Biomedical subjects

W R Gower

Publications and source records attributed to W R Gower.

At least 19 recordsLinked to original sources

PubMed2005

Four peptide hormones decrease the number of human breast adenocarcinoma cells.

BACKGROUND: A family of six hormones, i.e. atrial natriuretic peptide, brain natriuretic peptide, C-natriuretic peptide, long-acting natriuretic peptide, vessel dilator, and kaliuretic peptide's main known biologic properties are sodium and water excreting and blood pressure lowering. METHODS AND MATERIALS: These six hormones, each at their 1-microm concentrations, were evaluated for their ability to decrease the number and/or proliferation of breast adenocarcinoma cells in culture for 24, 48, 72, and 96 h. RESULTS: Within 24 h, vessel dilator, long-acting natriuretic peptide, kaliuretic peptide, atrial natriuretic peptide and 8-bromo-cyclic GMP, a cell-permeable analogue of their intracellular mediator cyclic GMP (each at 1 microm), decreased the number of breast adenocarcinoma cells 60%, 31%, 27%, 40%, and 31%, respectively. There was no proliferation in the 3 days following this decrease in breast adenocarcinoma cell number. These same hormones decreased DNA synthesis 69% to 85% (P < 0.001). Brain natriuretic peptide and CNP did not decrease the number of breast adenocarcinoma cells or inhibit their DNA synthesis. Vessel dilator, long-acting natriuretic peptide, kaliuretic peptide and 8-bromo-cyclic GMP (each at 1 microM) decreased the number of cells in the S phase of the cell cycle by 62%, 33%, 50%, and 39%, respectively (all P < 0.05). Natriuretic peptide receptors-A and -C were present in the breast adenocarcinoma cells. CONCLUSIONS: Four peptide hormones significantly decrease the number of human breast adenocarcinoma cells within 24 h and inhibit the proliferation of these cells for at least 96 h. Their mechanism of doing so involves inhibition of DNA synthesis and a decrease in cells in the S phase of the cell cycle mediated in part by cyclic GMP.

Adenocarcinoma↗

PubMed2005

Five cardiac hormones decrease the number of human small-cell lung cancer cells.

BACKGROUND: Four peptide hormones of a family of six hormones, i.e. atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-natriuretic peptide (CNP), long acting natriuretic peptide (LANP), vessel dilator and kaliuretic peptide, significantly decrease the number of adenocarcinoma cells in culture. The present investigation was designed to determine whether these peptide hormones' effects are specific to adenocarcinomas or whether they might decrease the number of cancer cells of a different type of cancer, i.e. small-cell lung cancer. METHODS AND MATERIALS: These six hormones were evaluated for their ability to decrease the number and/or proliferation of human small-cell lung cancer cells in culture for 24, 48, 72, and 96 h. RESULTS: Within 24 h, vessel dilator, LANP, kaliuretic peptide, ANP and their intracellular mediator cyclic GMP, each at 1 microM, decreased the number of small-cell lung cancer cells by 63% (P < 0.001), 21% (P < 0.05), 30% (P < 0.05), 39% (P < 0.05), and 31% (P < 0.05), respectively. There was no proliferation in the 3 days following this decrease in cell number. These same hormones decreased DNA synthesis 68% to 82% (P < 0.001). Brain natriuretic peptide and CNP did not decrease the number of small-cell lung cancer cells or inhibit their DNA synthesis at 1 microM or 10 microM concentrations. Dose-response curves revealed that at 100 microM, the vessel dilator decreased 92% of the cancer cells in 24 h while BNP had no effect, but CNP caused a 39% decrease. Western blots revealed that the natriuretic peptide receptors A- and C- were present in these cancer cells. CONCLUSIONS: Five peptide hormones significantly decrease the number of human small-cell lung cancer cells within 24 h and inhibit their proliferation for at least 96 h. Their mechanism of doing so involves inhibition of DNA synthesis mediated in part by cyclic GMP.

Adenocarcinoma↗

PubMed2004

Novel therapeutic approach for cancer using four cardiovascular hormones.

BACKGROUND: The atrial natriuretic peptide (ANP) gene synthesizes four cardiovascular hormones, i.e. vessel dilator, long-acting natriuretic peptide, kaliuretic peptide and ANP, which decrease the number of human pancreatic adenocarcinoma cells in culture by 65%, 47%, 37%, and 34%, respectively. METHODS AND MATERIALS: None of the cardiovascular hormones has been investigated to determine whether they inhibit the growth of cancers in vivo. These four hormones were evaluated for their ability to inhibit the growth of human pancreatic adenocarcinomas in athymic mice. RESULTS: Vessel dilator (139 ng min(-1) kg(-1) of body weight) infused for 14 days completely stopped the growth of human pancreatic adenocarcinomas in athymic mice (n = 14) with a decrease in their tumour volume, while the tumour volume increased 69-fold (P < 0.001) in the placebo (n = 30)-treated mice. When these peptide hormones (each at 1.4 microg min(-1) kg(-1) body weight) were infused for 4 weeks, vessel dilator, long-acting natriuretic peptide and kaliuretic peptide decreased tumour volume after 1 week by 49%, 28%, and 11%, respectively, with a one- and 20-fold increase in the tumour volume in ANP- and placebo-treated mice. Cyclic GMP (2.4 microg min(-1) kg(-1) body weight) inhibited after 1 week the growth of this cancer 95%. CONCLUSIONS: These results suggest that these peptide hormones have useful anticancer properties, as they each inhibited the growth of the human pancreatic adenocarcinomas in vivo and three of the four peptide hormones decreased the volume of the tumours (up to 49%, i.e. vessel dilator). Part of their mechanism of action appears to be mediated by cyclic GMP.

Adenocarcinoma↗

PubMed2003

Reciprocal paracrine pathways link atrial natriuretic peptide and somatostatin secretion in the antrum of the stomach.

Atrial natriuretic peptide (ANP) as well as its receptor, NPR-A, have been identified in gastric antral mucosa, suggesting that ANP may act in a paracrine fashion to regulate gastric secretion. In the present study, we have superfused antral mucosal segments obtained from rat stomach to examine the paracrine pathways linking ANP and somatostatin secretion in this region.ANP (0.1 pM to 0.1 microM) caused a concentration-dependent increase in somatostatin secretion (EC(50), 0.3 nM). The somatostatin response to ANP was unaffected by the axonal blocker tetrodotoxin but abolished by addition of the selective NPR-A antagonist, anantin. Anantin alone inhibited somatostatin secretion by 18+/-3% (P<0.005), implying that endogenous ANP, acting via the NPR-A receptor, stimulates somatostatin secretion. Somatostatin (1 pM to 1 microM) caused a concentration-dependent decrease in ANP secretion (EC(50), 0.7 nM) that was abolished by addition of the somatostatin subtype 2 receptor (sst2) antagonist, PRL2903. Neutralization of ambient somatostatin with somatostatin antibody (final dilution 1:200) increased basal ANP secretion by 70+/-8% (P<001), implying that endogenous somatostatin inhibits ANP secretion. We conclude that antral ANP and somatostatin secretion are linked by paracrine feedback pathways: endogenous ANP, acting via the NPR-A receptor, stimulates somatostatin secretion, and endogenous somatostatin, acting via the sst2 receptor, inhibits ANP secretion.

Animals↗

PubMed2003

Four peptides decrease the number of human pancreatic adenocarcinoma cells.

BACKGROUND: Long-acting natriuretic peptide, vessel dilator, kaliuretic peptide and atrial natriuretic peptide are four peptide hormones synthesized by the same gene. Their main known biologic properties are sodium and water excretion and blood pressure lowering in both animals and humans. METHODS AND MATERIALS: These four peptide hormones, each at their 1-microm concentrations, were evaluated for their ability to decrease the number and/or proliferation of human pancreatic adenocarcinoma cells in culture at 24, 48, 72 and 96 h. RESULTS: Vessel dilator, long-acting natriuretic peptide, kaliuretic peptide and atrial natriuretic peptide decreased the number of human pancreatic adenocarcinoma cells in culture by 65% (P<0.001), 47% (P<0.01), 37% (P<0.05) and 34% (P<0.05), respectively, within 24 h. This decrease was sustained without any proliferation of the cancer cells occurring in the 3 days following this decrease in number. The mechanism of these peptide hormones' decrease in cancer cell number and antiproliferative effects was a 83% (P<0.001) or greater inhibition of DNA synthesis but not owing to enhanced apoptosis, i.e. programmed cell death. The two known mediators of these peptide hormones' mechanism(s) of action, i.e. cyclic GMP and prostaglandin E2, inhibited DNA synthesis in these adenocarcinoma cells by 51% and 23%, respectively. CONCLUSIONS: Four peptide hormones significantly decrease the number of pancreatic adenocarcinoma cells within 24 h and inhibit the proliferation of these cells for at least 96 h. Their mechanism of doing so is via inhibition of DNA synthesis mediated in part by cyclic GMP.

Adenocarcinoma↗

PubMed2003

Gastric atrial natriuretic peptide regulates endocrine secretion in antrum and fundus of human and rat stomach.

Atrial natriuretic peptide (ANP) is present in gastric mucosa and preferentially binds to two subtypes of natriuretic peptide receptors (NPR), NPR-A and NPR-C. The present study examines the role of endogenous ANP in regulating endocrine secretion in rat and human stomachs. NPR-A protein expression and transcripts were identified in rat antral and fundic mucosa by Western blot and RT-PCR. In superfused rat and human antral and fundic segments, ANP (0.1 pM to 0.1 microM) caused a concentration-dependent increase in somatostatin secretion. In antrum, this was accompanied by a decrease in gastrin, and in fundus, this was accompanied by a decrease in histamine secretion. Changes in gastrin and histamine secretion reflected changes in somatostatin secretion and were abolished by somatostatin antibody. The NPR-A receptor antagonist anantin 1) inhibited basal somatostatin secretion and 2) abolished the somatostatin, gastrin, and histamine responses to ANP. We conclude that endogenous ANP, acting via the NPR-A receptor, stimulates somatostatin secretion from both antrum and fundus of rat and human stomach. Stimulation of somatostatin secretion is coupled to inhibition of gastrin secretion in the antrum and inhibition of histamine secretion in the fundus.

Animals↗

PubMed2002

hNT neurons express an immunosuppressive protein that blocks T-lymphocyte proliferation and interleukin-2 production.

Ntera2/D1 cells had an A1 B8 Bw6 Cw7 DR3 DR52 major histocompatibility complex (MHC) genotype. Its neuronal derivative, hNT neurons, expressed A1 B8 Bw6 MHC class I molecules, but did not activate, and its hNT supernatant suppressed allogeneic mixed lymphocyte cultures (MLC) >98% (p<0.01), phytohemagglutinin (PHA)-activated T-cell proliferation >87% (p<0.01), even 48 h after stimulation, suppressed phorbol 12-myristate 13-acetate (PMA)/ionomycin-induced T-cell proliferation >99% (p<0.001), and reduced interleukin-2 (IL-2) production (p<0.01), while maintaining T cells in a quiescent G(0)/G(1) state without lowering their viability. This immunosuppressive activity was attributed to a 40-100-kDa anionic hNT protein with an isoelectric point of 4.8.

Brain Tissue Transplantation↗

PubMed2001

Evidence for an atrial natriuretic peptide-like gene in plants.

The presence of a gene found in the animal kingdom expressing a peptide hormonal system in plants has never been demonstrated. However, there is at least one potential hormonal system in plants (i.e., the atrial natriuretic peptide-like hormonal system) based upon high-performance gel permeation chromatography and radioimmunoassay evidence. In plants, atrial natriuretic-like peptides enhance the flow of water up stems to leaves and flowers. The present investigation was designed to determine within plants the presence of the atrial natriuretic peptide (ANP) gene as defined by Southern blot hydridization, indicating the presence of the ANP gene sequence, and by Northern blots assessing the ability of this gene to express ANP prohormone mRNA. Southern blots of English ivy (Hedra helix) genomic DNA revealed that the ANP gene sequence was present in its roots, stems, and leaves. Northern blot analysis of total plant RNA isolated from leaves, roots, and stems of Hedra helix revealed a single 0.85-kilobase prohormone ANP transcript in stems similar to that detected in rat heart. Semiquantitative analysis suggested that ANP gene expression was less in English ivy compared with that of rat heart atria but similar to the amount found in extra atrial rat tissues when corrected for total RNA when quantitated by 2D scanning. The demonstration of the ANP gene sequences and expression of the ANP-like gene in plants suggests that plants and animals may have evolved much more similarly than previously thought.

Animals↗

PubMed2001

Atrial natriuretic hormone, vessel dilator, long-acting natriuretic hormone, and kaliuretic hormone decrease the circulating concentrations of total and tree T4 and free T3 with reciprocal increase in TSH.

The present investigation was designed to determine whether atrial natriuretic peptides (ANPs) consisting of amino acids 1-30 [i.e. long-acting natriuretic hormone (LANH)], 31-67 (vessel dilator), 79-98 (kaliuretic hormone), and 99-126 (atrial natriuretic hormone [ANH]) of the 126-amino acid ANH prohormone decrease the circulating concentrations of total and free T4 and/or free T3 in healthy humans (n = 30). Vessel dilator, kaliuretic hormone, LANH, and ANH decreased the circulating concentrations of total T4 by 61%, 58%, 47%, and 55% and of free T4 by 60%, 67%, 79%, and 79%, whereas free T3 decreased 72%, 67%, 71%, and 67% (P < 0.05 for each), respectively, when infused at 100 ng/kg BW x min for 60 min. Vessel dilator, kaliuretic hormone, LANH, and ANH simultaneously increased circulating TSH concentrations 4- to 12.5-fold (P < 0.004). The decreases in T4 and T3 with reciprocal increases in TSH lasted 2-3 h after cessation of the respective ANP infusions. The reciprocal increase in TSH with the decreases in T4 and T3 suggests that their modulation of T4 and T3 concentrations occurs in the thyroid rather than in the pituitary or hypothalamus, because TSH would be decreased in the circulation if their inhibitory effects were in either the hypothalamus or pituitary.

Adult↗

PubMed2000

Increased bioactivity of rat atrial extracts: relation to aging and blood pressure regulation.

The purpose of this study was to evaluate the possible role of atrial factor(s) in the regulation of cardiovascular homeostasis and their relationship to aging. Rats were anesthetized and received jugular vein, carotid artery, and bilateral ureteral catheterization. After a half-hour equilibration period, the rats received 0.5 ml of atrial extract with a concentration of proANP (atrial natriuretic peptide) of 150 microg/ml prepared from either aged (18-20 month, "aged extract group", n = 12) or young (2-3 month, "young extract group", n = 12) rats. Mean arterial pressure (MAP) and renal function were monitored over five 20-minute periods. The atrial extract caused MAP to fall significantly in the aged extract group (p < .05) but MAP was unchanged in young extract group. There was a significant difference in MAP between the two groups (p < .05). Urine output increased significantly in both groups after extract infusion (p < .05 in both cases). Sodium and potassium excretion showed similar responses. However, the diuresis, natriuresis, and kaliuresis after extract infusion would have been expected to be relatively lower in the aged extract group compared to the young extract group considering the significantly lower MAP in the aged extract group. High performance gel permeation chromatography (HP-GPC) analysis of the atrial extract showed an increased quantity of a large molecular weight C-terminal peptide in atrial extracts from aged rats compared to young rat atria. Plasma levels of ANP and proANP 1-30 both increased significantly after extract infusion in both aged and young groups, and there was no significant difference in ANP concentration between the two groups. However, the concentration of proANP 1-30 was significantly increased in the aged group compared to the young group after extract infusion. These results suggest that changes in the structure or processing of proANP in aging may contribute to the different hemodynamic responses.

Age Factors↗

PubMed2000

Regulation of atrial natriuretic peptide gene expression in gastric antrum by fasting.

Atrial natriuretic peptide (ANP) gene expression was localized in the rat gastric antrum using immunohistochemistry and in situ hybridization to mucosal cells in the lower portion of the antropyloric glands. Colocalization of immunoreactive ANP, long-acting natriuretic peptide, i.e., proANP-(1-30), and serotonin in these cells identified them to be enterochromaffin cells. Fasting for 72 h in 8-mo-old (adult) rats produced a significant (P < 0.05) decrease in the levels of ANP prohormone mRNA, immunoreactive proANP-(1-30) and ANP to approximately 33% of that of fed rats. Fasting in 1-mo-old rats had no effect on these parameters. Transcripts for natriuretic peptide receptor subtypes NPR-A, NPR-B, and NPR-C were found in both mucosa and muscle tissues of the antrum. ANP, brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) stimulated the production of cGMP in antral mucosa in vitro with a potency of ANP > BNP >> CNP, suggesting that these receptors were functional. We conclude that fasting decreases ANP prohormone mRNA and its gene products, long-acting natriuretic peptide, and ANP in the antrum of adult rats.

Animals↗

PubMed1999

Elevated atrial natriuretic peptides and early renal failure in type 2 diabetic Goto-Kakizaki rats.

The present investigation was designed to determine if atrial natriuretic peptides (ANPs) are increased in a spontaneous model of non-obese type 2 diabetes, the Goto-Kakizaki (GK) rat. Four peptide hormones originating from the ANP prohormone were increased twofold (P < .05) to sixfold (P < .01) in the circulation of GK rats compared with nondiabetic Wistar rats from which the GK colony was originally derived. Thus, ANP, long-acting natriuretic peptide (LANP), vessel dilator, and kaliuretic peptide were (mean +/- SE) 497 +/- 78, 1,285 +/- 105, 457 +/- 45, and 385 +/- 87 pg/mL in GK rats, versus 78 +/- 23, 542 +/- 77, 137 +/- 26, and 134 +/- 33 pg/mL, respectively, in Wistar rats. In evaluating the cause of the increased ANPs, the blood volume of GK rats (16.2 +/- 0.4 mL) was significantly (P < .01) increased compared with Wistar rats (9.5 +/- 0.3 mL). The ventricles of GK rats were not dilated when examined by transthoracic echocardiography, but the venous system was markedly distended. GK rats had a 48% to 79% decrease in renal function (ie, increased serum creatinine and blood urea nitrogen [BUN]) compared with Wistar rats. These results indicate that circulating ANPs are increased in the GK spontaneously diabetic rat secondary to (1) increased blood volume, which leads to increased synthesis and release of ANPs, and (2) renal failure, which results in a delayed metabolic processing of these peptides. The early combined increases of the four atrial peptides collectively may contribute to the hyperfiltration that occurs in early diabetes mellitus.

Animals↗

PubMed1999

Atrial natriuretic-like peptide and its prohormone within metasequoia.

Metasequoia glyptostroboides was one of the dominant conifers in North America, Asia, and Europe for more than 100 million years since the late Cretaceous Albian Age, but Quaternary glaciations drove the Metasequoia population to apparent extinction. A small pocket of Metasequoia, however, was found in central China in the 1940s representing the only surviving population of this "living fossil" species. Atrial natriuretic peptide, a 28-amino-acid peptide hormone that causes sodium and water excretion in animals, has been found to be part of the first peptide hormonal system in lower plants. The existence of this hormonal system has never been examined within trees of any genus. High-performance gel permeation chromatography of the leaves and stems (i.e., branches) of Metasequoia followed by atrial natriuretic peptide radioimmunoassay revealed an ANP-like peptide and its prohormone (i.e., approximately 13,000 mol wt) were present in both leaves and stems of this conifer. The elution profile of ANP-like peptide in stems of Metasequoia had a shoulder to the left of where pure synthetic ANP elutes suggesting the possibility of a slightly larger peptide eluting within this shoulder secondary to alternate processing of the ANP-like prohormone and similar to what occurs with the kidney of animals. The elution profile of ANP-like peptide in the leaves of Metasequoia revealed two peaks; one where ANP elutes and a second peak suggesting a smaller peptide that has been metabolically processed. The presence of the ANP-like prohormone strongly suggests that ANP-like gene expression is occurring in both leaves and stems of Metasequoia since this prohormone is the gene product of this hormonal system. The presence of the ANP-like hormonal system in trees implies that this hormonal system may have been present early in land plant evolution to allow trees to reach heights of greater than 30 feet where a water flow-enhancing substance is absolutely necessary for water flow to occur to these heights.

Atrial Natriuretic Factor↗

PubMed1998

Directed antisense therapy confirms the role of protein kinase C-alpha in the tumorigenicity of pancreatic cancer.

BACKGROUND: The level of expression of the alpha isoform of protein kinase C (PKC-alpha) has been shown to correlate inversely with the pathologic differentiation of human pancreatic cancers. METHODS: We stably transfected a moderately differentiated pancreatic cell line (HPAC) to overexpress PKC-alpha and examined the survival rates compared with parent HPAC according to an orthotopic model. Next we used a PKC-alpha antisense oligonucleotide specifically to down-regulate this isoform in vitro and examine the effect of treatment in vivo again according to the orthotopic model. RESULTS: Animals implanted with the overexpressing cell line had a mortality rate almost twice that of those implanted with the parent cell line (P < .01). Treatment with antisense oligonucleotide in increasing concentrations down-regulated PKC-alpha mRNA by Northern blot analysis and reverse transcriptase-polymerase chain reaction. Animals treated with antisense oligonucleotide after orthotopic implantation of pancreatic cancer cells survived statistically longer than those treated with vehicle alone (P = .005). Treatment with a scrambled oligonucleotide also conferred a survival benefit compared with vehicle alone (P < .01). CONCLUSIONS: Tumorigenicity of pancreatic cancer is related directly to PKC-alpha expression in vivo as demonstrated by decreased survival when overexpressed. PKC-alpha expression can be down-regulated directly (antisense) and indirectly (scrambled) in vitro, which subsequently confers a dramatic survival benefit in vivo.

Adenocarcinoma↗

PubMed1997

Matrix metalloproteinase inhibition attenuates human pancreatic cancer growth in vitro and decreases mortality and tumorigenesis in vivo.

Matrix metalloproteinases (MMP) are enzymes responsible for extracellular matrix degradation, a critical component influencing the growth and metastatic potential of cancer. The purpose of this study was to determine the in vitro effects of MMP inhibition on human pancreatic cancer cells and to document its effect on cancer growth in vivo. The effect of MMP inhibition was determined using the MMP inhibitor BB-94 and a moderately differentiated pancreatic cancer cell line (HPAC). In vitro, a dose response curve was generated over 5 days utilizing the MTT [3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. In vivo, using an established orthotopic model for pancreatic cancer (LD100 = 80 days), 22 nude mice with orthotopic tumors (30 were implanted) received either BB-94 or vehicle beginning 4 days prior to implantation and continuing to death or sacrifice on Day 70. Mice were weighted weekly. At death/sacrifice, tumors were weighted, volume determined, and metastases/ distant spread documented. In vitro, BB-94 had little effect on HPAC proliferation at 40 ng/ml but achieved progressively greater to near complete inhibition at doses up to 4000 ng/ml while maintaining cell viability. In vivo, BB-94 significantly increased length of survival (69 +/- 0.1 days vs. 56 +/- 3.1 days) and necropsy weight (25.7 +/- 1.67 g vs. 19.8 +/- 1.14 g) while decreasing metastatic rate (1 vs. 20) and tumor size (0.14 +/- 0.02 g vs. 0.65 +/- 0.1 g). MMP inhibition limits HPAC proliferation in a dose-dependent fashion without direct cytotoxic effects in vitro. Mice harboring orthotopic tumors treated with BB-94 demonstrated significant reductions in tumor weight, volume, and metastases which corresponded to increased animal weight and prolonged survival.

Animals↗

PubMed1997

Tissue-specific cytokine production during experimental acute pancreatitis. A probable mechanism for distant organ dysfunction.

Our purpose was to determine if cytokines are produced systemically during acute pancreatitis. Proinflammatory cytokines are elevated during acute pancreatitis and have been implicated in the progression of pancreatitis-associated multiple organ dysfunction. Whether these mediators are produced within all tissues or very few specific organs is not known. Edematous pancreatitis was induced in adult male mice by IP injection of cerulein. Necrotizing pancreatitis was induced in young female mice by feeding a choline-deficient, ethionine supplemented diet. Animals were sacrificed as pancreatitis worsened, with multiple organs prepared for tissue mRNA and protein analysis by RT-PCR and immunoblotting. Pancreatitis severity was established by histologic grading and serum amylase and lipase. There was no cytokine mRNA or protein detectable prior to the induction of pancreatitis. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1 beta) mRNA and protein were detected within the pancreas early in the course of pancreatitis in both models, coinciding with the development of hyperamylasemia (both P < 0.001). Interleukin-6 was produced in the pancreas after pancreatitis was more fully developed (P < 0.001). IL-1 beta and TNF-alpha were subsequently produced in large amounts in lung, liver, and spleen but never within kidney, cardiac muscle, or skeletal muscle. A significant delay between pancreatic and distant organ cytokine production was always observed. It is concluded that proinflammatory cytokines are produced within the pancreas and within organs known to develop dysfunction during severe pancreatitis. Cytokine production is tissue specific, correlates with disease severity, and occurs within the pancreas first and subsequently within distant organs.

Actins↗

PubMed1996

Differentiation of pancreatic ductal carcinoma cells associated with selective expression of protein kinase C isoforms.

BACKGROUND: The signal transduction pathways important in regulating the growth and differentiation of malignant cells are poorly understood. Recent evidence has implicated activation of the protein kinase C (PKC) family of signaling proteins in pancreatic carcinoma during cytokine-induced cytostasis and differentiation. METHODS: A human pancreatic adenocarcinoma (HPAC) cell line was exposed to tumor necrosis factor-alpha (TNF-alpha; 40 ng/ml) for 6 days. Cytostasis and viability were confirmed by daily MTT [(3(4,5)-dimethyl-thiazol-2-yl) 2,5-diphenyl-tetrazolium bromide] and trypan exclusion assay. Protein fractions were isolated daily and subjected to immunoblot analysis for the normal (terminally differentiated) pancreatic ductal cell marker carbonic anhydrase II (CA II) as well as specific PKC isoforms (alpha, beta, gamma, eta, and zeta). RESULTS: Growth arrest occurred in HPAC cells after exposure to TNF-alpha for 48 h, with viability maintained above 90% throughout the 6-day time course. CA II immunoreactivity was not detected in untreated controls but appeared after 2 days of TNF-alpha exposure, peaking on day 6. Concurrently, TNF-alpha induced the selective downregulation of PKC-alpha, whereas PKC-gamma levels increased. PKC-beta and PKC-eta immunoreactivity did not change. The atypical PKC-zeta isoform developed a doublet banding pattern in response to TNF-alpha, although overall PKC-zeta levels did not change. CONCLUSIONS: TNF-alpha-induced growth arrest and differentiation in HPAC cells is associated with the selective downregulation of PKC-alpha and upregulation of PKC-gamma.

Carbonic Anhydrases↗

PubMed1996

Increased release of kaliuretic peptide during immersion-induced central hypervolemia in cirrhotic humans.

Kaliuretic peptide is a recently discovered potent stimulator of potassium and water excretion. Its role in modulating renal water handling in cirrhotic patients has not been defined. The responses of circulating kaliuretic peptide and atrial natriuretic factor in 8 cirrhotic subjects to water immersion were significantly greater (p < 0.05) than those of 7 healthy volunteers. With cessation of immersion, atrial natriuretic factor decreased within 30 min to preimmersion values, whereas kaliuretic peptide remained significantly elevated > 1 h, suggesting a slower clearance for kaliuretic peptide. The peak diuretic response to immersion corresponded in a temporal fashion to the peak circulating concentration of kaliuretic peptide, suggesting a possible physiological role of kaliuretic peptide in modulating volume homeostasis in cirrhotic humans.

Adult↗