Ulinastatin activates the renin–angiotensin system to ameliorate the pathophysiology of severe acute pancreatitis

Liu, Ruixia; Qi, Haifeng; Wang, Jing; Yan, Wei; Cui, Lijian; Wen, Yiping; Yin, Chenghong

doi:10.1111/jgh.12584

Cited by 22 publications

(16 citation statements)

References 39 publications

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“…These data, together with a previous study (27), demonstrated that exogenous Ang-(1-7) may affect the balance of Ang-(1-7)/Ang II in addition to ACE2/ACE in AP. This is also consistent with previous animal experiments; that identified that ulinastatin significantly ameliorated pancreatic pathology through upregulating ACE2 and Ang (1-7) in addition to the serum biochemistry indicators of CAE-induced SAP mice (28). The re-establishment of the balance of RAS through upregulating Ang-(1-7) and ACE2 expression, which can ameliorate apoptosis, may possess clinical therapeutic potential.…”

Section: Discussionsupporting

confidence: 92%

Angiotensin-(1–7) attenuates caerulein-induced pancreatic acinar cell apoptosis

Cui

Liu

et al. 2017

Molecular Medicine Reports

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Extensive apoptosis of pancreatic acinar cells frequently occurs in acute pancreatitis (AP), and has been identified to be closely associated with the decrease of pancreatic parenchymal cells and pancreatic damage. The present study aimed to investigate the possible effect of angiotensin (Ang)-(1-7) on caerulein (CAE)-induced pancreatic acinar cell apoptosis. Mouse pancreatic acinar cancer cells (MPC-83) were divided into 4 groups: Control group; CAE group; CAE + Ang-(1-7) group; and CAE + Ang-(1-7) antagonist (A779) group. The control group consisted of normal MPC-83 cells without special treatment. The CAE group was stimulated with 10 nmol/l CAE and harvested at 2, 6, 12, 24 and 48 h. For the CAE + Ang-(1-7) group and CAE + A779 group, the CAE-induced pancreatic acinar cells were mock pretreated or pretreated with different concentrations of Ang-(1-7) or A779 (10-7 , 10-6 or 10-5 mol/l) for 30 min. Caspase-3 is a critical executioner of apoptosis, as it is either partly or completely responsible for the proteolytic cleavage of numerous key proteins including the nuclear enzyme poly (ADP-ribose) polymerase. Activation of caspase-3 requires proteolytic processing of its inactive zymogen into activated p17 and p12 fragments. Thus, the present study investigated the apoptotic markers, including cleaved caspase-3, B-cell lymphoma 2 (Bcl-2), Bcl-2-like protein 4 (Bax) and renin-angiotensin system (RAS) pathway related proteins (ACE2 and Mas receptor). The results demonstrated that the cleaved caspase-3 levels were increased in the CAE group (P<0.05), peaking at 24 h, and declined when incubated with Ang-(1-7). Following treatment with Ang-(1-7), levels of the anti-apoptotic protein Bcl-2 rose dramatically in a dose-dependent manner. The ratio of the pro-apoptotic protein Bax to the anti-apoptotic protein Bcl-2 dropped notably, which demonstrated a tendency towards curbing apoptosis. In addition, the cleaved caspase-3 levels, and the ratio of Bax to Bcl-2 in the CAE + A779 group presented a significant rise compared with the CAE group. It was concluded that Ang-(1-7) may possess an inhibitory effect on CAE-induced pancreatic acinar cell apoptosis and that appropriate interventions in RAS may attenuate pancreatic injury during AP.

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Section: Discussionsupporting

confidence: 92%

Angiotensin-(1–7) attenuates caerulein-induced pancreatic acinar cell apoptosis

Cui

Liu

et al. 2017

Molecular Medicine Reports

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“…In this study, serum IL-10 was reduced 24h and on 4 th day after AP induction in the AP group as compared with control group. This was in accordance with Liu et al, 2014 [38] who found decrease in serum IL-10 in ceruleininduced SAP mice. IL-10 is anti-inflammatory cytokine that correlates with the severity of pancreatitis.…”

Section: Discussionsupporting

confidence: 93%

Comparative Histological Study on The Effect of Bone Marrow-Derived Mesenchymal Stem Cells Versus Wheat Germ Oil on Acute Pancreatitis in A Rat Model

Aboulkhair

Nasr

Radwan

et al. 2019

Egyptian Journal of Histology

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Background: Acute pancreatitis (AP) is a common inflammatory disorder of digestive system. Mesenchymal stem cells (MSCs) and Wheat germ oil (WGO) could improve AP through their anti-inflammatory and antioxidant effects. Objective: Evaluate and compare the possible therapeutic effects of Bone marrow derived Mesenchymal Stem Cells (BMSCs) versus WGO on AP. Materials and Methods: 47 adult male albino rats were divided into 4 groups. Control group I (no.=12). AP was induced in the remaining 35 rats by a single intra peritoneal (I.P) injection of L-arginine (250 mg/100g). 5 rats died within the 1st hour after AP induction, the rest were divided randomly into group II (AP group; no.=10) that received no treatment, group III (BMSCs group; no.=10) and group IV (WGO group; no.=10). One hour after AP induction, group III was injected I.P. by 1ml of PKH26 labeled BMSCs (1x106 cells/ml) and group IV received WGO in a dose of 3 ml/kg body weight by oral gavage every 24 h for 3 successive days. Blood samples were collected 24 hours and on the 4 th day after AP induction for biochemical assessment of serum amylase, lipase, interleukin-1β and interleukin-10. Then, animals were sacrificed and specimens from the pancreas were prepared for Hematoxylin and eosin (HandE) stain and immune-histochemical staining using inducible Nitric Oxide Synthase (iNOS) and insulin antibodies. Morphometric measurements using image analyzer were done. Results: Group II showed extensive pancreatic damage associated with increase in serum amylase, lipase and interleukin-1B levels and reduction in interleukin-10 level. A significant increase in the area % of iNOS immunostaining and non-significant change in insulin immunostaining were detected. On the other hand, BMSCs group and WGO group showed improvement in the biochemical, histological and immunohistochemical results with better results in BMSCs group. Conclusion: BMSCs possess better therapeutic efficacy in treating AP compared with WGO.

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“…Oruc et al (25) demonstrated that the activation of the RAS is closely associated with AP. In addition, previous studies conducted by the present research group have shown that SAP is associated with upregulation of the ACE2-Ang-(1-7)-Mas axis and promotes increased circulating levels of Ang-(1-7) (26)(27)(28). however, whether the ACE2-Ang-(1-7)-Mas axis serves a protective role in the pathogenesis of pancreatitis, and the signaling pathway through which the ACE2-Ang-(1-7)-Mas axis protects pancreatic cells from inflammation remain unknown.…”

Section: Introductionsupporting

confidence: 56%

Angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axis prevents pancreatic acinar cell inflammatory response via inhibition of the p38 mitogen-activated protein kinase/nuclear factor-κB pathway

Cui

Hou

et al. 2017

Int J Mol Med

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The aim of the present study was to investigate the role of the angiotensin-converting enzyme (ACE)2-angiotensin‑(Ang)-(1-7)-Mas axis in the pathogenesis of pancreatitis and the association between this axis and the p38 mitogen-activated protein kinase (p38 MAPK)/nuclear factor (NF-κB) signaling pathway in pancreatic acinar cells. Mouse pancreatic acinar cancer (MPC-83) cells were stimulated with 10 nM caerulein (CAE) to create an in vitro model of acute pancreatitis, and collected for analysis at 2, 6, 12, 24 and 48 h post stimulation. In addition, cells were pretreated with different concentrations of Ang‑(1‑7), Ang‑(1‑7) antagonist A779, p38 MAPK inhibitor SB203580 or ACE2 inhibitor DX600 for 30 min, and then stimulated with CAE for 24 h. The ACE2, Mas receptor, p38 MAPK, phosphorylated (p)-p38 MAPK and NF-κB expression levels were evaluated using western blotting and immunofluorescence. p38 MAPK, NF-κB, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8 and IL-10 mRNA expression levels were assessed using reverse transcription-quantitative polymerase chain reaction. The results of the immunofluorescence assay demonstrated that ACE2 and p38 MAPK were present mainly in the cytoplasm, while the Mas receptor was located mainly in the cell membrane. ACE2, p38 MAPK and p-p38 MAPK protein levels were significantly increased (P<0.05) following stimulation with CAE compared with those in the control group and peaked at 24 h. Mas receptor protein levels were significantly upregulated (P<0.05) between 6 and 24 h, peaking at 12 h. Ang‑(1‑7) and SB203580 downregulated p-p38 MAPK and NF-κB expression and the mRNA levels of inflammatory factors IL-6, TNF-α and IL-8, but upregulated the mRNA level of inflammatory factor IL-10 compared with those treated with CAE alone. These results were supported by the opposite outcomes observed for cells treated with A779 or DX600. Therefore, it was concluded that the ACE2-Ang‑(1‑7)-Mas axis significantly inhibits pancreatitis by inhibition of the p38 MAPK/NF-κB signaling pathway.

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Ulinastatin activates the renin–angiotensin system to ameliorate the pathophysiology of severe acute pancreatitis

Cited by 22 publications

References 39 publications

Angiotensin-(1–7) attenuates caerulein-induced pancreatic acinar cell apoptosis

Angiotensin-(1–7) attenuates caerulein-induced pancreatic acinar cell apoptosis

Comparative Histological Study on The Effect of Bone Marrow-Derived Mesenchymal Stem Cells Versus Wheat Germ Oil on Acute Pancreatitis in A Rat Model

Angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axis prevents pancreatic acinar cell inflammatory response via inhibition of the p38 mitogen-activated protein kinase/nuclear factor-κB pathway

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