Biomedical subjects

C M Townsend

Publications and source records attributed to C M Townsend.

At least 91 records · Page 5Linked to original sources

PubMed1994

Bombesin inhibits growth of pancreatic ductal adenocarcinoma (H2T) in nude mice.

Bombesin (BBS), a tetradecapeptide, stimulates growth of various types of cells, including fibroblasts and human small cell lung cancer, and has been termed the universal "on-switch" due to its ability to stimulate the release of numerous hormones. In addition, BBS receptors have been identified in normal and neoplastic pancreatic tissue. A pancreatic ductal adenocarcinoma cell line (H2T), established in our laboratory, possesses specific binding sites for BBS. The purpose of this study was to examine the effect of BBS on the growth of H2T tumors transplanted into athymic nude mice. H2T cells (5 x 10(6) cells/mouse) were injected s.c. into the interscapular region of the nude mice and then the mice were randomized into two groups (n = 10/group). Mice received either 0.1 ml of saline with 0.1% bovine serum albumin (BSA) (control) or 0.1 ml BBS (5 micrograms/kg) intraperitoneally, three times/day. Tumor area was measured twice weekly until the mice were killed (day 32), when tumor and normal pancreas were removed, weighted, and assayed for DNA and protein content. Administration of BBS significantly inhibited H2T tumor area, weight, and DNA and protein content. Conversely, growth of normal pancreas, removed as an in vivo bioassay so as to ensure the efficacy of BBS, was stimulated. We conclude that BBS is a growth inhibitory factor for H2T tumors and that different mechanisms may be responsible for the differential growth effects elicited by normal and neoplastic pancreas in response to BBS.

Animals↗

PubMed1994

Lovastatin inhibits pancreatic cancer growth regardless of RAS mutation.

Lovastatin, an inhibitor of the rate-limiting enzyme of cholesterol synthesis, inhibits growth of pancreatic cancer cells. A possible mechanism of this inhibition is that lovastatin inhibits the activity of RAS protein by depleting farnesyl (an intermediate of cholesterol synthesis). The K-ras gene is frequently mutated in pancreatic cancers and RAS protein requires farnesyl to be bound to the cell membrane and thereby activated. To investigate whether lovastatin inhibition of cell growth depends upon the presence of ras mutation, codons 12/13 and 61 of ras genes were examined by the dideoxynucleotide chain-terminating method in five pancreatic cell lines (human CAPAN2, CAV, MIA Paca2, PANCi, and hamster H2T) on which lovastatin exerted a growth-inhibitory effect. These codons play a major role in tumorigenic mutation of ras genes. Lovastatin inhibited cell growth by 99% (MIA), 97% (H2T), 78% (CAV), 41% (CAPAN2), and 23% (PANC1), respectively, when cells were treated with 2.5 micrograms/ml lovastatin for 6 days. Activating point mutations were found in codon 12 of the K-ras gene (wild type:GGT) in MIA (GTT), H2T (GAT), CAPAN2 (TGT), and PANC1 (GAT) but not in CAV. In addition, the CAV cell line did not have a mutation in either H- or N-ras genes. Lovastatin inhibited the growth of CAV cells even though this cell line did not have ras mutation, suggesting that lovastatin inhibition of pancreatic cancer cell growth is not directly dependent on the presence of ras mutation.

Animals↗

PubMed1994

Age-dependent increase of neurotensin expression in the ileum.

The proliferative activity of gut mucosa is increased with aging. Neurotensin (NT), a tridecapeptide localized to the distal small bowel, stimulates growth of gut mucosa; the effects of aging on gut NT are not known. Young (4-mo-old), adult (1-yr-old), and aged (2-yr-old) male Fischer 344 rats were killed; the ileal mucosa was scraped, weighed, and extracted for measurement of NT mRNA by slot-blot and Northern hybridization; and the relative NT transcription rate was determined by a nuclear run-on assay. In addition, NT tissue content and plasma levels were determined by radioimmunoassay, and full-thickness sections of ileum were examined for age-dependent alterations of NT endocrine cell (N-cell) number using immunohistochemical staining. Slot-blot and Northern-blot analyses showed that the steady-state levels of NT mRNA were increased threefold in the adult group and eightfold in the aged rats. In addition, NT peptide content and plasma levels were significantly increased in the aged group. The dramatic increases in the abundance of NT mRNA were not associated with increases in either NT transcription or N-cell number. In summary, we have demonstrated an age-dependent increase in the constitutive levels of ileal NT mRNA that appears not to be due to concomitant increases in transcription, suggesting that NT mRNA is increased by mechanisms involving mainly a posttranscriptional process. In addition, we have shown corresponding increases in the levels of both tissue and plasma NT with aging, indicating that expression of NT does not remain the same throughout life but actually increases with aging in the rat.

Aging↗

PubMed1994

Effect of aging on neurotensin-stimulated growth of rat small intestine.

The proliferative activity of gut mucosa is altered with aging; the potential for the aged gut to respond to trophic stimuli is not known. The purpose of this study was to determine whether there are age-related differences in the effects of the trophic gut peptide neurotensin (NT) on the structure and function of small bowel mucosa. NT (300 micrograms/kg) or saline (control) was injected subcutaneously at 8-h intervals for 5 days in rats of two age groups, young (2 mo) and aged (24 mo). On day 6, rats were killed, and the gut mucosa (proximal and distal small bowel) was scraped, weighed, and analyzed for DNA, RNA, and protein content and for disaccharidase (sucrase and maltase) activity. In a second experiment, the groups of rats and the protocol for NT administration were identical; however, when the rats were killed, the distal gut was removed for histological evaluation of crypt and villus length (mm) and density (no./cm gut segment) and bromodeoxyuridine immunohistochemistry. NT produced significant increases in mucosal growth (wt, DNA, RNA, and protein) in both age groups when compared with age-matched controls; the increase of growth measurements was the greatest in the small bowel mucosa of the aged rats. In addition, NT increased crypt density in both groups; only the aged group treated with NT demonstrated increases in crypt depth and villus height. Specific activities of sucrase and maltase did not change with NT treatment in either of the age groups. We conclude that the proliferative potential of small bowel mucosa is maintained with aging in response to administration of NT.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1994

Temporal-specific and spatial-specific patterns of neurotensin gene expression in the small bowel.

Expression of the neurotensin/neuromedin N (NT/N) gene is developmentally regulated in a temporal- and spatial-specific pattern in the small bowel. The purpose of our study was to determine 1) whether the temporal expression of NT/N could be altered by ectopic placement of small bowel and 2) whether the spatial-specific expression of NT/N could be altered by different diets. We found that the relative temporal pattern of NT/N expression was unchanged in rat jejunal and ileal xenografts implanted into the flanks of athymic nude mice. To determine whether the spatial-specific pattern of NT/N expression could be altered by different luminal nutrients, 28-day-old rats were randomized to receive chow or chemically defined liquid diets for 60 days at which time the jejunoileum was divided into eight equal segments, and NT/N expression was analyzed. The normal pattern of increasing levels of NT/N mRNA along the jejunum-to-ileum axis was not altered by any of the liquid diets. In contrast to NT/N, we found that expression of sucrase-isomaltase varied greatly depending on both location and type of luminal nutrients. We conclude that the strict temporal- and spatial-specific pattern of NT/N expression is not affected by either location or luminal contents, thus suggesting an intrinsic program of NT/N gene expression. Furthermore, we speculate that the NT/N gene may provide a useful endocrine paradigm to investigate the factors regulating the establishment and maintenance of certain cell lineage-specific patterns along the cephalocaudal axis of the gut.

Aging↗

PubMed1994

Characterization of functional neurotensin receptors on human lymphocytes.

BACKGROUND: Neurotensin, a tridecapeptide, regulates gut motility, secretion, and mucosal growth; an immunomodulatory role for neurotensin has been postulated but not clearly defined. The purpose of this study was to determine whether neurotensin receptors (NTR) are present on peripheral blood lymphocytes (PBLs) and to characterize binding, functional, and molecular properties. METHODS: Iodine 125 labeled-neurotensin binding was determined for both human PBLs and the T-cell lines, Molt-4 and Jurkat, by Scatchard analysis. To analyze functional capacity of the NTR, PBLs were cultured in the presence of phytohemagglutinin (1 microgram/ml) with or without neurotensin and harvested at 48 hours after an 8-hour pulse of tritiated thymidine. For molecular analyses, RNA extracted from PBLs and T-cell lines was analyzed by either Northern hybridization with a labeled NTR cDNA or ribonuclease protection with an antisense human NTR probe. RESULTS: Scatchard analyses of neurotensin binding to human PBLs and MOLT-4 showed two classes of binding sites with different affinities. Incubation of phytohemagglutinin-stimulated PBLs with neurotensin significantly enhanced proliferation. Northern hybridization showed mRNA of the authentic NTR or a receptor subtype of close homology in PBLs and the T-cell lines; ribonuclease protection analysis identified the authentic human NTR in the MOLT-4 cell line. CONCLUSIONS: Using a combination of molecular techniques and Scatchard analysis, we have demonstrated the presence of a cell surface NTR with a high affinity for neurotensin on human PBLS and the MOLT-4 cell line. The functional role of NTR has been established by enhanced proliferation with addition of neurotensin. These data provide further evidence for a link between neurotensin and the immune system and suggest that neurotensin may play an important regulatory role in gut mucosal immune responses in vivo.

Blotting, Northern↗

PubMed1994

Experimental gene therapy of human colon cancer.

BACKGROUND: Gastrin regulates growth of human colon cancer cells by activation of the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA). Gastrin and 8-Br-cAMP, a membrane-permeable cAMP analog, inhibit growth of HCT116 cells; both stimulate growth of LoVo cells. This dual effect on growth may be explained by relative amounts of the regulatory subunit (RI alpha or RII beta) of PKA within the cancer cells. Antisense oligodeoxynucleotides (ASO) to either RI alpha or RII beta inhibit protein translation of the target mRNA by sequence-specific binding; subsequently, cellular PKA content and the cAMP-mediated growth may be altered. We determined whether ASO to either the RI alpha or RII beta subunit altered the cAMP-mediated growth of HCT116 and LoVo human colon cancer cells. METHODS: HCT116 cells were treated with RII beta ASO (15 mumol/L, 4 days) and then treated with 8-Br-cAMP (25 mumol/L); tritiated thymidine incorporation was measured after 24 hours, and the cell number was determined on alternate days. Protein and mRNA levels of the RII beta subunit were determined by Western and Northern blotting, respectively. Similar studies with an ASO against the RI alpha subunit were performed on LoVo cells. RESULTS: RII beta ASO reversed the cAMP-mediated inhibition of growth of HCT116 cells, and RII beta ASO decreased the protein level of the RII beta subunit. RII beta ASO did not alter the basal growth of HCT116 cells. RI alpha ASO reversed the cAMP-mediated stimulation of growth of LoVo cells. CONCLUSIONS: The regulatory subunits of PKA are potential targets to alter growth of human colon cancer cells. Gene therapy directed to alter specific steps in signal transduction pathways may provide new therapeutic strategies.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1994

Activation of hepatic proliferation-associated transcription factors by lipopolysaccharide.

BACKGROUND: The hepatic acute-phase response is the result of reprogramming of gene expression in the liver. Similar acute-phase responses occur in regenerating liver after partial hepatectomy and are preceded by increases in the expression of a set of transcriptional regulatory proteins that are encoded by "immediate-early" genes. The purpose of this study was to determine whether acute systemic inflammation after lipopolysaccharide injection induces hepatic immediate-early genes that are induced by partial hepatectomy. METHODS: Two- to 4-month-old Balb/c mice received intraperitoneal Escherichia coli lipopolysaccharide (0111:B4; 100 micrograms), and total liver RNA, nuclear protein extracts, or total liver protein lysates were obtained at 0, 1, 3, 12, and 24 hours. RNA blot hybridization analysis was used to determine steady-state messenger RNA levels for c-jun, jun-B, jun-D, c-fos, fos-B, fra-1, nup475, and zif268. Specific nuclear protein-binding activity was determined by gel mobility shift assay. The protein c-Jun was detected by antibody-blocking experiments, and Jun-B was detected by gel supershift assay of the activating protein (AP-1) complex. Steady-state Jun-B levels were determined by immunoblot analysis. RESULTS: Intraperitoneal injection of lipopolysaccharide is followed by induction (from fivefold to 13-fold) of c-jun, jun-B, c-fos, zif268, and nup475 messenger RNAs in the liver. Lipopolysaccharide induced increases in AP-1 and Zif268 consensus DNA-binding activity in mouse liver. The proteins c-Jun and Jun-B are detected in the AP-1 complex after administration of lipopolysaccharide. CONCLUSIONS: The induction of hepatic immediate-early genes after lipopolysaccharide is similar to that that follows partial hepatectomy. These transcription factors likely have important roles in the reprogramming of gene expression that leads to the acute-phase response.

Animals↗

PubMed1994

In vitro relationship between magnesium and insulin secretion.

Magnesium, the most abundant intracellular divalent cation, is known to play an essential role in many normal cell functions, such as fluid and electrolyte transport, enzyme activity, and cell proliferation. It is known that magnesium deficiency or hypomagnesaemia induces hyperinsulinism, while hypermagnesaemia inhibits insulin secretion: however, the mechanism controlling the intracellular level of free magnesium and its role in the insulin-secretory mechanism of pancreatic beta cells (RIN m5F cells) are still unclear. Using a fluorescent indicator (mag-fura-2) we have found that the influx of magnesium appears to be voltage-dependent and is sensitive to blockade of the voltage-dependent calcium channel in RIN m5F cells; the efflux of magnesium appears to be voltage- and cyclic AMP-independent. We have observed that depletion of extracellular magnesium potentiates insulin secretion from RIN m5F cells. This finding has led us to speculate on two possible mechanisms through which extracellular magnesium participates in the regulation of insulin secretion: (1) extracellular magnesium may regulate ATP-sensitive potassium channels, and (2) extracellular magnesium may act as a competitive inhibitor of the calcium influx mediated through the voltage-dependent calcium channel. In addition to the role of extracellular magnesium, the changes in the intracellular levels of free magnesium observed during secretagogue-stimulated insulin secretion may alter magnesium-sensitive enzymes or systems, which may play regulatory roles in signal transduction. Elucidation of the role of magnesium in the insulin secretory mechanism will be beneficial for understanding the insulin secretory mechanism of pancreatic beta cells and may be helpful in treating insulin-related abnormalities in patients with hypo- or hypermagnesaemia.

Animals↗

PubMed1993

Biomolecular advances in gastrointestinal hormones.

Gastrointestinal hormones are chemical messengers that regulate a broad range of physiologic functions. Although primarily expressed within tissues of the gut, these peptide hormones are widely distributed throughout the body and act on multiple target tissues. Furthermore, these regulatory peptides can exist in multiple molecular forms that may bind to multiple cell-surface receptors coupled to one of several possible signal transduction systems leading to diverse biologic responses. With such an expansive field to study, it is not surprising that gut endocrinologists have embraced the new techniques that are emerging from the revolution of molecular biology. Beginning with the first construction of a recombinant DNA molecule by Paul Berg in 1971, molecular biology has developed many new techniques that have been rapidly adopted by gut endocrinologists to enable a more detailed understanding of gastrointestinal function. The merging of these two fields has led to a new area of research, molecular gut endocrinology, or the study of gut physiology and endocrinology at the level of individual molecules (ranging from polypeptide-surface receptors to small-molecule second messengers to DNA sequences). Gut cells are constantly bombarded by numerous hormones, and the tightly regulated physiologic status of each cell is becoming more clearly understood.

Animals↗

PubMed1993

Novel action of transforming growth factor beta 1 in functioning human pancreatic carcinoid cells.

We have shown recently that 5-HT is an autocrine growth stimulatory factor for a cell line (BON) that is derived from a human pancreatic carcinoid tumor. This action is mediated by a 5-HT receptor-linked decrease of cyclic adenosine monophosphate (AMP) production, but not mediated by a 5-HT receptor-linked stimulation of phosphatidylinositol hydrolysis. The BON cells also express transforming growth factor betas (TGF beta s) (1, 2, and 3) and release TGF beta into their medium. In this study, we examined the effects of TGF beta on the secretion of 5-HT, on signal transduction pathways involved in 5-HT secretion, and on growth of BON cells. TGF beta 1 inhibited basal and acetylcholine-stimulated release of 5-HT, but did not inhibit isobutylmethylxanthine-stimulated release of 5-HT. TGF beta 1 inhibited both basal and acetylcholine-stimulated hydrolysis of phosphatidylinositol in a dose dependent manner, but did not affect cyclic AMP production. TGF-beta 1 inhibited growth of BON cells in culture; this effect was reversed by exogenously administered 5-HT. Three different specific and saturable TGF beta 1 binding sites were identified; binding assays performed after mild acid wash (0.1% acetic acid, pH 2.5) conditions uncovered TGF beta receptors that were apparently occupied by endogenously produced TGF beta species. Affinity cross-linking assay showed that BON cells had three different TGF beta binding proteins. These results suggest that TGF beta 1 can inhibit growth of BON cells by altering secretory responses of 5-HT by means of receptor-mediated inhibition of phosphatidylinositol hydrolysis. We conclude that growth of BON cells is regulated, at least in part, by the opposing receptor-mediated autocrine actions of 5-HT and TGF beta.

Affinity Labels↗

PubMed1993

Age-related changes in duodenal adaptation after distal small bowel resection in rat.

Two groups of male Fisher 344 rats (young: 4 months old; aged: 25 months old) underwent either 70% distal small bowel resection or sham operation (small bowel transection). Rats from each treatment group of each age were sacrificed on the 10th (N = 15: young rats; N = 13: aged rats) or 20th (N = 15: young; N = 13: aged) postoperative day (POD), and the duodenal mucosa was weighed and assayed for DNA, RNA, and protein contents, as well as for specific activities of the disaccharidase, sucrase, maltase, and lactase. Compared to the sham operation, distal small bowel resection significantly increased DNA by 48%, RNA by 122%, and protein by 75% in young rats and DNA by 40%, RNA by 92%, and protein by 71% in aged rats on the 20th POD. Both young and aged rats showed similar adaptive hyperplasia on the 10th POD. On the 20th POD after distal small bowel resection, specific activities of all tested enzymes were significantly increased in young rats (sucrase +86%, maltase +110% and lactase +64%), but showed no significant changes in aged rats. These findings suggest that the duodenum of aged rats may have sufficient proliferative potential to respond to distal small bowel resection, but that the mechanisms governing return of function in response to distal small bowel resection are inhibited in aged rats, compared to those mechanisms in the young.

Adaptation, Physiological↗

PubMed1993

Differential effect of submandibular gland resection on the growth of pancreatic cancer in cheek pouch and subcutaneous tissue.

Exogenous administration of epidermal growth factor (EGF) enhances tumor growth of H2T, a hamster pancreatic cancer that is inoculated in the cheek pouch. The effect of endogenous EGF on tumor growth, however, is not known. The main source of EGF in the body is the submandibular glands. This study examined the influence of submandibular gland resection (SMx) on H2T tumor growth in the cheek pouch and compared it to the growth in SC tissue. Bilateral SMx or sham operation was performed on male Syrian golden hamsters. In 30 hamsters (n = 15 for each operation group), 5 x 10(4) and 5 x 10(5) H2T cells were inoculated in the bilateral cheek pouches and intrascapular SC tissue, respectively (Exp. 1). In another 30 hamsters (n = 15 for each operation group), 5 x 10(5) and 1 x 10(6) H2T cells were inoculated at the same sites (Exp. 2). Two longest perpendicular diameters of the tumor were measured once a week for 12 wk (Exp. 1) or 8 wk (Exp. 2), and the tumor area was calculated. The tumor area in the cheek pouch became significantly smaller in the SMx group than the sham-operated group after the 8th wk (Exp. 1) or the 7th wk (Exp. 2). On the other hand, the tumor area in the SC tissue did not show any difference between groups through the experiments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Insulinlike growth factor-binding protein modulates the growth response to insulinlike growth factor 1 by human gastric cancer cells.

BACKGROUND: This study determined whether the resistance to the mitogenic effect of insulinlike growth factor 1 (IGF-1) in AGS (we found that IGF-1 had almost no effect on the growth of AGS) cells is caused by the absence of IGF-1 receptor on the cells or by the interference of endogenous IGFs and IGF-binding protein (IGFBP). METHODS: IGF-1 receptors were examined by radioligand binding assay. The protein in conditioned medium and the molecular weight of IGF-1 receptors on AGS cells were determined by affinity cross-linking with 125I-IGF-1 followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Messenger RNAs for IGF-1, IGF-2, and IGFBP-4 were detected by Northern analysis. RESULTS: AGS cells possessed a single class of high-affinity binding sites for IGF-1 (dissociation constant [Kd], 0.51), with a binding capacity approximately 4 x 10(4) sites per cell. The size of the alpha subunit of IGF-1 receptors on cell membranes was approximately 130 kilodaltons. des (1-3) IGF-1, a truncated IGF-1 with very low affinity to IGFBPs, stimulated AGS cell growth in dose-dependent fashion. The medium conditioned by AGS cells contained IGFBPs of 27-32 and 37-42 kilodaltons. AGS cells expressed messenger (mRNA) RNAs for IGF-2 and IGFBP-4 but not for IGF-1, whereas another gastric carcinoma cell line (SIIA), whose growth is stimulated by IGF-1, expressed mRNA IGF-2 but did not express mRNA for IGF-1 or IGFBP-4: CONCLUSIONS: The relative absence of growth response of AGS cells to IGF-1 is due to the endogenously produced IGFBPs sequestering IGF-1 and preventing receptor interaction.

Adenocarcinoma↗

PubMed1993

Bombesin stimulates intracellular Ca2+ mobilization but not proliferation on human colon cancer cells.

Increases in intracellular Ca2+ ([Ca2+]i) levels mediated by bombesin (BBS) are believed to be important signals leading to stimulation of DNA synthesis and an increase in cellular proliferative rate. Since the role of BBS on growth of normal or malignant cells in the GI tract is still unclear, we examined whether BBS affects in vitro growth of human colon cancer cells (COLO 320, HCT116 and LoVo). We also examined the effect of BBS on intracellular Ca2+ levels to determine if the growth-regulatory effect of BBS is mediated through increases in [Ca2+]i. Levels of [Ca2+]i in response to BBS were measured by single cell fluorescence after loading with fura-2. BBS stimulated the mobilization of [Ca2+]i in COLO 320, LoVo, and HCT116 cells in a dose-dependent fashion, but did not affect in vitro growth. These findings suggest that the BBS-mediated increase in [Ca2+]i does not always correlate with the growth-regulatory effect of BBS.

Bombesin↗

PubMed1993

Bombesin stimulates growth of colon cancer in mice and decreases their survival.

Bombesin (BBS) stimulates cellular proliferation of both normal and transformed cells. The mouse colon cancer cells (MC-26) possess specific binding sites for BBS. The purpose of this study, therefore, was to examine the effect of chronic administration of BBS on in vivo growth of MC-26 tumours in Balb/c mice and on survival of tumour-bearing mice. Three groups of mice (n = 10 each) inoculated with MC-26 cells received either saline containing 0.1% bovine serum albumin (BSA), or BBS (5 micrograms kg-1 or 20 micrograms kg-1) dissolved with 0.1% BSA saline by intraperitoneal route three times a day for 15 days. BBS increased weight, DNA and RNA contents of MC-26 tumours. To examine the effect of BBS on survival rates of mice with MC-26 tumours, three groups of mice (n = 20 each) were treated for 31 days, as above. One group of mice inoculated with MC-26 cells received 0.1% BSA saline; the other group of MC-26-inoculated mice and the control group without tumour received BBS (5 micrograms kg-1) dissolved with 0.1% BSA saline. BBS significantly decreased the survival rate of mice bearing MC-26 tumours (median survival; saline group: 42.5 days, BBS group: 32.0 days, P = 0.037). None of the mice in the control group died during the experiment. BBS may stimulate in vivo growth of MC-26 cells through specific receptors.

Animals↗

PubMed1993

Effect of 5-HT3 receptor antagonist (ondansetron) on functioning human pancreatic carcinoid cells.

5-Hydroxytryptamine (5-HT) is a mitogen for selected cell types. We have reported that 5-HT is an autocrine growth factor for functioning human pancreatic carcinoid (BON) cells; autocrine growth effect is transmitted by 5-HT1A but not 5-HT1C/2 receptors, activation of which decreases cyclic AMP production through a pertussis toxin-sensitive inhibitory GTP-binding protein. In this study, the effect of 5-HT3 receptor antagonist, ondansetron, on BON was examined. Ondansetron did not affect growth of BON cells and also affected neither stimulation of phosphatidylinositol hydrolysis or inhibition of cyclic AMP production evoked by 5-HT in BON cells. Ondansetron, however, inhibited mobilization of intracellular calcium evoked by 5-HT. Present findings suggest that BON cells possess 5-HT3 receptors, but their roles in pancreatic carcinoid cells are still unknown.

Calcium↗

PubMed1993

Role of polyamine biosynthesis during gut mucosal adaptation after burn injury.

The induction of ornithine decarboxylase (ODC) mRNA and of ODC enzyme activity are important events in gut repair after cutaneous burn injury. ODC catalyzes the rate-limiting step in the biosynthesis of polyamines that are necessary for normal cell growth; alpha-difluoromethylornithine (DFMO) specifically inhibits ODC activity. The purpose of this study was to examine the role of polyamines in the adaptive response of gut mucosa after burn injury. In experiment 1, male Sprague-Dawley rats (250 to 300 g; n = 6/group) were randomized into sham, 60% burn, or 60% burn plus DFMO. In experiment 2, rats with either a 60% burn or 60% burn plus DFMO treatment received spermidine by gavage. We measured ODC activity, polyamine levels, and DNA content at 0, 12, 24, and 48 hours postburn in the mucosa of both the proximal and distal small intestine. Burn injury produced early atrophy (by 12 hours postburn) of the gut mucosa characterized by decreased mucosal weight and DNA content. Increased ODC activity and polyamine content in both the proximal and distal gut mucosa of burned rats preceded restoration of mucosal weight and DNA content that occurred at 48 hours postburn; these responses were prevented by DFMO treatment. Spermidine administration failed to accelerate gut mucosal recovery after burn injury alone, but oral administration of spermidine reversed the inhibitory action of DFMO on gut mucosal repair. These data suggest that the early increases of gut ODC activity and polyamine levels after burn injury are crucial cellular events for the repair of subsequent gut mucosa.

Adaptation, Physiological↗