HEART PROTEIN SYNTHESIS AFTER CECAL LIGATION & PUNCTURE (CLP) IN THE RAT

Sepsis-induced skeletal muscle atrophy and weakness are due in part to decreased mTORC1-mediated protein synthesis and increased proteolysis via the autophagy-lysosomal system and ubiquitin-proteasome pathway. The REDD1 (regulated in development and DNA damage-1) protein is increased in sepsis and can negatively regulate mTORC1 activity. However, the contribution of REDD1 to the sepsis-induced change in muscle protein synthesis and degradation has not been determined. Sepsis was produced by cecal ligation and puncture in female REDD1−/− or wild-type (WT) mice, and end points were assessed 24 h later in gastrocnemius; time-matched, pair-fed controls of each genotype were included. Sepsis increased REDD1 protein 300% in WT mice, whereas REDD1 was absent in REDD1−/− muscle. Sepsis decreased protein synthesis and phosphorylation of downstream targets of mTORC1 (S6K1 Thr389, rpS6 Ser240/244, 4E-BP1 Ser65) in WT but not REDD1−/− mice. However, Akt and PRAS40 phosphorylation was suppressed in both sham and septic muscle from REDD1−/− mice despite unaltered PDK1, PP2A, or TSC2 expression. Sepsis increased autophagy as indicated by decreased ULK1 Ser757 phosphorylation and p62 abundance and increased LC3B-II/I in WT mice, whereas these changes were absent in septic REDD1−/− mice. Conversely, REDD1 deletion did not prevent the sepsis-induced decrease in IGF-I mRNA or the concomitant increase in IL-6, TNFα, MuRF1, and atrogin1 mRNA expression. Lastly, 5-day survival in a separate set of septic mice did not differ between WT and REDD1−/− mice. These data highlight the central role of REDD1 in regulating both protein synthesis and autophagy in skeletal muscle during sepsis.

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Melatonin Alleviates Renal Injury in Mouse Model of Sepsis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.697643 ◽

2021 ◽

Vol 12 ◽

Author(s):

Liyang Chen ◽

Zhijian Han ◽

Zhiguang Shi ◽

Chao Liu ◽

Qiulun Lu

Keyword(s):

Renal Injury ◽

Oxidant Stress ◽

Mrna Level ◽

Cecal Ligation ◽

Kidney Injury ◽

Protective Role ◽

Cecal Ligation Puncture ◽

Species Production

Melatonin (N-acetyl-5-methoxytryptamine; MLT) has been shown to have a renal-protective effect against kidney injury. However, the mechanisms underlying the protective role of MLT in sepsis-induced renal injury are yet to be revealed. In this study, MLT alleviated renal dysfunction with the increase of BUN (blood urea nitrogen) and SCR (serum creatinine) and reduction of fibrosis in the CLP (cecal ligation puncture) model. RNA-seq analysis showed that MLT repressed the oxidant stress in response to kidney injury. Our in vitro study showed that MLT suppresses LPS-induced accumulation of ROS (reactive oxygen species) production via SOD2 downregulation and Nox4 upregulation in HK-2 cells. Furthermore, we found that MLT alleviated the inflammatory response, with the mRNA-level reduction of Il-1α, Il-1β, Mcp-1, and Tgf-β1. Taken together, in evaluating the therapeutic effect of MLT on sepsis-induced acute kidney injury, the results showed that MLT alleviated renal damage by regulating the production of ROS.

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Trigonoside II mitigates sepsis-induced myocardial injury via reduction in oxidative stress and regulation of TLR- 4/NF-kB inflammatory pathway

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i6.6 ◽

2020 ◽

Vol 19 (6) ◽

pp. 1161-1166

Author(s):

Fengru Wang ◽

Lili Wu ◽

Qun Liang

Keyword(s):

Oxidative Stress ◽

Myocardial Injury ◽

Caspase 3 ◽

Cecal Ligation ◽

Rat Serum ◽

Inflammatory Pathway ◽

Post Surgery ◽

Tnf Α ◽

Protein Expressions ◽

Cecal Ligation Puncture

Purpose: To investigate the protective effect of trigonoside II against sepsis-induced myocardial injury in rats, and the mechanism involved. Methods: Adult male Sprague Dawley rats (n = 30) weighing 200 - 230 g (mean weight = 215 ± 15 g) were used for this study. The rats were randomly assigned to 3 groups (10 rats/group): sham, cecal ligation puncture (CLP), and trigonoside II. Rats in the treatment group received trigonoside II at a dose of 2 mg/kg intraperitoneally (i.p.) at 3, 12 and 24 h post-surgery. Sepsis was induced using CLP method. Lactate dehydrogenase (LDH) and creatine kinase (CK-MB) activities, and hemodynamic functions were determined in the rats. The levels of interleukin (IL)-1β and IL-6, and tumor necrosis factor α (TNF-α) were assayed in rat serum. Oxidative stress and myocardial cell apoptosis were determined by measuring malondialdehyde (MDA) levels, while activities of glutathione peroxidase (GPx), superoxide dismutase (SOD) and myeloperoxidase (MPO), as well as levels of expression of bax, bcl-2 and caspase-3 were also assessed. Results: Treatment of myocardial injury rats with trigonoside II led to significant reductions in the activities of LDH, CK-MB and MPO, and decreases in levels of IL-1β, IL-6 and TNF-α (p < 0.05). It also significantly reversed the effects of sepsis on rat hemodynamic functions (p < 0.05). Trigonoside IItreatment significantly reduced MDA levels in rat myocardial tissues, but significantly increased SOD and GPx activities (p < 0.05). It significantly down-regulated protein expressions of NF-kB and TLR-4 in myocardial tissues (p < 0.05). The number of apoptotic cells and activity of caspase-3 were significant increased in myocardial tissues of rats in CLP group, when compared with sham group, but were reduced significantly in myocardial tissues of trigonoside II-treated rats (p < 0.05). Similarly, trigonoside II treatment down-regulated the protein expressions of caspase-3 and bax, but upregulated bcl-2 protein expression in the rat myocardial tissues (p < 0.05). Conclusion: The results of this study indicate that trigonoside II confers protection on sepsis-induced myocardial injury via reduction in oxidative stress and regulation of TLR-4/NF-kB inflammatory pathway. Keywords: Cecal ligation puncture, Myocardial injury, Oxidative stress, Sepsis, Trigonoside II

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In vivo observation of mesenteric leukocyte-endothelial interactions after cecal ligation/puncture and surgical sepsis source control

Clinics ◽

10.1590/s1807-59322007000300018 ◽

2007 ◽

Vol 62 (3) ◽

pp. 321-326 ◽

Cited By ~ 7

Author(s):

Naomi K. Nakagawa ◽

José Jukemura ◽

Priscila Aikawa ◽

Rafael A. Nogueira ◽

Luiz F. Poli-de-Figueiredo ◽

...

Keyword(s):

Cecal Ligation ◽

Source Control ◽

Cecal Ligation Puncture

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Vascular endothelial growth factor is an important determinant of sepsis morbidity and mortality

Journal of Experimental Medicine ◽

10.1084/jem.20060375 ◽

2006 ◽

Vol 203 (6) ◽

pp. 1447-1458 ◽

Cited By ~ 180

Author(s):

Kiichiro Yano ◽

Patricia C. Liaw ◽

Janet M. Mullington ◽

Shu-Ching Shih ◽

Hitomi Okada ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Cecal Ligation ◽

Morbidity And Mortality ◽

Vascular Endothelial ◽

Cardiac Physiology ◽

Pathophysiological Role ◽

Cecal Ligation Puncture ◽

Endothelial Growth Factor ◽

Circulating Levels

Sepsis, the systemic inflammatory response to infection, is a leading cause of morbidity and mortality. The mechanisms of sepsis pathophysiology remain obscure but are likely to involve a complex interplay between mediators of the inflammatory and coagulation pathways. An improved understanding of these mechanisms should provide an important foundation for developing novel therapies. In this study, we show that sepsis is associated with a time-dependent increase in circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in animal and human models of sepsis. Adenovirus-mediated overexpression of soluble Flt-1 (sFlt-1) in a mouse model of endotoxemia attenuated the rise in VEGF and PlGF levels and blocked the effect of endotoxemia on cardiac function, vascular permeability, and mortality. Similarly, in a cecal ligation puncture (CLP) model, adenovirus–sFlt-1 protected against cardiac dysfunction and mortality. When administered in a therapeutic regimen beginning 1 h after the onset of endotoxemia or CLP, sFlt peptide resulted in marked improvement in cardiac physiology and survival. Systemic administration of antibodies against the transmembrane receptor Flk-1 but not Flt-1 protected against sepsis mortality. Adenovirus-mediated overexpression of VEGF but not PlGF exacerbated the lipopolysaccharide-mediated toxic effects. Together, these data support a pathophysiological role for VEGF in mediating the sepsis phenotype.

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