scholarly journals 4119 Cholecystokinin (CCK) Receptor Antagonist Reverses Nonalcoholic Steatohepatitis (NASH) by Reducing Hepatic Macrophages and Inflammatory Cytokines

2020 ◽  
Vol 4 (s1) ◽  
pp. 93-94
Author(s):  
Martha Gay ◽  
Anita Safronenka ◽  
Hong Cao ◽  
Robin Tucker ◽  
Narayan Shivapurkar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Receptor Antagonist ◽  
Inflammatory Cytokines ◽  
Receptor Expression ◽  
Receptor Blockade ◽  
High Fat ◽  
Cck Receptors ◽  
Cytokines And Chemokines ◽  
Hepatic Macrophages ◽  
Cck Receptor Antagonist

OBJECTIVES/GOALS: NASH increases the risk of cirrhosis and liver cancer. High-fat diets increase CCK levels and CCK receptors have been identified on fibroblasts and immune cells. We hypothesized that CCK receptor blockade could prevent NASH by altering the hepatic microenvironment and macrophage activation. METHODS/STUDY POPULATION: Female mice were fed a Choline Deficient Ethionine supplemented (CDE) saturated fat diet or control high-fat diet for 18 weeks. Mice in each group were treated with a CCK receptor antagonist, proglumide (0.1 mg/ml) in the drinking water or regular water. Resected livers were stained for H&E for features of NASH and F4/80 for macrophages analysis. Liver RNA was evaluated for the expression of cytokines and chemokines using an 84-gene Profiler array (Qiagen). Oxidative stress was analyzed by qRT-PCR for heat shock proteins (HSPs) 27, 60, 70 and 90 and for glutathione by a fluorometric assay. Differences in CDE fed and CDE/proglumide-treated mouse livers were evaluated. RESULTS/ANTICIPATED RESULTS: Livers from mice on the CDE diet displayed histologic features of NASH that were prevented by proglumide. Cytokines and chemokines expression, especially CCL20 and CCL2, were increased in the CDE fed mice and these levels were reduced greater than 20-fold with proglumide. Infiltration of F4/80+ macrophages was markedly increased in the CDE livers and these were reduced by > 50% (p < 0.0001) with proglumide. RNA expression of HSP70 (p = 0.006) and HSP27 (p = 0.011) were reduced with proglumide. Hepatic glutathione concentration more than doubled in the CDE/proglumide treated mice compared to CDE mice. CCK-B receptor expression increased in the CDE-fed mouse livers compared to controls. DISCUSSION/SIGNIFICANCE OF IMPACT: CCK receptor blockade decreases NASH by reducing hepatic macrophages, oxidative stress, and blocking inflammatory cytokines and chemokines. This data supports our novel hypothesis that CCK receptors play a role in NASH and proglumide may provide an innovative treatment for this condition.

scholarly journals Dietary fat stimulates pancreatic cancer growth and promotes fibrosis of the tumor microenvironment through the cholecystokinin receptor

2018 ◽  
Vol 315 (5) ◽  
pp. G699-G712 ◽  
Author(s):  
Sandeep Nadella ◽  
Julian Burks ◽  
Abdulhameed Al-Sabban ◽  
Gloria Inyang ◽  
Juan Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Receptor Antagonist ◽  
Dietary Fat ◽  
Tumor Suppressor Genes ◽  
Saturated Fat ◽  
Cancer Growth ◽  
High Fat ◽  
Cck Receptors ◽  
Cck Receptor Antagonist

The gastrointestinal peptide cholecystokinin (CCK) is released from the duodenum in response to dietary fat to aid in digestion, and plasma CCK levels are elevated with the consumption of high-fat diets. CCK is also a trophic peptide for the pancreas and has also been shown to stimulate growth of pancreatic cancer. In the current investigation, we studied the influence of a diet high in saturated fat on the growth of pancreatic cancer in syngeneic murine models before the mice became obese to exclude the confounding factors associated with obesity. The high-fat diet significantly increased growth and metastasis of pancreatic cancer compared with the control diet, and the stimulatory effect was blocked by the CCK-receptor antagonist proglumide. We then selectively knocked out the CCK receptor on the pancreatic cancer cells using clustered regularly interspaced short palindromic repeats technology and showed that without CCK-receptors, dietary fat was unable to stimulate cancer growth. We next demonstrated that dietary fat failed to influence pancreatic cancer xenograft growth in genetically engineered CCK peptide knockout mice. The tumor-associated fibrosis that is so prevalent in the pancreatic cancer microenvironment was significantly decreased with CCK-receptor antagonist therapy because fibroblasts also have CCK receptors. The CCK-receptor antagonist proglumide also altered tumor metalloprotease expression and increased tumor suppressor genes by a PCR array. Our studies confirm that a diet high in saturated fat promotes growth of pancreatic cancer and the action is mediated by the CCK-receptor pathway. NEW & NOTEWORTHY Diets high in long-chain saturated fats promote growth of pancreatic cancer independent of obesity. The mechanism through which dietary fat promotes cancer is mediated through the cholecystokinin (CCK) receptor pathway. Therapy with a CCK-receptor antagonist altered the tumor microenvironment by reducing fibrosis, increasing cluster of differentiation 8+ lymphocytes, increasing tumor suppressor genes, and thus decreasing metastases. Use of CCK-receptor antagonist therapy with standard chemotherapy for pancreatic cancer may improve response by altering the tumor microenvironment.

scholarly journals Spirulina Lipids Alleviate Oxidative Stress and Inflammation in Mice Fed a High-Fat and High-Sucrose Diet

Marine Drugs ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 148 ◽  
Author(s):  
Yuhong Yang ◽  
Lei Du ◽  
Masashi Hosokawa ◽  
Kazuo Miyashita
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Cytokines ◽  
Lipid Hydroperoxide ◽  
Mrna Levels ◽  
High Fat ◽  
Inflammatory Status ◽  
Sucrose Diet ◽  
High Sucrose Diet ◽  
High Sucrose ◽  
Pro Inflammatory Cytokines

High-fat and high-sucrose diet (HFHSD)-induced obesity leads to oxidative stress and chronic inflammatory status. However, little is known about the beneficial effects of total lipids extracted from Spirulina. Hence, in the present study, Spirulina lipids were extracted with chloroform/methanol (SLC) or ethanol (SLE) and then their effects on oxidative stress and inflammation in the mice fed a HFHSD were investigated. The results show that the major lipid classes and fatty acid profiles of SLC and SLE were almost similar, but the gamma-linolenic acid (GLA) and carotenoid contents in SLE was a little higher than that in SLC. Dietary 4% SLC or SLE for 12 weeks effectively decreased the hepatic lipid hydroperoxide levels as well as increased the activities and mRNA levels of antioxidant enzymes in the mice fed a HFHSD. In addition, supplementation with SLC and SLE also markedly decreased the levels of serum pro-inflammatory cytokines and the mRNA expression of pro-inflammatory cytokines in the liver and epididymal white adipose tissue of mice fed a HFHSD, and the effects of SLC and SLE were comparable. These findings confirm for the first time that dietary Spirulina lipids could alleviate HFHSD-induced oxidative stress and inflammation.

Blockade of type A, but not type B, CCK receptors postpones satiety in rhesus monkeys

1993 ◽  
Vol 265 (3) ◽  
pp. R620-R624 ◽  
Author(s):  
T. H. Moran ◽  
P. J. Ameglio ◽  
H. J. Peyton ◽  
G. J. Schwartz ◽  
P. R. McHugh
Keyword(s):  
Food Intake ◽  
Receptor Antagonist ◽  
Rhesus Monkeys ◽  
Type A ◽  
Intragastric Administration ◽  
Maximal Effect ◽  
Type B ◽  
Cck Receptors ◽  
Total Food Intake ◽  
Cck Receptor Antagonist

The exogenous administration of the brain/gut peptide cholecystokinin (CCK) inhibits food intake in a variety of species, including subhuman primates and humans. To determine the role of endogenously released CCK in the control of food intake in rhesus monkeys, we examined the ability of the selective type A and type B CCK antagonists devazepide and L-365260 to affect total daily food intake and various meal patterns. Various doses of the antagonists were administered intragastrically 30 min before a daily 4-h feeding period. One-gram food pellets were delivered in response to lever pulls, and intake was computer monitored. Intragastric administration of the type A CCK receptor antagonist devazepide (10-320 micrograms/kg) significantly increased food intake in a dose-related fashion. The threshold for increasing intake was 32 micrograms/kg, and a maximal effect was obtained at a dose of 100 micrograms/kg that increased total 4-h food intake by 47%. The effect of devazepide on food intake was mediated by significant increases in the size and duration of the initial meal, lengthening of the subsequent intermeal interval, and a decrease in the satiety ratio (intermeal interval/1st meal size). In contrast, intragastric administration of the type B CCK receptor antagonist L-365260 (3.2-320 micrograms/kg) did not significantly affect total food intake or any of the meal parameters. These data demonstrate that endogenously released CCK acting through type A CCK receptors plays a role in regulating food intake in rhesus monkeys.

CCK is involved in both peripheral and central mechanisms controlling food intake in chickens

1997 ◽  
Vol 272 (1) ◽  
pp. R334-R340 ◽  
Author(s):  
A. Rodriguez-Sinovas ◽  
E. Fernandez ◽  
X. Manteca ◽  
A. G. Fernandez ◽  
E. Gonalons
Keyword(s):  
Food Intake ◽  
Receptor Antagonist ◽  
Receptor Type ◽  
Receptor Antagonists ◽  
Cck Receptors ◽  
High Affinity ◽  
Increase Food Intake ◽  
Cck Receptor Antagonist ◽  
Cck Receptor Antagonists ◽  
Voluntary Food Intake

The aim of this work was to study the involvement of cholecystokinin (CCK) in the control of food intake in chickens. The following aspects were studied: 1) the effects of intravenous and intracerebroventricular sulfated octapeptide of CCK (CCK-8s) on voluntary food intake; 2) the effects of two CCK-receptor antagonists. L-365,260 and L-364,718, on food intake; and 3) the ability of such drugs to block the effects of CCK-8s on food intake in the chicken. Intravenous and intracerebroventricular CCK-8s caused a decrease in food intake. Intraperitoneal L-365,260, a CCK-receptor antagonist with low affinity for the two CCK receptors described in the chicken, increases food intake. Intracerebroventricular L-364,718, a drug that has high affinity for the chicken central CCK-receptor type, increased food intake. The effect of intravenous CCK-8s on food intake was not blocked by L-364,718 or L-365,260, whereas that of intracerebroventricular CCK-8s was blocked by intracerebroventricular L-364,718. It is concluded that central endogenous CCK plays a role in the control of food intake, which is dependent on central CCK-receptor type; nevertheless, peripheral CCK also decreases food intake acting on the peripheral CCK-receptor type. The fact that intracerebroventricular L-364,718 is able to increase food intake is related to its high affinity for the central CCK-receptor type of this species. Finally, three different speculations that might explain the fact that intraperitoneal L-365,260 increases food intake are discussed.

Resistance to oxidative stress by chronic infusion of angiotensin II in mouse kidney is not mediated by the AT2 receptor

2005 ◽  
Vol 288 (6) ◽  
pp. F1191-F1200 ◽  
Author(s):  
Sebastiaan Wesseling ◽  
David A. Ishola ◽  
Jaap A. Joles ◽  
Hans A. Bluyssen ◽  
Hein A. Koomans ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Renal Injury ◽  
Renal Cortex ◽  
Lipid Peroxide ◽  
Receptor Expression ◽  
Heme Oxygenase 1 ◽  
Receptor Blockade ◽  
Ang Ii ◽  
Nitric Oxide Metabolites

Wild-type mice are resistant to ANG II-induced renal injury and hence form an attractive model to study renal defense against ANG II. The present study tested whether ANG II induces expression of antioxidative genes via the AT2 receptor in renal cortex and thereby counteracts prooxidative forces. ANG II was infused in female C57BL/6J mice for 28 days and a subgroup received AT2 receptor antagonist (PD-123,319) for the last 3 days. ANG II induced hypertension and aortic hypertrophy; proteinuria and renal injury were absent. Urinary nitric oxide metabolites (NOx) were decreased, and lipid peroxide (TBARS) excretion remained unchanged. Expression of NADPH oxidase components was decreased in renal cortex but induced in aorta. Heme oxygenase-1 (HO-1) was induced in both renal cortex and aorta. In contrast, ANG II suggestively increased AT2 receptor expression in kidney but not in aorta. AT2 receptor blockade enhanced hypertension in ANG II-infused mice, reversed ANG II effects on NOx excretion, but did not affect TBARS. Despite its prohypertensive effect, expression of prooxidative genes in the renal cortex decreased rather than increased after short-term AT2 receptor blockade and renal HO-1 induction after ANG II was normalized. Thus chronic ANG II infusion in mice induces hypertension but not oxidative stress. In contrast to the response in aorta, gene expression of components of NADPH-oxidase was not enhanced in renal cortex. Although ANG II administration induced renal cortical AT2 receptor expression, blockade of that receptor did not unveil the AT2 receptor as intrarenal dampening factor of prooxidative forces.

Electrical physiological evidence for highand low-affinity vagal CCK-A receptors

1999 ◽  
Vol 277 (2) ◽  
pp. G469-G477 ◽  
Author(s):  
Ying Li ◽  
Jinxia Zhu ◽  
Chung Owyang
Keyword(s):  
Receptor Antagonist ◽  
Receptor Field ◽  
Cck Receptors ◽  
Physiological Conditions ◽  
Nodose Ganglia ◽  
Afferent Fibers ◽  
Electrophysiological Studies ◽  
Vagal Afferent ◽  
Cck Receptor Antagonist ◽  
Afferent Response

We have demonstrated that under physiological conditions CCK acts through vagal high-affinity CCK-A receptors to mediate pancreatic secretion. In this study, we evaluated the vagal afferent response to endogenous CCK in rats and defined the CCK-receptor affinity states and the vagal-receptive field responsive to CCK stimulation using electrophysiological studies. Experiments were performed on anesthetized rats prepared with bile-pancreatic fistula. Plasma CCK levels were elevated by diverting bile-pancreatic juice (BPJ). The single-unit discharge of sensory neurons supplying the gastrointestinal tract was recorded from the nodose ganglia. All units studied were either silent or they had a very low resting discharge frequency. Thirty-two single units were studied extensively; seven were shown to be stimulated by diversion of BPJ (2.6 ± 2 impulses/min at basal to 40 ± 12 impulses/min after diversion). Acute subdiaphragmatic vagotomy or perivagal capsaicin treatment abolished the response. The CCK-A-receptor antagonist CR-1409, but not the CCK-B antagonist L-365260, blocked the vagal response to endogenous CCK stimulation. Infusion of the low-affinity CCK-receptor antagonist CCK-JMV-180 completely blocked the vagal afferent response to the diversion of BPJ in three of seven rats tested but had no effect on the response in the remaining four. In a separate study, we demonstrated that gastric, celiac, or hepatic branch vagotomy abolished the response in different subgroups of neurons. In conclusion, under physiological conditions, CCK acts on both high- and low-affinity CCK-A receptors present on distinct vagal afferent fibers. The vagal CCK-receptor field includes the regions innervated by the gastric, celiac, and hepatic vagal branches. This study provides electrophysiological evidence that vagal CCK receptors are present on the vagal gastric, celiac, and hepatic branches and may occur in high- and low-affinity states.

scholarly journals Polydatin Reduces Cardiotoxicity and Enhances the Anticancer Effects of Sunitinib by Decreasing Pro-Oxidative Stress, Pro-Inflammatory Cytokines, and NLRP3 Inflammasome Expression

2021 ◽  
Vol 11 ◽  
Author(s):  
Vincenzo Quagliariello ◽  
Massimiliano Berretta ◽  
Simona Buccolo ◽  
Martina Iovine ◽  
Andrea Paccone ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Renal Cell ◽  
Renal Tumors ◽  
H9c2 Cell ◽  
Cytokines And Chemokines ◽  
Pro Inflammatory Cytokines

Renal cell carcinoma (RCC) represents the main renal tumors and are highly metastatic. Sunitinib, a recently-approved, multi-targeted Tyrosine Kinases Inhibitor (TKi), prolongs survival in patients with metastatic renal cell carcinoma and gastrointestinal stromal tumors, however a dose related cardiotoxicity was well described. Polydatin (3,4’,5-trihydroxystilbene-3-β-d-glucoside) is a monocrystalline compound isolated from Polygonum cuspidatum with consolidated anti-oxidant and anti-inflammatory properties, however no studies investigated on its putative cardioprotective and chemosensitizing properties during incubation with sunitinib. We investigated on the effects of polydatin on the oxidative stress, NLRP3 inflammasome and Myd88 expression, highlighting on the production of cytokines and chemokines (IL-1β, IL-6, IL-8, CXCL-12 and TGF-β) during treatment with sunitinib. Exposure of cardiomyocytes and cardiomyoblasts (AC-16 and H9C2 cell lines) and human renal adenocarcinoma cells (769‐P and A498) to polydatin combined to plasma-relevant concentrations of sunitinib reduces significantly iROS, MDA and LTB4 compared to only sunitinib-treated cells (P&lt;0.001). In renal cancer cells and cardiomyocytes polydatin reduces expression of pro-inflammatory cytokines and chemokines involved in myocardial damages and chemoresistance and down-regulates the signaling pathway of NLRP3 inflammasome, MyD88 and NF-κB. Data of the present study, although in vitro, indicate that polydatin, besides reducing oxidative stress, reduces key chemokines involved in cancer cell survival, chemoresistance and cardiac damages of sunitinib through downregulation of NLRP3-MyD88 pathway, applying as a potential nutraceutical agent in preclinical studies of preventive cardio-oncology.

Effects of M1 and CCK antagonists on latency of pancreatic amylase response to intestinal stimulants

2000 ◽  
Vol 279 (2) ◽  
pp. G411-G416
Author(s):  
Elke Niebergall-Roth ◽  
Stephan Teyssen ◽  
Manfred V. Singer
Keyword(s):  
Receptor Antagonist ◽  
Blood Circulation ◽  
Amylase Activity ◽  
Cck Receptors ◽  
M1 Receptor ◽  
Before And After ◽  
M1 Receptors ◽  
Cck Antagonists ◽  
Cck Receptor Antagonist ◽  
Sustained Increase

In six conscious dogs with gastric and duodenal cannulas, secretin (164 pmol · kg−1 · h−1 iv) was given to provide a flow of pancreatic juice of ∼1 drop/s. Amylase activity was measured in each drop before and after rapid intravenous injection of caerulein (7.4 pmol/kg) or intraduodenal injection of l-tryptophan (1 mmol), sodium oleate (3 mmol), and HCl (3 mmol). All experiments were repeated in the presence of the M1 receptor antagonist telenzepine (81 nmol · kg−1 · h− iv) and the cholecystokinin (CCK) receptor antagonist L-364718 (0.1 mg/kg iv). Latency of amylase response (time between injection of stimulant and sustained increase in amylase activity greater than mean + 3 SD of prestimulatory activity) to tryptophan (17 ± 7 s; n = 6) and oleate (16 ± 5 s) was significantly ( P < 0.05) shorter than to caerulein (28 ± 4 s) and HCl (120 ± 47 s). Telenzepine significantly increased the latency of amylase response to tryptophan and oleate by >10-fold but not the latency to caerulein or HCl. L-364718 abolished the amylase response to all stimulants. These findings indicate that the early amylase response to intraduodenal tryptophan and oleate is mediated by a neural enteropancreatic reflex ending on M1 receptors rather than by hormone release. However, the activation of (possibly vagal) CCK receptors is essential to run the reflex. The early amylase response to intraduodenal HCl is probably mediated by the release of CCK into the blood circulation.

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