Oxidant/Antioxidant Status Is Impaired in Sepsis and Is Related to Anti-Apoptotic, Inflammatory, and Innate Immunity Alterations

Miliaraki, Marianna; Briassoulis, Panagiotis; Ilia, Stavroula; Michalakakou, Kalliopi; Karakonstantakis, Theodoros; Polonifi, Aikaterini; Bastaki, Kalliopi; Briassouli, Efrossini; Vardas, Konstantinos; Pistiki, Aikaterini; Θεοδωρακοπούλου, Μαρία; Tavladaki, Theonymfi; Spanaki, Anna‐Maria; Kondili, Eumorfia; Dimitriou, Helen; Venihaki, Maria; Tsiodras, Sotirios; Georgopoulos, Dimitrios; Mantzourani, Marina; Nanas, Serafeim; Armaganidis, Apostolos; Daikos, George L.; Papassotiriou, Ioannis; Briassoulis, George

doi:10.3390/antiox11020231

Cited by 17 publications

(14 citation statements)

References 73 publications

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“…The cellular redox status is determined by the balance between antioxidants and oxidants. The oxidative state of the cell is defined by an imbalance between these two, which can result in apoptosis or necrosis [ 1 ]. Reactive oxygen species (ROS) are primarily responsible for the high susceptibility of brain cells to oxidative stress [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Ethnopharmacological Effects of Urtica dioica, Matricaria chamomilla, and Murraya koenigii on Rotenone-Exposed D. melanogaster: An Attenuation of Cellular, Biochemical, and Organismal Markers

et al. 2022

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Natural antioxidants derived from plants have been proven to have significant inhibitory effects on the free radicals of living organisms during actively metabolization. Excessive production of free radicals increases the risk of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and motor sclerosis. This study aimed to compare the ethnopharmacological effects of Urtica dioica (UD), Matricaria chamomilla (MC), and Murraya koenigii (MK) on the amelioration of rotenone-induced toxicity in wild-type Drosophila melanogaster (Oregon R+) at biochemical, cellular, and behavioral levels. Phytoextracts were prepared from all three plants, i.e., UD, MC, and MK (aqueous and ethanolic fractions), and their bioactive compounds were evaluated using in vitro biochemical parameters (DPPH, ABTS, TPC, and TFC), UV-Vis, followed by FT-IR and HPLC. Third instar larvae and freshly eclosed flies were treated with 500 µM rotenone alone or in combination with UD, MC, and MK for 24 to 120 h. Following exposure, cytotoxicity (dye exclusion test), biochemical (protein estimation and acetylcholinesterase inhibition assays), and behavioral assays (climbing and jumping assays) were performed. Among all three plant extracts, MK exhibited the highest antioxidant properties due to the highest TPC, TFC, DPPH, and ABTS, followed by UD, then MC. The overall trend was MK > UD > MC. In this context, ethnopharmacological properties mimic the same effect in Drosophila, exhibiting significantly (p < 0.05) reduced cytotoxicity (trypan blue), improved biochemical parameters (proteotoxicity and AChE activity), and better behavioral parameters in the organisms cotreated with phyto extracts compared with rotenone. Conclusively, UV-Vis, FTIR, and HPLC analyses differentiated the plant extracts. The findings of this research may be beneficial in the use of select herbs as viable sources of phyto-ingredients that could be of interest in nutraceutical development and various clinical applications.

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Section: Introductionmentioning

confidence: 99%

Ethnopharmacological Effects of Urtica dioica, Matricaria chamomilla, and Murraya koenigii on Rotenone-Exposed D. melanogaster: An Attenuation of Cellular, Biochemical, and Organismal Markers

et al. 2022

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“…It was also found that these factors are related to anti-apoptotic, inflammatory, and innate immunity alterations in sepsis. 53 Therefore, the relationship between these three signaling pathways and the subsequent release of eCIRP and eCIRP-induced inflammation, as well as the extent that modulating necroptosis will have on these pathways/inflammatory phenomena remain areas for future investigation.…”

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confidence: 99%

Necroptosis-Mediated eCIRP Release in Sepsis

Reilly¹,

Tan²,

Murao³

et al. 2022

JIR

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Extracellular cold-inducible RNA-binding protein (eCIRP) is an endogenous pro-inflammatory mediator that exacerbates injury in inflammation and sepsis. The mechanisms in which eCIRP is released have yet to be fully explored. Necroptosis is a programmed cell death that is dependent on the activation of mixed lineage kinase domain-like pseudo kinase (MLKL) which causes the release of damage-associated molecular patterns. We hypothesize that eCIRP is released through necroptosis and intensifies inflammation in sepsis. Methods: RAW264.7 cells were treated with pan-caspase inhibitor z-VAD (15 μM) 1 h before stimulation with LPS (1 μg/mL). Necroptosis inhibitor, Necrostatin-1 (Nec-1) (10 μM) was added to the cells with LPS simultaneously. After 24 h of LPS stimulation, cytotoxicity was determined by LDH assay. eCIRP levels in the culture supernatants and phospho-MLKL (p-MLKL) from cell lysates were assessed by Western blot. p-MLKL interaction with the cell membrane was visualized by immunofluorescence. Sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). Mice were treated with Nec-1 (1 mg/kg) or DMSO. 20 h post-surgery, serum and peritoneal fluid levels of eCIRP, TNF-α and IL-6 were determined by ELISA. H&E staining of lung tissue sections was performed. Results: We found that in RAW264.7 cells, LPS+z-VAD induces necroptosis as evidenced by an increase in p-MLKL levels and causes eCIRP release. Nec-1 reduces both p-MLKL activation and eCIRP release in LPS+z-VAD-treated RAW264.7 cells. Nec-1 also inhibits the release of eCIRP, TNF-α and IL-6 in the serum and peritoneal fluid in CLP-induced septic mice. We predicted a transient interaction between eCIRP and MLKL using a computational model, suggesting that eCIRP may exit the cell via the pores formed by p-MLKL. Conclusion:Necroptosis is a novel mechanism of eCIRP release in sepsis. Targeting necroptosis may ameliorate inflammation and injury in sepsis by inhibiting eCIRP release.

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“…Oxidative stress, a significant promoter and mediator of the systemic inflammatory response, is considered crucial in the pathophysiology of sepsis 60. The early phase of sepsis is characterised by an excessive formation of ROS and RNS, including superoxide and nitric oxide.…”

Section: Discussionmentioning

confidence: 99%

Adjuvant Lipoic acid Injection in Sepsis treatment in China (ALIS study): protocol for a randomised, single-blind, placebo-controlled trial

Hu¹,

Zhou²,

Huang³

et al. 2023

BMJ Open

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IntroductionSepsis is a life-threatening immune disorder resulting from an dysregulated host response to infection. Adjuvant therapy is a valuable complement to sepsis treatment. Lipoic acid has shown potential in attenuating sepsis-induced immune dysfunction and organ injury in vivo and in vitro studies. However, clinical evidence of lipoic acid injection in sepsis treatment is lacking. Hence, we devised a randomised controlled trial to evaluate the efficacy and safety of lipoic acid injection in improving the prognosis of sepsis or septic shock patients.Methods and analysisA total of 352 sepsis patients are planned to be recruited from intensive care units (ICUs) at eight tertiary hospitals in China for this trial. Eligible participants will undergo randomisation in a 1:1 ratio, allocating them to either the control group or the experimental group. Both groups received routine care, with the experimental group also receiving lipoic acid injection and the control group receiving placebo. The primary efficacy endpoint is 28-day all-cause mortality. The secondary efficacy endpoints are as follows: ICU and hospital mortality, ICU and hospital stay, new acute kidney injury in ICU, demand and duration of life support, Sequential Organ Failure Assessment (SOFA)/Acute Physiology and Chronic Health Evaluation II (APACHE II) and changes from baseline (ΔSOFA/ΔApache II), arterial blood lactate (LAC) and changes from baseline (ΔLAC), blood procalcitonin, high-sensitivity C-reactive protein, interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) and changes from baseline on day 1 (D1), D3, D5 and D7. Clinical safety will be assessed through analysis of adverse events.Ethics and disseminationThe study was approved by the Ethics Committee of Maoming People’s Hospital (approval no. PJ2020MI-019-01). Informed consent will be obtained from the participants or representatives. The findings will be disseminated through academic conferences or journal publications.Trial registrationChiCTR2000039023.

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Oxidant/Antioxidant Status Is Impaired in Sepsis and Is Related to Anti-Apoptotic, Inflammatory, and Innate Immunity Alterations

Cited by 17 publications

References 73 publications

Ethnopharmacological Effects of Urtica dioica, Matricaria chamomilla, and Murraya koenigii on Rotenone-Exposed D. melanogaster: An Attenuation of Cellular, Biochemical, and Organismal Markers

Ethnopharmacological Effects of Urtica dioica, Matricaria chamomilla, and Murraya koenigii on Rotenone-Exposed D. melanogaster: An Attenuation of Cellular, Biochemical, and Organismal Markers

Necroptosis-Mediated eCIRP Release in Sepsis

Adjuvant Lipoic acid Injection in Sepsis treatment in China (ALIS study): protocol for a randomised, single-blind, placebo-controlled trial

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