Effect Of Cerulein Research Articles

Da Cheng Qi Decoction Alleviates Cerulein-Stimulated AR42J Pancreatic Acinar Cell Injury via the JAK2/STAT3 Signaling Pathway.

Background Acute pancreatitis (AP) is a common acute abdomen inflammation, characterized by the dysregulation of digestive enzyme production and secretion. Many studies have shown that Da Cheng Qi Decoction (DCQD) is a secure, effective prescription on AP. In this study, cerulein-stimulated AR42J cells damage model was established to further explore the feasibility and underlying mechanism of DCQD as a potential inhibitor of JAK2/STAT3 pathway for the treatment of AP. Methods Cell viability of DCQD was measured using a cell counting Kit-8 assay. Pancreatic biochemical markers such as amylase, lipase, and C-reactive protein production were measured by assay kits, respectively. Cytokines (TNF-α, IL-6, IL-10, and IL-1β) were assayed by ELISA. Protein location and protein expression were detected by immunofluorescence staining and Western blotting, respectively. Gene expression was assessed by real-time PCR. For mechanistic analysis of the effect of DCQD on JAK2/STAT3 signaling pathway, selective JAK2 inhibitor (Fedratinib) and STAT3 inhibitor (Stattic) as well as STAT3 activator (Garcinone D) were used. Results DCQD protected cells by regulating cerulein-induced inflammation and reducing the secretion of pancreatic biochemical markers. Moreover, DCQD could not only inhibit the nuclear translocation of p-STAT3, but also decrease the mRNA expression of JAK2 and STAT3 as well as the ratio of p-JAK2/JAK2 and p-STAT3/STAT3 in protein level. Additionally, DCQD could regulate the mRNA and protein expression of JAK2/STAT3 downstream effectors, Bax and Bcl-XL. The activated effect of cerulein on JAK2/STAT3 pathway was also reversed by JAK2 inhibitor Fedratinib or STAT3 inhibitor Stattic. And the overexpression of JAK2/STAT3 pathway, via STAT3 activator Garcinone D, did exert damage on cells, which bore a resemblance to cerulein. Conclusion The activation of JAK2/STAT3 pathway may play a key role in the pathogenesis of cerulein-stimulated AR42J pancreatic acinar cell injury. DCQD could improve inflammatory cytokines and cell injury, which might be mediated by suppressing the activation of JAK2/STAT3 signaling pathway.

Bmi1 is required for murine pancreatic cancer initiation

RESULTS: Snail over-expression in KrasG12D mice significantly increased mast cell and granulocyte infiltration to the pancreatic tumor microenvironment. Snail over-expression in KrasG12D mice did not increase T-regulatory cell or macrophage infiltration to the pancreatic tumor microenvironment. Cerulein-induced pancreatitis in KrasG12D mice increased mast cell infiltration, and Snail over-expression appears to potentiate the effect of cerulein in these mice.

Regional differences in the effects of various doses of cerulein upon the small‐intestinal migrating motor complex in fasted and non‐fasted sheep

There are no precise data concerning the effect of cerulein on the small-intestinal migrating motor complex (MMC) in sheep. Thus, the effort was directed towards the elucidation of the role of cerulein, a cholecystokinin (CCK) amphibian analogue, in the regulation of MMC cycle in conscious fasted and non-fasted sheep in various regions of the small intestine. In six sheep, equipped with bipolar electrodes in the entire small intestine and with one duodenal strain gauge force transducer in four of these animals, the continuous myoelectric and motor activity recordings were performed. During control period, two normal consecutive MMC cycles were recorded in fasted and non-fasted animals and then cerulein was slowly injected at the dose 1 (during 30 s), 10 (during 30 s or 60 s) or 100 ng/kg (during 30 s, 60 s or 120 s) or infused at the dose 0.5 or 1.5 ng/kg/min during 60 min. After cerulein administration at least two consecutive MMC cycles were also recorded. It was found that cerulein in moderate and higher doses injected in both fasted and non-fasted animals, especially during phase 2a or 2b MMC, inhibited phase 3 in the duodenum in at least one-third of the experiments and significantly increased the MMC cycle duration. The application of 100 ng/kg of cerulein during 120 s in the course of phase 2b MMC prolonged cycle duration from 70 +/- 21 to 113 +/- 19 min (p < 0.05) or from 51 +/- 18 to 113 +/- 19 min (p < 0.01) in fasted and non-fasted sheep respectively. The first phase 3 MMC arriving after cerulein administration at the highest dose was usually abnormal in approximately 60% of the experiments. The second phase 3 observed following the hormone injection was abnormal much less frequently and to the lesser extent. Furthermore, both cerulein doses significantly shortened the duration of phase 3 MMC either in fasted (from approximately 5.5-6.5 cpm to 4-5 cpm) or in non-fasted sheep (from approximately 4.5-5.5 to 3-4.5 cpm). The effects of cerulein exhibited the dose-response character. They were more pronounced when cerulein was injected during phase 2b or 2a MMC when compared with phase 1 MMC. The effects of cerulein on the ileal MMC were less evident, although the inhibition of the ileal phase 3 in response to both higher injected doses was observed occasionally. Infusions of cerulein in non-fasted sheep exerted similar effects as cerulein injections. It was stated that cerulein exerts marked regulatory effect upon the small-intestinal MMC in sheep. Although it remains uncertain whether the efficient doses of cerulein used in the present study correspond to physiological or pharmacological doses of CCK it seems likely that most of these doses were physiological. Thus, it is concluded that cerulein participates in the control of MMC cycles in the digestive and interdigestive states in sheep. It is possible that CCK is a physiological regulator of the ovine small-intestinal MMC.

Supraphysiologic concentrations of cerulein induce apoptosis in the rat pancreatic acinar cell line AR4-2J.

Little is known as yet about the role of apoptosis in pancreatic damage. This study evaluated the effects of supraphysiologic concentrations of the cholecystokinin (CCK) analog, cerulein, which causes cell damage in vitro and acute pancreatitis in vivo, on cell proliferation and DNA fragmentation in the rat pancreatic acinar cell line AR4-2J. Cerulein inhibited the cell proliferation of AR4-2J time- and dose-dependently to approximately 60% of the control level at 10(-6) M after 72 h. DNA fragmentation, as assessed by both electrophoresis and enzyme-linked immunosorbent assay (ELISA), occurred at cerulein concentrations > or = 10(-8) M. The maximal DNA fragmentation as measured by ELISA was reached after 24 h. Cerulein at concentrations > or = 10(-9) M induced wild-type p53. Glutathione (1 mM) diminished the effects of cerulein on both cell proliferation and DNA fragmentation, whereas spermine (100 microM), which partially attenuated DNA fragmentation, did not have an effect on cell proliferation. The CCK-A-receptor antagonist loxiglumide completely abolished the effect of cerulein on DNA fragmentation. The serine-protease inhibitor FUT-175 (10 microM), the cysteine-protease inhibitor NCO-700 (5 mM), and ethylene glycol tetraacetic acid (EGTA; 500 microM) all had no effects on the changes in cell proliferation and DNA fragmentation induced by cerulein. The data suggest that supraphysiologic concentrations of cerulein rapidly induce apoptosis in AR4-2J cells and only later inhibit cell proliferation. These effects are mediated by CCK-A receptors. Cerulein-induced apoptosis may involve the induction of wild-type p53 or glutathione depletion or both.

Lack of Effect of Cerulein on Pancreatic Growth of Rats Fed a Low-Protein Diet

The effect of dietary protein deficiency and protein concentration of the diet on the pancreatic trophic response to a CCK analogue (cerulein) were studied. Rats were fed for 14 days with semipurified diets containing 5, 30, or 60% casein. During the final 4 days, they received 2 micrograms/kg cerulein or gelatin vehicle subcutaneously three times/day, and the effects on pancreatic weight and pancreatic content of protein, RNA, DNA, amylase, and chymotrypsin were determined. Cerulein failed to increase significantly any pancreatic parameter in rats fed 5% casein, while stimulating significant increases in almost all parameters in rats fed 30 and 60% casein diets. In the absence of cerulein treatment, increases in dietary protein levels caused progressive increases in all pancreatic growth parameters with the exception of amylase. In the presence of cerulein, increases in dietary protein concentrations caused progressive increases in pancreatic growth parameters (except amylase), which were maximal at 30% casein concentration of the diet for most parameters. The results confirm that pancreatic growth is stimulated by increasing protein concentration of the diet and indicate that a low protein diet, acting through a deficiency of dietary nitrogen and essential amino acids, limits the pancreatic trophic response to CCK or analogues. These results explain the failure of trypsin inhibitors to stimulate pancreatic growth in rats fed low levels of dietary protein.

Effect of cerulein on in vivo release of acetylcholine from the rat striatum

An effect of cerulein on in vivo release of acetylcholine (ACh) from the rat striatum was examined by means of intracerebral dialysis. Intraperitoneal administration of cerulein (25–200 μg/kg) enhanced a spontaneous release of ACh in a dose-dependent manner. Intraperitoneal administration of cerulein (100 μg/kg) also enhanced the K +-evoked (30 mM) release of ACh. Bilateral subdiaphragmatic vagotomy reduced the increase of both K +-evoked and that of spontaneous release of ACh induced by cerulein administration. Pretreatment with haloperidol (0.5 mg/kg, i.p.) had no effect on increase in spontaneous release of ACh brought about by cerulein administration (100 μg/kg, i.p.). These results suggested that peripherally administered cerulein stimulated striatal cholinergic neurons, that its stimulatory effect on striatal ACh release was not mediated by striatal dopamine D 2 receptors and that the action of cerulein was, in part, mediated via vagal afferent impulses.

O-298 - Effect of cerulein on the in vivo release of acetylcholine from rat striatum

O-298 - Effect of cerulein on the in vivo release of acetylcholine from rat striatum

Effect of cerulein on [formula omitted] release of acetylcholine from rat brain : Masanori Shimoyama and Shozo Kito, Third Department of Internal Medicine, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734, Japan

Effect of cerulein on [formula omitted] release of acetylcholine from rat brain : Masanori Shimoyama and Shozo Kito, Third Department of Internal Medicine, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734, Japan

Excessive Doses of Cerulein Stimulate Pancreatic Growth in Suckling Rats but Damage the Pancreas of Weaned Rats

The cerulein-stimulated pancreatic growth response was evaluated in 4- and 11-day-old female suckling CFY rats and compared with the pancreatic response of cerulein-treated 24-day-old weaned rats. Cerulein was given subcutaneously in saline in 1-, 10- and 100-micrograms/kg doses t.i.d. The increase in pancreatic DNA content was regarded as an index for hyperplasia, and the increase in pancreatic weight, protein content and enzyme activity related to milligrams of DNA as an index for hypertrophy. Three-day administration of 1- and 10-micrograms/kg doses of cerulein increased the pancreatic trypsin/DNA ratio, and doses of 100 micrograms/kg cerulein evoked pancreatic hypertrophy and hyperplasia in 4-day-old rats. Ten-day administration of 1- and 10-micrograms/kg doses induced pancreatic hypertrophy and hyperplasia, while the 100-micrograms/kg doses induced pancreatic hypertrophy in 11-day-old rats. In 24-day-old weaned rats, the 3-day administration of 1-microgram/kg doses resulted in hypertrophy of the gland, while the 100-micrograms/kg doses of cerulein evoked pancreatic aplasia and atrophy. It is concluded that the growth-promoting effect of cerulein on the newborn rat pancreas is age- and dose-dependent.

Modulating effect of cerulein on benzodiazepine receptors

Subcutaneous administration of caerulein (100-500 micrograms/kg) significantly reduced the development of picrotoxin (8 mg/kg) seizures in male mice. The same doses of caerulein inhibited 3H-flunitrazepam binding in in vivo experiments. Proglumide, an antagonist of cholecystokinin receptors, in low dose (5 mg/kg) potentiated the effects of caerulein (100 micrograms/kg), whereas the administration of proglumide in high dose (25 mg/kg) reduced the action of caerulein on 3H-flunitrazepam binding and picrotoxin seizures. Caerulein (5-1000 nM) decreased 3H-flunitrazepam binding in in vitro experiments only after supplementation of the binding medium with 120 mM NaCl and 5mM KCl. The results suggest the possible interaction of caerulein with chloride ionophor. It seems probable that the direct interaction of caerulein with chloride ionophor in involved in the inhibitory effect of caerulein on picrotoxin seizures and 3H-flunitrazepam binding.

Stimulation of [3H]spiroperidol binding after prolonged neuroleptic therapy by the cholecystokinin octapeptide analog cerulein

Evidence has recently been obtained that cholecystokinin and its analog cerulein have marked antipsychotic action on patients with schizophrenia who are resistant to neuroleptics; this is the basis for interest in this study of the effect of cerulein, a high-affinity analog of the octapeptide cholecystokinin, on binding of tritium-spiroperidol in vivo. Considering the apormorphine-like action of cerulein, this biochemical analysis was undertaken in the form of a comparative study with N-propyl-norapomorphine, a high-affinity analogy of apomorphine.