Flavonoids as Anticancer Agents

Nutrients, Год журнала: 2020, Номер 12(2), С. 457 - 457

Опубликована: Фев. 12, 2020

Flavonoids are polyphenolic compounds subdivided into 6 groups: isoflavonoids, flavanones, flavanols, flavonols, flavones and anthocyanidins found in a variety of plants. Fruits, vegetables, plant-derived beverages such as green tea, wine cocoa-based products the main dietary sources flavonoids. have been shown to possess wide anticancer effects: they modulate reactive oxygen species (ROS)-scavenging enzyme activities, participate arresting cell cycle, induce apoptosis, autophagy, suppress cancer proliferation invasiveness. dual action regarding ROS homeostasis—they act antioxidants under normal conditions potent pro-oxidants cells triggering apoptotic pathways downregulating pro-inflammatory signaling pathways. This article reviews biochemical properties bioavailability flavonoids, their activity its mechanisms action.

Язык: Английский

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Emerging connectivity of programmed cell death pathways and its physiological implications

Nature Reviews Molecular Cell Biology, Год журнала: 2020, Номер 21(11), С. 678 - 695

Опубликована: Сен. 1, 2020

Язык: Английский

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Cuproptosis: a copper-triggered modality of mitochondrial cell death

Cell Research, Год журнала: 2022, Номер 32(5), С. 417 - 418

Опубликована: Март 30, 2022

Язык: Английский

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Targeting immunogenic cell death in cancer

Molecular Oncology, Год журнала: 2020, Номер 14(12), С. 2994 - 3006

Опубликована: Ноя. 12, 2020

Immunogenic cell death (ICD) is a type of cancer triggered by certain chemotherapeutic drugs, oncolytic viruses, physicochemical therapies, photodynamic therapy, and radiotherapy. It involves the activation immune system against in immunocompetent hosts. ICD comprises release damage-associated molecular patterns (DAMPs) from dying tumor cells that result tumor-specific responses, thus eliciting long-term efficacy anticancer drugs combining direct killing antitumor immunity. Remarkably, subcutaneous injection undergoing has been shown to provoke vaccine effects vivo. DAMPs include surface exposure calreticulin (CRT) heat-shock proteins (HSP70 HSP90), extracellular adenosine triphosphate (ATP), high-mobility group box-1 (HMGB1), I IFNs members IL-1 cytokine family. In this review, we discuss modalities connected ICD, exposed during mechanism which they activate system. Finally, therapeutic potential challenges harnessing immunotherapy.

Язык: Английский

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Mitochondrial DNA in inflammation and immunity

EMBO Reports, Год журнала: 2020, Номер 21(4)

Опубликована: Март 23, 2020

Review23 March 2020Open Access Mitochondrial DNA in inflammation and immunity Joel S Riley Corresponding Author [email protected] orcid.org/0000-0001-9170-5716 Cancer Research UK Beatson Institute, Glasgow, Institute of Sciences, University Search for more papers by this author Stephen WG Tait orcid.org/0000-0001-7697-132X Information *,1,2 1Cancer 2Institute *Corresponding author. Tel: +44 141 330 6283; E-mail: 8703; EMBO Reports (2020)21:e49799https://doi.org/10.15252/embr.201949799 See the Glossary abbreviations used article. PDFDownload PDF article text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Mitochondria are cellular organelles that orchestrate a vast range biological processes, from energy production metabolism cell death inflammation. Despite seemingly symbiotic relationship, mitochondria harbour within them potent agonist innate immunity: their own genome. Release mitochondrial into cytoplasm out extracellular milieu activates plethora different pattern recognition receptors immune responses, including cGAS-STING, TLR9 inflammasome formation leading to, among others, robust type I interferon responses. In Review, we discuss how mtDNA can be released mitochondria, various inflammatory pathways triggered release its myriad consequences health disease. 5hmC 5-Hydroxymethylcytosine 5mC 5-Methylcytosine AGS Aicardi–Goutieres syndrome AIM2 Absent melanoma 2 APC Antigen-presenting ASC Apoptosis-associated speck-like protein containing CARD ATP Adenosine triphosphate BAK Bcl-2 homologous antagonist/killer BAX Bcl-2-associated X BID BH3 interacting-domain Caspase activation recruitment domain CD47 Cluster differentiation 47 CDN Cyclic dinucleotide cGAMP guanosine monophosphate–adenosine monophosphate cGAS GMP-AMP synthase CLR C-type lectin receptor CMPK2 Cytidine/Uridine kinase DAMP Damage-associated molecular DC Dendritic DNase Deoxyribonuclease dsDNA Double-stranded ER Endoplasmic reticulum EV Extracellular vesicle GTP Guanosine-5′-triphosphate HMGB1 High-mobility group 1 HSV-1 Herpes simplex virus-1 IAP Inhibitor apoptosis IFNAR Interferon-α/β IFN-β Interferon-β IFN-γ Interferon-γ IL-18 Interleukin-18 IL-1R Interleukin-1 IL-1β Interleukin-1β IL-6 Interleukin-6 IRF3 Interferon regulatory factor 3 ISG Interferon-stimulated gene K+ Potassium LPS Lipopolysaccharide LRR Leucine-rich repeat MAPK Mitogen-activated MAVS anti-viral signalling MDA5 Melanoma differentiation-associated 5 MEF Mouse embryonic fibroblast MiDAS dysfunction-associated senescence MI Myocardial infarction MOMP outer membrane permeabilisation mPTP permeability transition pore NASH Non-alcoholic fatty liver disease NET Neutrophil trap NF-κB Nuclear kappa-light-chain-enhancer activated B cells NLRC4 NLR Family Domain Containing 4 Nucleotide oligomerisation domain-like NLRP1 Pyrin NLRP3 NACHT, PYD domain-containing NOD ODN Oligodeoxynucleotide OPA1 Optic Atrophy Dynamin Like GTPase PAMP Pathogen-associated pDC Plasmacytoid dendritic PD-L1 Programmed death-ligand PINK1 Phosphatase tensin homolog-induced PMA Phorbol 12-myristate 13-acetate PNPase Polynucleotide phosphorylase PRR Pattern RAGE Receptor advanced glycation endproducts RIG-I Retinoic acid-inducible RIP1 Receptor-interacting serine/threonine-protein RLR gene-I-like RNP IC Ribonucleotide complex ROS Reactive oxygen species SAMDH1 Sterile alpha motif HD SIRS Systemic response SLE lupus erythematosus ssDNA Single-stranded STING Stimulator genes SUV3 Suppressor Var1 TBK1 TANK-binding TFAM Transcription A, Toll-like 9 TLR TNF Tumour necrosis TREX1 Three Prime Repair Exonuclease tRNA Transfer RNA VDAC Voltage-dependent anion channel Introduction Serving as first line defence, system guards us against insults invading microorganisms. Infection pathogenic agents is detected (PRRs) which recognise specific pathogen-associated patterns (PAMPs). PRRs broadly classified four distinct groups: NOD-like (NLRs), (TLRs), retinoic gene-I (RIG-I)-like (RLRs) (CLRs) 1. Upon detection PAMP, initiate multitude pathways, culminate up-regulation interferons, pro-inflammatory chemokines cytokines. These prime adaptive create hostile environment microorganism survive. Additionally, damage-associated (DAMPs) triggers arise itself, such proteins or DNA, activate 2. appeared eukaryotic about two billion years ago α-proteobacterium, what thought an endosymbiotic relationship 3, 4. Over time, these bacteria evolved become much-studied organelle know today, playing crucial roles metabolism, calcium homeostasis death. Nevertheless, they have maintained independent genome, encodes 37 genes, comprised 13 mRNAs forming key components oxidative phosphorylation system, addition ribosomal 22 tRNAs An estimated 1,000 located all which, except those encoded mtDNA, translated cytosol imported 5. itself circular molecule double-stranded (ds)DNA. both heavy light strand results long, full-length transcripts processed RNase enzymes produce mature mRNA, RNA. mammals, polymerase responsible replication γ, but POLγ cannot replicate dsDNA, helicase Twinkle required act directly before unwind structure. Newly synthesised single-stranded (ss)DNA bound DNA-binding prevent secondary structure attack nucleases. has recently been reviewed extensively elsewhere 6; here, focus on unique aspects make it immunostimulatory. We will then ejected under circumstances cGAS-STING signalling, inflammasomes receptors. also role neutrophil traps (NETs) transfer between cells. stimulator Potentially stemming bacterial origin, sensed "foreign", suggesting seen differently "self" One example methylation status, where many studies reported hypomethylated compared nuclear 7, 8, despite presence methyltransferases 9, 10. Some groups aberrant 5-methylcytosine (5mC) 5-hydroxymethylcytosine (5hmC) at CpG motifs 9-14, although others proposed technical limitations work using sensitive techniques report devoid 15. Clearly, effort determining precise degree if showing absence correct, would unmethylated similar could potentially TLR9, absent (AIM2) 15-18. transcription may represent rich source potential activators receptors; example, RNA:DNA hybrids form during transcription, long stretches R-loops composed with non-template recognised 16. exists matrix close proximity electron transport chain, major reactive species. Due this, particularly vulnerable oxidation, resulting mutations contribute pathogenesis cancer 17, diabetes 18 ageing 19. It was had limited capacity repair mtDNA; however, multiple now well characterised 20. often schematically represented plasmid structure; over-simplification. Rather, super-resolution imaging revealed densely compacted nucleoids consisting one copy number 21, most notable A (mtTFA, commonly referred TFAM). might assumed compaction structures shields recognition, not case shall further fact, shown immunostimulatory 13, 14. landmark study 2004, Collins et al found injecting joints mice resulted localised arthritis. Further investigation dependent oxidatively damaged bases injection oligodeoxynucleotide (ODN) same sequence without oxidised residue no effect. The observation elicit responses opened whole new field research, appreciated stimulate PRRs, cGAS, (Fig 1). subsequent occurs infection, neurodegeneration, rest Review. Figure Overview engaged DNAMitochondrial (mtDNA) trigger endosomal via cytosolic (AIM2 NLRP3). Top: binds endosome eliciting NF-κB-dependent program. Middle: recognises endoplasmic (ER)-localised triggering response. Bottom: mtDNA-dependent activity leads caspase-1-dependent maturation IL-1 IL-8. Download figure PowerPoint infection Through necessity, elegant systems detect DNA. (cGAS) direct detector, dimer 23, 24. undergoes conformational change facilitates conversion 2′3′-cyclic (cGAMP) 25-31. second messenger, (ER)-resident (STING) inducing C-terminal tail. (TBK1) recruited phosphorylates (IRF3), hundreds stimulatory (ISGs) potently 32 2). primarily avoid persistent self-DNA nucleus, recent present nucleus 33, 34 plasma 35. attempt resolve discrepancies Volkmann 36 reveals model than sensing paradigm. authors show majority nuclear, propose must "desequestered" prior full activation. However, remains unclear tethered compartment. were able 37-39. White Rongvaux explored context (discussed later Review), whereas West provided evidence deficiency promotes stress mis-packaged ejection bind initiating 39 Of pathophysiological relevance, (HSV-1) vesicular stomatitis virus (VSV) stress, depletion entrance cytoplasm. cytoplasmic conferring state cell. Importantly, Tfam+/− cells, exhibit resistant VSV wild-type heightened expression owing release. Mechanistically, nuclease, UL12.5, localises degrades complete loss infected 40, 41. Removal does appear impact HSV 42. Furthermore, exonuclease effective viral maintain cell-to-cell infectivity, though whether related UL12.5's mtDNA-targeted nuclease unknown 43. signallingVarious stresses lead Alternatively, (MOMP) Once cytoplasmic, catalyses messenger 2′3′ cyclic GMP–AMP (2′3′cGAMP) GTP. adaptor kinase. Active Curiously, viruses, dengue virus, elicits response, being DNA-specific 44. Several causes predominantly cytosol, 45, 46 47. Dengue strategies circumvent mtDNA-induced encoding proteases target degradation, thus ensuring persistence 46, 48, 49. pathogen Mycobacterium tuberculosis IRF3-dependent 50-52. This solely due mycobacterium other identified ensuing 53. strain-dependent dynamics M. tuberculosis-induced mtDNA. Previous observed cytochrome c tuberculosis, indicating there possible BAX/BAK-dependent detail later) infection-related 54 Pathogen-infected secrete Aarreberg discovers link secretion cGAS-STING-dependent surrounding bystander Interestingly, stimulation increases mass, decreases induces 55. detectable death, mechanism release, rule (see below). time implicated cell-intrinsic defence 56-58, suggest plays initiation During programmed pro-apoptotic permeabilise allow passage molecules move inner space caspase cascade, rapid 59. showed apoptotic activation, promiscuous manner, vivo mildly elevated levels blood, level sufficient induce interferon-stimulated 37, 38 3). suggests caspases play dampening dying maintaining "immune-silent" nature cleave (MAVS), 60, supporting notion dampen High-resolution expanded our understanding membrane, inhibition pores grow dramatically, herniation extrusion 61-63 caspase-inhibited conditions, down-regulation inhibitor (IAPs), NF-κB-inducing (NIK) transcriptional program, release-induced 64. cytokines up-regulated after serve promote macrophage 64, 65. anti-tumour effects, highlighting therapeutic treatment Collectively, help reconcile unresolved questions remain. Firstly, regulated process, so, how? size small ions minutes 61, insufficient nucleoid probably only transient, 66-69. Secondly, differences permeabilisation, varying degrees 62, implying factors permeabilisation. Finally, physiological relevance death-related unknown. Most types undergo caspase-dependent vivo, presumably limiting any mtDNA-driven some types, instance cardiomyocytes, display deficient downstream 70. Such generate greater healthy serving "early warning" instructing transcribe important survival 4) 71, 72. 3. inflammationFollowing enables caspase-activating intermembrane space. Following macropores causing membrane. (dsRNA) released. Collective MAVS, NF-κB. anti-inflammatory, part, through cleavage inactivation molecules. Non-cell autonomous effects mtDNA(A) encounter, neutrophils extrude (both mitochondrial) forms microbes. properties, pathological diseases lupus. (B) exosomes intact neighbouring impacting recipient Inflammatory non-cell effects. cGAS-induced gap junctions possess dsRNA known immunogenic 73. arises lights strands rapidly degraded not, nearly origin. polynucleotide accumulation dsRNA, when depleted, accumulates driven 74. Silencing suppresses strongly escape 74 patients decrease PNPT1, protein, serum event, spreading BAX/BAK pores, culminating conditions sub-lethal called minority MOMP, genomic instability transformation 75. Brokatsky invasion machinery 76. study, pathogens nevertheless can, (presumably pores), stimulating cytokine How else mitochondria? Another (mPTP) 77, 78. exact composition unclear, seems consensus cyclophilin D 79. spans high concentration stresses. predicted efflux smaller 1.5 kDa, much 80, 81. fragments pass 82, 83. sustained opening swelling rupture permit involvement ruled chitosan, vaccine adjuvant, appears cGAS-STING- mPTP-dependent possibly rigorously assessed 84. intriguing experiencing caused lack endonuclease G formed oligomers voltage-dependent (VDAC) 85. As 86, 87, tested lupus-like Using VDAC1 VBIT-4, reduce symptoms lupus-prone mice, providing rationale VDAC-mediated Therapeutic targeting There currently intense interest development inhibitors pathway, depending humans, systemic Aicardi–Goutières (AGS) involved 88. For TREX1, exonuclease, frequently mutated human (SLE) 89-91, co-deletion STING, (IFNAR) rescues phenotype 92-98. Accumulation defining characteristic SLE, deletions DNA- RNA-related SAMDH1, RnaseH2 frequent 99-102. Gain-of-function 103, 104. II humans autoinflammation increased IFN 105 arthritis 106. degradation dead engulfed macrophages 98, 106, 107, 108, 109 contribution TLRs 108. (MI) another condition involve strong component. King 110 ischaemic engulfment drives Genetic pharmacological disruption improved outcomes post-MI, proposing axis suitable intervention 110, 111. While clear per se, heart 112-114. inhibiting pathway settings beneficial patients. Small 115, 116 117 developed, antag

Язык: Английский

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Mitochondrial control of inflammation

Nature reviews. Immunology, Год журнала: 2022, Номер 23(3), С. 159 - 173

Опубликована: Июль 25, 2022

Язык: Английский

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Regulated cell death (RCD) in cancer: key pathways and targeted therapies

Signal Transduction and Targeted Therapy, Год журнала: 2022, Номер 7(1)

Опубликована: Авг. 13, 2022

Regulated cell death (RCD), also well-known as programmed (PCD), refers to the form of that can be regulated by a variety biomacromolecules, which is distinctive from accidental (ACD). Accumulating evidence has revealed RCD subroutines are key features tumorigenesis, may ultimately lead establishment different potential therapeutic strategies. Hitherto, targeting with pharmacological small-molecule compounds been emerging promising avenue, rapidly progressed in many types human cancers. Thus, this review, we focus on summarizing not only apoptotic and autophagy-dependent signaling pathways, but crucial pathways other subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis lysosome-dependent (LCD) cancer. Moreover, further discuss current situation several improve cancer treatment, such single-target, dual or multiple-target compounds, drug combinations, some new strategies would together shed light future directions attack vulnerabilities drugs for purposes.

Язык: Английский

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Signaling pathways and defense mechanisms of ferroptosis

FEBS Journal, Год журнала: 2021, Номер 289(22), С. 7038 - 7050

Опубликована: Июнь 6, 2021

As a type of lytic cell death driven by unrestricted lipid peroxidation and subsequent plasma membrane damage, ferroptosis occurs develops because sophisticated signals regulatory mechanisms. The reactive oxygen species (ROS) used to initiate come from variety sources, including iron‐mediated Fenton reactions, mitochondrial ROS, membrane‐associated ROS the NOX protein family. Polyunsaturated fatty acid‐containing phospholipids are main substrates in ferroptosis, which is positively regulated enzymes, such as ACSL4, LPCAT3, ALOXs, or POR. Selective activation autophagic degradation pathways promotes increasing iron accumulation cause peroxidation. In contrast, system xc – ‐glutathione–GPX4 axis plays central role limiting peroxidation, although other antioxidants (such coenzyme Q10 tetrahydrobiopterin) can also inhibit ferroptosis. A nuclear mechanism defense against NFE2L2‐dependent antioxidant response transcriptionally upregulating expression cytoprotective genes. Additionally, damage caused ferroptotic stimulus be repaired ESCRT‐III‐dependent scission machinery. this review, we summarize recent progress understanding signaling mechanisms

Язык: Английский

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Hallmarks of Health

Cell, Год журнала: 2020, Номер 184(1), С. 33 - 63

Опубликована: Дек. 18, 2020

Язык: Английский

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Breakdown of an Ironclad Defense System: The Critical Role of NRF2 in Mediating Ferroptosis

Cell chemical biology, Год журнала: 2020, Номер 27(4), С. 436 - 447

Опубликована: Апрель 1, 2020

Ferroptosis is a non-apoptotic mode of regulated cell death that iron and lipid peroxidation dependent. As new mechanistic insight into ferroptotic effectors how they are in different disease contexts uncovered, our understanding the physiological pathological relevance this continues to grow. Along these lines, host pharmacological modulators pathway have been identified, targeting proteins involved homeostasis; generation reduction peroxides; or cystine import glutathione metabolism. Also, note, many components ferroptosis cascade target genes transcription factor nuclear erythroid 2-related 2 (NRF2), indicating its critical role mediating response. In review, we discuss vitro, vivo, clinical evidence disease, including brief discussion upstream mediators cascade, NRF2, treat ferroptosis-driven diseases.

Язык: Английский

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