Stem cell-derived exosomes prevent pyroptosis and repair ischemic muscle injury through a novel exosome/circHIPK3/ FOXO3a pathway DOI Creative Commons
Bing Yan, Yu Zhang, Chun Liang

et al.

Theranostics, Journal Year: 2020, Volume and Issue: 10(15), P. 6728 - 6742

Published: Jan. 1, 2020

Rational: Ischemic injury of the skeletal muscle remains a serious clinical problem and currently there is no effective therapy. The aim present study to determine whether human umbilical cord mesenchymal stem cells- derived exosomes (UMSC-Exo) could repair ischemic by releasing circular RNA. Methods Results: To create hindlimb ischemia, we surgically ligated left femoral artery in C57BL/6 mice. Using circRNA-seq analyses total RNA from control muscles, found reduced expression circHIPK3 muscle. explore role injury, mice were randomly assigned into three groups after surgery: 1) vehicle; 2) UMSC-Exo; 3) UMSC-Exo siRNA targeting (UMSC-Exo /si-circHIPK3). treatment significantly increased improved blood perfusion, running distance force, which reversed injection /si-circHIPK3, suggesting that improve function circHIPK3. also inhibited ischemia induced pyroptosis - cell death caused inflammasome as evidenced activation NLRP3, cleaved caspase-1, subsequent increase IL-1β IL-18, effects /si-circHIPK3. Bioinformatic analysis identified miR-421/FOXO3a potential target for circHIPK3, was confirmed luciferase reporter assay. Knockdown C2C12 cells resulted miR-421. We established an vitro model stimulating with LPS ATP. ATP miR-421, prevented UMSC-Exo. Western blot showed levels NLRP3 caspase-1 when treated FOXO3a presence miR-421 inhibitor, Importantly, upregulated but si-circHIPK3 present. Conclusions: loss/gain-of method, demonstrated direct prevent turn down regulate resulting FOXO3a, leading inhibition release IL-18.

Language: Английский

Low-Dose Methotrexate for the Prevention of Atherosclerotic Events DOI Open Access
Paul M. Ridker, Brendan M. Everett, Aruna D. Pradhan

et al.

New England Journal of Medicine, Journal Year: 2018, Volume and Issue: 380(8), P. 752 - 762

Published: Nov. 10, 2018

Inflammation is causally related to atherothrombosis. Treatment with canakinumab, a monoclonal antibody that inhibits inflammation by neutralizing interleukin-1β, resulted in lower rate of cardiovascular events than placebo previous randomized trial. We sought determine whether an alternative approach inhibition low-dose methotrexate might provide similar benefit.We conducted randomized, double-blind trial (at target dose 15 20 mg weekly) or matching 4786 patients myocardial infarction multivessel coronary disease who additionally had either type 2 diabetes the metabolic syndrome. All participants received 1 folate daily. The primary end point at onset was composite nonfatal infarction, stroke, death. Near conclusion trial, but before unblinding, hospitalization for unstable angina led urgent revascularization added point.The stopped after median follow-up 2.3 years. Methotrexate did not result interleukin-6, C-reactive protein levels placebo. final occurred 201 group and 207 (incidence rate, 4.13 vs. 4.31 per 100 person-years; hazard ratio, 0.96; 95% confidence interval [CI], 0.79 1.16). original 170 167 3.46 3.43 1.01; CI, 0.82 1.25). associated elevations liver-enzyme levels, reductions leukocyte counts hematocrit higher incidence non-basal-cell skin cancers placebo.Among stable atherosclerosis, reduce fewer (Funded National Heart, Lung, Blood Institute; CIRT ClinicalTrials.gov number, NCT01594333.).

Language: Английский

Citations

1079
Recent advances in the mechanisms of NLRP3 inflammasome activation and its inhibitors DOI Creative Commons
Yang Yang, Huanan Wang,

Mohammed Kouadir

et al.

Cell Death and Disease, Journal Year: 2019, Volume and Issue: 10(2)

Published: Feb. 12, 2019

Abstract The NLRP3 inflammasome is a multimeric protein complex that initiates an inflammatory form of cell death and triggers the release proinflammatory cytokines IL-1β IL-18. has been implicated in wide range diseases, including Alzheimer’s disease, Prion type 2 diabetes, some infectious diseases. It found variety stimuli danger-associated molecular patterns (DAMPs, such as silica uric acid crystals) pathogen-associated (PAMPs) can activate inflammasome, but specific regulatory mechanisms activation remain unclear. Understanding will enable development its inhibitors to treat NLRP3-related In this review, we summarize current understanding well specifically directly target NLRP3.

Language: Английский

Citations

1058
NLRP3 inflammasome in cancer and metabolic diseases DOI
Bhesh Raj Sharma, Thirumala‐Devi Kanneganti

Nature Immunology, Journal Year: 2021, Volume and Issue: 22(5), P. 550 - 559

Published: March 11, 2021

Language: Английский

Citations

757
Reappraising the role of inflammation in heart failure DOI
Luigi Adamo, Cibele Rocha‐Resende, Sumanth D. Prabhu

et al.

Nature Reviews Cardiology, Journal Year: 2020, Volume and Issue: 17(5), P. 269 - 285

Published: Jan. 22, 2020

Language: Английский

Citations

565
Pharmacological Inhibitors of the NLRP3 Inflammasome DOI Creative Commons
Ayesha Zahid, Bofeng Li, Arnaud John Kombe Kombe

et al.

Frontiers in Immunology, Journal Year: 2019, Volume and Issue: 10

Published: Oct. 25, 2019

Inflammasomes play a crucial role in innate immunity by serving as signaling platforms which deal with plethora of pathogenic products and cellular associated stress damage. By far, the best studied most characterized inflammasome is NLRP3 inflammasome, consists (nucleotide-binding domain leucine-rich repeat (NLR) pyrin containing receptor 3), ASC (apoptosis-associated speck-like protein caspase recruitment domain), procaspase-1. Activation mediated highly diverse stimuli. Upon activation, recruits adapter protein, procaspase-1 resulting its cleavage inducing maturation, secretion inflammatory cytokines pyroptosis. However, aberrant activation implicated various diseases including diabetes, atherosclerosis, metabolic syndrome, cardiovascular, neurodegenerative diseases; raising tremendous clinical interest exploring potential inhibitors inflammasome. Recent investigations have disclosed pathway were validated through

Language: Английский

Citations

560
Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease DOI Open Access
Antonio Abbate, Stefano Toldo, Carlo Marchetti

et al.

Circulation Research, Journal Year: 2020, Volume and Issue: 126(9), P. 1260 - 1280

Published: April 23, 2020

The intracellular sensing protein termed NLRP3 (for NACHT, LRR, and PYD domains-containing 3) forms a macromolecular structure called the inflammasome. inflammasome plays major role in inflammation, particularly production of IL (interleukin)-1β. IL-1β is most studied IL-1 family cytokines, including 11 members, among which are IL-1α IL-18. Here, we summarize preclinical clinical findings supporting key pathogenetic cytokines formation, progression, complications atherosclerosis, ischemic (acute myocardial infarction), nonischemic injury to myocardium (myocarditis) progression heart failure. We also review clinically available inhibitors, although not currently approved for cardiovascular indications, discuss other approved, as well oral inhibitors development. Canakinumab, antibody, prevented recurrence events patients with prior acute infarction large phase III trial, 10 061 world-wide. Phase II trials show promising data anakinra, recombinant receptor antagonist, ST-segment–elevation or failure reduced ejection fraction. Anakinra improved outcomes pericarditis, it now considered standard care second-line treatment recurrent/refractory pericarditis. Rilonacept, soluble chimeric fusion neutralizing IL-1β, has shown results study In conclusion, there overwhelming evidence linking pathogenesis diseases. future will likely include targeted block isoforms, possibly across wide spectrum

Language: Английский

Citations

555
The NLRP3 inflammasome in acute myocardial infarction DOI
Stefano Toldo, Antonio Abbate

Nature Reviews Cardiology, Journal Year: 2017, Volume and Issue: 15(4), P. 203 - 214

Published: Nov. 16, 2017

Language: Английский

Citations

541
The signal pathways and treatment of cytokine storm in COVID-19 DOI Creative Commons
Lan Yang,

Xueru Xie,

Zikun Tu

et al.

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

Published: July 7, 2021

Abstract The Coronavirus Disease 2019 (COVID-19) pandemic has become a global crisis and is more devastating than any other previous infectious disease. It affected significant proportion of the population both physically mentally, destroyed businesses societies. Current evidence suggested that immunopathology may be responsible for COVID-19 pathogenesis, including lymphopenia, neutrophilia, dysregulation monocytes macrophages, reduced or delayed type I interferon (IFN-I) response, antibody-dependent enhancement, especially, cytokine storm (CS). CS characterized by hyperproduction an array pro-inflammatory cytokines closely associated with poor prognosis. These excessively secreted initiate different inflammatory signaling pathways via their receptors on immune tissue cells, resulting in complicated medical symptoms fever, capillary leak syndrome, disseminated intravascular coagulation, acute respiratory distress multiorgan failure, ultimately leading to death most severe cases. Therefore, it clinically important understand initiation develop effective treatment strategies COVID-19. Herein, we discuss latest developments immunopathological characteristics focus current research status involved. We also induction, function, downstream signaling, existing potential interventions targeting these related signal pathways. believe comprehensive understanding will help better effectively control this disease diseases.

Language: Английский

Citations

508
Pyroptosis in inflammatory diseases and cancer DOI Creative Commons

Zhiping Rao,

Yutong Zhu,

Peng Yang

et al.

Theranostics, Journal Year: 2022, Volume and Issue: 12(9), P. 4310 - 4329

Published: Jan. 1, 2022

Pyroptosis is a lytic and inflammatory type of programmed cell death that usually triggered by inflammasomes executed gasdermin proteins. The main characteristics pyroptosis are swelling, membrane perforation, the release contents. In normal physiology, plays critical role in host defense against pathogen infection. However, excessive may cause immoderate continuous responses involves occurrence diseases. Attractively, as immunogenic death, can serve new strategy for cancer elimination inducing pyroptotic activating intensely antitumor immunity. To make good use this double-edged sword, molecular mechanisms, therapeutic implications related diseases need to be fully elucidated. review, we first systematically summarize signaling pathways then present available evidences indicating cancer. Based on this, focus recent progress strategies inhibit treatment diseases, those induce therapy. Overall, should shed light future directions provide novel ideas using powerful tool fight

Language: Английский

Citations

344
Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials DOI
Paul M. Ridker, Deepak L. Bhatt, Aruna D. Pradhan

et al.

The Lancet, Journal Year: 2023, Volume and Issue: 401(10384), P. 1293 - 1301

Published: March 6, 2023

Language: Английский

Citations

328