Necroptosis protects against exacerbation of acute pancreatitis

AbstractThe sensing of various extrinsic stimuli triggers the receptor-interacting protein kinase-3 (RIPK3)-mediated signaling pathway, which leads to mixed-lineage kinase-like (MLKL) phosphorylation followed by necroptosis. Although necroptosis is a form of cell death and is involved in inflammatory conditions, the roles of necroptosis in acute pancreatitis (AP) remain unclear. In the current study, we administered caerulein to Ripk3- or Mlkl-deficient mice (Ripk3−/− or Mlkl−/− mice, respectively) and assessed the roles of necroptosis in AP. We found that Ripk3−/− mice had significantly more severe pancreatic edema and inflammation associated with macrophage and neutrophil infiltration than control mice. Consistently, Mlkl−/− mice were more susceptible to caerulein-induced AP, which occurred in a time- and dose-dependent manner, than control mice. Mlkl−/− mice exhibit weight loss, edematous pancreatitis, necrotizing pancreatitis, and acinar cell dedifferentiation in response to tissue damage. Genetic deletion of Mlkl resulted in downregulation of the antiapoptotic genes Bclxl and Cflar in association with increases in the numbers of apoptotic cells, as detected by TUNEL assay. These findings suggest that RIPK3 and MLKL-mediated necroptosis exerts protective effects in AP and caution against the use of necroptosis inhibitors for AP treatment.

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NLRP3 Deficiency Alleviates Severe Acute Pancreatitis and Pancreatitis-Associated Lung Injury in a Mouse Model

BioMed Research International ◽

10.1155/2018/1294951 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 8

Author(s):

Qiang Fu ◽

Zhensheng Zhai ◽

Yuzhu Wang ◽

Lixia Xu ◽

Pengchong Jia ◽

...

Keyword(s):

Acute Pancreatitis ◽

Lung Injury ◽

Severe Acute Pancreatitis ◽

Nlrp3 Inflammasome ◽

Early Death ◽

Neutrophil Infiltration ◽

Multiple Organ ◽

Dependent Manner ◽

Dose Dependent ◽

Nlrp3 Expression

The rapid production and release of a large number of inflammatory cytokines can cause excessive local and systemic inflammation in severe acute pancreatitis (SAP) and multiple organ dysfunction syndrome (MODS), especially pancreatitis-associated acute lung injury (P-ALI), which is the main cause of early death in patients with SAP. The NLRP3 inflammasome plays an important role in the maturation of IL-1β and the inflammatory cascade. Here, we established a model of SAP using wild-type (NLRP3+/+) and NLRP3 knockout (NLRP3-/-) mice by intraperitoneal injections of caerulein (Cae) and lipopolysaccharide (LPS). Pathological injury to the pancreas and lungs, the inflammatory response, and neutrophil infiltration were significantly mitigated in NLRP3-/- mice. Furthermore, INF-39, an NLRP3 inflammasome inhibitor, could reduce the severity of SAP and P-ALI in a dose-dependent manner. Our results suggested that SAP and P-ALI were alleviated by NLRP3 deficiency in mice, and thus, reducing NLRP3 expression may mitigate SAP-associated inflammation and P-ALI.

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Effects of Propentofylline on Hypoxia—Hypoglycemia-Induced Calcium Accumulation in Gerbil Hippocampal Slices

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1992.41 ◽

1992 ◽

Vol 12 (2) ◽

pp. 301-305 ◽

Cited By ~ 12

Author(s):

Fumito Kadoya ◽

Akira Mitani ◽

Tatsuru Arai ◽

Kiyoshi Kataoka

Keyword(s):

Cerebral Ischemia ◽

Intracellular Calcium ◽

Neuronal Damage ◽

Hippocampal Slices ◽

Dependent Manner ◽

Protective Effects ◽

Calcium Accumulation ◽

Xanthine Derivative ◽

Acute Increase ◽

Dose Dependent

The xanthine derivative propentofylline (HWA 285) has been reported to show protective effects against neuronal damage induced by cerebral ischemia. In the present study, microfluorometry was used to investigate the effect of propentofylline on the hypoxia–hypoglycemia-induced intracellular calcium accumulation in gerbil hippocampal slices. When slices were superfused with hypoxic–hypoglycemic medium that did not contain propentofylline, an acute increase in calcium accumulation was detected 75–200 s (mean latency of 123 s) after the beginning of hypoxia–hypoglycemia. When slices were superfused with hypoxic–hypoglycemic mediums that contained 10 μ M, 100 μ M, and 1 m M propentofylline, the latency of the acute increase in calcium accumulation was prolonged in all subregions of the hippocampus in a dose-dependent manner: mean latencies in field CA1 were 146, 168, and 197 s after hypoxia–hypoglycemia, respectively. This retardation in calcium accumulation may be involved in the mechanisms by which propentofylline diminishes ischemic injury.

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Hepatoprotective effects of Sapium sebiferum in paracetamol-induced liver injury

Bangladesh Journal of Pharmacology ◽

10.3329/bjp.v10i2.22576 ◽

2015 ◽

Vol 10 (2) ◽

pp. 393 ◽

Cited By ~ 3

Author(s):

Liaqat Hussain ◽

Muhammad Sajid Hamid Akash ◽

Madeha Tahir ◽

Kanwal Rehman

Keyword(s):

Liver Injury ◽

Serum Levels ◽

Therapeutic Effects ◽

Sapium Sebiferum ◽

Dependent Manner ◽

Protective Effects ◽

Drug Induced ◽

Standard Drug ◽

Hepatoprotective Effects ◽

Dose Dependent

Sapium sebiferum leaves were used to determine its hepatoprotective effects against paracetamol-induced hepatotoxicity in mice. A dose dependent study was conducted using two different doses (200 mg/kg and 400 mg/kg) of the extract of S. sebiferum against toxic effects of paracetamol (500 mg/kg) in experimental animal model. Silymarin (50 mg/kg) was used as standard drug to compare therapeutic effects of S. sebiferum with control and paracetamol-treated groups. Paracetamol significantly increased the serum levels of liver enzyme markers like alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, and direct bilirubin. The extract showed protective effects by normalizing the liver enzymes markers in a dose dependent manner. Histopathological results confirmed the hepatoprotective effects of leaves of S. sebiferum. We conclude that leaves of S. sebiferum have strong hepatoprotective effects against paracetamol-induced liver injury and can be used in liver injuries caused by drug-induced toxicity.

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Ezetimibe Attenuates Oxidative Stress and Neuroinflammation via the AMPK/Nrf2/TXNIP Pathway after MCAO in Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/4717258 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Jing Yu ◽

Wen-na Wang ◽

Nathanael Matei ◽

Xue Li ◽

Jin-wei Pang ◽

...

Keyword(s):

Oxidative Stress ◽

Ischemic Stroke ◽

Brain Infarction ◽

Neutrophil Infiltration ◽

Artery Occlusion ◽

Receptor Protein ◽

Related Factor ◽

Protective Effects ◽

Sprague Dawley ◽

Interacting Protein

Oxidative stress and neuroinflammation play essential roles in ischemic stroke-induced brain injury. Previous studies have reported that Ezetimibe (Eze) exerts antioxidative stress and anti-inflammatory properties in hepatocytes. In the present study, we investigated the effects of Eze on oxidative stress and neuroinflammation in a rat middle cerebral artery occlusion (MCAO) model. One hundred and ninety-eight male Sprague-Dawley rats were used. Animals assigned to MCAO were given either Eze or its control. To explore the downstream signaling of Eze, the following interventions were given: AMPK inhibitor dorsomorphin and nuclear factor erythroid 2-related factor 2 (Nrf2) siRNA. Intranasal administration of Eze, 1 h post-MCAO, further increased the endogenous p-AMPK expression, reducing brain infarction, neurologic deficits, neutrophil infiltration, microglia/macrophage activation, number of dihydroethidium- (DHE-) positive cells, and malonaldehyde (MDA) levels. Specifically, treatment with Eze increased the expression of p-AMPK, Nrf2, and HO-1; Romo-1, thioredoxin-interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3), Cleaved Caspase-1, and IL-1β were reduced. Dorsomorphin and Nrf2 siRNA reversed the protective effects of Eze. In summary, Eze decreases oxidative stress and subsequent neuroinflammation via activation of the AMPK/Nrf2/TXNIP pathway after MCAO in rats. Therefore, Eze may be a potential therapeutic approach for ischemic stroke patients.

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Physicochemical Properties of Collagen from Acaudina Molpadioides and Its Protective Effects against H2O2-Induced Injury in RAW264.7 Cells

Marine Drugs ◽

10.3390/md18070370 ◽

2020 ◽

Vol 18 (7) ◽

pp. 370

Author(s):

Jie Li ◽

Yan Li ◽

Yuyao Li ◽

Zuisu Yang ◽

Huoxi Jin

Keyword(s):

Sulfonic Acid ◽

Antioxidant Activities ◽

Physicochemical Characterization ◽

Raw264.7 Cells ◽

Composition Analysis ◽

Dependent Manner ◽

Protective Effects ◽

Dose Dependent ◽

Zeta Potential Analysis ◽

Improve Cell Viability

Collagen is a promising biomaterial used in the beauty and biomedical industries. In this study, the physicochemical characterization, antioxidant activities, and protective effects against H2O2-induced injury of collagen isolated from Acaudina molpadioides were investigated. The amino acid composition analysis showed that the collagen was rich in glycine (Gly), alanine (Ala), and glutamic acid (Glu), but poor in tyrosine (Tyr) and phenylalanine (Phe). Zeta potential analysis revealed that the isoelectric point (pI) of collagen from Acaudina molpadioides was about 4.25. It possessed moderate scavenging activities of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radicals in a dose-dependent manner. In addition, the collagen was able to effectively improve cell viability and morphology, inhibit the production of Malondialdehyde (MDA), and increase the activities of Superoxide Dismutase (SOD) and Glutathione Peroxidase (GSH-Px) in cultured RAW264.7 cells, resulting in a protective effect against H2O2-induced injury. Overall, the results showed that collagen extracted from A. molpadioides has promising prospects in the beauty and cosmetics industries.

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Isoliquiritigenin Ameliorates Acute Pancreatitis in Mice via Inhibition of Oxidative Stress and Modulation of the Nrf2/HO-1 Pathway

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/7161592 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 26

Author(s):

Xinnong Liu ◽

Qingtian Zhu ◽

Min Zhang ◽

Tao Yin ◽

Rong Xu ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Pancreatitis ◽

Tissue Injury ◽

Pancreatic Tissue ◽

Zinc Protoporphyrin ◽

Dependent Manner ◽

Protective Effects ◽

Stress Injury ◽

Oxidative Stress Injury ◽

Flavonoid Monomer

Oxidative stress plays a crucial role in the pathogenesis of acute pancreatitis (AP). Isoliquiritigenin (ISL) is a flavonoid monomer with confirmed antioxidant activity. However, the specific effects of ISL on AP have not been determined. In this study, we aimed to investigate the protective effect of ISL on AP using two mouse models. In the caerulein-induced mild acute pancreatitis (MAP) model, dynamic changes in oxidative stress injury of the pancreatic tissue were observed after AP onset. We found that ISL administration reduced serum amylase and lipase levels and alleviated the histopathological manifestations of pancreatic tissue in a dose-dependent manner. Meanwhile, ISL decreased the oxidative stress injury and increased the protein expression of the Nrf2/HO-1 pathway. In addition, after administering a Nrf2 inhibitor (ML385) or HO-1 inhibitor (zinc protoporphyrin) to block the Nrf2/HO-1 pathway, we failed to observe the protective effects of ISL on AP in mice. Furthermore, we found that ISL mitigated the severity of pancreatic tissue injury and pancreatitis-associated lung injury in a severe acute pancreatitis model induced by L-arginine. Taken together, our data for the first time confirmed the protective effects of ISL on AP in mice via inhibition of oxidative stress and modulation of the Nrf2/HO-1 pathway.

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NEMO-Binding Domain Peptide Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Inhibiting the NF-κB Signaling Pathway

Mediators of Inflammation ◽

10.1155/2016/7349603 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 6

Author(s):

Jianhua Huang ◽

Li Li ◽

Weifeng Yuan ◽

Linxin Zheng ◽

Zhenhui Guo ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Signaling Pathway ◽

Binding Domain ◽

Dependent Manner ◽

Protective Effects ◽

Lps Challenge ◽

Domain Peptide ◽

Nemo Binding Domain ◽

Dose Dependent

The aim of the present study is to investigate the protective effects and relevant mechanisms exerted by NEMO-binding domain peptide (NBD) against lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in mice. The ALI model was induced by intratracheally administered atomized LPS (5 mg/kg) to BABL/c mice. Half an hour before LPS administration, we treated the mice with increasing concentrations of intratracheally administered NBD or saline aerosol. Two hours after LPS administration, each group of mice was sacrificed. We observed that NBD pretreatment significantly attenuated LPS-induced lung histopathological injury in a dose-dependent manner. Western blotting established that NBD pretreatment obviously attenuated LPS-induced IκB-αand NF-κBp65 activation and NOX1, NOX2, and NOX4 overexpression. Furthermore, NBD pretreatment increased SOD and T-AOC activity and decreased MDA levels in lung tissue. In addition, NBD also inhibited TNF-αand IL-1βsecretion in BALF after LPS challenge. In conclusion, NBD protects against LPS-induced ALI in mice.

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Antinociceptive and Anti-edematous Activities of the Essential Oils of Two Balkan EndemicLaserpitium Species

Natural Product Communications ◽

10.1177/1934578x1400900135 ◽

2014 ◽

Vol 9 (1) ◽

pp. 1934578X1400900 ◽

Cited By ~ 3

Author(s):

Višnja Popović ◽

Silvana Petrović ◽

Maja Tomić ◽

Radica Stepanović-Petrović ◽

Ana Micov ◽

...

Keyword(s):

Essential Oil ◽

Essential Oils ◽

Antinociceptive Effect ◽

Dependent Manner ◽

Paw Edema ◽

Oral Gavage ◽

Inflammatory Conditions ◽

Pressure Test ◽

Male Wistar Rats ◽

Dose Dependent

In this paper antinociceptive and anti-edematous effects are examined of the essential oils of the underground parts of two Balkan endemic Laserpitium species (Apiaceae), L. zernyi and L. ochridanum. Furthermore, the essential oil of the underground parts of L. ochridanum is chemically characterised by GC and GC-MS. Antinociceptive and anti-edematous effects were measured in a rat model of localized inflammation, induced by carrageenan, using apparatus for the modified paw-pressure test, and plethysmometer, respectively. The effects of both Laserpitium essential oils were measured after oral gavage administration to male Wistar rats in doses of 25, 50 and 100 mg/kg. The main constituents of L. ochridanum essential oil were: α-pinene (33.2%), α-bisabolol (10.3%) and chamazulene (14.9%). The essential oil of L. zernyi was previously shown to be rich in α-pinene (31.6%) and α-bisabolol (30.9%). Both examined essential oils produced a significant dose-dependent antinociceptive effect. The corresponding ED50±SEM in producing antinociception were 45.9±4.9 mg/kg and 42.4±2.1 mg/kg for L. zernyi and L. ochridanum oil, respectively. Both essential oils also significantly reduced paw edema in a dose-dependent manner. The estimated ED50±SEM values for the anti-edematous effect were 36.3±4.5 mg/kg for L. zernyi oil and 45.1±11.3 mg/kg for L. ochridanum oil. These results suggest that the essential oils of both investigated Laserpitium species may be effective against pain and edema present in various inflammatory conditions.

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Interaction of complement and leukocytes in severe acute pancreatitis: potential for therapeutic intervention

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00016.2006 ◽

2006 ◽

Vol 291 (5) ◽

pp. G844-G850 ◽

Cited By ~ 17

Author(s):

Werner Hartwig ◽

Martina Klafs ◽

Michael Kirschfink ◽

Thilo Hackert ◽

Lutz Schneider ◽

...

Keyword(s):

Acute Pancreatitis ◽

Complement Activation ◽

Necrotizing Pancreatitis ◽

Weight Ratio ◽

Dry Weight ◽

Organ Injury ◽

Sham Operation ◽

Midline Laparotomy ◽

Complement Inhibition ◽

Edematous Pancreatitis

In acute pancreatitis, local as well as systemic organ complications are mediated by the activation of various inflammatory cascades. The role of complement in this setting is unclear. The aim of the present study was to determine the level of complement activation in experimental pancreatitis, to evaluate the interaction of complement and leukocyte-endothelium activation, and to assess the effects of complement inhibition by soluble complement receptor 1 (sCR1) in this setting. Necrotizing pancreatitis was induced in Wistar rats by the combination of intravenous cerulein and retrograde infusion of glycodeoxycholic acid into the biliopancreatic duct; edematous pancreatitis was induced by intravenous cerulein only. In control animals, a sham operation (midline laparotomy) was performed. Complement activation, leukocyte sequestration, and pancreatic as well as pulmonary injury were assessed in the presence/absence of sCR1. Increased levels of C3a were found in necrotizing but not in edematous pancreatitis. When complement activation in necrotizing pancreatitis was blocked by sCR1, levels of C3a and total hemolytic activity (CH50) were decreased. Leukocyte-endothelial interaction, as assessed by intravital microscopy, and pancreatic as well as pulmonary organ injury (wet-to-dry weight ratio, MPO activity, and histology) were ameliorated by sCR1. As a result of the present study, necrotizing but not edematous pancreatitis is characterized by significant and early complement activation. Based on the interaction of complement and leukocytes, complement inhibition by sCR1 may be a valuable option in the treatment of leukocyte-associated organ injury in severe pancreatitis.

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SDF-1/CXCR4 mediates acute protection of cardiac function through myocardial STAT3 signaling following global ischemia/reperfusion injury

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00365.2011 ◽

2011 ◽

Vol 301 (4) ◽

pp. H1496-H1505 ◽

Cited By ~ 58

Author(s):

Chunyan Huang ◽

Hongmei Gu ◽

Wenjun Zhang ◽

Mariuxi C. Manukyan ◽

Weinian Shou ◽

...

Keyword(s):

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Global Ischemia ◽

Dependent Manner ◽

Protective Effects ◽

Stat3 Signaling ◽

Stromal Cell Derived Factor ◽

Myocardial Ischemia Reperfusion ◽

Dose Dependent ◽

Cxcr4 Axis

Stromal cell-derived factor-1α (SDF-1) has been reported to mediate cardioprotection through the mobilization of stem cells into injured tissue and an increase in local angiogenesis after myocardial infarction. However, little is known regarding whether SDF-1 induces acute protection following global myocardial ischemia/reperfusion (I/R) injury and if so, by what molecular mechanism. SDF-1 binding to its cognate receptor CXCR4 has been shown to activate STAT3 in a variety of cells. STAT3 is a cardioprotective factor and may mediate SDF-1/CXCR4-induced acute protection. We hypothesized that SDF-1 would improve myocardial function through CXCR4-increased STAT3 activation following acute I/R. Isolated mouse hearts were subjected to 25-min global ischemia/40-min reperfusion and divided into groups of 1) vehicle; 2) SDF-1; 3) AMD3100, a CXCR4 inhibitor; 4) SDF-1 + AMD3100; 5) Stattic, a STAT3 inhibitor; 6) SDF-1 + Stattic; 7) cardiomyocyte-restricted ablation of STAT3 (STAT3KO); 8) STAT3KO + SDF-1; 9) Ly294002, an inhibitor of the Akt pathway; and 10) SDF-1 + Ly294002. Reagents were infused into hearts within 5 min before ischemia. SDF-1 administration significantly improved postischemic myocardial functional recovery in a dose-dependent manner. Additionally, pretreatment with SDF-1 reduced cardiac apoptotic signaling and increased myocardial STAT3 activation following acute I/R. Inhibition of the SDF-1 receptor CXCR4 neutralized these protective effects by SDF-1 in hearts subjected to I/R. Notably, inhibition of the STAT3 pathway or use of STAT3KO hearts abolished SDF-1-induced acute protection following myocardial I/R. Our results represent the first evidence that the SDF-1/CXCR4 axis upregualtes myocardial STAT3 activation and, thereby, mediates acute cardioprotection in response to global I/R.

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