scholarly journals C/EBPδ protects from radiation-induced intestinal injury and sepsis by suppression of inflammatory and nitrosative stress

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sudip Banerjee ◽  
Qiang Fu ◽  
Sumit K. Shah ◽  
Stepan B Melnyk ◽  
Esta Sterneck ◽  
...  
Keyword(s):  
Nitrosative Stress ◽  
Intestinal Barrier ◽  
Intestinal Injury ◽  
Nuclear Antigen ◽  
Intestinal Damage ◽  
Oxidative And Nitrosative Stress ◽  
Tnf Α ◽  
Radiation Induced ◽  
Villous Height ◽  
Proliferating Cell

Abstract Ionizing radiation (IR)-induced intestinal damage is characterized by a loss of intestinal crypt cells, intestinal barrier disruption and translocation of intestinal microflora resulting in sepsis-mediated lethality. We have shown that mice lacking C/EBPδ display IR-induced intestinal and hematopoietic injury and lethality. The purpose of this study was to investigate whether increased IR-induced inflammatory, oxidative and nitrosative stress promote intestinal injury and sepsis-mediated lethality in Cebpd−/− mice. We found that irradiated Cebpd−/− mice show decreased villous height, crypt depth, crypt to villi ratio and expression of the proliferation marker, proliferating cell nuclear antigen, indicative of intestinal injury. Cebpd−/− mice show increased expression of the pro-inflammatory cytokines (Il-6, Tnf-α) and chemokines (Cxcl1, Mcp-1, Mif-1α) and Nos2 in the intestinal tissues compared to Cebpd+/+ mice after exposure to TBI. Cebpd−/− mice show decreased GSH/GSSG ratio, increased S-nitrosoglutathione and 3-nitrotyrosine in the intestine indicative of basal oxidative and nitrosative stress, which was exacerbated by IR. Irradiated Cebpd-deficient mice showed upregulation of Claudin-2 that correlated with increased intestinal permeability, presence of plasma endotoxin and bacterial translocation to the liver. Overall these results uncover a novel role for C/EBPδ in protection against IR-induced intestinal injury by suppressing inflammation and nitrosative stress and underlying sepsis-induced lethality.

scholarly journals Alterations of the extracellular matrix of lung during zinc deficiency

2011 ◽  
Vol 108 (1) ◽  
pp. 62-70 ◽  
Author(s):  
Verónica S. Biaggio ◽  
Natalia R. Salvetti ◽  
María V. Pérez Chaca ◽  
Susana R. Valdez ◽  
Hugo H. Ortega ◽  
...  
Keyword(s):  
Proliferating Cell Nuclear Antigen ◽  
Nitrosative Stress ◽  
Health Interventions ◽  
The Other ◽  
Male Rats ◽  
Nuclear Antigen ◽  
Zn Deficiency ◽  
Oxidative And Nitrosative Stress ◽  
Fibrotic Process ◽  
Proliferating Cell

Suboptimal intake of Zn is one of the most common nutritional problems worldwide. Previously, we have shown that Zn deficiency (ZD) produces oxidative and nitrosative stress in the lung of rats. We analyse the effect of moderate ZD on the expression of several intermediate filaments of the cytoskeleton, as well as the effect of restoring Zn during the refeeding period. Adult male rats were divided into three groups: Zn-adequate control (CO) group; ZD group; Zn-refeeding group. CerbB-2 and proliferating cell nuclear antigen (PCNA) expression was increased in the ZD group while the other parameters did not change. During the refeeding time, CerbB-2, cytokeratins, vimentin and PCNA immunostaining was higher than that in the CO group. The present findings indicate that the overexpression of some markers could lead to the fibrotic process in the lung. Perhaps ZD implications must be taken into account in health interventions because an inflammation environment is associated with ZD in the lung.

scholarly journals CBP22, a Novel Bacteriocin Isolated from Clostridium butyricum ZJU-F1, Protects against LPS-Induced Intestinal Injury through Maintaining the Tight Junction Complex

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Tenghao Wang ◽  
Jie Fu ◽  
Xiao Xiao ◽  
Zeqing Lu ◽  
Fengqin Wang ◽  
...  
Keyword(s):  
High Performance ◽  
Serum Levels ◽  
Exchange Chromatography ◽  
Intestinal Injury ◽  
Clostridium Butyricum ◽  
Intestinal Damage ◽  
Barrier Dysfunction ◽  
Net Charge ◽  
E Coli ◽  
Tnf Α

A novel bacteriocin secreted by Clostridium butyricum ZJU-F1 was isolated using ammonium sulfate fractionation, cation exchange chromatography, affinity chromatography, and reverse-phase high-performance liquid chromatography (RP-HPLC). The bacteriocin, named CBP22, contained 22 amino acids with the sequence PSAWQITKCAGSIAWALGSGIF. Analysis of its structure and physicochemical properties indicated that CBP22 had a molecular weight of 2264.63 Da and a +1 net charge. CBP22 showed activity against E. col K88, E. coli ATCC25922, and S. aureus ATCC26923. The effects and potential mechanisms of bacteriocin CBP22 on the innate immune response were investigated with a lipopolysaccharide- (LPS-) induced mouse model. The results showed that pretreatment with CBP22 prevented LPS-induced impairment in epithelial tissues and significantly reduced serum levels of IgG, IgA, IgM, TNF-α, and sIgA. Moreover, CBP22 treatment increased the expression of the zonula occludens and reduced permeability as well as apoptosis in the jejunum in LPS-treated mice. In summary, CBP22 inhibits the intestinal injury and prevents the gut barrier dysfunction induced by LPS, suggesting the potential use of CBP22 for treating intestinal damage.

scholarly journals Co-Exposure of Cardiomyocytes to IFN-γ and TNF-α Induces Mitochondrial Dysfunction and Nitro-Oxidative Stress: Implications for the Pathogenesis of Chronic Chagas Disease Cardiomyopathy

2021 ◽  
Vol 12 ◽  
Author(s):  
João Paulo Silva Nunes ◽  
Pauline Andrieux ◽  
Pauline Brochet ◽  
Rafael Ribeiro Almeida ◽  
Eduardo Kitano ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Fatty Acid ◽  
Mitochondrial Dysfunction ◽  
Chagas Disease ◽  
Nitrosative Stress ◽  
Acid Oxidation ◽  
Oxidative And Nitrosative Stress ◽  
Human Cardiomyocytes ◽  
Tnf Α ◽  
Ifn Γ

Infection by the protozoan Trypanosoma cruzi causes Chagas disease cardiomyopathy (CCC) and can lead to arrhythmia, heart failure and death. Chagas disease affects 8 million people worldwide, and chronic production of the cytokines IFN-γ and TNF-α by T cells together with mitochondrial dysfunction are important players for the poor prognosis of the disease. Mitochondria occupy 40% of the cardiomyocytes volume and produce 95% of cellular ATP that sustain the life-long cycles of heart contraction. As IFN-γ and TNF-α have been described to affect mitochondrial function, we hypothesized that IFN-γ and TNF-α are involved in the myocardial mitochondrial dysfunction observed in CCC patients. In this study, we quantified markers of mitochondrial dysfunction and nitro-oxidative stress in CCC heart tissue and in IFN-γ/TNF-α-stimulated AC-16 human cardiomyocytes. We found that CCC myocardium displayed increased levels of nitro-oxidative stress and reduced mitochondrial DNA as compared with myocardial tissue from patients with dilated cardiomyopathy (DCM). IFN-γ/TNF-α treatment of AC-16 cardiomyocytes induced increased nitro-oxidative stress and decreased the mitochondrial membrane potential (ΔΨm). We found that the STAT1/NF-κB/NOS2 axis is involved in the IFN-γ/TNF-α-induced decrease of ΔΨm in AC-16 cardiomyocytes. Furthermore, treatment with mitochondria-sparing agonists of AMPK, NRF2 and SIRT1 rescues ΔΨm in IFN-γ/TNF-α-stimulated cells. Proteomic and gene expression analyses revealed that IFN-γ/TNF-α-treated cells corroborate mitochondrial dysfunction, transmembrane potential of mitochondria, altered fatty acid metabolism and cardiac necrosis/cell death. Functional assays conducted on Seahorse respirometer showed that cytokine-stimulated cells display decreased glycolytic and mitochondrial ATP production, dependency of fatty acid oxidation as well as increased proton leak and non-mitochondrial oxygen consumption. Together, our results suggest that IFN-γ and TNF-α cause direct damage to cardiomyocytes’ mitochondria by promoting oxidative and nitrosative stress and impairing energy production pathways. We hypothesize that treatment with agonists of AMPK, NRF2 and SIRT1 might be an approach to ameliorate the progression of Chagas disease cardiomyopathy.

scholarly journals Polysaccharides extracted from Rheum tanguticum ameliorate radiation-induced enteritis via activation of Nrf2/HO-1

2020 ◽  
Vol 62 (1) ◽  
pp. 46-57
Author(s):  
Tian Zhang ◽  
Lei Shi ◽  
Yan Li ◽  
Wei Mu ◽  
HaoMeng Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Early Stage ◽  
Underlying Mechanism ◽  
Intestinal Injury ◽  
Inflammatory Factors ◽  
Multiple Time ◽  
Intestinal Damage ◽  
Time Points ◽  
Radiation Induced ◽  
Rheum Tanguticum

ABSTRACT Radiation-induced enteritis is a major side effect in cancer patients undergoing abdominopelvic radiotherapy. The Nrf2/HO-1 pathway is a critical endogenous antioxidant stress pathway, but its precise role in radiation-induced enteritis remains to be clarified. Polysaccharides extracted from Rheum tanguticum (RTP) can protect the intestinal cells from radiation-induced damage, but the underlying mechanism is unknown. SD rats and IEC-6 cells were exposed to 12 or 10 Gy X-ray radiation. Rat survival, and histopathological and immunohistochemical profiles were analyzed at different time points. Indicators of oxidative stress and inflammatory response were also assessed. Cell viability, apoptosis and Nrf2/HO-1 expression were evaluated at multiple time points. Significant changes were observed in the physiological and biochemical indexes of rats after radiation, accompanied by significant oxidative stress response. The mRNA and protein expression of Nrf2 peaked at 12 h after irradiation, and HO-1 expression peaked at 48 h after irradiation. RTP administration reduced radiation-induced intestinal damage, upregulated Nrf2/HO-1, improved physiological indexes, significantly decreased apoptosis and inflammatory factors, and upregulated HO-1, particularly at 48 h after irradiation. In conclusion, Nrf2 is activated in the early stage of radiation-induced intestinal injury and plays a protective role. RTP significantly ameliorates radiation-induced intestinal injury via the regulation of Nrf2 and its downstream protein HO-1.

scholarly journals Dose-dependent effects of adalimumab in neonatal rats with hypoxia/reoxygenation-induced intestinal damage

2020 ◽  
Author(s):  
Halil Kocamaz ◽  
Özmert MA Özdemir ◽  
Nilay Şen Türk ◽  
Yaşar Enli ◽  
Barbaros Şahin ◽  
...  
Keyword(s):  
Low Dose ◽  
Treated Group ◽  
Intestinal Injury ◽  
Control Group ◽  
High Dose ◽  
Intestinal Damage ◽  
Neonatal Rats ◽  
Tnf Α ◽  
Dose Dependent ◽  
Hypoxia Reoxygenation

Tumor necrosis factor-alpha (TNF-α) has an important role in hypoxia/reoxygenation (H/R)-induced intestinal damage. It was shown that blocking TNF-α with infliximab has beneficial effects on experimental necrotizing enterocolitis and hypoxic intestinal injury. However, there is no data about the effect of adalimumab on H/R-induced intestinal damage. Therefore, we aimed to determine potential dose-dependent benefits of adalimumab in such damage in neonatal rats. Wistar albino rat pups were assigned to one of the four groups: control group, hypoxia group, low-dose adalimumab (5 mg/kg/day) treated group (LDAT), and high-dose adalimumab (50 mg/kg/day) treated group (HDAT). On the fourth day of the experiment, all rats except for the control group were exposed to H/R followed by euthanasia. Malondialdehyde (MDA), myeloperoxidase (MPO), TNF-α, total antioxidant capacity (TAC), and total oxidant capacity (TOC) were measured in intestinal tissue. TAC and TOC values were used to calculate the oxidative stress index (OSI). Histopathological injury scores (HIS) were also evaluated in the tissue samples. MDA levels were significantly lower in the LDAT and HDAT groups (p < 0.001). TNF-α levels were significantly lower in the LDAT group (p < 0.001). OSI was significantly higher in the H/R group than in the control and LDAT groups (p < 0.001). Mean HIS values in the LDAT group were significantly lower than those in the H/R and HDAT groups (p < 0.001). This experimental study showed that low-dose adalimumab appears to have a beneficial effect on intestinal injury induced with H/R in neonatal rats.

Mitochondrial DNA: A Biomarker of Disease Severity in Necrotizing Enterocolitis

2019 ◽  
Vol 30 (01) ◽  
pp. 085-089
Author(s):  
Edoardo Bindi ◽  
Bo Li ◽  
Haitao Zhou ◽  
Maarten Janssen Lok ◽  
Mashriq Alganabi ◽  
...  
Keyword(s):  
Necrotizing Enterocolitis ◽  
Intestinal Ischemia ◽  
Organ Damage ◽  
Intestinal Injury ◽  
Intestinal Damage ◽  
Tnf Α ◽  
Polymerase Chain ◽  
Factor Α ◽  
Mtdna Markers ◽  
Necrosis Factor

Abstract Introduction There is a need to develop sensitive markers to diagnose or monitor the severity of intestinal damage in necrotizing enterocolitis (NEC). Mitochondrial deoxyribonucleic acid (mtDNA) is increased in the intestine and blood of adults in response to intestinal ischemia and can trigger secondary organ damage. We hypothesize that mtDNA is increased during experimental NEC and that mtDNA levels are correlated to the degree of intestinal injury. Materials and Methods NEC was induced in C57BL/6 mice (n = 18) (approval: 44032) by gavage feeding with hyperosmolar formula, hypoxia, and lipopolysaccharide administration from postnatal day (P) 5 to 9. Breastfed pups served as control (n = 15). Blood was collected by cardiac puncture and terminal ileum was harvested on P9. Reverse transcription quatitative polymerase chain reaction was used to measure mtDNA (markers COX3, CYTB, ND1) and inflammatory cytokines (interleukin 6 [IL-6] and tumor necrosis factor-α[TNF-α]) in blood and ileum. Intestinal injury was scored blindly by four investigators and classified as no/minor injury (score 0 or 1) or NEC (score ≥2). Results mtDNA is significantly increased in gut and blood of NEC mice (p < 0.05). Furthermore, mtDNA increases in intestine and blood proportionally to the degree of intestinal injury as indicated by a positive correlation with histological scoring and inflammation (r = 0.6; p < 0.05) (expression of IL-6 and TNF-α). Conclusion Following NEC intestinal injury, mtDNA is released from the intestine into circulation. The blood level of mtDNA is related to the degree of intestinal injury. mtDNA can be a novel marker of intestinal injury and can be useful for monitoring the progression of NEC.

scholarly journals mtDNA-STING pathway promotes necroptosis-dependent enterocyte injury in intestinal ischemia reperfusion

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Xufei Zhang ◽  
Jie Wu ◽  
Qinjie Liu ◽  
Xuanheng Li ◽  
Sicheng Li ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Intestinal Barrier ◽  
Intestinal Injury ◽  
Tnf Α ◽  
Gut Homeostasis ◽  
Sting Pathway ◽  
Intestinal Ischemia Reperfusion ◽  
The Relationship

AbstractIntestinal ischemia reperfusion (I/R) injury is the important pathogenesis for acute intestinal barrier disruption. The STING signaling is associated with gut homeostasis and barrier integrity. However, the biological function and regulation of STING signaling in intestinal I/R injury are not yet fully understood. As the ligand of STING signaling, the mitochondrial DNA (mtDNA) has been found to be associated with necroptosis. It still remains unknown whether mtDNA-STING signaling triggers intestinal necroptosis in intestinal I/R injury. We found that circulating RIPK3 was significantly increased and had a positive correlation with markers of enterocyte injury in critically ill patients with intestinal injury. Moreover, the levels of circulating mtDNA were also associated with the levels of circulating RIPK3. To explore the relationship between mtDNA and intestinal necroptosis, mice were treated with the intraperitoneal injection of mtDNA, and necroptosis signaling was remarkably activated and the inhibition of necroptosis alleviated mtDNA-induced intestinal injury. Furthermore, STING knockout mice showed an alleviated intestinal necroptosis. In intestinal I/R injury, mtDNA was released from IECs and necroptosis was also triggered, companied with a significant decrease of RIPK3 in the intestine. STING knockout mice markedly attenuated intestinal necroptosis and intestinal I/R injury. Finally, we found that mtDNA-mediated STING signaling triggered necroptosis through synergistic IFN and TNF-α signaling in primary IECs. Our results indicated that mtDNA-STING signaling can contribute to intestinal I/R injury by promoting IEC necroptosis. STING-mediated both IFN and TNF-α signaling can trigger intestinal nercroptosis.

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