48 results on '"McFadden D"'
Search Results
2. Pterostilbene Induces Mitochondrially-Derived Apoptosis in Breast Cancer in Vitro Via Bax Activation and Cytosolic Calcium Overload
- Author
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Moon, D., primary, Lomas, S., additional, McDonald, D., additional, and McFadden, D., additional
- Published
- 2012
- Full Text
- View/download PDF
3. Inositol Hexaphosphate (IP6) inhibits cellular proliferation and VEGF production in melanoma
- Author
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Rizvi, I., Ng, A., Riggs, D., Jackson, B., Cunningham, C., and McFadden, D.
- Published
- 2006
- Full Text
- View/download PDF
4. Vitamin E and the Y4 Agonist BA-129 Decrease Prostate Cancer Growth and Production of Vascular Endothelial Growth Factor
- Author
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Yu, A., Somasundar, P., Balsubramaniam, A., Rose, A. T., Vona-Davis, L., and McFadden, D. W.
- Subjects
- *
CANCER , *PEPTIDES - Abstract
Background. A biologically active form of vitamin E, α-tocopherol succinate (ATS), has been shown to induce apoptosis of hormone-refractory prostate cancer in vitro and inhibit cell growth in vivo. The gastrointestinal hormone peptide YY (PYY) has growth inhibitory activity against multiple cancer cell lines and is synergistic with ATS against breast and pancreatic cancer growth. BA-129, a specific Y4 receptor agonist, has growth inhibitory effects on pancreatic cancer in vitro. We investigated the effects of BA-129 and ATS on prostate cancer growth and evaluated their effects on vascular endothelial growth factor (VEGF) production.Methods. A hormone-refractory human prostate cancer cell line, PC-3, was treated with ATS alone at 10 pg/ml, PYY or BA-129 alone at doses of 75 and 500 pmol/ml, or a combination of the two agents. Cell growth was measured by MTT assay and hemocytometry using trypan blue. Quantitative measurement of VEGF was performed by ELISA. Statistical analysis was achieved by ANOVA.Results. ATS exhibited significant (P < 0.05) growth inhibitory effects in prostate cancer cells. PYY also inhibited growth (P < 0.05). ATS treatment reduced VEGF production (P < 0.05). PYY treatment increased VEGF. When ATS was given in combination with BA-129, VEGF production was further reduced (P < 0.05).Conclusions. Both PYY and ATS inhibit growth in hormone-refractory prostate cancer, with augmentation when used in combination. VEGF production is inhibited by vitamin E, but increased by PYY. ATS abolishes the augmented VEGF response to PYY. Our data suggest that PYY is involved in the regulation of VEGF production and prostate cancer growth. [Copyright &y& Elsevier]
- Published
- 2002
- Full Text
- View/download PDF
5. Change is good! The Journal of Surgical Research: 2014-2015.
- Author
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McFadden D and Souba WW
- Subjects
- Biomedical Research, Editorial Policies, General Surgery, Periodicals as Topic trends
- Published
- 2015
- Full Text
- View/download PDF
6. Improved survival of patients with pseudomyxoma peritonei receiving intraperitoneal chemotherapy with cytoreductive surgery: a systematic review and meta-analysis.
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McBride K, McFadden D, and Osler T
- Subjects
- Adenocarcinoma, Mucinous mortality, Adenocarcinoma, Mucinous surgery, Antineoplastic Agents adverse effects, Humans, Infusions, Parenteral, Injections, Intraperitoneal, Peritoneal Neoplasms mortality, Peritoneal Neoplasms surgery, Pseudomyxoma Peritonei mortality, Pseudomyxoma Peritonei surgery, Adenocarcinoma, Mucinous drug therapy, Antineoplastic Agents administration & dosage, Peritoneal Neoplasms drug therapy, Pseudomyxoma Peritonei drug therapy
- Abstract
Background: Pseudomyxoma peritonei (PMP) is an uncommon but lethal variant of adenocarcinoma. Many recent case series have reported improved survival with the combination of cytoreductive surgery and intraperitoneal chemotherapy (IPEC) in treating PMP. The aim of this study was to analyze the published studies for improved survival with this treatment strategy., Methods: Data from all studies using IPEC in treating PMP were analyzed. We searched PubMed, MEDLINE, and the Cochrane Library (through September 2011). Studies were limited to English and PMP with appendiceal origin. Twenty-nine studies were identified, with 15 studies from different treatment centers that were specifically analyzed for differences in 5-y mortality and morbidity. Observed to expected (OE) ratios were calculated for both mortality and morbidity., Results: Mean and median 3-y, 5-y, and 10-y survival rates were 77.18%/77.85%, 76.63%/79.5%, and 57.3%/55.9%, respectively. Of the 10 studies that had sufficient data to calculate OE ratios from the 5-year mortality data, two had OE ratios lower than 1. Of the 11 studies that had data sufficient to calculate OE ratios from the morbidity data, four had OE ratios that were less than 1., Conclusions: Combining cytoreductive surgery and IPEC improves the survival of patients with PMP, regardless of treatment modality. Although this treatment strategy is associated with an increased risk of morbidity, the increase in survival may be acceptable in proposing an alternative to debulking procedures alone., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
7. Pterostilbene induces mitochondrially derived apoptosis in breast cancer cells in vitro.
- Author
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Moon D, McCormack D, McDonald D, and McFadden D
- Subjects
- Apoptosis Regulatory Proteins, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Calcium metabolism, Cell Line, Tumor, Cytochromes c metabolism, Female, Humans, Intracellular Signaling Peptides and Proteins analysis, Mitochondria metabolism, Mitochondrial Proteins analysis, Superoxide Dismutase metabolism, bcl-2-Associated X Protein analysis, Antioxidants pharmacology, Apoptosis drug effects, Breast Neoplasms pathology, Mitochondria drug effects, Stilbenes pharmacology
- Abstract
Background: The ability of a breast cancer cell to evade apoptosis has a key role in tumor progression and sensitivity to treatment. High levels of Bcl-2-associated X protein (Bax) in tumor cells have been found to promote apoptosis and sensitize cells to anti-cancer therapies. Bcl-2-associated X protein redistribution to the mitochondrial membrane results in the release of proapoptotic factors including cytochrome C, second-mitochondrial-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low PI (Smac/DIABLO), and Ca(2+). We aimed to explore this pathway in cancerous breast cell lines treated with the naturally occurring antioxidant 3,5-dimethoxy-4-hydroxystilbene (pterostilbene)., Methods: We used whole cell lysates +/- Bax SiRNA from the cell lines MCF-7 and MDA-MB-231 in an enzyme-linked immunosorbent assay to quantify Bax, cytochrome C, Smac/DIABLO expression, and manganese superoxide dismutase (MnSOD) activity after treatment with pterostilbene. We quantified cell death using histone-related DNA complexes from cytosolic and mitochondrial fractions and used methylthiazol tetrazolium assay to analyze cell proliferation, in the presence of Bax-silencing or scrambled RNA. We measured changes in cytosolic calcium using the ratiometric calcium-sensitive dye fura-2-AM using an inverted ratiometric monochromator microscope., Results: Treatment of MCF-7 and MDA-MB-231 (MDA) cells with pterostilbene caused concentration-dependent increases in intracellular Bax at all doses tested. RNA silencing of Bax resulted in reduced rates of apoptosis in both cells types and increased cell survival when treated with pterostilbene. We observed an increase in cytochrome C in MDA cells after treatment with pterostilbene. The MCF-7 cells showed a net increase in cytosolic cytochrome C, with a corresponding reduction in mitochondrial cytochrome C after treatment with 50 and 75 μmol/L pterostilbene. We observed this again in Smac/DIABLO expression in both cell types. In MCF-7 cells, pterostilbene treatment caused an increase in cytosolic but a decrease in mitochondrial Smac/DIABLO protein concentrations. Pterostilbene significantly increase MnSOD activity in MDA-MB-231 cells. Finally, pterostilbene resulted in significant increases in cytosolic calcium concentrations., Conclusions: The natural dietary compound pterostilbene has an anti-proliferative effect and induces apoptosis in breast cancer cells in vitro via Bax activation and overexpression, resulting in increased MnSOD, Smac/DIABLO, and cytochrome C activity and cytosolic Ca(2+) overload., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
8. Pterostilbene ameliorates tumor necrosis factor alpha-induced pancreatitis in vitro.
- Author
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McCormack D, McDonald D, and McFadden D
- Subjects
- Acinar Cells cytology, Acinar Cells metabolism, Animals, Anti-Inflammatory Agents pharmacology, Cell Line, Drug Interactions, In Vitro Techniques, Interleukin-1beta metabolism, Interleukin-6 metabolism, Lipase metabolism, Pancreatitis pathology, Pterocarpus chemistry, Rats, STAT3 Transcription Factor metabolism, Acinar Cells drug effects, Pancreatitis chemically induced, Pancreatitis drug therapy, Stilbenes pharmacology, Tumor Necrosis Factor-alpha pharmacology
- Abstract
Background: We have previously demonstrated that pterostilbene, a compound in blueberries, exerts antiproliferative effects against pancreatic adenocarcinoma. However, little is known about the anti-inflammatory effects of pterostilbene in pancreatitis. Therefore, the aim of this study was to evaluate the effect of pterostilbene on inflammatory markers in an in vitro pancreatitis model. We hypothesized that pterostilbene would ameliorate the immediate inflammatory response in tumor necrosis factor alpha (TNF-α)-induced pancreatitis through downregulation of signal transducer and activator of transcription 3 (STAT3) and inhibition of TNF-α-induced secretion of lipase and proinflammatory cytokines interleukins (ILs) 1β and 6., Methods: AR42J acinar cells were pretreated with TNF-α to induce pancreatitis followed by 25 and 50 μM pterostilbene for 15 and 30 min. Secretion of lipase was quantified using a lipase assay and used as a marker of TNF-α-induced pancreatitis. Detection of STAT3, IL-1β, and IL-6 was performed using enzyme-linked immunosorbent assay. Analysis of variance and Tukey post hoc analysis were used for statistical analysis., Results: TNF-α increased the secretion of lipase, IL-1β, and IL-6. Pterostilbene treatment inhibited TNF-α-induced secretion of lipase (P<0.01 and P<0.001), IL-1β (P<0.05), and IL-6 (P<0.05 and P<0.01). Inhibition of STAT3 by pterostilbene occurred with treatment doses of 25 and 50 μM (P<0.001 and P<0.01)., Conclusions: The dietary compound pterostilbene exerts an anti-inflammatory effect in pancreatitis through downregulation of STAT3 and decreased the secretion of lipase, IL-1β, and IL-6. Pterostilbene's amelioration of pancreatitis in vitro makes it an advantageous anti-inflammatory agent. Further studies are necessary to determine pterostilbene's role as a protective or therapeutic agent in pancreatitis., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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9. Pterostilbene and cancer: current review.
- Author
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McCormack D and McFadden D
- Subjects
- Animals, Drug Evaluation, Preclinical, Humans, Plant Extracts therapeutic use, Stilbenes pharmacology, Blueberry Plants, Neoplasms drug therapy, Phytotherapy, Stilbenes therapeutic use
- Abstract
Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is an antioxidant that is primarily found in blueberries. Studies suggest that pterostilbene exhibits the hallmark characteristics of an effective anticancer agent based on its antineoplastic properties in several common malignancies. In vitro models have shown that pterostilbene inhibits cancer growth through alteration of the cell cycle, induction of apoptosis, and inhibition of metastasis. In vivo, pterostilbene inhibits tumorigenesis and metastasis with negligible toxicity. Pterostilbene has also been shown to be effective as an inducer of antioxidant capacity in multiple cancer cell lines that may facilitate its function as an anticarcinogenic compound. Additionally, preliminary studies show that pterostilbene exhibits much greater bioavailability compared with other stilbene compounds; however the exact pharmacologic mechanism of pterostilbene and its effects in humans are still under investigation. In this review, we present a comprehensive summary of the antineoplastic mechanisms of pterostilbene based on the results of preclinical studies and highlight recent advances in the study of this dietary compound., (Copyright © 2012 Elsevier Inc. All rights reserved.)
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- 2012
- Full Text
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10. The operating room dashboard.
- Author
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Park KW, Smaltz D, McFadden D, and Souba W
- Subjects
- Costs and Cost Analysis, Decision Making, Hospitals, University, Humans, Operating Rooms economics, Operating Rooms standards, Robotics, Surgical Procedures, Operative economics, Operating Rooms organization & administration, Surgical Procedures, Operative standards
- Published
- 2010
- Full Text
- View/download PDF
11. The Journal of Surgical Research Editorial Board--2010.
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McFadden D and Souba WW
- Subjects
- Specialties, Surgical, Editorial Policies
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- 2010
- Full Text
- View/download PDF
12. Developing the young academic surgeon.
- Author
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Staveley-O'Carroll K, Pan M, Meier A, Han D, McFadden D, and Souba W
- Subjects
- Humans, Workforce, Academic Medical Centers, Career Choice, Faculty, Medical supply & distribution, General Surgery education
- Abstract
In the past, the process of developing the young academic surgeon was arguably less strategic, one that was often not deliberately managed and monitored, leading in some cases to academic drift and disillusionment. Once upon a time it was assumed that greatness was genetic and that the next triple threat would emerge when a pre-programmed set of genes was turned on. Today, as the complexities and vicissitudes of our work increase, it is practically impossible for even the most gifted young person to be successful without careful attention to career development. Faculty development must be deliberate and strategic--every junior faculty member is unique and will require a customized career development plan that is well thought out, linked to measurable goals, monitored routinely and buttressed by effective mentoring. This approach will require time and commitment--precious commodities that are in short supply as the demands on our time are only escalating. By recruiting the right people (those who fit with the organization's values and goals) and providing the right environment, we can optimize the growth and satisfaction of our young faculty and, in so doing, create departments that are leaders in carrying out our missions of research, education and patient care. We cannot afford to have our young people fail--it is simply too costly, both from a financial and a human perspective.
- Published
- 2005
- Full Text
- View/download PDF
13. Neutral endopeptidase determines the severity of pancreatitis-associated lung injury.
- Author
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McFadden D
- Subjects
- Animals, Humans, Mice, Models, Animal, Pancreatitis complications, Lung Diseases immunology, Neprilysin metabolism, Pancreatic Elastase adverse effects, Pancreatitis immunology
- Published
- 2005
- Full Text
- View/download PDF
14. Developing the young academic surgeon.
- Author
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Staveley-O'Carroll K, Pan M, Meier A, Han D, McFadden D, and Souba W
- Subjects
- Humans, Workforce, Academic Medical Centers, Career Choice, Faculty, Medical supply & distribution, General Surgery education
- Abstract
In the past, the process of developing the young academic surgeon was arguably less strategic, one that was often not deliberately managed and monitored, leading in some cases to academic drift and disillusionment. Once upon a time it was assumed that greatness was genetic and that the next triple threat would emerge when a pre-programmed set of genes was turned on. Today, as the complexities and vicissitudes of our work increase, it is practically impossible for even the most gifted young person to be successful without careful attention to career development. Faculty development must be deliberate and strategic--every junior faculty member is unique and will require a customized career development plan that is well thought out, linked to measurable goals, monitored routinely and buttressed by effective mentoring. This approach will require time and commitment--precious commodities that are in short supply as the demands on our time are only escalating. By recruiting the right people (those who fit with the organization's values and goals) and providing the right environment, we can optimize the growth and satisfaction of our young faculty and, in so doing, create departments that are leaders in carrying out our missions of research, education and patient care. We cannot afford to have our young people fail--it is simply too costly, both from a financial and a human perspective.
- Published
- 2004
- Full Text
- View/download PDF
15. In vitro anticancer effects of a novel immunostimulant: keyhole limpet hemocyanin.
- Author
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Riggs DR, Jackson B, Vona-Davis L, and McFadden D
- Subjects
- Adjuvants, Immunologic administration & dosage, Aged, Breast Neoplasms pathology, Cell Division drug effects, Dose-Response Relationship, Drug, Female, Hemocyanins administration & dosage, Humans, Male, Middle Aged, Pancreatic Neoplasms pathology, Prostatic Neoplasms pathology, Tumor Cells, Cultured drug effects, Adjuvants, Immunologic therapeutic use, Breast Neoplasms drug therapy, Hemocyanins therapeutic use, Pancreatic Neoplasms drug therapy, Prostatic Neoplasms drug therapy
- Abstract
Background: Keyhole limpet hemocyanin (KLH) is a recently described immune stimulant and hapten carrier derived from a circulating glycoprotein of the marine mollusk Megathura crenulata. It has been reported to be a potent form of intravesical immunotherapy for the treatment of transitional cell carcinoma of the bladder and has been used in a variety of genitourinary tumors. We hypothesized that KLH would be effective against other cancer cells in vitro., Methods: Multiple cancer cell lines were tested, including estrogen-dependent breast (MCF-7), estrogen-independent breast (ZR75-1), pancreas (PANC-1, MIA-PaCa), and prostate (DU145). Serial twofold dilutions of KLH were prepared in sterile 96-well plates. Dose-response curves were performed beginning with a concentration of 100 microg of KLH/well and ending at a concentration of 0.8 ng/well. Cells were added at concentrations of 5 x 10(4) cells per well. Cell viability was evaluated at 24 and 72 h by MTT assay at an absorbance of 570 nm., Results: Significant (P < 0.05) cancer cell growth inhibition was observed in four of the five cell lines tested at both time treatment intervals. The breast cancer line ZR75-1 exhibited a mean growth inhibition of 43 +/- 1.1% (range 37 to 59%) at 72 h, whereas treated MCF-7 cells had an average of 39 +/- 9.1% growth inhibition (range 35 to 44%) at these same concentrations. Treated PANC-1 cells had a mean growth inhibition of 19 +/- 0.8% (range 4 to 46%) at 72 h. The DU145 prostate cancer cell line averaged a 6 +/- 1.3% growth inhibition (range -19 to 55%) over the concentrations tested., Conclusions: The direct growth inhibition of multiple tumor cell-lines exhibited by KLH is significant and warrants further in vitro mechanistic studies and in vivo experiments. Investigation into the efficacy and mechanism of response could directly lead to more effective treatment regimens for patients suffering from these diseases.
- Published
- 2002
- Full Text
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16. Platelet activating factor antagonism reduces the systemic inflammatory response in a murine model of acute pancreatitis.
- Author
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Lane JS, Todd KE, Gloor B, Chandler CF, Kau AW, Ashley SW, Reber HA, and McFadden DW
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- Acute Disease, Amylases blood, Animals, Disease Models, Animal, Female, Interleukin-1 blood, Lung immunology, Lung metabolism, Mice, Pancreatitis pathology, Peroxidase analysis, Platelet Activating Factor immunology, Tumor Necrosis Factor-alpha metabolism, Imidazoles pharmacology, Leucine analogs & derivatives, Leucine pharmacology, Pancreatitis drug therapy, Pancreatitis immunology, Platelet Activating Factor antagonists & inhibitors
- Abstract
Background: The platelet activating factor (PAF) antagonist, Lexipafant, has been used in experimental models and clinical trials to treat severe acute pancreatitis (AP). The purpose of this study was to determine whether Lexipafant reduces the local and systemic components of AP in a murine model of mild, edematous AP., Materials and Methods: Forty-eight female Swiss-Webster mice were divided into four groups. Group 1 received 50 microl of saline ip every hour for 6 h (sham). Group 2 received saline treatment, plus Lexipafant (25 mg/kg dose ip, every 3 h starting 1 h after the first saline injection) (sham/Lex). Group 3 received cerulein (50 microg/kg dose ip, every hour for 6 h) (AP). Group 4 received AP, plus therapeutic treatment with Lexipafant (AP/Lex). Animals were sacrificed 3 h after the last injection. Serum cytokine levels were determined by ELISA. Standard assays were performed for serum amylase activity and lung myeloperoxidase activity (MPO). Histology was scored by two blinded investigators., Results: Serum cytokines (TNFalpha, IL-1beta), lung MPO, and serum amylase activity were reduced by PAF antagonism. Histology showed a trend toward improvement with Lexipafant, but did not reach statistical significance., Conclusion: The PAF antagonism reduces the severity of systemic inflammation when given after the induction of mild AP in mice. These results suggest that Lexipafant may be useful in the treatment of mild pancreatitis after its clinical onset., (Copyright 2001 Academic Press.)
- Published
- 2001
- Full Text
- View/download PDF
17. Alpha-tocopherol succinate inhibits growth of gastric cancer cells in vitro.
- Author
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Rose AT and McFadden DW
- Subjects
- Cell Survival drug effects, Humans, Stomach Neoplasms pathology, Tocopherols, Tumor Cells, Cultured, Vitamin E pharmacology, Antineoplastic Agents pharmacology, Stomach Neoplasms drug therapy, Vitamin E analogs & derivatives
- Abstract
Background: Vitamin E in the form of alpha-tocopherol succinate (ATS) has been shown to inhibit growth of several cancer cell lines in vitro, including pancreas, breast, and prostate. No data exist on the effect of ATS on gastric cancer cell viability., Methods: A gastric cancer cell line in suspension form, KATO-III, was plated in 96-well plates at 30,000 cells per well with 100 microl RPMI media. The cells were allowed to incubate for 24 h and were then treated with ATS at doses of 25, 50, or 100 microg/ml. The ATS was dissolved in 1% EtOH solution and control cells received an identical solution of EtOH without ATS. Treated cells were incubated for 24, 48, or 72 h. At the completion of the treatment period, MTT assay was performed to determine cell viability. Statistical analysis was performed using Student's t test., Results: All doses of ATS resulted in inhibition of growth of the KATO-III cells. Both 100 and 50 microg/cc doses inhibited growth at all time points (P<0.005), with 48- and 72-h treatments more effective than 24-h treatment. At 24 and 48 h, 100 microg/cc was more effective at inhibition of growth than 50 microg/ml (P<0.005), but by 72 h the effects of the doses were equivalent; 25 microg/ml inhibited cell growth only at 48 and 72 h. At all time points, 50 and 100 microg/ml doses were more effective at inhibiting cell growth than 25 microg/ml. Conclusions. ATS inhibits gastric carcinoma cell growth in vitro in a dose- and time-dependent fashion. In vivo studies are indicated to further evaluate the potential benefit of this antioxidant against gastric cancer., (Copyright 2001 Academic Press.)
- Published
- 2001
- Full Text
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18. Hypericin and photodynamic therapy decreases human pancreatic cancer in vitro and in vivo.
- Author
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Liu CD, Kwan D, Saxton RE, and McFadden DW
- Subjects
- Animals, Anthracenes, Humans, Mice, Mice, Nude, Perylene pharmacokinetics, Perylene therapeutic use, Tissue Distribution, Tumor Cells, Cultured, Antineoplastic Agents therapeutic use, Pancreatic Neoplasms drug therapy, Perylene analogs & derivatives, Photochemotherapy
- Abstract
Background: The treatment of pancreatic cancer has remained dismal despite advances in medical and surgical care. Recent preclinical data have revealed that hypericin, a photochemical dye, is activated by green light and generates toxic radical species in tumors. We hypothesized that interstitial hypericin and laser phototherapy would decrease pancreatic cancer growth., Methods: MiaPaCa-2 and PANC-1 cells were grown in tissue culture. In vitro experiments were performed with addition of 10 microg of hypericin/500,000 cancer cells. Cells were incubated with hypericin for 2 h. Cells were then exposed to KTP532 green laser light for 1 min at 0.6 W using a cylindrical diffuser tip. Cell growth was measured by MTT assay 24 h after laser treatment, N = 12. MiaPaCa-2 cells were implanted subcutaneously and orthotopically in pancreas of nude mice. After 5 weeks, both tumors were injected with 100 microg of hypericin followed by insertion of a cylindrical diffuser tip into the tumor center. Mice received 200J KTP laser light at 1.0 W in two sites. Tumors were measured before and 4 weeks after laser treatment., Results: Both in vitro and in vivo mice data showed a significant decrease in growth of pancreatic cancer. Pancreatic cancer cell growth was suppressed by 66.1 +/- 0.2%, n = 12, P < 0.01, ANOVA. Subcutaneous shoulder tumors were suppressed by 91.2 +/- 2.3%, n = 12, P < 0.001, and orthotopically grown pancreatic tumors were suppressed by 42.2 +/- 8.1%, n = 12, P < 0.05, compared to pretreatment sizes. Data expressed as percentage reduction vs paired controls in the MTT assay and vs pre-photodynamic therapy in mice experiments. Paired Student's t tests were performed vs pretreatment sizes., Conclusion: Both in vitro and in vivo results revealed a significant decrease in pancreatic cancer cell growth. Laser or dye alone had no effect, indicating that intratumor hypericin and laser therapy may prove useful in unresectable pancreatic cancer., (Copyright 2000 Academic Press.)
- Published
- 2000
- Full Text
- View/download PDF
19. Lysophosphatidic acid stimulates intestinal restitution via cytoskeletal activation and remodeling.
- Author
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Hines OJ, Ryder N, Chu J, and McFadden D
- Subjects
- Actins metabolism, Animals, Calcium metabolism, Cell Line, Dose-Response Relationship, Drug, Duodenum enzymology, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Intestinal Mucosa cytology, Intestinal Mucosa metabolism, Pertussis Toxin, Protein-Tyrosine Kinases metabolism, Rats, Stress, Mechanical, Virulence Factors, Bordetella pharmacology, Wound Healing drug effects, Cytoskeleton drug effects, Cytoskeleton metabolism, Duodenum cytology, Lysophospholipids pharmacology
- Abstract
Background: The gastrointestinal tract heals superficial wounds by a process of epithelial migration termed restitution. Restitution is an important response for preventing conditions like stress gastritis, ulcer disease, celiac sprue, ischemia-reperfusion injury, bacterial translocation during shock, and inflammatory bowel disease. The purpose of this study was to determine the effect of a platelet product, lysophosphatidic acid (LPA), on intestinal restitution., Materials and Methods: IEC-6 cells were used to study the effect of LPA on intracellular calcium mobilization, actin stress fiber formation, and actin and FAK protein levels. An in vitro model of restitution was utilized to determine the LPA-stimulated IEC-6 migration., Results: LPA administration stimulated intracellular calcium mobilization in a dose-dependent fashion with typical peak and plateau phases suggestive of a receptor-mediated response. Actin stress fiber formation occurred within 15 min after LPA treatment and was especially apparent at 2 h. This response was accompanied by higher actin and FAK protein levels. LPA also stimulated IEC-6 migration 3-fold within 24 h. All of these effects were completely inhibited by pertussis toxin., Conclusions: Exposure of IEC-6 cells to LPA results in significant calcium mobilization and cytoskeletal remodeling within minutes. This activity is accompanied by increased actin and FAK levels. Cellular migration is significantly enhanced by LPA. These responses seem to be due to pertussis-sensitive G-protein-associated receptors. The ability of LPA to potentiate intestinal cell restitution appears, in part, to be mediated by effects on intestinal cell cytoskeletal structure., (Copyright 2000 Academic Press.)
- Published
- 2000
- Full Text
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20. Improving the Surgeon's participation in research: is It a problem of training or priority?
- Author
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Ko CY, Whang EE, Longmire WP Jr, and McFadden DW
- Subjects
- Adult, Aged, Aged, 80 and over, Data Collection, Education, Medical, Humans, Medicine standards, Middle Aged, Specialization, Attitude of Health Personnel, Education, Medical, Graduate standards, General Surgery education, General Surgery standards, Research
- Abstract
Background: Although numerous important contributions have originated from basic science research performed by surgeons, it seems that such dedicated work is becoming increasingly difficult to accomplish. What are the reasons for this change and what improvements can be made? This study aims to characterize the basic research training and careers of senior academic surgeons to assess and devise strategies for sustaining productive and quality surgical research., Methods: A 25-item survey was sent to 850 senior-level members of academic societies, including the Association of Academic Surgeons, Society of University Surgeons, and American Surgical Association. It addressed each surgeon's clinical and research training and career, as well as opinions concerning surgical research., Results: Three hundred seventy-seven (44%) surveys were received. Mean age was 64 years, and 73% were full professors. Seventy-two percent of respondents performed basic science research during training, and for 71% of this group, research was a significant reason for choosing a clinical specialty. Ninety-one percent performed research in the same specialty area during and after training. Of those who performed research during training, a full 99% continued to perform research on completion of training. However, 38% stopped performing basic research by age 39. Seventeen and twenty-three percent stopped basic research between 40 and 49 and between 50 and 59 years of age, respectively. The most common factors causing them to stop were increased clinical load (40%) and increased administrative duties (38%). For respondents who had stopped research prior to age 40, 73% cited increased clinical load as the primary reason. Eighty-five percent felt a dedicated research period should be included in surgery training., Conclusions: Most respondents had participated in basic research during training, and continued similar research after training. However, an overwhelming clinical practice at the junior faculty level seemed to hinder research. We conclude: (1) the majority consensus is that research training is integral to the development of academic surgeons; (2) such research training opportunities appear adequate; however, (3) faculty performing research, particularly at the junior level, need to be better protected from other academic duties, such as clinical practice and administration. The challenge to the leadership of academic surgery will be to enhance such research productivity in the context of increasing academic demands., (Copyright 2000 Academic Press.)
- Published
- 2000
- Full Text
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21. Peptide YY and vitamin E inhibit hormone-sensitive and -insensitive breast cancer cells.
- Author
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Heisler T, Towfigh S, Simon N, and McFadden DW
- Subjects
- Cell Division drug effects, Cell Survival drug effects, Coloring Agents, Female, Humans, Receptors, Estrogen analysis, Tetrazolium Salts, Thiazoles, Tocopherols, Tumor Cells, Cultured chemistry, Tumor Cells, Cultured cytology, Tumor Cells, Cultured drug effects, Vitamin E pharmacology, Breast Neoplasms, Carcinoma, Ductal, Breast, Peptide YY pharmacology, Vitamin E analogs & derivatives
- Abstract
We have shown that peptide YY, an endogenous gut hormone, and vitamin E succinate (VES) inhibit pancreatic cancer cell growth in vitro. We hypothesized that PYY and VES would inhibit breast cancer cell viability regardless of the hormone receptor status. Human breast ZR-75 ductal carcinoma (estrogen receptor negative) and MCF-7 adenocarcinoma (estrogen receptor positive) cells were cultured and exposed to VES (10 pg/ml), PYY (500 pmol), or both agents together. MTT assay was performed at 24, 48, and 72 h to evaluate cell viability. At every time interval, PYY and VES significantly inhibited cell growth compared to control. The effects of PYY were similar in magnitude to those of VES. Combining the agents resulted in a significant additive inhibition of growth with the greatest effect seen at 72 h. We have shown that PYY and vitamin E inhibit in vitro growth of breast cancer cells with variable hormone receptor status. When used in combination, the agents have a significant increase in effect. Further studies are ongoing to define the mechanism of action of these agents and to translate the experiments to an in vivo model., (Copyright 2000 Academic Press.)
- Published
- 2000
- Full Text
- View/download PDF
22. Intestinal ischemia and the gut-liver axis: an in vitro model.
- Author
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Towfigh S, Heisler T, Rigberg DA, Hines OJ, Chu J, McFadden DW, and Chandler C
- Subjects
- Animals, Cell Survival, Cells, Cultured, Interleukin-6 analysis, Interleukin-6 biosynthesis, Rats, Tumor Necrosis Factor-alpha analysis, Tumor Necrosis Factor-alpha biosynthesis, Intestines blood supply, Ischemia complications, Kupffer Cells physiology, Systemic Inflammatory Response Syndrome etiology
- Abstract
Background: Sustained intestinal ischemic injury often leads to shock and multiorgan failure, mediated in part by a cytokine cascade. Animal models have also identified a central role of Kupffer cells in amplification of cytokines following intestinal ischemia. To better understand this gut-liver axis, we developed an in vitro model., Materials and Methods: Kupffer cells were isolated from rat livers by arabinogalactan gradient ultracentrifugation and adherence purification. Cells were grown in RPMI medium in 5% CO(2). Rat intestinal epithelial cells, IEC-6, were cultured under normoxic or anoxic (90% N(2), 10% CO(2)) conditions for 2, 12, and 24 h. Kupffer cells were then grown in the conditioned medium of the IEC-6 cultures. After 24 h, the medium was replaced with fresh medium. This final Kupffer cell supernatant was tested for tumor necrosis factor alpha and interleukin-6 production by ELISA. Trypan blue exclusion was performed to assess cell viability., Results: Intestinal and Kupffer cells remained viable during the experimental time. Production of both tumor necrosis factor alpha and interleukin-6 by Kupffer cells increased with increasing ischemia time of the intestinal cells., Conclusions: Consistent with animal studies of intestinal ischemia, this study found an increase in cytokine production by Kupffer cells following hypoxia of intestinal cells. This in vitro model offers a new tool to study the expression of cytokines, proteins, and messengers involved in the cascade of events that follow intestinal ischemia., (Copyright 2000 Academic Press.)
- Published
- 2000
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23. Peptide YY augments gross inhibition by vitamin E succinate of human pancreatic cancer cell growth.
- Author
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Heisler T, Towfigh S, Simon N, Liu C, and McFadden DW
- Subjects
- Cell Division drug effects, Drug Synergism, Humans, Pancreatic Neoplasms pathology, Tocopherols, Tumor Cells, Cultured, Vitamin E pharmacology, Pancreatic Neoplasms drug therapy, Peptide YY pharmacology, Vitamin E analogs & derivatives
- Abstract
Background: Vitamin E succinate (VES) significantly inhibits cell growth in vitro in breast, prostate, and skin cancer cell lines. Our study demonstrated similar inhibitory effects on Mia PaCa-2 pancreatic cancer cells at the same concentration of VES (10 pg/ml). Peptide YY (PYY) also inhibits pancreatic cancer cell growth in vitro. We observed a significant additive effect on growth inhibition in Mia PaCa cells treated with both VES and PYY., Methods: Human pancreatic ductal adenocarcinoma Mia PaCa-2 cells were cultured and treated once with either 10 pg/ml of VES or 500 pmols of PYY or with both agents together. The control group received an equivalent volume of solvents. MTT assay was performed at 24, 48, and 72 h to evaluate cell viability., Results: Pancreatic cancer cell growth was reduced in all groups treated with PYY and VES. Student's t test was used to analyze the data for each treatment group. At 72 h, both PYY and vitamin E significantly inhibited cell growth compared to control. Combining the agents resulted in a dramatic additive inhibition of growth., Conclusion: PYY and vitamin E both inhibit growth of pancreatic cancer cells in vitro with a significant increase in effect when used in combination., (Copyright 2000 Academic Press.)
- Published
- 2000
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24. Hypophosphorylated retinoblastoma protein is associated with G2 arrest in esophageal squamous cell carcinoma.
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Rigberg DA, Kim FS, Sebastian JL, Kazanjian KK, and McFadden DW
- Subjects
- Blotting, Western, Carcinoma, Squamous Cell genetics, Enzyme-Linked Immunosorbent Assay, Esophageal Neoplasms genetics, G2 Phase radiation effects, Humans, Phosphorylation, Retinoblastoma Protein genetics, Tumor Cells, Cultured radiation effects, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Esophageal Neoplasms metabolism, Esophageal Neoplasms pathology, G2 Phase physiology, Retinoblastoma Protein metabolism
- Abstract
Hypophosphorylated retinoblastoma (Rb) gene product binds critical transcription factors, leading to G1 arrest in a number of conditions, including following DNA damage. We have previously shown that irradiated esophageal squamous cell carcinoma (ESSC) cells undergo predominantly G2 arrest, with increases in inhibitors of Rb phosphorylation. We thus hypothesized that this G2 arrest would be accompanied by increases in hypophosphorylated Rb protein (pRb). We sequenced the Rb genes of three human ESSC lines (KYSE) following reverse transcription polymerase chain reaction of exons A-E. Western gels were performed on protein extracts for pRb. Cells were irradiated at 6 Gy, and protein was extracted at 6 h. ELISA was used to measure hypophosphorylated pRb in radiated versus control cells. Student's t test was used to compare results. All lines had wild-type Rb genes. Western gels confirmed the presence of pRb. There were significant increases in hypophosphorylated pRb in all three lines following irradiation (no line with less than a 100% increase). We have thus shown that irradiation-induced G2 arrest occurs in association with wild-type Rb genes and that there is associated hypophosphorylation of pRb. This supports our data describing a further role for other G1 mediators, such as p21, in G2 arrest. Further investigations into therapies to expoit this cell cycle checkpoint are warranted and planned., (Copyright 1999 Academic Press.)
- Published
- 1999
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25. Peptide YY inhibits growth of human breast cancer in vitro and in vivo.
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Grisé KR, Rongione AJ, Laird EC, and McFadden DW
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- Animals, Breast Neoplasms metabolism, Carcinoma, Ductal, Breast metabolism, Cell Division drug effects, Cell Survival, Coloring Agents, Cyclic AMP metabolism, Female, Humans, Intracellular Membranes metabolism, Mice, Mice, Nude, Tetrazolium Salts, Thiazoles, Tumor Cells, Cultured, Breast Neoplasms pathology, Carcinoma, Ductal, Breast pathology, Peptide YY pharmacology
- Abstract
Background: Hormonal manipulation is important in the treatment of breast cancer. Gastrointestinal hormones may have antiproliferative effects on malignancies arising outside the gastrointestinal tract. Peptide YY (PYY) suppresses growth of, and levels of, intracellular cyclic adenosine monophosphate (cAMP) in pancreatic adenocarcinoma. We hypothesized that PYY would inhibit growth of breast cancer., Materials and Methods: MCF-7 human breast infiltrative ductal carcinoma cells in 96-well plates were treated with PYY at 1.25 pmol/mcl. Control wells received an equal volume of bovine serum albumin to mimic experimental conditions. In vitro survival was determined by MTT assays, which reflect cell viability by measuring mitochondrial NADH-dependent dehydrogenase activity. MCF-7 cells in six-well plates were treated with PYY or albumin as described above. Intracellular cAMP levels in cell lysates were determined with a tritiated cAMP assay. One million MCF-7 cells were injected into mammary fat pads of 20 female athymic nude mice. Pellets releasing PYY at 400 pmol/kg/h were placed subcutaneously in 10 mice 24 h prior to cell inoculation. Tumors were harvested after 21 days, weighed, and measured with vernier calipers., Results: PYY reduced in vitro growth by 40% (P < 0.001). Intracellular cAMP levels in PYY-treated cells were 62.4% less than those of controls (P < 0.001). Tumors from control mice weighed twice as much as those from PYY-treated mice (P < 0.006); volume of PYY-exposed tumors was one-third that of controls (P < 0.005)., Conclusions: PYY inhibits growth of breast cancer in vitro and in vivo and may be of benefit in the treatment of this malignancy. The reduction in intracellular cAMP levels may contribute to the observed suppression of cell proliferation., (Copyright 1999 Academic Press.)
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- 1999
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26. Antisense blockade of p21/WAF1 decreases radiation-induced G2 arrest in esophageal squamous cell carcinoma.
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Rigberg DA, Blinman TA, Kim FS, Cole MA, and McFadden DW
- Subjects
- Cyclin-Dependent Kinase Inhibitor p21, Cyclins genetics, Cyclins physiology, Enzyme Inhibitors, Flow Cytometry, Oligonucleotides, Antisense genetics, Protein Kinase Inhibitors, Transfection, Tumor Cells, Cultured, Carcinoma, Squamous Cell pathology, Cyclins antagonists & inhibitors, Esophageal Neoplasms pathology, G2 Phase radiation effects, Oligonucleotides, Antisense pharmacology
- Abstract
Introduction. The p21 cyclin-dependent kinase inhibitor arrests the cell cycle following DNA damage at the G1-S checkpoint. Recent literature has also demonstrated a role for p21 in G2 arrest. Studies with esophageal squamous cell carcinoma (ESSC) lines have shown that radiation-induced p21 protein induction is associated with G2 arrest. The aim of this study was to determine if p21 blockade would affect this G2 arrest pattern. Method. We transfected the ESSC line KYSE 170 with antisense p21 mRNA oligonucleotides or scrambled 20-mer p21 control oligonucleotides using a lipofectant reagent. Cells were exposed to 6 Gy or used as controls. p21 levels were determined by ELISA. Cell cycle arrest pattern was determined via flow cytometry. Student's t test and ANOVA were used to compare p21 levels and percentages of G2 arrest. Results. Irradiated/scrambled cells expressed 10.1 ng/ml of p21 protein compared to irradiated/antisense cells at 2.1 ng/ml (P < 0.05), demonstrating successful blockade of p21. Irradiated cells displayed prominent G2 arrest following 6 Gy doses, but there was a decrease from 65 to 44% G2 phase when p21 was blocked (P < 0.05). Conclusions. We have demonstrated that G2 arrest accompanying irradiation of ESSC cells decreases when p21 protein production is blocked via antisense oligonucleotides. These data support a role for p21 in mediating G2 arrest in these cells., (Copyright 1999 Academic Press.)
- Published
- 1999
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27. p21 expression is increased by irradiation in esophageal squamous cell carcinoma.
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Rigberg DA, Kim FS, Blinman TA, Cole MA, Lane JS, So J, and McFadden DW
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- Cell Survival, Cyclin-Dependent Kinase Inhibitor p21, Cyclins analysis, Enzyme-Linked Immunosorbent Assay, Exons, Gamma Rays, Genes, p53 genetics, Humans, Introns, Mutation, Tumor Cells, Cultured, Carcinoma, Squamous Cell metabolism, Cyclins genetics, Esophageal Neoplasms metabolism, Gene Expression radiation effects
- Abstract
The p21 cyclin-dependent kinase inhibitor blocks cell cycle transition and replication in response to DNA damage. Although required for p53-mediated cell cycle arrest, p21 expression can also be initiated via p53-independent pathways. This study examines the postirradiation expression of p21 in squamous cell carcinoma (SCC) of the esophagus to determine whether this p21 production is p53-dependent or independent. We sequenced p53 exons 5-8 and the exon-intron junctions of four esophageal SCC lines, KYSEs 30, 150, 410, and 960. We exposed these same lines to increasing doses of radiation (3 to 24 Gy) and subsequently extracted their total protein. The p21 content of the protein was then determined via p21 ELISA. The same cell lines were also irradiated for determination of clonogenic survival over the course of 7 days. Cells were counted via a Coulter machine. KYSE 30 and 410 were found to have mutations in their p53 genes, while KYSEs 150 and 960 had wild-type p53 genomes. All cell lines produced basal levels of p21 (from 3.2 to 7.8 ng/ml) and all lines increased production in response to radiation (6.4 to 16.8 ng/ml at 3 Gy, P < 0.05 for all lines vs. their controls). Cells displayed dose-dependent mortality in response to radiation, with only minor differences in survival between two of the lines. All of the esophageal SCC lines studied produced basal p21 and increased p21 with irradiation. p21 production was independent of p53 status. Previous reports have failed to detect elevation of p21 expression in esophageal SCC, and this is the first report of radiation-induced p21 expression in esophageal cell lines.
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- 1998
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28. Interleukin-10 prevents early cytokine release in severe intraabdominal infection and sepsis.
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Rongione AJ, Kusske AM, Ashley SW, Reber HA, and McFadden DW
- Subjects
- Abdomen, Acute physiopathology, Acute Disease, Animals, Cecum injuries, Female, Mice, Interleukin-1 blood, Interleukin-10 pharmacology, Interleukin-6 blood, Intestinal Diseases physiopathology, Sepsis physiopathology, Tumor Necrosis Factor-alpha metabolism
- Abstract
Early release of macrophage-derived proinflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6, are important in the pathogenesis of septic shock and multisystem organ failure in various models of sepsis. IL-10 is a mediator that inhibits cytokine release from activated macrophages. The aim of this study was to determine if IL-10 would decrease serum cytokine elevation in a murine model of cecal ligation and puncture (CLP). CLP in animals is a model that closely mimics the physiologic changes seen in human sepsis. Four groups of 14 female Swiss-Webster mice were used. Group 1 underwent laparotomy alone, groups 2, 3, and 4 underwent laparotomy and CLP. Groups 1 and 2 received intraperitoneal (IP) saline injections to serve as control vehicle. Group 3 (prophylactic) received 10,000 U IP IL-10 1 hr prior to CLP and every 3 hr thereafter. Group 4 (therapeutic) received 10,000 U IP IL-10 1 hr following CLP and every 3 hr thereafter. Animals were sacrificed at 3 and 9 hr following CLP. Serum TNF-alpha, IL-1 beta, and IL-6 were determined by enzyme-linked immunosorbent assay (ELISA), CLP produced a significant rise in serum TNF,IL-6, and IL-1 in untreated controls. Prophylactic or therapeutic administration of IL-10 significantly attenuated this early rise in serum cytokines. These results support the hypothesis that (1) CLP produces an early systemic rise in macrophage-derived cytokines and (2) IL-10 given either before or after the onset of CLP-induced intraabdominal infection and sepsis is able to inhibit this early release of macrophage-derived systemic mediators. IL-10 has potential clinical benefits in the therapeutic management of intraabdominal infection and sepsis.
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- 1997
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29. Epidermal growth factor selectively enhances functional enterocyte adaptation after massive small bowel resection.
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Dunn JC, Parungo CP, Fonkalsrud EW, McFadden DW, and Ashley SW
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- Animals, Blotting, Western, DNA analysis, Female, Ileum drug effects, Ileum metabolism, Intestine, Small drug effects, Intestine, Small metabolism, Membrane Glycoproteins metabolism, Monosaccharide Transport Proteins metabolism, Proteins analysis, Rats, Rats, Inbred Lew, Sodium-Glucose Transporter 1, Sodium-Potassium-Exchanging ATPase metabolism, Sucrase metabolism, Adaptation, Physiological, Epidermal Growth Factor pharmacology, Ileum pathology, Intestine, Small surgery
- Abstract
After massive small bowel resection, the intestine adapts to compensate. In addition to proliferation, enterocytes also undergo selective functional adaptation. In this study we examined the effect of intraperitoneal administration of epidermal growth factor (EGF) on the expression of the brush border dissacharidase sucrase, the sodium glucose cotransporter (SGLT1), and the sodium-potassium ATPase pump (NaK ATPase) by enterocytes in the remnant intestine after massive small bowel resection. Adult Lewis rats underwent either ileal transection or 70% proximal intestinal resection. These animals were subdivided into groups that received either saline or EGF intraperitoneally for 1 week. Ilea from each group were harvested 4 weeks postoperatively. Enterocytes were separated from these segments by calcium chelation. The total protein from the isolated cells was subjected to Western blot analysis. Administration of EGF to animals that underwent transection did not significantly alter the expression of sucrase, SGLT1, or NaK ATPase. After intestinal resection, the expressions of sucrase and SGLT1 were significantly increased. The combination of EGF administration and intestinal resection resulted in a further increase in SGLT1 expression. The intraperitoneal administration of EGF selectively enhanced the expression of SGLT1 by enterocytes after massive small bowel resection. Administration of EGF to sham-operated animals did not have similar effects. These results suggest that EGF augments the adaptive response and may therefore have a therapeutic role in the management of patients with short bowel syndrome.
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- 1997
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30. Epidermal growth factor improves intestinal adaptation during somatostatin administration in vivo.
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Liu CD, Rongione AJ, Shin MS, Ashley SW, and McFadden DW
- Subjects
- Analysis of Variance, Animals, Cell Membrane metabolism, Epidermal Growth Factor administration & dosage, Female, Gene Expression drug effects, Humans, Infusions, Parenteral, Intestine, Small drug effects, Intestine, Small metabolism, Microvilli drug effects, Microvilli metabolism, Monosaccharide Transport Proteins biosynthesis, RNA, Messenger biosynthesis, Rats, Rats, Sprague-Dawley, Sodium-Potassium-Exchanging ATPase biosynthesis, Somatostatin administration & dosage, Epidermal Growth Factor pharmacology, Intestine, Small surgery, Somatostatin pharmacology
- Abstract
Somatostatin (SMS) is administered to patients with short bowel syndrome and enterocutaneous fistulae. Previous studies have shown detrimental effects of SMS on intestinal adaptation after bowel resection. We examined whether administration of epidermal growth factor (EGF) could reverse the deleterious effects of SMS seen after enterectomy. Sixty-four Sprague-Dawley rats underwent an 80% small bowel resection or transection as control. Rats received either SMS at 50 ng x kg(-1) x h(-1), EGF/Urogastrone at 1.5 microg x kg(1-) x h(-1), or both via subcutaneous miniosmotic pumps. Samples were obtained at 1 day and 1 week after surgery for histologic examination, analysis of apical Na+/glucose cotransporter protein and mRNA expression, and analysis of basolateral Na+/K+ ATPase protein and mRNA expression. Protein expression was analyzed by Western blotting whereas mRNA expression was compared by ribonuclease protection assay. Histologically, villus to crypt length after intestinal resection showed increased adaptation in EGF/SMS vs SMS treated animals in both jejunum and ileum. Analysis of mRNA and protein of epithelial transporters show early increases when EGF is administered with SMS vs SMS only. We conclude that combination therapy using EGF and SMS may be beneficial to intestinal adaptation after small bowel resection. Both histologic and molecular data suggest an enhanced absorptive potential and adaptation of the remaining intestine when EGF is administered.
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- 1996
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31. Enterocyte functional adaptation following intestinal resection.
- Author
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Whang EE, Dunn JC, Joffe H, Mahanty H, Zinner MJ, McFadden DW, and Ashley SW
- Subjects
- Animals, Intestinal Absorption, Intestines cytology, Intestines physiology, Rats, Rats, Sprague-Dawley, Sodium metabolism, Adaptation, Physiological, Intestines surgery
- Abstract
Following massive small bowel resection, the remaining intestine undergoes compensatory adaptation to maintain absorptive capacity. The purpose of this study was to determine the relative importance of mucosal hyperplasia and functional adaptation by individual enterocytes in this process. Distal ileum was harvested from rats 2 weeks following 70% small bowel resection or transection with reanastomosis. Transport parameters were determined in Ussing chambers. Short-circuit current (Isc) responses to additions of 3-0-methylglucose were measured to assess Na+/glucose cotransporter kinetics. Microvillus absorptive surface areas were calculated with computer-assisted morphometric modeling. These surface area values were used to normalize transport parameters. Ileal absorptive surface area was 70% greater in resection tissues than in transection tissues (P < 0.05). Na+ and Cl- fluxes were generally lower in the resection group. Na+/glucose cotransporter delta Isc max (an index of cotransporter quantity) for resection and transection tissues were 0.3 +/- 0.1 and 1.8 +/- 0.3, respectively (P < 0.05). Km (an index of cotransporter affinity for substrate) did not differ significantly. Following intestinal resection, ileal surface area increases; however, transport parameters, when normalized to absorptive surface area values, diminish. During early postresection adaptation, expansion of ileal absorptive surface area due to hyperplasia seems to play a greater role than upregulation of enterocyte Na+, Cl- , and glucose absorption.
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- 1996
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32. Amiloride inhibits meal-stimulated colonic absorption.
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Whang EE, Dunn JC, Liu CD, Newton T, Zinner MJ, McFadden DW, and Ashley SW
- Subjects
- Animals, Chlorides metabolism, Dogs, Dose-Response Relationship, Drug, Female, Food, Sodium metabolism, Amiloride pharmacology, Colon metabolism, Intestinal Absorption drug effects, Sodium Channel Blockers, Sodium-Hydrogen Exchangers antagonists & inhibitors
- Abstract
Meal-stimulated colonic absorption has recently been described, but the cellular transport mechanisms mediating this response are unknown. The purpose of this study was to determine the contribution of Na+ transport pathways to colonic proabsorption. Distal colonic Thiry-Vella loops were constructed in six dogs. Absorption was measured by infusing the loops with a physiological electrolyte solution containing [14C] polyethylene glycol as the impermeant marker. In the first set of experiments, the dose dependence of amiloride-induced inhibition of basal colonic absorption was determined. In the second set of experiments the effect of amiloride, which inhibits both Na+ channels and Na+/H+ exchange in colonocytes, on meal-stimulated colonic absorption was determined. Luminal amiloride inhibited basal colonic absorption in a dose-dependent manner, with significant reductions in Na+ absorption occurring with concentrations of 10(-2)M and higher. Infusion with 10(-3)M amiloride, a concentration that did not alter basal absorption, resulted in significant reductions in postprandial water, Na+, and Cl- absorption. These results suggest that meal-stimulated colonic absorption is mediated, at last in part, by transcellular Na+ absorptive pathways.
- Published
- 1996
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33. A novel synthetic analog of peptide YY, BIM-43004, given intraluminally, is proabsorptive.
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Liu CD, Hines OJ, Whang EE, Balasubramaniam A, Newton TR, Zinner MJ, Ashley SW, and McFadden DW
- Subjects
- Animals, Dogs, Female, Malabsorption Syndromes drug therapy, Neurosecretory Systems physiology, Peptides administration & dosage, Intestinal Absorption drug effects, Peptides pharmacology
- Abstract
Peptide YY (PYY), a proabsorptive hormone, is released into the circulation and lumen of the small intestine after a meal. We have recently found that intraluminal PYY is proabsorptive in the ileum. The purpose of this study was to examine the effects of intraluminal administration of a new substituted PYY (22-36) analog on intestinal absorption of electrolytes and water. Twelve conditioned 20-kg dogs had 25-cm jejunal, 25-cm ileal, or 20-cm colonic Thiry-Vella fistulas (TVF) surgically constructed under general anesthesia (jejunal and ileal TVF, N = 6, and colonic TVF, N = 6). After a 2-week recovery period, the animals received the intraluminal PYY analog, BIM-43004, in the ileum (200 pmole/kg) or colon (300 pmole/kg) for 60 min after a 90-min steady-state basal period was confirmed. The TVF were perfused with an isotonic buffer solution containing [14C]polyethylene glycol as a volume marker. Ion and water transport were measured every 15 min. Net water absorptions were significant in the ileum and colon but not in the jejunum upon intraluminal administration of the PYY analog, BIM-43004. Colonic water absorptions were increased more than twofold above basal absorption rates and ileal absorptions were increased more than 1.5-fold upon addition of intraluminal BIM-43004. Sodium and chloride ion absorption in the colon and ileum paralleled water fluxes. We are describing for the first time a synthetic peptide analog of PYY that produces significant water and electrolyte absorption in the ileum and colon when administered luminally. This synthetic analog may have therapeutic potential in patients with malabsorptive disorders.
- Published
- 1995
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34. Human pancreatic cancer growth is inhibited by peptide YY and BIM-43004-1.
- Author
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Liu CD, Balasubramaniam A, Saxton RE, Paiva M, and McFadden DW
- Subjects
- Cyclic AMP analysis, Humans, Pancreatic Neoplasms pathology, Peptide Fragments pharmacology, Peptide YY, Tumor Cells, Cultured, Pancreatic Neoplasms drug therapy, Peptides pharmacology
- Abstract
Exogenous peptide YY (PYY) decreases pancreatic exocrine secretion, pancreatic endocrine function, and pancreatic blood flow. We hypothesized that pancreatic cancer cell growth may be inhibited by PYY and a new synthetic analog, BIM-43004-1. Two human pancreatic ductal adenocarcinomas, PANC-1 and Mia PaCa-2, were examined in tissue cultures. Viable pancreatic cancer cells were counted with trypan blue on a hemocytometer slide. Cells (10K, 20K, 40K, and 80K) were cultured and allowed to grow for 36 hr (n = 14/cell concentration). Pancreatic cancer cells received either PYY or BIM-43004-1 at various concentrations. Control tissue cultures received an equivalent volume of saline inoculation. After incubation with the above peptides for 24 hr, MTT tetrazolium bromide was added to assay mitochondrial activity of pancreatic cancer cells in response to PYY and its analog. MTT assay reveals a significant decrease in pancreatic cancer cell growth when PYY and BIM-43004-1 are added to the cell culture. Results in Mia PaCa-2 reveal a 24% cell growth reduction after exposure to PYY and a 23% reduction in cell growth when treated with BIM-43004-1. In PANC-1 cells, a 25% reduction in growth of cells is noted after PYY treatment and a 24% reduction in growth after BIM-43004-1 treatment. (means +/- SEM, P < 0.05 by Student's t test). Our results reveal a significant reduction in human ductal pancreatic cancer growth when treated with either PYY or its analog, BIM-43004-1. These agents may be useful hormonal adjuncts in the chemotherapy of pancreatic adenocarcinoma.
- Published
- 1995
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35. Pancreatic peptide YY mRNA levels increase during adaptation after small intestinal resection.
- Author
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Liu CD, Hines OJ, Whang EE, Laird EC, Skotzko MJ, Zinner MJ, Ashley SW, and McFadden DW
- Subjects
- Animals, Base Sequence, Female, Glucagon genetics, Molecular Probes genetics, Molecular Sequence Data, Nucleic Acid Hybridization, Peptide YY, Polymerase Chain Reaction, Postoperative Period, Rats, Rats, Sprague-Dawley, Ribonucleases, Transcription, Genetic, Adaptation, Physiological, Intestine, Small physiopathology, Intestine, Small surgery, Pancreas metabolism, Peptides genetics, RNA, Messenger metabolism
- Abstract
Peptide YY (PYY) is a 36-amino-acid peptide known to inhibit pancreatic and gastrointestinal secretion. Immediately following small bowel resection, intestinal PYY mRNA and plasma PYY levels rise. The purpose of this study was to determine whether PYY expression changes in the pancreas during the adaptive period after extensive small bowel resection. Female Sprague-Dawley rats (250 g) underwent 70% small intestinal resection or transection alone as control. Animals were sacrificed at 6 hr, 24 hr, 1 week, or 2 weeks following operation (N = 5/time group). Pancreatic tissue was harvested and RNA was isolated by the guanididium-thiocyanate method. PYY mRNA was analyzed by reverse transcriptase PCR, standardized to glyceraldehyde-3-phosphate dehydrogenase, and semiquantitated by Southern blotting and 32P cpm. Ribonuclease protection assay was used to confirm PCR results. PYY mRNA expression was increased 9 1/2-fold beginning 6 hr after resection compared to transection (P < 0.05). PYY mRNA levels remain elevated, 2 1/4-fold greater than control after 2 weeks (P < 0.05) as analyzed by reverse transcriptase PCR and ribonuclease protection assay. Quantitation by ribonuclease protection assay reveals a gradual elevation of PYY mRNA levels in transected animals compared to a nonoperated rat starting at 1 and 2 weeks. Pancreatic PYY mRNA levels increase rapidly after extensive intestinal resection and remain elevated 2 weeks postoperatively. These results confirm for the first time that the increase in PYY seen after extensive intestinal resection also occurs in extraintestinal sites. In the pancreas, elevated PYY levels may inhibit exocrine secretion, reducing luminal volume, and thereby facilitating intestinal adaptation.
- Published
- 1995
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36. Amino acids mediate postprandial jejunal proabsorption.
- Author
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Hines OJ, Bilchik AJ, Ashley SW, Whang EE, Liu CD, Zinner MJ, and McFadden DW
- Subjects
- Amino Acids classification, Animals, Chlorides metabolism, Dogs, Female, Sodium metabolism, Water metabolism, Amino Acids physiology, Eating physiology, Intestinal Absorption physiology, Jejunum metabolism
- Abstract
Ingestion of a meal stimulates small intestinal ion and water transport. Current evidence suggests that this response, termed proabsorption, is primarily mediated by the apical Na+/glucose cotransporter. Like glucose, the majority of amino acid absorption occurs by Na(+)-dependent, secondary active transport. The purpose of this study was to determine the role of amino acid transport in meal-induced jejunal ion and water absorption in vivo. Exteriorized, neurovascularly intact jejunal loops measuring 25 cm were created in six female mongrel dogs, and the dogs were allowed to recover for 2 weeks. After an overnight fast, the loops were perfused with a standard buffer containing 10 mM aspartate, leucine, glycine, or lysine. Net water and electrolyte absorption before and after a mixed meal was calculated using [14C]polyethylene glycol as a volume marker. Aspartic acid, leucine, glycine, and lysine are each transported by a separate transporter system. Except for lysine, each amino acid significantly (P < 0.05) potentiated sodium and water absorption after a meal. In addition, this effect was at least as great as that seen with 10 mM glucose. These results demonstrate that amino acid transporter, like the Na+/glucose cotransporter, mediates meal-induced jejunal sodium and water absorption and may be as important in the proabsorptive response.
- Published
- 1995
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37. Adaptation of the Na+/glucose cotransporter following intestinal resection.
- Author
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Hines OJ, Bilchik AJ, Zinner MJ, Skotzko MJ, Moser AJ, McFadden DW, and Ashley SW
- Subjects
- Animals, Base Sequence, Colon metabolism, Ileum metabolism, Jejunum metabolism, Molecular Sequence Data, Monosaccharide Transport Proteins genetics, Postoperative Period, RNA, Messenger metabolism, Rats, Rats, Inbred Lew, Adaptation, Physiological, Intestinal Mucosa metabolism, Intestines surgery, Monosaccharide Transport Proteins metabolism
- Abstract
Following massive small bowel resection, the remaining intestine adapts to compensate for lost absorptive capacity. Although the Na+/glucose cotransporter plays a critical role in nutrient, fluid, and electrolyte transport in the small intestine, its role in adaptation following resection has not been defined. To examine this, we sought to determine whether there were changes in the expression of the Na+/glucose cotransporter, SGTL1, at the messenger RNA level. Lewis rats underwent either transection or 70% small bowel resection and reanastomosis. The animals were sacrificed at intervals following operation. Jejunum proximal to the anastomosis and ileum and colon distal to the anastomosis were harvested and analyzed for Na+/glucose mRNA by reverse transcriptase-polymerase chain reaction and Southern blot. Blots were semiquantitated by 32P labeling and standardized to beta-actin. Histologic sections and analysis of DNA, RNA, and protein content revealed hyperplastic changes. Following resection, mRNA for the Na+/glucose cotransporter in the jejunum increased significantly (P < 0.05) by 1 week and remained elevated. In the ileum, an almost fivefold increase occurred at 6 hr and persisted throughout the study (P < 0.05). The early response was greater in the ileum, distal to the reanastomosis, than that in the jejunum (P < 0.05). In contrast, there was no change in the small amount of transporter mRNA detected in the colon. These results suggest that, in addition to mucosal hyperplasia, the intestinal response to resection involves upregulation of transporter mRNA by the individual enterocyte. This transcriptional increase in the Na+/glucose cotransporter appears to be an early response by the intestine and may be important in maintaining overall intestinal transport capacity following resection.
- Published
- 1994
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38. Extrapancreatic cholinergic nerves mediate cholecystokinin-stimulated pancreatic polypeptide release.
- Author
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Kuvshinoff BW, Brodish RJ, Fink AS, and McFadden DW
- Subjects
- Animals, Atropine pharmacology, Benzodiazepinones pharmacology, Cholecystokinin antagonists & inhibitors, Devazepide, Dogs, Fistula, Kinetics, Pancreas drug effects, Pancreas metabolism, Pancreatic Polypeptide blood, Stomach surgery, Time Factors, Denervation, Pancreas innervation, Pancreatic Ducts surgery, Pancreatic Polypeptide metabolism, Sincalide pharmacology
- Abstract
Although vagal cholinergic stimulation is the predominant regulatory mechanism governing the release of pancreatic polypeptide (PP), recent studies suggest that cholecystokinin (CCK) is also an important mediator. The present study examined the role of cholinergic neural pathways in the PP response to exogenous CCK-8 using a selectively denervated canine pancreas model. Chronic denervated pancreatic preparations were created in five dogs, while five dogs underwent sham laparotomy as controls. On study days, the fasted animals were infused intravenous CCK-8 (40 or 400 pmole/kg/hr) for 60 min both with and without atropine (20 micrograms/kg/hr). Plasma was collected at 20-min intervals and PP levels were determined by radioimmunoassay. CCK-8 elicited a dose-dependent increase in circulating PP in dogs with a neurally intact pancreas. Atropine and pancreatic denervation eliminated the PP response to CCK-8 at 40 pmole/kg/hr (P < 0.01) and inhibited the PP response to CCK-8 at 400 pmole/kg/hr (P < 0.05). The high dose of CCK-8 still elicited a small PP response in the denervated dogs (P < 0.05), which was subsequently abolished by the addition of atropine. These findings suggest that extrapancreatic cholinergic nerves are essential components of CCK-stimulated PP release, and that intrapancreatic cholinergic activity may play a limited role.
- Published
- 1994
- Full Text
- View/download PDF
39. Peptide YY inhibits pancreatic secretion via cholinergic pathways.
- Author
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Brodish RJ, Kuvshinoff BW, Fink AS, and McFadden DW
- Subjects
- Animals, Bethanechol, Bethanechol Compounds pharmacology, Bicarbonates metabolism, Cholecystokinin pharmacology, Denervation, Dogs, Pancreas drug effects, Pancreas innervation, Peptide YY, Proteins metabolism, Secretin pharmacology, Pancreas metabolism, Parasympathetic Nervous System physiology, Peptides pharmacology
- Abstract
The influence of extrapancreatic nerves and intrapancreatic cholinergic activity on the inhibition of pancreatic exocrine secretion by peptide YY (PYY) was studied in conscious dogs. Chronic pancreatic fistulae were created in five mongrel dogs while a second group of five dogs also underwent complete pancreatic denervation. After recovery, a continuous infusion of secretin (62 ng/kg/hr) and cholecystokinin (50 ng/kg/hr) was administered over 2 hr. An infusion of PYY (400 pm/kg/hr) was then given randomly, during either the first or second experimental hour. The experiments were then replicated with a continuous background infusion of (90 micrograms/kg/hr) bethanechol, a cholinergic agonist. The secretin/cholecystokinin-induced bicarbonate and protein outputs were significantly inhibited by PYY in both the innervated and denervated animals. In the denervated animals, bethanechol eliminated the inhibitory effects of PYY. We conclude that extrapancreatic nerves do not mediate the inhibitory effects of PYY. The results suggest that PYY inhibits secretin/cholecystokinin-induced pancreatic response by an intrapancreatic cholinergic mechanism.
- Published
- 1993
- Full Text
- View/download PDF
40. Roux-en-Y jejunal bypass abolishes postprandial neuropeptide Y release.
- Author
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Rudnicki M, McFadden DW, Sheriff S, and Fischer JE
- Subjects
- Animals, Dietary Fats, Intestinal Mucosa metabolism, Intestine, Small physiology, Male, Neuropeptide Y blood, Rats, Rats, Sprague-Dawley, Receptors, Neuropeptide Y metabolism, Time Factors, Anastomosis, Roux-en-Y, Eating physiology, Jejunum physiology, Neuropeptide Y metabolism
- Abstract
Numerous physiologic aberrations occur after Roux-en-Y bypass procedures. Neuropeptide Y (NPY), a 36 amino acid polypeptide, has been shown to have many effects on gastrointestinal physiology, including alterations in blood flow, motility, and secretion and absorption. Recent work demonstrating a postprandial increase in circulating NPY prompted this investigation into its potential roles after Roux-en-Y bypass. Three groups of rats underwent Roux-en-Y cholangiojejunostomy, jejunojejunostomy, or proximal jejunal transection with reanastomosis. After a 3-month recovery, the animals were tested with both mixed and fat meals. Control animals had rapid increases in circulating NPY after the mixed meal. This response was not seen in either of the Roux-en-Y groups (P less than 0.05). No animals had circulating changes in NPY after the fat meal. Additionally, small intestinal NPY receptor analysis revealed high NPY affinity to the epithelial cells of the proximal small intestine. Our results demonstrate a dependence of postprandial NPY release on proximal small intestinal continuity that is abolished by Roux-en-Y bypass of a jejunal segment. The absence of postprandial elevation in plasma NPY after proximal jejunal bypass and the abundance of NPY receptors in the proximal small intestine merits further investigation into the physiologic roles of NPY in the foregut.
- Published
- 1992
- Full Text
- View/download PDF
41. Extrinsic neural contribution to ileal peptide YY (PYY) release.
- Author
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Rudnicki M, Kuvshinoff BW, and McFadden DW
- Subjects
- Animals, Dogs, Female, Glucose pharmacology, In Vitro Techniques, Male, Peptide YY, Sincalide pharmacology, Ileum innervation, Ileum metabolism, Peptides metabolism
- Abstract
Peptide YY (PYY) release into the ileal lumen is stimulated by cholecystokinin (CCK) and glucose ingestion. Previous data have implicated vagal activity in the mediation of PYY release into both the systemic circulation and the ileal lumen. The present study was designed to evaluate extrinsic neural involvement in CCK and glucose-stimulated circulating and ileal intraluminal PYY release. Distal ileal Thiry-Vella loops (TVL) of 25 cm were created in seven mongrel dogs. On separate days fasted dogs were given continuous infusions of CCK at 500 ng/kg/hr during the first hour of the study or an oral glucose (1.5 g/kg) tolerance test (OGTT) was performed. Peripheral blood samples and ileal effusates were collected before tests and following either CCK or glucose stimulation for 120 min at 20-min intervals. Ileal PYY recoveries were measured by the instillation and collection of 20 cc of normal saline from the TVL for each 20-min period. The dogs were again tested after surgical denervation of the TVL. OGTT resulted in a significant rise of PYY recovery from the TVL (P less than 0.05), while not affecting circulating PYY. Intravenous CCK resulted in significant increases in both plasma and ileal PYY concentrations (P less than 0.05). Denervation of the TVL decreased PYY recovery from the TVL after both CCK and OGTT, whereas this procedure did not affect circulating PYY levels or basal luminal levels. These data demonstrate the inhibition of CCK- and glucose-stimulated ileal PYY recovery from denervated ileal loops. The extrinsic neural pathways are involved in the mediation of glucose- and CCK-stimulated mechanisms for ileal PYY release.
- Published
- 1992
- Full Text
- View/download PDF
42. Vagal cooling blocks circulating neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) release.
- Author
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Rudnicki M, Rigel DF, and McFadden DW
- Subjects
- Animals, Dogs, Gastrointestinal Hormones blood, Heart Rate, Osmolar Concentration, Peptide YY, Cold Temperature, Nerve Block methods, Neuropeptide Y blood, Pancreatic Polypeptide blood, Peptides blood, Vagus Nerve physiology
- Abstract
Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) are regulatory peptides that constitute a new family of gastrointestinal and neural peptides. The influence of vagal integrity on NPY, PYY, and PP basal and postprandial release was evaluated using a new technique of reversible cryogenic cervical vagal blockade in an awake canine model. Cooling coils were placed around bilateral cervical vagal trunks in five dogs along with omocervical arterial catheters. Vagal transmission was monitored by pulse and arterial pressure monitoring. Cryogenic blockade of vagal nerves was performed by circulating a mixture of 0 degrees C ethanol and water through the cooling coils. NPY, PYY, and PP were measured using standard radioimmunoassays. Vagal cooling decreased basal NPY and PYY levels (P less than 0.05) but not PP. After a standard meal, vagal cooling blocked the postprandial rise seen in circulating NPY and PP (P less than 0.05). These data demonstrate a technique of reversible vagal blockade to evaluate the role of cervical vagal integrity in gastrointestinal endocrinology. Cryogenic vagal blockade inhibits the postprandial rise of circulating PP into the circulation. Vagal pathways appear to contribute to fasting activity of PYY and NPY releasing cells. Inhibited meal-stimulated release of NPY supports a role for vagal modulation of postprandial NPY release into the circulation.
- Published
- 1991
- Full Text
- View/download PDF
43. The effect of SMS 201-995 on meal and CCK-stimulated peptide YY release.
- Author
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Kuvshinoff BW, Rudnicki M, and McFadden DW
- Subjects
- Animals, Dogs, Gastrointestinal Hormones metabolism, Injections, Intravenous, Peptide YY, Eating drug effects, Octreotide pharmacology, Peptides metabolism, Sincalide pharmacology
- Abstract
Somatostatin is known to inhibit the postprandial release of most gastrointestinal hormones. The aim of the present study was to evaluate the effect of an analog of somatostatin, SMS 201-995 (120 ng/kg/hr), on both meal-induced and cholecystokinin octapeptide (CCK-8, 500 ng/kg/hr)-induced peptide YY (PYY) release. Six mongrel dogs with distal ileal Thiry-Vella loops were used in this study. PYY was measured in both plasma and ileal luminal effluent. SMS 201-995 did not affect interdigestive plasma or ileal luminal PYY concentrations. CCK-8 and a fat meal both stimulated PYY release into the circulation. SMS 201-995 completely inhibited the CCK-8 and fat-stimulated circulatory release of PYY. Both CCK-8 and a mixed meal increased ileal luminal PYY recovery. SMS 201-995 inhibited CCK-8-induced, but not meal-induced, ileal luminal PYY recovery. These findings support previous studies that describe independent circulatory and ileal luminal PYY release. We conclude that both somatostatin and CCK may have a regulatory role in postprandial circulatory release of PYY.
- Published
- 1991
- Full Text
- View/download PDF
44. The postprandial circulatory and ileal intraluminal release of neuropeptide Y in conscious dogs.
- Author
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Rudnicki M, McFadden DW, Balasubramaniam A, Nussbaum MS, and Fischer JE
- Subjects
- Animals, Dogs, Fasting, Female, Male, Neuropeptide Y blood, Osmolar Concentration, Eating physiology, Ileum metabolism, Neuropeptide Y metabolism
- Abstract
Neuropeptide Y (NPY), a 36-amino-acid peptide, was measured in the peripheral circulation and ileal lumen of conscious dogs using a sensitive radioimmunoassay. Fasting NPY concentrations averaged 448 +/- 15 pg/ml in the peripheral blood and 364 +/- 23 pg/ml in the ileal effluent. Following a mixed meal, circulating NPY levels rose to 499 +/- 37 pg/ml (P less than 0.05), whereas recoverable quantities of ileal intraluminal NPY fell to 257 +/- 19 pg/ml (P less than 0.05). Neither fat nor glucose meals significantly changed circulating or ileal intraluminal NPY recovery. These results demonstrate release of NPY into the blood and ileal lumen for the first time and support NPY as a candidate gut hormone.
- Published
- 1990
- Full Text
- View/download PDF
45. Addition of L-glutamine to total parenteral nutrition and its effects on portal insulin and glucagon and the development of hepatic steatosis in rats.
- Author
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Li SJ, Nussbaum MS, McFadden DW, Zhang FS, LaFrance RJ, Dayal R, and Fischer JE
- Subjects
- Animals, Body Weight drug effects, DNA metabolism, Glutamine pharmacology, Intestine, Small metabolism, Intestine, Small pathology, Lipid Metabolism, Liver metabolism, Male, Portal Vein, Proteins metabolism, Rats, Rats, Inbred Strains, Fatty Liver etiology, Glucagon blood, Glutamine administration & dosage, Insulin blood, Parenteral Nutrition, Total adverse effects
- Abstract
Infusion of total parenteral nutrition (TPN) with excess carbohydrate calories leads to hepatic steatosis in rats and is associated with an elevated portal insulin/glucagon molar ratio. Previously we have shown that adding glucagon to TPN prevents and reverses hepatic steatosis in rats, possibly by increasing hepatic lipid export. It has been reported that steatosis is eliminated in rats by the addition of L-glutamine to TPN. In this study, we examined the effect of glutamine on portal insulin and glucagon levels and the development of hepatic steatosis. Adult rats (n = 19) received internal jugular catheters: Group 1 (n = 6), saline (3 cc/hr) and chow ad libitum; Group 2 (n = 7), 25% dextrose base TPN; Group 3 (n = 6), 25% dextrose base TPN with 2% glutamine. The infusion rate of TPN was 1.2 cc/100 g body wt/hr. Daily nitrogen balance was determined and at 7 days, portal venous blood was drawn for insulin and glucagon radioimmunoassay, livers were removed for histology and lipid content determination, and the small intestines were removed for mucosal protein and DNA content determination. Panlobular vacuolization of the hepatocytes was noted on histology in Group 2 (TPN) while Group 1 (chow) and Group 3 (TPN + glutamine) showed normal liver morphology. Hepatic lipid content was significantly elevated in Group 2 (P less than 0.05). The portal insulin/glucagon molar ratio was increased because of excessive portal venous insulin in Group 2 (TPN). In contrast, portal glucagon was significantly elevated while the insulin/glucagon ratio and hepatic lipid content did not increase above control levels in the glutamine-supplemented Group 3 rats.(ABSTRACT TRUNCATED AT 250 WORDS)
- Published
- 1990
- Full Text
- View/download PDF
46. Endogenous peptide YY is dependent on jejunal exposure to gastrointestinal contents.
- Author
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Rudnicki M, McFadden DW, Liwnicz BH, Balasubramaniam A, Nussbaum MS, Dayal R, and Fischer JE
- Subjects
- Animals, Dietary Fats pharmacology, Eating, Gastrointestinal Contents, Gastrointestinal Hormones blood, Immunohistochemistry, Intestinal Mucosa blood supply, Intestinal Mucosa cytology, Intestinal Mucosa metabolism, Peptide YY, Peptides metabolism, Rats, Rats, Inbred Strains, Jejunum physiology, Peptides blood
- Abstract
Peptide YY (PYY), a homolog of pancreatic polypeptide, has been shown to be released after stimulation of colonic mucosa with bile and fatty acids. In this study proximal jejunal and biliary involvement in the regulation of circulating PYY and the distribution of PYY-containing cells in rat intestine was evaluated. Six rats underwent proximal jejunal bypass, six rats had Roux-en-Y cholangiojejunostomies, and six sham-operated rats were used as controls. Three months after surgery feeding studies using either a mixed meal or a pure fat meal were performed in unanesthetized animals and venous blood was collected for plasma PYY radioimmunoassays. After the feeding studies, fresh specimens were taken from multiple areas of the intestine for immunohistochemical analysis. The surgical procedures did not significantly affect basal PYY plasma levels. Both mixed and fat meals significantly increased circulating PYY in control animals. Exclusion of the proximal jejunum resulted in inhibition of postprandial PYY release. The PYY response in rats with Roux-en-Y cholangiojejunostomies was blunted after a mixed meal and delayed after a fat meal. The incidence of PYY-containing cells increased along the functional gut in all rats. The bypassed jejunum in both experimental groups of animals contained fewer PYY-staining cells than sham-operated rats. Our results suggest that the exclusion of a segment of proximal jejunum from gastrointestinal continuity in rats leads to an inhibition of postprandial PYY release. PYY release may be controlled in part by stimulatory neural and/or endocrine signals originating from the proximal jejunum.
- Published
- 1990
- Full Text
- View/download PDF
47. Reversal of hepatic steatosis in rats by addition of glucagon to total parenteral nutrition (TPN).
- Author
-
Li SJ, Nussbaum MS, McFadden DW, Dayal R, and Fischer JE
- Subjects
- Animals, Fatty Liver drug therapy, Fatty Liver metabolism, Fatty Liver pathology, Glucagon blood, Glucagon therapeutic use, Insulin blood, Lipid Metabolism, Liver metabolism, Liver pathology, Liver physiopathology, Liver Function Tests, Male, Portal Vein, Rats, Rats, Inbred Strains, Fatty Liver therapy, Glucagon administration & dosage, Parenteral Nutrition, Total
- Abstract
Infusion of total parenteral nutrition (TPN) with excess carbohydrate calories leads to hepatic steatosis in rats that is associated with an elevated portal insulin/glucagon molar ratio. Previously we have shown that adding glucagon to TPN prevents hepatic steatosis in rats. In this study we attempted to reverse the steatosis by adding glucagon to TPN after 1 week of TPN alone. Adult rats (n = 28) received internal jugular catheters: Group 1 (n = 7), saline (3 cc/h) and chow ad libitum; Group 2 (n = 7), 25% dextrose base TPN solution for 1 week; Group 3 (n = 7), 25% dextrose base TPN for 2 weeks; Group 4 (n = 7), 25% dextrose base TPN for 1 week and then glucagon (15 micrograms/100 g/day) added to TPN for the second week. The infusion rate of TPN was 1.2 ml/100 g/hr (40% kcal greater than control). At 7 days (Group 2) and 14 days (Groups 1, 3, and 4) portal and peripheral venous blood levels were drawn for insulin and glucagon radioimmunoassay, blood glucose determination, and liver function tests; livers were removed for histology and lipid content determination. Blood glucose was equivalent among all groups. Liver function tests were within normal limits. Panlobular vacuolization of the hepatocytes was noted on histology in Groups 2 and 3. Hepatic lipid content was significantly elevated in Group 3. The portal insulin/glucagon molar ratio was increased because of excessive portal venous insulin in Groups 2 and 3 (P less than 0.05 by ANOVA). In contrast, portal venous insulin and the insulin/glucagon molar ratio did not increase in Group 4 and hepatic lipid infiltration was absent when glucagon was added to the TPN solution after 1 week of TPN solution alone. The results suggest that the addition of glucagon to hypertonic dextrose TPN is not only protective in preventing hepatic steatosis, but may reverse steatosis, possibly by increasing hepatic lipid export.
- Published
- 1989
- Full Text
- View/download PDF
48. Independent release of peptide YY (PYY) into the circulation and ileal lumen of the awake dog.
- Author
-
McFadden DW, Rudnicki M, Nussbaum MS, Balasubramaniam A, and Fischer JE
- Subjects
- Animals, Dietary Carbohydrates pharmacology, Dietary Fats pharmacology, Dietary Proteins pharmacology, Dogs, Glucose pharmacology, Peptide YY, Peptides blood, Ileum metabolism, Peptides metabolism
- Abstract
Peptide YY (PYY) is a recently discovered polypeptide found in the endocrine cells of the distal small intestine, colon, and rectum. This study was designed to evaluate the postprandial release of PYY into the peripheral blood and the ileal lumen in response to different ingested nutrients. Six adult conditioned mongrel dogs had 25-cm distal ileal Thiry-Vella segments surgically constructed. After a 2-week postoperative recovery period the animals were fed meals consisting of protein (2 g/kg), fat (5 g/kg), or glucose (1.5 g/kg). Circulating and ileal intraluminal PYY concentrations were measured by a sensitive radioimmunoassay developed in our laboratory. Significant increases in circulating PYY levels were seen only after the fat meal in dogs. Ileal intraluminal PYY concentrations were significantly greater than those concentrations seen in the peripheral blood. A significant rise in ileal intraluminal PYY was seen only after the glucose meal without concomitant changes in circulating PYY. These findings document independent release mechanisms of PYY into the circulation and ileal lumen of the awake dog. We believe that the release of PYY into the canine circulation and into the ileal lumen after feeding may be dependent on the type of nutrient ingested and may serve to regulate the diverse physiologic roles of PYY in the gastrointestinal tract.
- Published
- 1989
- Full Text
- View/download PDF
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