scholarly journals Resveratrol Suppresses Severe Acute Pancreatitis-Induced Microcirculation Disturbance through Targeting SIRT1-FOXO1 Axis

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Yuping Rong ◽  
Jun Ren ◽  
Wei Song ◽  
Renshen Xiang ◽  
Yuhang Ge ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Severe Acute Pancreatitis ◽  
Mrna Level ◽  
Dry Weight ◽  
Underlying Mechanism ◽  
Vital Role ◽  
Protective Mechanism ◽  
Ang Ii ◽  
Microcirculation Disturbance ◽  
Microcirculatory Function

Background. Resveratrol (RSV), one of the SIRT1 agonists, has the ability of alleviating severe acute pancreatitis (SAP); however, the concrete protective mechanism remains unknown. It is noteworthy that microcirculation disturbance plays a vital role in SAP, and the SIRT1/FOX1 axis can regulate microcirculation. Therefore, this study is aimed at ascertaining what is the underlying mechanism of the protective effect of RSV on SAP, and whether it is associated with alleviating microcirculation disturbance by regulating the SIRT1/FOX1 axis. Method. The model of SAP was induced by retrograde injection of sodium taurodeoxycholate into the bile duct of the rats. The pancreatic wet/dry weight, ET/NO, and TXB2/6-keto-PGF1α ratios; microcirculatory function; and SIRT1 activity were examined. ELISA was used to examine the serum level of lipase, amylase, hemorheology, ET, NO, TXB2, and 6-keto-PGF1α and the content of SIRT1, VEGF, Ang I, and Ang II in the pancreas. RT-PCR was used to examine the mRNA level of VEGF, Ang I, and Ang II. Western blotting was used to detect SIRT1, FOXO1, and acetyl-FOXO1. Immunoprecipitation was used to examine the interaction of SIRT1 and FOXO1. Results. Resveratrol can significantly decrease the expression of lipase, amylase, acetyl-FOXO1, VEGF, Ang II, ET, NO, TXB2, and 6-keto-PGF1α and the ratio of wet/dry weight, ET/NO, and TXB2/6-keto-PGF1α by improving microcirculatory dysfunction and blood viscosity in SAP. Moreover, resveratrol can also promote the interaction of SIRT1 and FOXO1 and increase SIRT1 activity and the expression of SIRT1 and Ang I. The SIRT1 inhibitor, Sirtinol (EX527), obliviously reversed the effects of RSV on SAP. Conclusion. Resveratrol can protect rats against SAP, and its protective mechanism is associated with suppressing microcirculation disturbance through activating SIRT1-FOXO1 axis.

Placental Chorionic Plate-derived Mesenchymal Stem Cells Ameliorate Severe Acute Pancreatitis by Regulating Macrophages Polarization via Secreting TSG-6

2021 ◽  
Author(s):  
Qilin Huang ◽  
Xiumei Cheng ◽  
Chen Luo ◽  
Shuxu Yang ◽  
Shuai Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Pancreatitis ◽  
Severe Acute Pancreatitis ◽  
Systemic Inflammation ◽  
Therapeutic Efficacy ◽  
Pancreatic Injury ◽  
Protective Mechanism ◽  
M2 Polarization ◽  
Injured Tissue ◽  
Chorionic Plate

Abstract BackgroundMesenchymal stem cells (MSCs) hold promising potential to treat systemic inflammatory diseases including severe acute pancreatitis (SAP). In our previous study, placental chorionic plate-derived MSCs (CP-MSCs) were found to possess superior immunoregulatory capability. However, the therapeutic efficacy of CP-MSCs on SAP and their underlying mechanism remain unclear.MethodsThe survival and colonization of exogenous CP-MSCs were observed by bioluminescence imaging and CM-Dil labeling in rodent animal models of SAP. The therapeutic efficacy of CP-MSCs on SAP rats was evaluated by pathology scores, the levels of pancreatitis biomarkers as well as the levels of inflammatory factors in pancreas and serum. The potential protective mechanism of CP-MSCs in SAP rats was explored by selectively depleting M1 or M2 phenotype macrophages and knocking down the expression of TSG-6.ResultsExogenous CP-MSCs could survive and colonize in the injured tissue of SAP such as lung, pancreas, intestine and liver. Meanwhile, we found that CP-MSCs alleviated pancreatic injury and systemic inflammation by inducing macrophages to polarize from M1 to M2 in SAP rats. Furthermore, our data suggested that CP-MSCs induced M2 polarization of macrophages by secreting TSG-6, and TSG-6 played a vital role in alleviating pancreatic injury and systemic inflammation in SAP rats. Notably, we found that a high inflammation environment could stimulate CP-MSCs to secrete TSG-6.ConclusionExogenous CP-MSCs tended to colonize in the injured tissue, and reduced pancreatic injury and systemic inflammation in SAP rats through inducing M2 polarization of macrophages by secreting TSG-6. Our study provides a new treatment strategy for SAP, and initially explains the potential protective mechanism of CP-MSCs on SAP rats.

scholarly journals Dab1 Contributes to Angiotensin II-Induced Apoptosis via p38 Signaling Pathway in Podocytes

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Zhao Gao ◽  
Xinghua Chen ◽  
Kai Zhu ◽  
Ping Zeng ◽  
Guohua Ding
Keyword(s):  
Angiotensin Ii ◽  
Signaling Pathway ◽  
Underlying Mechanism ◽  
Vital Role ◽  
Protective Effects ◽  
Ang Ii ◽  
Induced Apoptosis ◽  
End Stage ◽  
Interfering Rna

Numerous studies have found that angiotensin II (Ang II) participates in podocyte apoptosis and exacerbates progression of end-stage kidney disease (ESKD). However, its underlying mechanism remains largely unexplored. As a homolog of Drosophila disabled (Dab) protein, Dab1 plays a vital role in cytoskeleton, neuronal migration, and proliferation. In the present study, our data revealed that Ang II-infused rats developed hypertension, proteinuria, and podocyte injury accompanied by Dab1 phosphorylation and increased reelin expression in kidney. Moreover, Ang II induced podocyte apoptosis in vitro. Dab1 phosphorylation and reelin expression in podocytes were increased after exposure to Ang II. Conversely, Dab1 small interfering RNA (siRNA) exerted protective effects on Ang II-induced podocyte apoptosis, resulting in decreased p38 phosphorylation and reelin expression. These results indicated that Dab1 mediated Ang II-induced podocyte apoptosis via p38 signaling pathway.

scholarly journals Protective Effect of Dachengqi Decoction on Pancreatic Microcirculatory in Severe Acute Pancreatitis via Down-regulating HMGB-TLR-4-IL-23-IL-17A Mediated Neutrophil Activation Though Targeting SIRT1

2021 ◽  
Author(s):  
Jia Wang ◽  
Lei Peng ◽  
Dan Chang ◽  
Da-qing Hong ◽  
Jiong Zhang
Keyword(s):  
Acute Pancreatitis ◽  
Cell Viability ◽  
Severe Acute Pancreatitis ◽  
Weight Ratio ◽  
Related Factors ◽  
Serum Lipase ◽  
Tnf Α ◽  
Wet Weight ◽  
Microcirculatory Function

Abstract BackgroundDachengqi decoction (DCQD), one of classic prescription of Chinese herbal medicine has been widely used in clinic to treat severe acute pancreatitis (SAP). The damage of pancreatic microcirculation plays key pathogenesis of SAP. However, little is known about the molecular pharmacological activity of DCQD on pancreatic microcirculation in SAP. Therefore, the purpose of the study attempted to confirm the improvement of DCQD on pancreatic microcirculation is associated with suppressing neutrophil mediated immune-inflammatory response through promoting the inactivation of HMGB1-TLR-4-IL-23-IL-17A axis via targeting the SIRT1 signal pathway in SAP.Material and MethodsSodium taurodeoxycholate and cerulein were used to establish model of SAP in vitro and vivo, respectively. The pancreatic pathological morphology, wet weight ratio, myeloperoxidase (MPO) activity, cell viability and microcirculatory function of the pancreas, as well as serum lipase and amylase expressions were evaluated. The expression levels of SIRT1, acety-HMGB1, TLR-4, HMGB1, IL-23, IL-17A, neutrophil chemokines (KC, LIX, and MIP-2), and inflammation-related factors (IL-6, IL-1β, and TNF-α), the translocation of HMGB1 and the interaction of SIRT-HMGB1 in the pancreas and serum were determined by ELISA real-time PCR, western blotting and immunoprecipitation.ResultsIn-vivo studies showed DCQD or neutralizing antibody (anti-23p19 or anti-IL-17A) could significantly decrease the activity of lipase, amylase, down-regulate the expression of CD68, MPO, wet/weight, IL-1β, IL-6, TNF-α,neutrophil chemokines (KC, LIX, MIP-2 ), alleviate pathological injury, and improve the microcirculatory function of the pancreas in rats with SAP. Moreover, DCQD remarkably augmented SIRT1 expression, promoted SIRT1 and HMGB1 combination, reduced HMGB1 translocation from nuclear to cytoplasm, and alleviated the expression of acetyl-HMGB1, HMGB1, IL-17A, TLR-4 and IL-23 in vitro and vivo with SAP. However, the intervention with EX527 (SIRT1 inhibitor) or r-HMGB1 (recombinant HMGB1) could obliviously reverse the above-mentioned influence of DCQD in SAP. In vitro, we confirmed that DCQD could decrease the acetylation, migration and release of HMGB1, and improve the decline of cell viability, SIRT1, SIRI-HMGB1 combination induced by cerulein with promoting macrophage to release IL-23 through HMGB1/TLR-4. ConclusionDCQD treatment improves SAP-induced pancreatic microcirculatory dysfunction by inhibiting neutrophil-mediated inflammation through the inactivation of HMGB1-TLR-4-IL-23-IL-17A signaling via Targeting SIRT1.Trial registration: No. 365, 2020.

scholarly journals Angiotensin‐(1‐7) Alleviates Autophagy Response Through the PI3K/Akt/mTOR Signaling Pathway in Severe Acute Pancreatitis

2021 ◽  
Author(s):  
Chunyun Li ◽  
Xiaozheng Yu ◽  
Yinan Guo ◽  
Xueyan Wang ◽  
Ruixia Liu ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Signaling Pathway ◽  
Severe Acute Pancreatitis ◽  
Underlying Mechanism ◽  
Mtor Signaling ◽  
Medical Emergency ◽  
Protein Markers ◽  
Mtor Signaling Pathway ◽  
Ar42j Cells ◽  
The Impact

Abstract Background: Severe acute pancreatitis (SAP) is a fatal medical emergency. The autophagy response is essential for cellular homeostasis, and plays an important role in SAP. We aimed to determine if angiotensin‐(1‐7), abbreviated as Ang1‐7, regulates the autophagy response in SAP and to elucidate the underlying mechanism.Methods: We used a rat model to investigate the effects of Ang1-7 on pancreatic pathomorphological damage and the autophagy response, which were evaluated using histological scoring and the quantification of the autophagy markers microtubule-associated protein 1 light chain 3 (LC3) and p62/SQSTM (p62) by western blotting and immunohistochemistry. We treated rat pancreatic acinar AR42J cells with caerulein (CAE) to build an in vitro model. To prevent degradation of the autophagy markers, so that we could determine the increase in autophagic vacuolization, we used chloroquine to inhibit autophagosome and lysosome fusion. The PI3K inhibitor BEZ235 was used to suppress PI3K/Akt/mTOR signaling. We observed the impact of Ang1-7 on the autophagy response and evaluated the underlying mechanism by detecting protein expressions of LC3 and p62.Results: In the rat SAP model, Ang1-7 significantly relieved pancreatic pathological damage. Ang1-7 also reduced autophagy protein markers, including the LC3-Ⅱ to LC3-Ⅰ ratio and the p62 level. In AR42J cells, the autophagy markers significantly increased after treatment with CAE and chloroquine. The autophagy response was significantly alleviated after treatment of the cells with Ang1-7, while blocking the PI3K/Akt/mTOR pathway remarkably counteracted this effect.Conclusions: Our results indicated that Ang1-7 alleviated the autophagy response in SAP via the PI3K/Akt/mTOR signaling pathway.

Effect of Baicalin on Inflammatory Mediator Levels and Microcirculation Disturbance in Rats With Severe Acute Pancreatitis

Pancreas ◽  
2009 ◽  
Vol 38 (7) ◽  
pp. 732-738 ◽  
Author(s):  
Xiping Zhang ◽  
Hua Tian ◽  
Chenjun Wu ◽  
Qian Ye ◽  
Xinge Jiang ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Severe Acute Pancreatitis ◽  
Inflammatory Mediator ◽  
Microcirculation Disturbance

Abstract 52: PPAR-γ Targeted by MicroRNA-130a Regulates Angiotensin II-Induced Cardiac Fibrosis

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Sudhiranjan Gupta ◽  
Li Li
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Myocardial Dysfunction ◽  
Critical Role ◽  
Pressure Overload ◽  
Underlying Mechanism ◽  
Dominant Negative ◽  
Protective Mechanism ◽  
Ang Ii

Aims: Cardiac fibrosis which occurs due to disruption of extracellular matrix network resulted in the accumulation of excess collagens and other matrix components leading to myocardial dysfunction. Angiotensin II (Ang II), a critical effector of this system has been implicated in the development of hypertension-induced cardiac fibrosis. In recent years, miRNAs have identified as an attractive targets for therapeutic intervention in various disease pathologies including cardiac fibrosis. However, the exact effect and underlying mechanism of miRNAs in cardiac fibrosis remains unclear. Here, we sought to investigate and test our hypothesis that miR-130a plays a critical role in the development of myocardial fibrosis by restoring PPARγ level. Methods and Results: We have identified a panel of novel miRNAs via miRNA array in Ang II infused mice heart. Among them, we found that miR-130a was upregulated both in pressure overload and Ang II infused models targeting PPARγ. Overexpressing miR-130a in cardiac fibroblast promoted the pro-fibrotic gene expression (collagen I/III, fibronectin and CTGF) and myofibroblasts differentiation. Inhibition miR-130a reversed the process and weakened these activities. Using luciferase-linked constitutive and dominant negative constructs of PPARγ, we determined the underlying mechanism of cardiac fibrosis occurred via targeting PPARγ. The in vivo inhibition of miR-130a by subcutaneous injections of LNA-based anti-miR-130a in mice subjected to Ang II infusion significantly reduced the severity of cardiac fibrosis, hypertrophy. The protective mechanism is associated with restoration of PPARγ level, reduction of pro-fibrotic genes and apoptosis; reversion of myofibroblasts differentiation and improved cardiac function. Conclusions: Our findings provide evidence that miR-130a plays a critical role in the progression of cardiac fibrosis by directly targeting PPARγ, and that inhibition of miR-130a reversed the cardiac fibrosis. We conclude that miR-130a may be a new marker for cardiac fibrosis and inhibition of miR-130a would be a promising strategy in the treatment of cardiac fibrosis.

scholarly journals Pro-inflammatory cytokine-driven PI3K/Akt/Sp1 signalling and H2S production facilitates the pathogenesis of severe acute pancreatitis

2017 ◽  
Vol 37 (2) ◽  
Author(s):  
Ying Liu ◽  
Ribin Liao ◽  
Zhanrong Qiang ◽  
Cheng Zhang
Keyword(s):  
Acute Pancreatitis ◽  
Severe Acute Pancreatitis ◽  
Rat Model ◽  
Intestinal Motility ◽  
Inhibitory Effect ◽  
Vital Role ◽  
Signalling Pathway ◽  
Pi3k Inhibitor Ly294002 ◽  
Tnf Α ◽  
Bowel Movements

Severe acute pancreatitis (SAP) is a disease usually associated with systemic organ dysfunction or pancreatic necrosis. Most patients with SAP suffer from defective intestinal motility in the early phase of the disease. Additionally, SAP-induced inflammation produces hydrogen sulphide (H2S) that impairs the gastrointestinal (GI) system. However, the exact mechanism of H2S in the regulation of SAP is yet to be elucidated. In the present paper, we used a rat model of SAP to evaluate the role of H2S on intestinal motility by counting the number of bowel movements and investigating the effect of H2S on inflammation. We treated colonic muscle cells (CMCs) with SAP plasma, tumour necrosis factor-α (TNF-α) or interleukin-6 (IL-6) and measured the expressions of H2S-producing enzymes cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS) and Sp1 and PI3K/Akt by using quantitative PCR, Western blotting and immunohistochemical detection. We used the PI3K inhibitor LY294002 and the siRNA si-Sp1 to suppress the activity of the PI3K/Akt/Sp1 signalling pathway. We found that, in the SAP rat model, H2S facilitated an inhibitory effect on intestinal motility and enhanced the inflammatory response caused by SAP (P<0.05). The expressions of CSE and CBS in CMCs were significantly increased after treatment with TNF-α or IL-6 (P<0.05). Blocking the PI3K/Akt/Sp1 pathway remarkably inhibited the synthesis of CSE and CBS. Our data demonstrated that H2S plays a vital role in the pathogenesis of SAP and that SAP is modulated by inflammation driven by the PI3K/Akt/Sp1 signalling pathway.

Prophylactic low-molecular-weight heparin administration protected against severe acute pancreatitis partially by VEGF/Flt-1 signaling in a rat model

2020 ◽  
Vol 39 (10) ◽  
pp. 1345-1354
Author(s):  
S Li ◽  
S Zhang ◽  
R Li ◽  
S Chen ◽  
S Chang ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Acute Pancreatitis ◽  
Western Blot ◽  
Severe Acute Pancreatitis ◽  
Rat Model ◽  
Low Molecular Weight Heparin ◽  
Sodium Taurocholate ◽  
Underlying Mechanism ◽  
Low Molecular Weight ◽  
Oxidative Response

Background: The present study was aimed to explore the effects and the underlying mechanism of prophylactic low-molecular-weight heparin (LMWH) treatment on taurocholate-induced severe acute pancreatitis (SAP) in a rat model. Methods: Rat SAP model was induced by injection of 4% sodium taurocholate into the pancreatic duct. LMWH was applied half an hour before the induction of pancreatitis at the dose of 200 IU/kg subcutaneous injection. The rats were euthanized at 1 h, 6 h, and 12 h after taurocholate-induced SAP. The inflammatory and oxidative response markers were assessed. And the vascular endothelial growth factor (VEGF) and Fms-related tyrosine kinase 1 (Flt-1) expression were evaluated by immunohistochemistry (IHC) and western blot methods. Results: The expression of inflammatory and oxidative response markers increased after induction of SAP. IHC and western blot results showed the VEGF and Flt-1 expression were increased in SAP group. Prophylactic LMWH administration reduced the inflammatory and oxidative response markers expression and decreased the expression of VEGF and Flt-1. Conclusions: This study suggested that prophylactic LMWH treatment mitigated the severity of pancreatitis in rat SAP model by anti-inflammation and oxidative response. The underlying mechanism may result from downregulating VEGF/Flt-1 signaling of LMWH in SAP rat model.

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