Inflammation and tumor progression: signaling pathways and targeted intervention

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: July 12, 2021

Abstract Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses tumor progression, potentially displaying opposing effects on therapeutic outcomes. Chronic inflammation facilitates progression treatment resistance, whereas induction of acute inflammatory reactions often stimulates the maturation dendritic cells (DCs) antigen presentation, leading anti-tumor immune responses. In addition, multiple signaling pathways, such as nuclear factor kappa B (NF-kB), Janus kinase/signal transducers activators transcription (JAK-STAT), toll-like receptor (TLR) cGAS/STING, mitogen-activated protein kinase (MAPK); factors, including cytokines (e.g., interleukin (IL), interferon (IFN), necrosis (TNF)-α), chemokines C-C motif chemokine ligands (CCLs) C-X-C (CXCLs)), growth factors vascular endothelial (VEGF), transforming (TGF)-β), inflammasome; well metabolites prostaglandins, leukotrienes, thromboxane, specialized proresolving mediators (SPM), have been identified pivotal regulators initiation resolution inflammation. Nowadays, local irradiation, recombinant cytokines, neutralizing antibodies, small-molecule inhibitors, DC vaccines, oncolytic viruses, TLR agonists, SPM developed specifically modulate in cancer therapy, with some these already undergoing clinical trials. Herein, we discuss crosstalk between processes. We also highlight potential targets for harnessing cancer.

Language: Английский

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Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications

Medicinal Research Reviews, Journal Year: 2021, Volume and Issue: 42(1), P. 259 - 305

Published: May 6, 2021

Abstract Ischemic stroke caused by arterial occlusion is the most common type of stroke, which among frequent causes disability and death worldwide. Current treatment approaches involve achieving rapid reperfusion either pharmacologically or surgically, both are time‐sensitive; moreover, blood flow recanalization often ischemia/reperfusion injury. However, even though neuroprotective intervention urgently needed in event exact mechanisms neuronal during ischemic still unclear, consequently, capacity for drug development has remained limited. Multiple cell pathways implicated pathogenesis stroke. Here, we have reviewed these potential pathways, including intrinsic extrinsic apoptosis, necroptosis, autophagy, ferroptosis, parthanatos, phagoptosis, pyroptosis. We also latest results pharmacological studies on summarized emerging targets with a focus clinical trials. These observations may help to further understand pathological events bridge gap between basic translational research reveal novel interventions.

Language: Английский

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The NLRP3 inflammasome drives inflammation in ischemia/reperfusion injury after transient middle cerebral artery occlusion in mice

Brain Behavior and Immunity, Journal Year: 2020, Volume and Issue: 92, P. 221 - 231

Published: Dec. 9, 2020

Cerebral ischemia induces a profound neuro-inflammatory response, but the underlying molecular mechanisms are poorly understood. Inflammasomes (NLRP1, NLRP3, NLRC4, AIM2) intracellular multi-protein complexes which can induce sets of pro-inflammatory cyto- and chemokines, thereby guide inflammation. We, here, assessed functional role NLRP3 in ischemia/reperfusion (I/R) injury mouse model transient cerebral ischemia.Ischemic stroke was induced C57Bl/6 mice by 60 min middle artery occlusion (tMCAO) 3, 7 or 23 h reperfusion, paradigm I/R injury. The expression patterns inflammasomes ischemic hemispheres were evaluated semiquantitative real-time PCR Western Blot analysis accompanied protein localization using immunocytochemistry. Finally, animals treated with inflammasome inhibitors Sulforaphane, Genipin, MCC950 vehicle, directly before upon recanalization after tMCAO. Stroke outcome assessed, including infarct size deficits, local inflammatory neuronal survival as well blood-brain barrier function on day 1 tMCAO.After tMCAO relative gene levels increased 20-30x within hemisphere translated into an neurons. Accordingly, NLRP3-modulator, Bruton's Tyrosine Kinase (BTK), NLRP3-inducible cytokine IL-1β significantly rose. Lesser non-significant changes seen for other inflammasomes. Application covering all specifically reduced volumes when given clear evidence activation caspase 1. This attenuating effect coincided less immune cell infiltration preservation integrity.Our data show that induction neurons drives neuroinflammation acute stroke. Early blockade protects from mitigating inflammation stabilizing barrier.

Language: Английский

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The association of neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and lymphocyte to monocyte ratio with post-thrombolysis early neurological outcomes in patients with acute ischemic stroke

Journal of Neuroinflammation, Journal Year: 2021, Volume and Issue: 18(1)

Published: Feb. 20, 2021

Abstract Background and purpose To investigate the association of neutrophil to lymphocyte ratio (NLR), platelet (PLR), monocyte (LMR) with post-thrombolysis early neurological outcomes including improvement (ENI) deterioration (END) in patients acute ischemic stroke (AIS). Methods AIS undergoing intravenous thrombolysis were enrolled from April 2016 September 2019. Blood cell counts sampled before thrombolysis. Post-thrombolysis END was defined as National Institutes Health Stroke Scale (NIHSS) score increase ≥ 4 within 24 h after ENI NIHSS decrease or complete recovery h. Multinomial logistic regression analysis performed explore relationship NLR, PLR, LMR ENI. We also used receiver operating characteristic curve assess discriminative ability three ratios predicting Results Among 1060 recruited patients, a total 193 (18.2%) diagnosed 398 (37.5%) model indicated that NLR (odds [OR], 1.385; 95% confidence interval [CI] 1.238–1.551, P = 0.001), PLR (OR, 1.013; CI 1.009–1.016, 0.680; 0.560–0.825, 0.001) independent factors for END. Moreover, 0.713; 0.643–0.791, served an factor Area under (AUC) discriminate 0.763, 0.703, 0.551, respectively. AUC 0.695, 0.530, 0.547, Conclusions associated may predict related

Language: Английский

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Thrombosis in Coronavirus disease 2019 (COVID-19) through the prism of Virchow’s triad

Clinical Rheumatology, Journal Year: 2020, Volume and Issue: 39(9), P. 2529 - 2543

Published: July 11, 2020

The pathogenesis of Coronavirus disease 2019 (COVID-19) is gradually being comprehended. A high number thrombotic episodes are reported, along with the mortality benefits heparin. COVID-19 can be viewed as a prothrombotic disease. We overviewed available evidence to explore this possibility. identified various histopathology reports and clinical case series reporting thromboses in COVID-19. Also, multiple coagulation markers support this. regarded risk factor for thrombosis. Applying principles Virchow's triad, we described abnormalities vascular endothelium, altered blood flow, platelet function that lead venous arterial Endothelial dysfunction, activation renin-angiotensin-aldosterone system (RAAS) release procoagulant plasminogen activator inhibitor (PAI-1), hyperimmune response activated platelets seem significant contributors thrombogenesis Stratifying should based on age, presence comorbidities, D-dimer, CT scoring, cell ratios. Isolated heparin therapy may not sufficient combat thrombosis There an urgent need newer avenues like protein C, PAI-1 antagonists, tissue activators (tPA). These augmented therapies targeting RAAS, antiplatelet drugs, repurposed antiinflammatory, antirheumatic drugs. Key Points • Venous through prism triad. activation, hyperviscosity, flow due hypoxia, immune reactions, hypercoagulability stratify patients at using scoring. Patients put dose therapy.

Language: Английский

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Annexin A1 protects against cerebral ischemia–reperfusion injury by modulating microglia/macrophage polarization via FPR2/ALX-dependent AMPK-mTOR pathway

Journal of Neuroinflammation, Journal Year: 2021, Volume and Issue: 18(1)

Published: May 22, 2021

Cerebral ischemia-reperfusion (I/R) injury is a major cause of early complications and unfavorable outcomes after endovascular thrombectomy (EVT) therapy in patients with acute ischemic stroke (AIS). Recent studies indicate that modulating microglia/macrophage polarization subsequent inflammatory response may be potential adjunct to recanalization. Annexin A1 (ANXA1) exerts potent anti-inflammatory pro-resolving properties models cerebral I/R injury. However, whether ANXA1 modulates post-I/R-induced has not yet been fully elucidated.We retrospectively collected blood samples from AIS who underwent successful recanalization by EVT analyzed levels longitudinally before correlation between 3-month clinical outcomes. We also established C57BL/6J mouse model transient middle artery occlusion/reperfusion (tMCAO/R) an vitro oxygen-glucose deprivation reoxygenation (OGD/R) BV2 microglia HT22 neurons explore the role Ac2-26, pharmacophore N-terminal peptide ANXA1, regulating I/R-induced activation polarization.The baseline pre-EVT were significantly lower 23 patients, as compared those healthy controls. They increased found controls 2-3 days post-EVT. The post-EVT positively correlated In model, we then Ac2-26 administered at start reperfusion shifted toward M2-phenotype penumbra, thus alleviating blood-brain barrier leakage neuronal apoptosis improving 3 post-tMCAO/R. protection was abrogated when mice received together WRW4, which specific antagonist formyl receptor type 2/lipoxin A4 (FPR2/ALX). Furthermore, interaction FPR2/ALX activated 5' adenosine monophosphate-activated protein kinase (AMPK) inhibited downstream mammalian target rapamycin (mTOR). These vivo findings validated through experiments.Ac2-26 microglial/macrophage alleviates inflammation FPR2/ALX-dependent AMPK-mTOR pathway. It investigated strategy for prevention treatment Plasma biomarker receiving EVT.

Language: Английский

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Intermittent theta-burst stimulation improves motor function by inhibiting neuronal pyroptosis and regulating microglial polarization via TLR4/NFκB/NLRP3 signaling pathway in cerebral ischemic mice

Journal of Neuroinflammation, Journal Year: 2022, Volume and Issue: 19(1)

Published: June 11, 2022

Neuronal pyroptosis and neuroinflammation with excess microglial activation are widely involved in the early pathological process of ischemic stroke. Repetitive transcranial magnetic stimulation (rTMS), as a non-invasive neuromodulatory technique, has recently been reported to be anti-inflammatory regulate function. However, few studies have elucidated role mechanism rTMS underlying regulating neuronal polarization.We evaluated motor function middle cerebral artery occlusion/reperfusion (MCAO/r) injury mice after 1-week intermittent theta-burst (iTBS) treatment phase or without depletion microglia by colony-stimulating factor 1 receptor (CSF1R) inhibitor treatment, respectively. We further explored morphological molecular biological alterations associated polarization via Nissl, EdU, TTC, TUNEL staining, electron microscopy, multiplex cytokine bioassays, western blot assays, immunofluorescence staining RNA sequencing.ITBS significantly protected against ischemia/reperfusion (I/R) injury-induced locomotor deficits damage, which probably relied on regulation innate immune inflammatory responses, evidenced sequencing analysis. The peak was confirmed later than that apoptosis during stroke, mainly located more severe peri-infarcted area compared apoptosis. Multiplex bioassays showed iTBS ameliorated high levels IL-1β, IL-17A, TNF-α, IFN-γ MCAO/r group elevated level IL-10. ITBS inhibited expression pyroptosis-associated proteins (i.e., Caspase1, IL-18, ASC, GSDMD, NLRP1) rather at border infarcted core. KEGG enrichment analysis demonstrated shifted M1/M2 phenotype balance curbing proinflammatory M1 (Iba1+/CD86+) enhancing M2 (Iba1+/CD206+) inhibiting TLR4/NFκB/NLRP3 signaling pathway. Depletion using CSF1R (PLX3397) eliminated functional improvements treatment.rTMS could alleviate I/R induced modulating polarization. It is expected these data will provide novel insights into mechanisms protecting potential targets

Language: Английский

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Neuroinflammation — a common thread in neurological disorders

Nature Reviews Neurology, Journal Year: 2019, Volume and Issue: 15(8), P. 429 - 430

Published: July 1, 2019

Language: Английский

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The Predictive Role of Systemic Inflammation Response Index (SIRI) in the Prognosis of Stroke Patients

Clinical Interventions in Aging, Journal Year: 2021, Volume and Issue: Volume 16, P. 1997 - 2007

Published: Dec. 1, 2021

Stroke is a disease associated with high mortality. Many inflammatory indicators such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte (PLR), lymphocyte to monocyte (LMR) and red blood cell distribution width (RDW) have been documented predict stroke prognosis, their predictive power limited. A novel indicator called systemic response index (SIRI) has advocated an essential role in the prognostic assessment of cancer infectious diseases. In this study, we attempted assess prognosis by SIRI. Moreover, compared SIRI other clinical parameters, including NLR, PLR, LMR RDW. This was retrospective cohort study. We obtained data 2450 patients from Multiparametric Intelligent Monitoring Intensive Care III database. used Cox proportional hazards models evaluate relationship between all-cause mortality sepsis. Receiver operating curve (ROC) analysis RDW for stroke. collected 180 First Affiliated Hospital Wenzhou Medical University, which Pearson's correlation coefficient National Institute Health scale (NIHSS). After adjusting multiple covariates, found that patients. Rising accompanied rising Besides, ROC showed area under significantly greater than test confirmed significant positive NIHSS. Elevated higher risk sepsis severity. Therefore, promising low-grade factor predicting outperformed LMR, power.

Language: Английский

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PKM2 promotes neutrophil activation and cerebral thromboinflammation: therapeutic implications for ischemic stroke

Blood, Journal Year: 2021, Volume and Issue: 139(8), P. 1234 - 1245

Published: Sept. 16, 2021

There is a critical need for cerebro-protective interventions to improve the suboptimal outcomes of patients with ischemic stroke who have been treated reperfusion strategies. We found that nuclear pyruvate kinase muscle 2 (PKM2), modulator systemic inflammation, was upregulated in neutrophils after onset both humans and mice. Therefore, we determined role PKM2 pathogenesis by using murine models preexisting comorbidities. generated novel myeloid cell-specific PKM2-/- mice on wild-type (PKM2fl/flLysMCre+) hyperlipidemic background (PKM2fl/flLysMCre+Apoe-/-). Controls were littermate PKM2fl/flLysMCre- or PKM2fl/flLysMCre-Apoe-/- Genetic deletion cells limited inflammatory response peripheral reduced neutrophil extracellular traps cerebral ischemia reperfusion, suggesting promotes hyperactivation setting stroke. In filament autologous clot recombinant tissue plasminogen activator models, irrespective sex, either infarcts enhanced long-term sensorimotor recovery. Laser speckle imaging revealed improved regional blood flow PKM2-deficient concomitant post-ischemic thrombo-inflammation (intracerebral fibrinogen, platelet [CD41+] deposition, infiltration, cytokines). Mechanistically, regulates inflammation promoting STAT3 phosphorylation. To enhance translational significance, inhibited translocation small molecule significantly short-term functional Collectively, these findings identify as therapeutic target brain salvage recovery reperfusion.

Language: Английский

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