggest that the anti-inflammatory and pro-apoptotic activity of TF-2 may be exploited therapeutically in cancer and other diseases associated with inflammation. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Gosslau A.,Wellgen Inc. | Gosslau A.,Rutgers University | Li S.,Wellgen Inc. | Ho C.-T.,Rutgers University | And 2 more authors.
Molecular Nutrition and Food Research | Year: 2011

The knowledge that natural products provide a rich source for therapeutic discovery has led to the development of many of the world's most commonly used drugs. In view of the growing need for effective anti-inflammatory agents, the potential for natural products to serve as safe and effective therapeutic agents has gained increasing attention. However, polymolecular extracts must be rigorously evaluated and chemically characterized to insure adequate consistency in performance. The research in this field has been plagued by inconsistencies due in part to inadequate chemical characterization and documentation, making comparison of results across studies very difficult. Analytical chemistry and molecular methods now exist to insure sufficient transparency to avoid this limitation. Further, our understanding of the complexity of inflammation has advanced to enable significant insight into the mechanism of action of these natural extracts. Here, we review the inflammatory pathways targeted by many therapeutic agents, discuss the value of natural products as anti-inflammatory agents, review approaches for their biological and chemical evaluation, and highlight challenges to the field. We present two examples highlighting the rigorous use of cell, molecular, and chemical methods for characterization and quality control as templates for future studies of anti-inflammatory activity of natural products. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Bays H.E.,Louisville Metabolic and Atherosclerosis Research Center | McKenney J.,National Clinical Research Inc. | Maki K.C.,Provident Clinical Research and Consulting Inc. | Doyle R.T.,Reliant Pharmaceuticals | And 4 more authors.
Mayo Clinic Proceedings | Year: 2010

OBJECTIVE: To evaluate the effects of prescription omega-3-acid ethyl esters on non - high-density lipoprotein cholesterol (HDL-C) levels in atorvastatin-treated patients with elevated non - HDL-C and triglyceride levels. PATIENTS AND METHODS: This study, conducted between February 15, 2007, and October 22, 2007, randomized patients with elevated non - HDL-C (>160 mg/dL) and triglyceride (≥250 mg/dL and ≤599 mg/dL) levels to double-blind treatment with prescription omega-3-acid ethyl esters, 4 g/d, or placebo for 16 weeks. Patients also received escalating dosages of open-label atorvastatin (weeks 0-8, 10 mg/d; weeks 9-12, 20 mg/d; weeks 13-16, 40 mg/d). RESULTS: Prescription omega-3-acid ethyl esters plus atorvastatin, 10, 20, and 40 mg/d, reduced median non - HDL-C levels by 40.2% vs 33.7% (P<.001), 46.9% vs 39.0% (P<.001), and 50.4% vs 46.3% (P<.001) compared with placebo plus the same doses of atorvastatin at the end of 8, 12, and 16 weeks, respectively. Prescription omega-3-acid ethyl esters plus atorvastatin also reduced median total cholesterol, triglyceride, and very low-density lipoprotein cholesterol levels and increased HDL-C levels to a significantly greater extent than placebo plus atorvastatin. Percent changes from baseline low-density lipoprotein-cholesterol, apolipoprotein A-I, and apolipoprotein B levels were not significantly different between groups at the end of the study. CONCLUSION: Prescription omega-3-acid ethyl esters plus atorvastatin produced significant improvements in non - HDL-C and other lipid parameters in patients with elevated non - HDL-C and triglyceride levels. © 2010 Mayo Foundation for Medical Education and Research.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 293.24K | Year: 2013

DESCRIPTION (provided by applicant): Type 2 Diabetes (T2D) is an inflammatory disease affecting 26 million people in the US (11%) and is predicted to affect more than 30% of adults in the US by 2050. The economic cost of T2D is over 200 billion a year. People with T2D suffer from hyperglycemia due to low insulin production, poor transport of insulin, or cellular resistance to insulin which can lead to retinopathy, nephropathy, neuropathy, and cardiovascular disease. Chronic inflammation in T2D is a leading cause of the progression of the disease. Obesity, also occurring at epidemic rates in the US, causes chronic low- grade inflammation thus contributing to T2D. Although current therapies can maintain glucose control and reduce insulin resistance, complications associated with chronic inflammation and organ damage drive the effort to develop drugs targeting specific steps in the inflammatory cascade. We propose that natural products have the potential to fill this therapeutic gap while reducing potential side effects and compensatory reactions requiring secondary treatment. To combat the inflammation that leads to T2D and its complications, we developed two naturally derived products: WG0401 and WG0301, which are both proprietary, novel, well-characterized,bioactive enhanced natural extracts. Both extracts show strong effects against inflammation as demonstrated in human cell-based bioassays and animal models of inflammation. Both were well tolerated in humans in previously conducted clinical trials and canbe Generally Regarded As Safe (GRAS), thereby reducing the time and expense of getting a product to market. Our goal is to develop a novel, effective medical food to control the underlying pathological effects of chronic inflammation that lead to T2D. Aim1. Demonstrate that WG0401 and WG0301 will reduce inflammatory metabolites that lead to complications of T2D. Biomarkers for T2D and inflammatory metabolites that play major roles in T2D will be measured in the Zucker diabetic fatty rat animal model of T2D that have been treated with WG0401 or WG0301. Successful results will show statistically significant improvement within treatment groups or between controls and treated rats. Aim 2. We propose that the inhibition of inflammatory genes reduces the metabolites measured in Aim 1. We will measure correlations between the gene products and the down-regulation of inflammatory metabolites and/or biomarkers for inflammation and T2D by WG0401 and WG0301 and compare to metformin and ibuprofen. Observation of a positive correlation supports our hypothesis. Aim 3. Select one of the two products based on the results above for further development. Successful completion of this project will enable the design and initiation of clinical trials in Phase II, using one of our extracts for the management of T2D. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Patients afflicted with Type 2 diabetes (T2D) suffer from chronic inflammation that leads to well-known and potentially devastating complications. The proposed project will determine the efficacy of two, proprietary WellGen GRAS certified natural extracts in the reduction of inflammation associated with T2D in a rat model. The goal of the proposed project is a novel and effective ingredient in a medical foodproduct for the management of T2D and its complications in the rapidly increasing number of T2D patients.

Wellgen Inc. | Date: 2010-03-01

Medicinal herb extracts; Nutritional food additives for medical purposes in the nature of natural food extracts derived from plants.

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