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Ghrelin, a circulating orexigenic hormone secreted from the stomach, stimulates appetite and food intake by activating the hypothalamic arcuate nucleus. Administration of exogenous ghrelin exerts anabolic effects, causing weight gain, increased adiposity, and decreased metabolism. Body temperature (BT), which is determined by the balance of heat production and heat loss, must be strictly regulated to maintain proper cellular function and metabolism. However, the role of ghrelin in thermoregulation remains unclear. In this study, we found that ghrelin was essential for decreasing BT when mice are placed under calorie restriction. Elevated ghrelin concentrations induced by fasting correlated with significant decreases in BT, a hibernation-like state called torpor. Ghrelin-deficient (Ghrl−/−) animals could not enter torpor. The BT of Ghrl−/− mice also remained high under restricted feeding, but the animals gradually entered precipitous hypothermia, indicating thermoregulatory impairment. These effects of ghrelin on thermoregulation were the result of suppression of sympathetic nervous system activity input to brown adipose tissue; in the absence of ghrelin, it was not possible to suppress uncoupling protein 1 (ucp1) expression and decrease BT in low-energy states. Together, these findings demonstrate that ghrelin is an essential circulating hormone involved in lowering BT. [ABSTRACT FROM AUTHOR]

This document is a retraction note from the journal Cancer Chemotherapy & Pharmacology. The article titled "Atrial natriuretic peptide protects against cisplatin-induced granulocytopenia" has been retracted due to errors in the calculation of results, statistical analysis, and reporting of sample numbers. The data in several figures are affected, and the primers used in one experiment were incorrect, rendering the data invalid. The corresponding author and other authors agree with the retraction. The publisher, Springer Nature, remains neutral in regards to jurisdictional claims and institutional affiliations. [Extracted from the article]

The aim of this study was to investigate the effect of activated ghrelin with dietary octanoic acids or medium-chain triglyceride (MCT) administration to underweight patient with chronic obstructive pulmonary disease (COPD). Eleven severe and very severe COPD patients received a 5-day treatment with edible MCT. Sequentially, 10 patients received a 3-week combination treatment with MCT and intravenous acyl ghrelin. Five-day MCT treatment increased endogenous acyl ghrelin (p = 0.0049), but the total ghrelin level was unchanged. MCT–ghrelin combination treatment improved the peak oxygen uptake (p = 0.0120) during whole treatment course. This effect was attributed to the resultant improvements in cardiac function by O2 pulse, and to the difference between inspired and expired oxygen concentration rather than minute ventilation. Addition of dietary MCT to ghrelin treatment improved the aerobic capacity of underweight COPD patients, likely by mechanisms of increased O2 delivery through improvements in primary cardiocirculatory and muscular crosstalk. [ABSTRACT FROM AUTHOR]

Purpose: Ghrelin was recently reported to promote recovery from hepatic injury. We hypothesized that it could also be associated with clinical recovery of the transplanted liver from ischemia and reperfusion injury. Our aims were to investigate perioperative ghrelin changes following pediatric living donor liver transplantation (LDLT) and to analyze the association of these changes with postoperative hepatic function.Methods: We measured plasma acyl ghrelin (AG) concentrations before surgery, at the end of surgery and on postoperative days (PODs) 1, 3 and 7 in 12 children who underwent LDLTs, and, as controls, pre- and post-operatively and on POD1 in 7 children who underwent benign abdominal mass resection. The correlations between the participants' ghrelin profiles and hepatic function-related data were evaluated.Results: AG levels significantly declined to 15.6% of preoperative levels after LDLT and almost returned to baseline on POD3. Post-operative AG levels were significantly reduced to a greater extent following LDLT than benign abdominal mass resection. AG levels on POD1 inversely correlated with aspartate aminotransferase levels and cold/total ischemia time (P < 0.05).Conclusion: These results suggest that reduced AG levels on POD1 may reflect the degree of damage to the transplanted liver due to ischemia and reperfusion injury. [ABSTRACT FROM AUTHOR]

Although hypoalbuminemia at admission is a risk for acute kidney injury (AKI) and mortality in patients with acute decompensated heart failure (ADHF), the clinical significance of decreased serum albumin levels (DAL) during ADHF therapy has not been elucidated. This study aimed to evaluate whether DAL was associated with AKI, and whether intravenous atrial natriuretic peptide (ANP) administration, which provides an effective treatment for ADHF but promotes albumin extravasation, was associated with DAL and AKI. A total of 231 consecutive patients with ADHF were enrolled. AKI was defined as ≥0.3 mg/dl absolute or 1.5-fold increase in serum creatinine levels within 48 h. AKI occurred in 73 (32%) of the 231 patients during ADHF therapy. The median value of decreases in serum albumin levels was 0.3 g/dl at 7 days after admission. When DAL was defined as ≥0.3 g/dl decrease in serum albumin levels, DAL occurred in 113 patients, and was independently associated with AKI. Of the 231 patients, 73 (32%) were treated with intravenous ANP. DAL occurred more frequently in patients receiving ANP than in those not receiving ANP (77 vs. 36%, p < 0.001), and ANP was independently associated with DAL. The incidence of AKI was higher in patients receiving ANP than in those not receiving ANP (48 vs. 24%, p < 0.001). ANP was independently associated with AKI. In conclusion, DAL is associated with AKI. Intravenous ANP administration may be one of the promoting factors of DAL, which leads to AKI, indicating a possible novel mechanism of AKI. [ABSTRACT FROM AUTHOR]

Purpose: Cisplatin is an effective chemotherapeutic agent used to treat a variety of malignant tumors. The major toxicity associated with cisplatin treatment is granulocytopenia. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, protects against toxicity in many organs, including the heart, blood vessels, lung, and kidney. The objective of this study was to investigate the myeloprotective effects of CNP in a mouse model of cisplatin-induced granulocytopenia.Methods: The mice were divided into two groups: cisplatin with vehicle and cisplatin with CNP. CNP (2.5 μg/kg/min via osmotic pump, subcutaneously) or vehicle administration was started two day before cisplatin injection, and continued until the mice were killed. At 0, 2, 4, 8, and 14 days after cisplatin injection (16 mg/kg, intraperitoneally as a single dose), we counted total and living cells and granulocyte/macrophage colony-forming units (CFU-GM) in bone marrow. In addition, at 0, 1, 2, and 4 days after cisplatin injection, we measured mRNA levels of CXC chemokine receptor 4 (CXCR4) and chemokine CXC ligand 12 (CXCL12) in bone marrow.Results: CNP significantly attenuated the reduction in bone marrow nucleated cell count and CFU-GM in bone marrow at 4 days after cisplatin injection. Four days after cisplatin injection, CNP significantly decreased the CXCR4 mRNA level in bone marrow, but had no effect on the level of CXCL12 mRNA.Conclusions: CNP exerts myeloprotective effects in cisplatin-induced granulocytopenia and decreases CXCR4 expression. [ABSTRACT FROM AUTHOR]

Purpose: Granulocytopenia is the major toxicity associated with cisplatin treatment. Atrial natriuretic peptide (ANP) is a cardiac hormone used clinically for the treatment of acute heart failure in Japan. ANP exerts a wide range of protective effects on various organs, including the heart, blood vessels, lungs, and kidneys. This study's objective was to investigate the protective effects of ANP on cisplatin-induced granulocytopenia in mice.Methods: The mice were divided into two groups: cisplatin with vehicle and cisplatin with ANP. ANP (1.5 μg/kg/min via osmotic pump, subcutaneously) or vehicle administration was started 1 day before cisplatin injection until the mice were killed. At 0, 2, 4, 8, and 14 days after cisplatin injection (16 mg/kg, intraperitoneally as a single dose), the white blood cell, red blood cell, and platelet counts were measured in the peripheral blood in both groups. The numbers of total and live cells and colony-forming unit-granulocyte-macrophage (CFU-GM) colonies in the bone marrow of the mice were also examined. In addition, at 0, 0.5, 1, and 2 days after cisplatin injection, serum granulocyte colony-stimulating factor (G-CSF) levels were measured.Results: ANP significantly attenuated the white blood cell count decrease in the peripheral blood 2 and 4 days after cisplatin injection. ANP also attenuated the decrease in the number of live cells and CFU-GM colonies in bone marrow 2, 4, and 8 days after cisplatin injection. ANP significantly increased serum G-CSF levels 1 day after cisplatin injection.Conclusions: ANP has protective effects in cisplatin-induced granulocytopenia, with increased G-CSF production. [ABSTRACT FROM AUTHOR]

Background: Ghrelin, a 28-amino acid peptide predominantly produced by the stomach, exerts powerful renal protective effects by increasing levels of insulin-like growth factor-1 (IGF-1). The aim of this study was to evaluate the effects of ghrelin on the incidence of renal dysfunction in patients receiving cisplatin-based chemotherapy.Methods: Forty patients with oesophageal cancer receiving cisplatin-based chemotherapy were assigned to either the ghrelin group (n=20), which received ghrelin (0.5 μg kg(-1) h(-1)) for 5 days, or a placebo group (n=20). The primary endpoint was serum creatinine. Secondary endpoints were serum cystatin C, chemotherapy-related adverse events, changes in serum ghrelin-related hormone levels, correlation between markers of renal injury and hormone concentrations, and effects on the second cycle of chemotherapy.Results: Blood acyl ghrelin, total ghrelin, and IGF-1 concentrations on day 4 were significantly higher in the ghrelin group. The renal dysfunction, serum creatinine and cystatin C levels, dose reduction, and delay in the initiation of the second cycle of chemotherapy were lower in the ghrelin group than in the control group. Serum creatinine levels were significantly correlated with serum IGF-1 levels.Conclusion: Continuous synthetic ghrelin administration during cisplatin-based chemotherapy attenuated renal dysfunction and harmful effects on subsequent chemotherapy, possibly by increasing IGF-1 levels. [ABSTRACT FROM AUTHOR]

Purpose: Ghrelin is mainly secreted from the stomach and plays a role in appetite, weight gain, and the promotion of a positive energy balance. The levels of ghrelin decrease immediately after gastrectomy. We herein investigated the effect of the administration of synthetic ghrelin to treat postoperative severe weight loss in a prospective, one-arm clinical trial to develop new strategies for weight gain. Methods: Ten patients (four distal gastrectomy and six total gastrectomy) received ghrelin treatment. Eligibility criteria included patients who underwent gastrectomy more than 1 year previously and 15 % body weight loss from the preoperative weight or a body mass index under 19. Synthetic human ghrelin (3 μg/kg) was administered to the patients twice a day for 1 week. Oral intake of calories, appetite [evaluated using the visual analog scale (VAS)], and body weight before and during administration of ghrelin were compared. Results: There was a significant difference in the oral food intake before and during treatment (before treatment: 1236 ± 409 kcal vs. during treatment: 1398 ± 365 kcal, p = 0.039), and the VAS for appetite significantly improved with each day of ghrelin administration ( p < 0.05). Significant amounts of body weight were gained (39.5 ± 6.8 vs. 40.1 ± 6.9, p = 0.037). Conclusions: The administration of synthetic ghrelin improved the food intake and was effective for treating appetite loss and body weight loss. Synthetic ghrelin may be a promising new therapy for severe body weight loss following gastrectomy. [ABSTRACT FROM AUTHOR]

Purpose: Ghrelin is a unique gastric hormone, which has pleiotropic biological functions, including anti-inflammatory effects. The aim of this study was to investigate the effects of administering ghrelin on reducing postoperative systemic inflammation in patients undergoing esophagectomy. Methods: The safety and effectiveness of postoperative ghrelin administration were investigated among twenty esophageal cancer patients who underwent esophagectomy between May 2010 and August 2011. Two different regimens of ghrelin administration, twice daily rapid drip infusion (3 μg/kg, twice a day) or continuous infusion (0.5 μg/kg/h), were employed. The duration of the systemic inflammatory response syndrome (SIRS) and the hematological parameters were compared between groups. Results: Patients treated with ghrelin showed shorter SIRS durations than controls (1.6 ± 2.7 vs. 4.1 ± 3.7 days, respectively; p = 0.0065) and also showed lower C-reactive protein concentrations than controls (11.0 ± 4.6 mg/dL vs. 15.3 ± 7.3 mg/mL, respectively, on postoperative day 3, p = 0.030). Ghrelin administration was not associated with any adverse events. The incidence of operative morbidity was equivalent between groups. The two ghrelin administration regimens showed similar durations of systemic inflammatory response (rapid drip: 2.2 ± 3.3 vs. continuous: 1.1 ± 1.9 days, p = 0.17). Conclusions: Postoperative ghrelin administration is safe and may suppress protracted postoperative inflammation in patients who undergo esophagectomies. [ABSTRACT FROM AUTHOR]

A substudy of ghrelin treatment in a multicenter trial previously revealed that administration of ghrelin improves the exercise capacity of underweight COPD patients. To clarify exertional dyspnea more precisely, exploratory analysis was conducted on data from the substudy. Of 20 underweight COPD patients who were randomized to pulmonary rehabilitation with intravenous ghrelin (2 μg/kg, n = 10) or placebo ( n = 10) twice daily for 3 weeks in the substudy, 16 (ghrelin = 9, placebo = 7) could be investigated for dyspnea break-point on the dyspnea-ratio (%) of Δoxygen uptake ( $${\dot{V}}_{{\rm O}_{2}}$$ ) (= peak minus resting $${\dot{V}}_{{\rm O}_{2}}$$ ) curve. A significant treatment effect of ghrelin on percentage $${\dot{V}}_{{\rm O}_{2}}$$ at the dyspnea break-point to Δ $${\dot{V}}_{{\rm O}_{2}}$$ ( p = 0.049) was achieved. In conclusion, underweight COPD patients benefitted from ghrelin treatment in terms of shifts to the early exercise phase of the dyspnea break-point during a standardized exercise program. [ABSTRACT FROM AUTHOR]

Purpose: Cisplatin is a highly effective chemotherapeutic agent used to treat various malignancies, but its utility is compromised by its nephrotoxicity. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, exhibits anti-inflammatory effects by activating its specific receptor, guanylyl cyclase (GC)-B. CNP and GC-B receptor are known to be expressed in both the vascular endothelium and the kidney. The objective of this study was to investigate the renoprotective effects of CNP in a mouse model of cisplatin-induced nephrotoxicity. Methods: C57BL/6 mice were divided into three groups: normal control mice; cisplatin (20 mg/kg, intraperitoneal) mice treated with vehicle; and cisplatin mice treated with CNP (2.5 µg/kg/min, subcutaneous). At 72 h after cisplatin injection, urine, blood and kidney samples were collected. Urine and blood samples were examined biochemically. Histological findings and gene expression in kidney tissue were evaluated. Results: CNP reduced histological renal tubular damage and apoptosis induced by cisplatin and suppressed plasma blood urea nitrogen and creatinine levels, which were elevated by cisplatin administration. CNP treatment decreased the expression of kidney injury molecule-1 and monocyte chemoattractant protein-1, which were elevated in the kidney by cisplatin administration. CNP treatment attenuated the decrease in GC-B expression in cisplatin-induced kidney injury. Conclusions: The present study is the first to show that CNP inhibits nephrotoxicity and kidney cell damage induced by cisplatin. The mechanism of action may involve down-regulation of inflammatory cytokine expression in cisplatin-induced kidney injury and attenuation of apoptosis in renal tubular cells. [ABSTRACT FROM AUTHOR]

Background and aim: The infusion of chronic angiotensin II (Ang II) has been shown to promote renal interstitial fibrosis. To evaluate the pathophysiological significance of the natriuretic peptide-GC-A system, we infused Ang II (1.0 mg/kg/day) in GC-A-deficient mice (GC-A-KO). Methods: We used 5 groups (Wild-Saline n = 12, Wild-Ang II n = 14, GC-A-KO-Saline n = 11, GC-A-KO-Ang II n = 13, and GC-A-KO-Ang II-Hydralazine n = 10). Saline or Ang II was infused subcutaneously using an osmotic minipump for 3 weeks. Hydralazine was administered orally (0.05 g/L in drinking water). Results: Systolic blood pressure was significantly higher in the GC-A-KO-Saline group (130 ± 12 mmHg) than in the Wild-Saline group (105 ± 30 mmHg), and was similar to that in the Wild-Ang II (141 ± 17 mmHg) and GC-A-KO-Ang II-Hydralazine (140 ± 20 mmHg) groups. Systolic blood pressure was significantly higher in the GC-A-KO-Ang II group (159 ± 21 mmHg) than in the 4 other groups. Renal tubular atrophy and interstitial fibrosis were significantly more severe in the GC-A-KO-Ang II group (atrophy 13.4 %, fibrosis 12.0 %) than in the Wild-Saline (0, 2.0 %), Wild-Ang II (2.9, 4.4 %), and GC-A-KO-Saline (0, 2.6 %) groups. Hydralazine could not inhibit this aggravation (GC-A-KO-Ang II-Hydralazine 13.5, 11.3 %). The expression of monocyte chemotactic protein-1 in tubular cells, and F4/80 and alpha-smooth muscle actin in the interstitium was clearly detected in the Ang II-infused wild and GC-A-KO groups and was associated with renal tubular atrophy and interstitial fibrosis. The expression of E-cadherin in tubular cells was absent in the Ang II-infused wild and GC-A-KO groups and was associated with renal tubular atrophy. Conclusions: The natriuretic peptide-GC-A system may play an inhibitory role in Ang II-induced renal tubular atrophy, interstitial fibrosis, and phenotypic transformation in renal tubular cells and fibroblasts. [ABSTRACT FROM AUTHOR]

Background: Repeated ghrelin administration leads to improvements in symptoms, muscle wasting and exercise tolerance in cachectic patients with pulmonary disease. We investigated the optimal ghrelin dose for underweight patients with chronic respiratory failure. Methods: In this multicenter, randomized, dose-comparison exploratory study, 44 cachectic patients with chronic respiratory failure were randomly assigned pulmonary rehabilitation with intravenous twice-daily administration of 1 or 2 μg/kg ghrelin for 3 weeks. The primary endpoint was improvement in 6-min walking distance (6MWD). The secondary endpoint was change in peak $${\dot{\text{V}}}$$ O. Results: Twenty-one patients were assigned to the 1 μg/kg ghrelin group and 23 to the 2 μg/kg ghrelin group. Change from baseline 6MWD after treatment was similar between groups(1 μg/kg: 53.9 m, 2 μg/kg: 53.9 m, p = 0.99). Mean change in peak $${\dot{\text{V}}}$$ O was significantly greater in the 2 μg/kg group (63.1 ml/min) than in the 1 μg/kg group (−63.8 ml/min, p = 0.048). Food intake and lean body mass significantly increased in both groups, and the St. George Respiratory Questionnaire score, body weight, and body mass index were remarkably improved in only the 2 μg/kg group, although there was no significant difference between groups. No treatment-related serious events were reported for either group. Conclusion: Improvements in the oxygen uptake capacity were greater in patients receiving 2 μg/kg ghrelin twice daily for 3 weeks than in those receiving 1 μg/kg, although exercise tolerance was similar between groups at the end of the 3-week treatment period. Thus, a twice daily dose of 2 μg/kg ghrelin is recommended over 1 μg/kg ghrelin for patients with chronic respiratory failure and weight loss. [ABSTRACT FROM AUTHOR]

Purpose: Cisplatin is an effective chemotherapeutic agent used in the treatment of a wide variety of malignancies. Acute kidney injury (AKI) is the major toxicity associated with cisplatin and sometimes necessitates a reduction in dose or discontinuation of treatment. Atrial natriuretic peptide (ANP) is secreted by the heart and exerts a wide range of renoprotective effects, including anti-inflammatory activity. The objective of this study was to investigate the protective effects of ANP on cisplatin-induced AKI in mice. Methods: Mice were randomly divided into three groups: control, cisplatin (20 mg/kg, intraperitoneal)/vehicle treatment, and cisplatin/ANP (1.5 μg/kg/min via osmotic-pump, subcutaneous) treatment. At 72 h after cisplatin injection, serum blood urea nitrogen and creatinine, urine albumin/creatinine, and renal expression of mRNAs encoding tumor necrosis factor-α, interleukin (IL)-1β, IL-6, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and transforming growth factor (TGF)-β were measured using real-time polymerase chain reaction. Histological changes were also evaluated. Results: ANP treatment significantly attenuated cisplatin-induced increases in serum blood urea nitrogen and creatinine, urine albumin/creatinine, and renal expression of IL-1β, IL-6, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 mRNAs. Cisplatin-induced renal dysfunction and renal tubular necrosis were thus attenuated by ANP treatment. Conclusions: Our results indicate that ANP exhibits a protective effect against cisplatin-induced AKI in mice. ANP may thus be of value in prophylactic strategies aimed at mitigating the adverse effects associated with chemotherapy agents, including cisplatin. [ABSTRACT FROM AUTHOR]

Purpose: Ghrelin may lead to weight gain by appetite stimulation. This prospective study investigated the association between weight loss and the ghrelin levels in patients after gastrectomy. Methods: Thirty-three males and eight females were enrolled in the study. The average age was 66 years. Measurements of the serum ghrelin level and an appetite questionnaire were performed preoperatively and at one, three, six and 12 months postoperatively. Results: The preoperative serum total ghrelin level was 51.6 ± 31.9 (fmol/ml ± SD), and that at one, three, six and 12 months postoperatively was 16.9 ± 9.0, 21.2 ± 16.0, 28.0 ± 19.1 and 29.6 ± 20.6 (fmol/ml ± SD), respectively. The appetite score was 2.02 ± 1.09 points at 1 month, and increased significantly to 2.61 ± 1.00 by 12 months. Conclusions: The ghrelin levels were reduced after gastrectomy and did not recover by 12 months postoperatively. Further studies are needed to evaluate these results as the basis of a therapeutic trial. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer patients who undergo gastrectomy suffer from a post-gastrectomy syndrome that includes weight loss, dumping syndrome, reflux esophagitis, alkaline gastritis, and finally malnutrition. It is important to ameliorate the post-gastrectomy symptoms to restore postoperative quality of life (QoL). The aim of this study was to investigate the effect of rikkunshito, a Japanese herbal medicine, on postoperative symptoms and ghrelin levels in gastric cancer patients after gastrectomy. Methods: Twenty-five patients who had undergone gastrectomy received 2.5 g of rikkunshito before every meal for 4 weeks, and a drug withdrawal period was established for the next 4 weeks. Changes in gastrointestinal hormones, including ghrelin, and appetite visual analog scale scores were measured, and QoL was estimated by using the European Organization for Research and Treatment of Cancer core questionnaire QLQ-C30. The Dysfunction After Upper Gastrointestinal Surgery for Cancer (DAUGS) scoring system was used to evaluate gastrointestinal symptoms after gastrectomy. Results: Sixteen men and nine women (mean age 61.9 years) were enrolled in the study. All patients had either stage I ( n = 24) or II ( n = 1) disease and had undergone either distal gastrectomy ( n = 17) or total gastrectomy ( n = 8) by a laparoscopy-assisted approach. The mean ratio of the acyl-/total ghrelin concentration increased significantly after rikkunshito administration (Pre: 7.8 ± 2.1, 4 weeks: 10.5 ± 1.7 %, p = 0.0026). The total DAUGS score, as well as the scores reflecting limited activity due to decreased food consumption, reflux symptoms, dumping symptoms, and nausea and vomiting significantly improved after rikkunshito administration. Conclusions: The present study demonstrated a significant attenuation of gastrointestinal symptoms after gastrectomy by treatment with rikkunshito. Rikkunshito is potentially useful to minimize gastrointestinal symptoms after gastrectomy. [ABSTRACT FROM AUTHOR]

Background and purpose: Ghrelin, a stomach-derived hormone, stimulates growth hormone secretion and appetite, and inhibits excessive inflammatory response. Plasma ghrelin might affect the inflammatory response to stressful surgical interventions. The aim of this study was to investigate the relationship between serial changes in plasma ghrelin concentrations and the postoperative clinical course after esophagectomy. Methods: The prospective cohort study subjects were 20 patients with esophageal cancer, who underwent esophagectomy with gastric tube reconstruction. Blood samples were taken six times perioperatively during the course of esophagectomy. Results: The plasma ghrelin level decreased to 33 % (range 15-90 %) on postoperative day (POD) 1, relative to the preoperative level, then recovered to about 50 % by POD 3-10. The duration of systemic inflammatory response syndrome (SIRS) was significantly longer in patients with a marked ghrelin reduction to <33 % on POD 1, than in those with less marked reduction of ≥33 % (6.1 ± 1.3 vs. 2.1 ± 0.6 days, P = 0.019). On POD 1, the only inflammatory marker that correlated with the duration of SIRS was the % ghrelin, whereas C-reactive protein, leukocyte count, and IL-6 did not. Conclusion: An early postoperative drop in plasma ghrelin correlated with prolonged SIRS after esophagectomy. Thus, the supplementation of low plasma ghrelin may help minimize excess inflammatory response in these patients. [ABSTRACT FROM AUTHOR]

Objective: The majority of ghrelin producing cells (GPC) are present in the fundic gland of the stomach and recognized as X/A like cells. The detailed distribution of GPC in the stomach is still unknown in healthy and pathological subjects. Methods: We investigated the detailed distribution of GPC in the stomach, especially in relation with chronic gastritis, using surgical specimens from 12 patients with early gastric cancer. Either the anterior or posterior half of the whole stomach, which was a counterpart of the tumor bearing side, was subjected for immunohistochemistry of ghrelin, and the number of total GPC were semi quantitatively evaluated as GPC score. GPC score was compared with the degree of chronic gastritis, serum ghrelin concentration and body weight. Results: GPC was not observed in the pyloric gland, but heterogeneously distributed in the fundic gland mainly in upper body and the greater curvature. The GPC score showed about nine-fold difference, which correlated well with the degree of chronic gastritis by Sydney score ( r = −0.84, P < 0.001). The serum ghrelin concentration was basically determined by the GPC score ( r = 0.75, P = 0.0047); however, the obese patients showed low serum ghrelin concentration in spite of the presence of abundant GPCs. In the low GPC score patients, serum ghrelin was constantly low regardless of their body weight. Conclusions: GPC was inversely correlated with progression of chronic gastritis. Its quantification using immunohistochemistry of the whole stomach was useful to comprehensively evaluate ghrelin profile. [ABSTRACT FROM AUTHOR]

Background and Aim: Ghrelin has distinct effects on gastrointestinal motility through the vagus nerve and gastric excitatory neural plexus. The objectives of this study were to investigate the dynamics of ghrelin and expression of neuromuscular markers in a newly established surgically manipulated rat model of gastric outlet obstruction (GOO), akin to the pyloric stricture associated with duodenal ulcer, advanced gastric cancer, and other conditions, in the clinical setting. Material and Methods: The rats were divided into two groups, a control group (sham operation) and the GOO group (proximal duodenal stricture). The animals were sacrificed 2 weeks after the operation. Plasma and gastric ghrelin were measured by radioimmunoassay. mRNA expression in the stomach of neural choline acetyltransferase (ChAT), c-kit, and membrane-bound stem cell factor (SCF) were analyzed by quantitative RT-PCR. In addition, gastric mRNA expression of the aforementioned were also evaluated 60 min after intraperitoneal administration of a synthetic GHS-R1a antagonist ([ d-Lys3] GHRP-6 6.0 mg/kg). Results: Mechanical GOO induced increases of fasting plasma ghrelin levels and hyperplasia of the gastric muscle layers, with enhanced expression of the gastric neuromuscular markers. Administration of [ d-Lys3] GHRP-6 normalized the enhanced expression of c-kit and SCF. Conclusion: GOO stimulates ghrelin dynamics and then enhances the mechanistic expression of gastric cellular communication network molecules between nerves and smooth muscle cells. [ABSTRACT FROM AUTHOR]

Ghrelin has cardioprotective properties and, recently, has been shown to improve endothelial function and reduce endothelin-1 (ET-1)-mediated vasoconstriction in peripheral vascular disease. Recently, we reported that ghrelin attenuates pulmonary hypertension (PH) caused by chronic hypoxia (CH), which we hypothesized in this study may be via suppression of the ET-1 pathway. We also aimed to determine whether ghrelin's ability to prevent alterations of the ET-1 pathway also prevented adverse changes in pulmonary blood flow distribution associated with PH. Sprague-Dawley rats were exposed to CH (10% O for 2 weeks) with daily subcutaneous injections of ghrelin (150 μg/kg) or saline. Utilizing synchrotron radiation microangiography, we assessed pulmonary vessel branching structure, which is indicative of blood flow distribution, and dynamic changes in vascular responsiveness to (1) ET-1 (1 nmol/kg), (2) the ET-1 receptor antagonist, BQ-123 (1 mg/kg), and (3) ACh (3.0 μg kg min). CH impaired blood flow distribution throughout the lung. However, this vessel 'rarefaction' was attenuated in ghrelin-treated CH-rats. Moreover, ghrelin (1) reduced the magnitude of endothelial dysfunction, (2) prevented an increase in ET-1-mediated vasoconstriction, and (3) reduced pulmonary vascular remodeling and right ventricular hypertrophy-all adverse consequences associated with CH. These results highlight the beneficial effects of ghrelin for maintaining optimal lung perfusion in the face of a hypoxic insult. Further research is now required to establish whether ghrelin is also an effective therapy for restoring normal pulmonary hemodynamics in patients that already have established PH. [ABSTRACT FROM AUTHOR]

Pituitary adenylate cyclase-activating polypeptide (PACAP)-27 and PACAP-38 are neuropeptides performing a variety of physiological functions. The PACAP-specific receptor PAC1 has several variants that result mainly from alternative splicing in the mRNA region encoding the first extracellular (EC1) domain and the third intracellular cytoplasmic (IC3) loop. To characterize the molecular forms of alternative splicing variants of PAC1, we examined the binding affinity and activation of two major second messenger pathways (cAMP production and changes in [Ca]) by PACAP-27. Activation of cAMP was influenced by the variant in both of the EC1 domain and IC3 loops. In the N form in the EC1 domain, the suppressive effect of the HOP1 form in the IC3 loop was enhanced. Regarding the intracellular calcium mobilization assay, the rank order of the potency of PACAP-27 for the different PAC1 isoforms was S/HOP1 >> N/R ≅ S/R >> N/HOP1. In particular, PACAP-27 exhibited remarkable potency of calcium mobilization in the S/HOP1-expressing cells at sub-picomolar concentrations even though the affinities of PACAP-27 to the four PAC1 isoforms were not significantly different. This suggests the specific functions of PACAP-27 due to PACAP-27 preferring PAC1 activation, and leads in clarification of the pleiotoropic function of PACAP. [ABSTRACT FROM AUTHOR]

Ghrelin, a novel peptide modified by n-octanoic acid at the third serine residue (Ser3), serves as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) 1a. The octanoyl modification at Ser3 is essential for receptor binding or growth hormone release. Here, we report the purification of caprine ghrelin and its physiological role in goats. The major form of caprine ghrelin is a 27 amino acid peptide that is octanoylated (C8:0) at Ser3 and lacks Gln14, which is present in rat and human ghrelin. Additionally, we identified various acyl modifications in caprine ghrelin: nonanoic (C9:0), decanoic (10:0), unsaturated octanoic acids (C8:1), and an unidentified fatty acid modification. We observed that differences in acyl modifications affected GHS-R1a activation. In addition, administration of synthetic bovine ghrelin increased plasma growth hormone (GH) levels in goats. Thus, the present study indicates a structural divergence in caprine ghrelin and suggests that ghrelin is involved in GH release in ruminants. [ABSTRACT FROM AUTHOR]

Bone remodeling, the function affected in osteoporosis, the most common of bone diseases, comprises two phases: bone formation by matrix-producing osteoblasts and bone resorption by osteoclasts. The demonstration that the anorexigenic hormone leptin inhibits bone formation through a hypothalamic relay suggests that other molecules that affect energy metabolism in the hypothalamus could also modulate bone mass. Neuromedin U (NMU) is an anorexigenic neuropeptide that acts independently of leptin through poorly defined mechanisms. Here we show that Nmu-deficient (Nmu−/−) mice have high bone mass owing to an increase in bone formation; this is more prominent in male mice than female mice. Physiological and cell-based assays indicate that NMU acts in the central nervous system, rather than directly on bone cells, to regulate bone remodeling. Notably, leptin- or sympathetic nervous system–mediated inhibition of bone formation was abolished in Nmu−/− mice, which show an altered bone expression of molecular clock genes (mediators of the inhibition of bone formation by leptin). Moreover, treatment of wild-type mice with a natural agonist for the NMU receptor decreased bone mass. Collectively, these results suggest that NMU may be the first central mediator of leptin-dependent regulation of bone mass identified to date. Given the existence of inhibitors and activators of NMU action, our results may influence the treatment of diseases involving low bone mass, such as osteoporosis. [ABSTRACT FROM AUTHOR]

Background: Ghrelin, an appetite-promoting peptide secreted from the stomach, is reported to enhance preprandial acid output, possibly through stimulation of the cephalic phase. The present study was designed to clarify the dynamics of ghrelin in H(2) receptor (H(2)R)-null mice by genetic H(2)R knockout.Methods: Fifteen-week- and 54-week-old H(2)R-null mice and their littermates were used. After evaluating the levels of food intake and body-weight increments, mice were killed, and the plasma and gastric active and total ghrelin levels were examined by radioimmunoassay, and gastric preproghrelin mRNA expression was examined by quantitative reverse transcriptase-polymerase chain reaction. Furthermore, each stomach specimen was evaluated by immunohistochemistry and transmission electron microscopy for ghrelin.Results: The levels of food intake and body-weight gain of the H(2)R-null mice were higher than those of wild-type mice. The gastric pH of the 54-week-old H(2)R-null mice was lower than that of the 15-week-old mice. Gastric preproghrelin mRNA expression, plasma ghrelin level, and density of ghrelin-immunoreactive cells in the gastric mucosa of the H(2)R-null mice were significantly increased compared with those of the wild-type mice. Ghrelin-positive immunogold density seen in the electron micrograph was significantly reduced in A-like cells of the H(2)R-null mouse stomach.Conclusions: Ghrelin production and secretion from A-like cells in the gastric fundus are upregulated in H(2)R-null mice, a genetic H(2)R knockout model. [ABSTRACT FROM AUTHOR]

Ghrelin, an appetite-promoting peptide secreted from the stomach, is reported to enhance preprandial acid output, possibly through stimulation of the cephalic phase. The present study was designed to clarify the dynamics of ghrelin in H2 receptor (H2R)-null mice by genetic H2R knockout. Fifteen-week- and 54-week-old H2R-null mice and their littermates were used. After evaluating the levels of food intake and body-weight increments, mice were killed, and the plasma and gastric active and total ghrelin levels were examined by radioimmunoassay, and gastric preproghrelin mRNA expression was examined by quantitative reverse transcriptase-polymerase chain reaction. Furthermore, each stomach specimen was evaluated by immunohistochemistry and transmission electron microscopy for ghrelin. The levels of food intake and body-weight gain of the H2R-null mice were higher than those of wild-type mice. The gastric pH of the 54-week-old H2R-null mice was lower than that of the 15-week-old mice. Gastric preproghrelin mRNA expression, plasma ghrelin level, and density of ghrelin-immunoreactive cells in the gastric mucosa of the H2R-null mice were significantly increased compared with those of the wild-type mice. Ghrelin-positive immunogold density seen in the electron micrograph was significantly reduced in A-like cells of the H2R-null mouse stomach. Ghrelin production and secretion from A-like cells in the gastric fundus are upregulated in H2R-null mice, a genetic H2R knockout model. [ABSTRACT FROM AUTHOR]

Acute hypoxia increases ventilatory drive in conscious animals, resulting in tachycardia. Sustained hypoxia changes the initial chemoreflex ventilatory increase to secondary ventilatory depression, which then evokes a gradual secondary heart rate (HR) reduction. Prostacyclin (PGI2) release is known to potentiate α2-adrenoreceptor (α2-AR) mediated inhibition of sympathoactivation during ischaemia and hypoxia. We examined whether α2-AR mediated sympathoinhibition was responsible for limiting hypoxic heart rate increases during initial sympathoactivation, and subsequent secondary HR depression, and if PGI2 is required for sympathoinhibition of HR. The responses of unrestrained PGI2 synthase deficient (PGID) and wild type (WT) mice to acute hypoxia (10% O2 for 30 min) were investigated by simultaneous telemetry, whole body plethysmography and open-flow respirometry. PGID mice exhibited potentiated $${\mathop V\limits^ \cdot }_{E} $$ ( p < 0.007) after intraperitoneal vehicle injection ( n = 8), but not so HR responses compared to WT mice during sustained hypoxia. Idazoxan (α2-AR antagonist, i.p. bolus 3 mg/kg) pretreatment did not change hypoxic ventilatory response in either group, but significantly elevated hypoxic HR in WT mice only ( p < 0.013). Sodium meclofenamate (cyclooxygenase inhibition, i.p. bolus 25 mg/kg) pretreatment eliminated the potentiated $${\mathop V\limits^ \cdot }_{E} $$ of PGID and caused significant basal hypotension that led to a transient hypertensive response to hypoxia. From these results, we suggest that α2-AR activation is required for coupling HR to central inspiratory drive during acute hypoxia, and that PGI2 is required to enhance the inhibition of sympathoactivation. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells are multipotent cells that can differentiate into cardiomyocytes and vascular endothelial cells. Here we show, using cell sheet technology, that monolayered mesenchymal stem cells have multipotent and self-propagating properties after transplantation into infarcted rat hearts. We cultured adipose tissue–derived mesenchymal stem cells characterized by flow cytometry using temperature-responsive culture dishes. Four weeks after coronary ligation, we transplanted the monolayered mesenchymal stem cells onto the scarred myocardium. After transplantation, the engrafted sheet gradually grew to form a thick stratum that included newly formed vessels, undifferentiated cells and few cardiomyocytes. The mesenchymal stem cell sheet also acted through paracrine pathways to trigger angiogenesis. Unlike a fibroblast cell sheet, the monolayered mesenchymal stem cells reversed wall thinning in the scar area and improved cardiac function in rats with myocardial infarction. Thus, transplantation of monolayered mesenchymal stem cells may be a new therapeutic strategy for cardiac tissue regeneration. [ABSTRACT FROM AUTHOR]

Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, which has been identified as an endogenous ligand for the GH secretagogues receptor. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated, not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach. Considering the haemodynamic and anabolic effects of GH, ghrelin may have beneficial effects on cardiac function and energy metabolism in heart failure through GH-dependent mechanisms. On the other hand, ghrelin has some GH-independent actions: ghrelin stimulates food intake and induces adiposity. Interestingly, ghrelin acts directly on the CNS to decrease sympathetic nerve activity. It also inhibits apoptosis of cardiomyocytes and endothelial cells. An experimental study has shown that repeated administration of ghrelin improves cardiac structure and function, and attenuates the development of cardiac cachexia in chronic heart failure (CHF). These results suggest that ghrelin has cardiovascular effects and regulates energy metabolism through GH-dependent and -independent mechanisms. Thus, administration of ghrelin may be a new therapeutic strategy for the treatment of severe CHF. [ABSTRACT FROM AUTHOR]

Neuromedin U (NMU) is a hypothalamic neuropeptide that regulates body weight and composition. Here we show that mice lacking the gene encoding NMU (Nmu-/- mice) develop obesity. Nmu-/- mice showed increased body weight and adiposity, hyperphagia, and decreased locomotor activity and energy expenditure. Obese Nmu-/- mice developed hyperleptinemia, hyperinsulinemia, late-onset hyperglycemia and hyperlipidemia. Notably, however, treatment with exogenous leptin was effective in reducing body weight in obese Nmu-/- mice. In addition, central leptin administration did not affect NMU gene expression in the hypothalamus of rats. These results indicate that NMU plays an important role in the regulation of feeding behavior and energy metabolism independent of the leptin signaling pathway. These characteristic functions of NMU may provide new insight for understanding the pathophysiological basis of obesity. [ABSTRACT FROM AUTHOR]

Rat ghrelin, a 28-amino acid residue peptide with an octanoyl group at the side chain of Ser3, was synthesized chemically by applying Fmoc/Bu strategy. An ester linkage between octanoic acid and the hydroxyl function of Ser3 was found to be maintained without serious damage during the final deprotection with trifluoroacetic acid (TFA). The most notable finding was the counter-ion-dependent stability change of the octanoyl moiety in the molecule. After consolidation of the counter-ion to TFA (TFA form), the octanoyl group persisted stably upon dissolution in water, whereas in the case of the acetate-form peptide, both de-octanoylation and dehydration (formation of the dehydro-Ala residue) occurred in aqueous solution at the same Ser3 residue. The amounts of these degraded products varied with factors such as solvent, temperature and times of lyophilization. These experimental findings lay the basis for performing the bioassay of ghrelin, which has an octanoyl moiety involved in its numerous biological activities thus far revealed. [ABSTRACT FROM AUTHOR]

Recently, an endogenous ligand has been described for the growth hormone secretagogue receptor (GHS-R), named ghrelin. It was originally isolated from the stomach, but it is also present in the hypothalamus, where the highest concentration of GHS-R has been detected. It is well established that synthetic GHSs exert their effects on the growth hormone (GH) axis principally via the hypothalamus, although they are also able to stimulate GH release directly from the pituitary. We have previously demonstrated the presence of GHS-R mRNA expression in normal and abnormal human pituitary. We have therefore now investigated the expression of the newly recognized endogenous ligand in rat as well as in human pituitary. We readily detected ghrelin mRNA message in normal rat pituitary using reverse transcriptase polymerase chain reaction with published primers. We then designed primers to the corresponding region on the human ghrelin sequence and successfully detected mRNA message in normal human pituitary, as well as in somatotroph, lactotroph, corticotroph, thyrotroph, and nonfunctioning adenomas. We confirmed the expected polymerase chain reaction product by direct sequencing. In conclusion, we suggest that in addition to the probable hypothalamic effects of ghrelin, the peptide is synthesized locally within the pituitary gland, where it may influence the release of GH in an autocrine or paracrine manner. [ABSTRACT FROM AUTHOR]

Reports on a study of the role of ghrelin in the hypothalamic regulation of energy homeostasis. Description of ghrelin which is an acylated peptide the stimulates the release of growth hormone from the pituitary gland; How intracerebroventricular injections of ghrelin strongly stimulated feeding in rats and increased body weight gain; Conclusion that ghrelin is a physiological mediator of feeding and probably has a function in growth regulation.

The histological localization was investigated of adrenomedullin (AM), a novel vasorelaxant peptide originally isolated from human pheochromocytoma. The immunohistological distribution was examined of AM in human, rat, and procine tissues using a polyclonal antibody to a fragment comprising C-terminal amino acids 40-52 of human adrenomedullin [AM(40-52)NH]. Almost all of the human pheochromocytoma and normal adrenal medullary cells of all three species were immunostained and found to be intensely positive for AM. Furthermore, AM-immunoreactive cells were present in the pancreatic islets, gastrointestinal neuroendocrine system, anterior pituitary, and choroid plexus with some degree of interspecies heterogeneity. These findings indicate that AM-immunoreactive cells are widely distributed in the endocrine and neuroendocrine system, suggesting that AM plays some important role in the control of systemic and local circulation and also of humoral secretion. [ABSTRACT FROM AUTHOR]

Presents details of experiments which show that LIM-kinase 1 (LIMK-1) a serine/theronine kinased containing LIM and PDZ domains, phosphorylates cofilin at Ser 3, both in vitro and in vivo. How LIMK-1 induces actin reorganization and reverses cofilin-induced actin depolymerization; Results.

We report studies of two unrelated Japanese patients with 17α-hydroxylase deficiency caused by mutations of the 17α-hydroxylase ( CYP17) gene. We amplified all eight exons of the CYP17 gene, including the exon-intron boundaries, by the polymerase chain reaction and determined their nucleotide sequences. Patient 1 had novel, compound heterozygous mutations of the CYP17 gene. One mutant allele had a guanine to thymine transversion at position +5 in the splice donor site of intron 2. This splice-site mutation caused exon 2 skipping, as shown by in vitro minigene expression analysis of an allelic construct, resulting in a frameshift and introducing a premature stop codon (TAG) 60 bp downstream from the exon 1-3 boundary. The other allele had a missense mutation of His (CAC) to Leu (CTC) at codon 373 in exon 6. These two mutations abolished the 17α-hydroxylase and 17,20-lyase activities. Restriction fragment length polymorphism (RFLP) analysis with a mismatch oligonucleotide showed that the patient’s mother and brother carried the splice-site mutation, but not the missense mutation. Patient 2 was homozygous for a novel 1-bp deletion (cytosine) at codon 131 in exon 2. This 1-bp deletion produces a frameshift in translation and introduces a premature stop codon (TAG) proximal to the highly conserved heme iron-binding cysteine at codon 442 in microsomal cytochrome P450 steroid 17α-hydroxylase (P450c17). RFLP analysis showed that the mother was heterozygous for the mutation. [ABSTRACT FROM AUTHOR]

We examined in detail changes in arterial plasma ANP concentration in response to volume load in conscious dogs. In a 5-min volume load experiment, 18 ml/kg of isosmotic and isooncotic 3% Dextran 40 in saline was infused over a period of 5 min. Mean left atrial pressure (MLAP) increased transiently by 7.6±0.9 mm Hg. Plasma ANP level (P-ANP) did not significantly increase. Assayed P-ANP levels were corrected for hemodilution. Corrected P-ANP (C-ANP) significantly increased from 206±17 to 348±34 pg/ml. However, the level of C-ANP did not reach a steady state. No significant linear correlation was found between increases in MLAP and normalized C-ANP. In a 45-min volume load experiment, the elevated level of MLAP caused by the 5-min volume load was maintained for 40 min by supplemental infusion. C-ANP significantly increased from 196±18 pg/ml to 435±73 ng/ml. The level of C-ANP reached a steady state. A close linear correlation was observed between increases in MLAP and normalized C-ANP. However, the peak time of C-ANP lagged 10 min behind MLAP. These results indicate that it takes 10 min for P-ANP to reach a steady state in fully responding to a volume load, and that the long-term volume load is a prerequisite to the response of the ANP providing system. [ABSTRACT FROM AUTHOR]

We examined direct effects of α-human atrial natriuretic polypeptide (α-hANP) on water and NaCl transport across the segments of Henle's loop by the in vitro microperfusion technique. In the medullary and the cortical thick ascending limb, 10 M α-hANP did not affect the transmural voltage ( V) and the lumen to bathCl flux whether it was added to the perfusate or to the bath. In the thin ascending limb, 10 M α-hANP did not affect the lumen to bathCl flux. The peptide may not affect permselectivity of the thin ascending limb, since it did not influence the diffusion potential generated in the presence of a NaCl gradient. In the descending limb, 10 M α-hANP did not affect osmotic water permeability, whether it was added to the perfusate or to the bathing fluid. From these observations, we conclude that α-hANP does not show direct effects on water and NaCl transport in the segments of Henle's loop at least under our experimental conditions. Therefore, natriuresis by α-hANP may be caused either by an action on nephron segments other than Henle's loop or by an action on renal vasculatures. [ABSTRACT FROM AUTHOR]

Amyloid deposition is a common pathological feature in insulinoma and in the islets of the pancreas in type-2 diabetic patients. The present immunohisto-chemical study revealed that normal B-cells, insulinoma, and amyloid deposits in insulinoma and diabetic pancreatic islets were commonly immunoreactive with antiserum to C-terminal synthetic tetradecapeptide of human islet amyloid polypeptide (IAPP) (24-37). Amyloid fibrils in insulinoma were also positive to IAPP by immunoelectron microscopy. A high level of IAPP was detected in the plasma and tissue of a insulinoma patient by radioimmunoassay suggesting that amyloid deposition in insulinoma is due to overproduction of IAPP. Amyloid deposits immunoreactive to IAPP were also seen in all diabetic pancreatic islets, but in no non-diabetic islets. There was much amyloid deposition in the islets of severe diabetics, whose B-cells demonstrated decreased immunoreactivities for IAPP and insulin. The IAPP content of the pancreas was 649.0 and 847.7 pg/mg wet weight in each of two diabetic patients, and 1034.6 and 1447.7 pg/mg wet weight in two non-diabetic patients. The present study revealed that IAPP is a bioactive peptide secreted from islet B-cells and are amyloidogenic peptide concerned in diabetogenensis and/or the progression of type-2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

In a two-step selective disulfide-bond-forming reaction of human uroguanylin, a 16-residue peptide with two intramolecular disulfide bonds, two compounds (I and II) were formed, which could be detected by RP-HPLC after the second disulfide-bond-forming reaction and were isolated as single entities. Their primary structures, molecular weights, and disulfide connectivities proved to be identical, but their optical rotation values were different, suggesting that they are topological isomers. Only compound I was found to increase the cGMP levels in cultured T84 cells significantly. The ratio of these compounds was affected by the order of the disulfide-bond-forming reactions, but not by the solvent used. The presence of a carboxyl-terminal leucine residue seems to be crucial for stabilizing the conformation of the two isomers. [ABSTRACT FROM AUTHOR]

An immunohistochemical study for islet amyloid polypeptide (IAPP) was made on the gastrointestinal (GI) tract and pancreas of man and rat, using antisera raised against a synthetic peptide of C-terminal human IAPP (24-37) and a synthetic peptide of rat IAPP (18-37). A large number of IAPP-immunoreactive cells were found in the pyloric antrum, and a small number in the body of the stomach in both man and rat. Cytoplasmic processes extended out from the bipolar peripheral region of the immunoreactive cells, rather like neuronal processes, and some appeared to make contact with other immunoreactive cells. In addition, small numbers of immunoreactive cells were also seen in the duodenum and rectum, whereas they were absent from the jejunum, ileum and large intestine. An examination was made for evidence of colocalization of IAPP-immunoreactive material with material immunoreactive for gastrin, somatostatin, vasoactive intestinal polypeptide, pancreatic polypeptide, insulin, and glucagon, but none was found. IAPP-immunoreactive cells were also found in the pancreas of non-diabetic and non-insulin-dependent diabetic patients, but they were completely absent from a patient with insulin-dependent diabetes mellitus despite the presence of IAPP in the plasma. The results of these studies suggest that the peptide may have a biological role in situ in the GI tract and, in addition to the pancreas, may be a possible source of plasma IAPP. [ABSTRACT FROM AUTHOR]

An immunohistochemical study using antiserum raised against synthetic chicken natriuretic polypeptide was used to investigate the distribution of this peptide in the chicken heart. Immunoreactive cells, both in the atrial and ventricular walls, were identified by electron microscopy, and electron-dense granules in the atrial and ventricular cardiocytes were revealed to be storage sites of the peptide. The electron-dense material, thought to be the peptide, was found in the sarcoplasmic reticulum, and it is suggested that a secretory pathway of the peptide through the latter to extracellular space, may be present, in addition to an exocytotic one. [ABSTRACT FROM AUTHOR]

Fatty acids are taken up and metabolized in the brain. In vitro uptake experiments on astrocytoma cells were carried out to assess the potential use of [1-C]octanoate as a positron emission tomography (PET) tracer for astroglial functions. Uptake of [1-C]octanoate increased in a time-dependent fashion until 60 min after application. The uptake of [1-C]octanoate showed similar results to that of [1-C]octanoate until 10 min. As for medium pH, [1-C]octanoate uptake increased gradually with the decrease in pH. We also examined the effects of glutamate, glucose deprivation and hypoxia on the uptake of octanoate and found that these conditions did not bring about any change in the extent of [1-C]octanoate uptake. These results show that the octanoate uptake was not influenced by any of several pathological conditions. When the number of astrocytes increases in the area of hypoglycemia or hypoxia near a brain lesion, the amount of octanoate uptake also increases, so this indicates the possibility thatC-octanoate will detect a brain lesion. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the regional distribution, molecular forms, and gene expression of adrenomedullin in the rat gastrointestinal tract and to examine physiological changes in gastric adrenomedullin after 24-h fasting. The tissue concentration was measured by radioimmunoassay. The molecular forms were analyzed by high performance liquid chromatography. mRNA levels were quantified by Northern blotting and cells positive for adrenomedullin immunoreactivity were localized by immunohistochemistry. A high concentration of adrenomedullin was found in stomach, cecum, and colon (450-520 fmol/g wet tissue). Adrenomedullin immunoreactivity was also detected in duodenum, jejunum, and ileum (200-250 fmol/g wet tissue). Transcripts of the adrenomedullin gene were widely expressed throughout the gastrointestinal tract. The major form of adrenomedullin immunoreactivity in stomach and colon corresponded precisely with authentic adrenomedullin peptide. Adrenomedullin immunoreactive cells were present in the gastrointestinal endocrine system. The concentration and mRNA level of gastric adrenomedullin after fasting were significantly increased compared with findings in controls. Adrenomedullin is ubiquitous in the gastrointestinal tract, and may be produced by endocrine cells. The results suggest that adrenomedullin, through its potent vasodilating activity, may play some role, in the stomach including the regulation of the mucosal blood flow. [ABSTRACT FROM AUTHOR]