Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options

Military Medical Research, Journal Year: 2022, Volume and Issue: 9(1)

Published: Oct. 9, 2022

Sepsis is a common complication of combat injuries and trauma, defined as life-threatening organ dysfunction caused by dysregulated host response to infection. It also one the significant causes death increased health care costs in modern intensive units. The use antibiotics, fluid resuscitation, support therapy have limited prognostic impact patients with sepsis. Although its pathophysiology remains elusive, immunosuppression now recognized major septic death. Sepsis-induced resulted from disruption immune homeostasis. characterized release anti-inflammatory cytokines, abnormal effector cells, hyperproliferation suppressor expression checkpoints. By targeting immunosuppression, especially checkpoint inhibitors, preclinical studies demonstrated reversal immunocyte dysfunctions established resistance. Here, we comprehensively discuss recent findings on mechanisms, regulation biomarkers sepsis-induced highlight their implications for developing effective strategies treat shock.

Language: Английский

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Organelle-specific regulation of ferroptosis

Cell Death and Differentiation, Journal Year: 2021, Volume and Issue: 28(10), P. 2843 - 2856

Published: Aug. 31, 2021

Language: Английский

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GPX4 in cell death, autophagy, and disease

Autophagy, Journal Year: 2023, Volume and Issue: 19(10), P. 2621 - 2638

Published: June 4, 2023

Selenoprotein GPX4 (glutathione peroxidase 4), originally known as PHGPX (phospholipid hydroperoxide glutathione peroxidase), is the main oxidoreductase in use of a reducing agent scavenging lipid peroxidation products. There are three isoforms: cytosolic (cGPX4), mitochondrial (mGPX4), and nuclear (nGPX4), with distinct spatiotemporal expression patterns during embryonic development adult life. In addition to inducing phenotype ferroptosis, loss can some cells trigger apoptosis, necroptosis, pyroptosis, or parthanatos, which mediates accelerates developmental defects, tissue damage, sterile inflammation. The interaction autophagic degradation pathway further modulates cell fate response oxidative stress. Impaired function implicated tumorigenesis, neurodegeneration, infertility, inflammation, immune disorders, ischemia-reperfusion injury. Additionally, R152H mutation promote Sedaghatian-type spinal metaphyseal dysplasia, rare fatal disease newborns. Here, we discuss roles classical functions well emerging GPX4-regulated processes death, autophagy, disease.Abbreviations: AA: arachidonic acid; cGPX4: GPX4; CMA: chaperone-mediated autophagy; DAMPs: danger/damage-associated molecular patterns; mGPX4: nGPX4: GSDMD-N: N-terminal fragment GSDMD; I/R: ischemia-reperfusion; PLOOH: phospholipid hydroperoxide; PUFAs: polyunsaturated fatty acids; RCD: regulated death; ROS: reactive oxygen species; Se: selenium; SSMD: spondylometaphyseal dysplasia; UPS: ubiquitin-proteasome system

Language: Английский

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Carbon Quantum Dots-Based Nanozyme from Coffee Induces Cancer Cell Ferroptosis to Activate Antitumor Immunity

ACS Nano, Journal Year: 2022, Volume and Issue: 16(6), P. 9228 - 9239

Published: May 27, 2022

Carbon quantum dots (CQDs) offer huge potential due to their enzymatic properties as compared natural enzymes. Thus, discovery of CQDs-based nanozymes with low toxicity from resources, especially daily food, implies a promising direction for exploring treatment strategies human diseases. Here, we report biocompatible nanozyme prepared chlorogenic acid (ChA), major bioactive product coffee. We found that ChA CQDs exhibited obvious GSH oxidase-like activities and subsequently promoted cancer cell ferroptosis by perturbation GPX4-catalyzed lipid repair systems. In vivo, dramatically suppressed the tumor growth in HepG2-tumor-bearing mice negligible side toxicity. Particularly, hepatoma H22-bearing mice, recruited massive tumor-infiltrating immune cells including T cells, NK macrophages, thereby converting "cold" "hot" tumors activating systemic antitumor responses. Taken together, our study suggests product-derived coffee can serve biologically safe anticancer therapeutics may aid development nanotechnology-based immunotherapeutic.

Language: Английский

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The role of autophagy in viral infections

Journal of Biomedical Science, Journal Year: 2023, Volume and Issue: 30(1)

Published: Jan. 18, 2023

Autophagy is an evolutionarily conserved catabolic cellular process that exerts antiviral functions during a viral invasion. However, co-evolution and co-adaptation between viruses autophagy have armed with multiple strategies to subvert the autophagic machinery counteract responses. Specifically, host cell quickly initiates degrade virus particles or components upon infection, while cooperating anti-viral interferon response inhibit replication. Degraded virus-derived antigens can be presented T lymphocytes orchestrate adaptive immune response. Nevertheless, some evolved ability in order evade degradation Others induce autophagy, but then hijack autophagosomes as replication site, secretion pathway promote maturation egress of particles, thereby increasing transmission efficiency. Interestingly, different unique types selective such exploiting regulate organelle degradation, metabolic processes, In short, this review focuses on interaction viruses, explaining how serves roles either proviral functions.

Language: Английский

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The interaction between STING and NCOA4 exacerbates lethal sepsis by orchestrating ferroptosis and inflammatory responses in macrophages

Cell Death and Disease, Journal Year: 2022, Volume and Issue: 13(7)

Published: July 28, 2022

Abstract The discovery of STING-related innate immunity has recently provided a deep mechanistic understanding immunopathy. While the detrimental effects STING during sepsis had been well documented, exact mechanism by which causes lethal remains obscure. Through single-cell RNA sequence, genetic approaches, and mass spectrometry, we demonstrate that promotes sepsis-induced multiple organ injury inducing macrophage ferroptosis in cGAS- interferon-independent manner. Mechanistically, Q237, E316, S322 CBD domain are critical binding sites for interaction with coiled-coil NCOA4. Their not only triggers ferritinophagy-mediated ferroptosis, but also maintains stability dimers leading to enhanced inflammatory response, reduces nuclear localization NCOA4, impairs transcription factor coregulator function Meanwhile, identified HET0016 high throughput screening, selective 20-HETE synthase inhibitor, decreased STING-induced peripheral blood mononuclear cells from patients mortality septic mice model. Our findings uncover novel between NCOA4 regulates immune response can be reversed HET0016, providing promising targets insights into sepsis.

Language: Английский

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The expanding role for small molecules in immuno-oncology

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(11), P. 821 - 840

Published: Aug. 18, 2022

Language: Английский

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STING mediates hepatocyte pyroptosis in liver fibrosis by Epigenetically activating the NLRP3 inflammasome

Redox Biology, Journal Year: 2023, Volume and Issue: 62, P. 102691 - 102691

Published: March 29, 2023

The activation of stimulator interferon genes (STING) and NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnections between these epigenetic regulation STING-NLRP3 axis hepatocyte during fibrosis remain unknown. STING NLRP3 inflammasome are activated fibrotic livers but suppressed by Sting knockout. knockout ameliorated hepatic pyroptosis, inflammation, fibrosis. In vitro, induces primary murine hepatocytes activating inflammasome. H3K4-specific histone methyltransferase WD repeat-containing 5 (WDR5) DOT1-like H3K79 (DOT1L) identified to regulate expression STING-overexpressing AML12 hepatocytes. WDR5/DOT1L-mediated methylation enhances regulatory transcription factor (IRF3) binding Nlrp3 promoter promotes STING-induced Moreover, hepatocyte-specific deletion downstream Gasdermin D (Gsdmd) attenuate RNA-sequencing metabolomics analysis show that oxidative stress metabolic reprogramming might participate NLRP3-mediated STING-NLRP3-GSDMD inhibition suppresses ROS generation. conclusion, this study describes a novel mechanism which STING-WDR5/DOT1L/IRF3-NLRP3 pathway inflammation

Language: Английский

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Autophagy-Dependent Ferroptosis in Cancer

Antioxidants and Redox Signaling, Journal Year: 2023, Volume and Issue: 39(1-3), P. 79 - 101

Published: Feb. 3, 2023

Significance: Autophagy is a self-degrading process that determines cell fate in response to various environmental stresses. In contrast autophagy-mediated survival, the signals, mechanisms, and effects of autophagy-dependent death remain obscure. The discovery ferroptosis provides paradigm for understanding relationship between aberrant degradation pathways excessive lipid peroxidation driving regulated death. Recent Advances: Ferroptosis was originally described as an autophagy-independent iron-mediated nonapoptotic Current studies reveal level intracellular autophagy positively correlated with sensitivity. Selective autophagic proteins (e.g., ferritin, SLC40A1, ARNTL, GPX4, CDH2) or organelles droplets mitochondria) promotes by inducing iron overload and/or peroxidation. Several upstream autophagosome regulators TMEM164), downstream receptors HPCAL1), danger signals DCN) are selectively required ferroptosis-related autophagy, but not starvation-induced autophagy. induction effective approach eliminate drug-resistant cancer cells. Critical Issues: How different activate modulate sensitivity fully understood. Identifying direct protein effectors ferroptotic remains challenge. Future Directions: Further molecular mechanics immune consequences critical development precision antitumor therapies. Antioxid. Redox Signal. 39, 79-101.

Language: Английский

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Interrelation between Programmed Cell Death and Immunogenic Cell Death: Take Antitumor Nanodrug as an Example

Small Methods, Journal Year: 2023, Volume and Issue: 7(5)

Published: Jan. 27, 2023

Abstract Programmed cell death (PCD, mainly including apoptosis, necrosis, ferroptosis, pyroptosis, and autophagy) immunogenic (ICD), as important mechanisms, are widely reported in cancer therapy, understanding the relationship between two is significant for clinical tumor treatments. Considering that vast nanodrugs developed to induce PCD ICD simultaneously, this review, interrelationship described using nanomedicines examples. First, an overview of patterns focus on morphological differences interconnections among them provided. Then apoptosis terms endoplasmic reticulum stress by introducing various treatments recent developments with inducible immunogenicity. Next, crosstalk non‐apoptotic (including signaling pathways introduced their through examples further illustrated. Finally, its application prospects development new nanomaterials summarized. This review believed deepen ICD, extend biomedical applications nanodrugs, promote progress therapy.

Language: Английский

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