PKM2 Activator TEPP-46 Attenuates Thoracic Aortic Aneurysm and Dissection by Inhibiting NLRP3 Inflammasome-Mediated IL-1β Secretion

2020 ◽  
Vol 25 (4) ◽  
pp. 364-376 ◽  
Author(s):  
Sheng Le ◽  
Hao Zhang ◽  
Xiaofan Huang ◽  
Shu Chen ◽  
Jia Wu ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Mouse Model ◽  
Pyruvate Kinase ◽  
Nlrp3 Inflammasome ◽  
Thoracic Aortic Aneurysm ◽  
Protective Role ◽  
Inflammasome Activation ◽  
Luminal Diameter ◽  
Pyruvate Kinase M2 ◽  
Aortic Aneurysm And Dissection

Background: The development of thoracic aortic aneurysm and dissection (TAAD) is mediated by inflammasome activation, which exacerbates the secretion of pro-inflammatory cytokines, chemokines, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). The glycolytic enzyme pyruvate kinase M2 (PKM2) has shown a protective role against various disorders with an inflammatory basis, such as sepsis, tumorigenesis, and diabetic nephropathy. However, its potential role in TAAD has not been investigated so far. Approach and Results: We analyzed aortic tissues from TAAD patients and the β-aminopropionitrile fumarate (BAPN)–induced mouse model of TAAD and observed elevated levels of PKM2 in the aortic lesions of both. Treatment with the PKM2 activator TEPP-46 markedly attenuated the progression of TAAD in the mouse model as demonstrated by decreased morbidity and luminal diameter of the aorta. In addition, the thoracic aortas of the BAPN-induced mice showed reduced monocytes and macrophages infiltration and lower levels of IL-1β, MMPs, and ROS when treated with TEPP-46. Furthermore, TEPP-46 treatment also suppressed the activation of the NOD-like receptor (NLR) family and pyrin domain–containing protein 3 (NLRP3) inflammasome by downregulating p-STAT3 and HIF1-α. Conclusion: Pyruvate kinase M2 plays a protective role in TAAD development, and its activation is a promising therapeutic strategy against the progression of TAAD.

Blockade of the NLRP3 Inflammasome Cascade Prevents Thoracic Aortic Aneurysm and Dissection Formation

2014 ◽  
Vol 186 (2) ◽  
pp. 521-522
Author(s):  
D. Wu ◽  
Y. Zheng ◽  
J.C. Choi ◽  
L. Zhang ◽  
J.S. Coselli ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Nlrp3 Inflammasome ◽  
Thoracic Aortic Aneurysm ◽  
Aortic Aneurysm And Dissection

scholarly journals Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer’s Disease

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 779
Author(s):  
Pradeep K. Shukla ◽  
David F. Delotterie ◽  
Jianfeng Xiao ◽  
Joseph F. Pierre ◽  
RadhaKrishna Rao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Gut Microbiota ◽  
Transgenic Mice ◽  
Nlrp3 Inflammasome ◽  
Inflammasome Activation ◽  
Gut Barrier Function ◽  
Elevated Expression ◽  
5Xfad Mice

Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is a major cause of death and disability among the older population. Despite decades of scientific research, the underlying etiological triggers are unknown. Recent studies suggested that gut microbiota can influence AD progression; however, potential mechanisms linking the gut microbiota with AD pathogenesis remain obscure. In the present study, we provided a potential mechanistic link between dysbiotic gut microbiota and neuroinflammation associated with AD progression. Using a mouse model of AD, we discovered that unfavorable gut microbiota are correlated with abnormally elevated expression of gut NLRP3 and lead to peripheral inflammasome activation, which in turn exacerbates AD-associated neuroinflammation. To this end, we observe significantly altered gut microbiota compositions in young and old 5xFAD mice compared to age-matched non-transgenic mice. Moreover, 5xFAD mice demonstrated compromised gut barrier function as evident from the loss of tight junction and adherens junction proteins compared to non-transgenic mice. Concurrently, we observed increased expression of NLRP3 inflammasome and IL-1β production in the 5xFAD gut. Consistent with our hypothesis, increased gut–microbial–inflammasome activation is positively correlated with enhanced astrogliosis and microglial activation, along with higher expression of NLRP3 inflammasome and IL-1β production in the brains of 5xFAD mice. These data indicate that the elevated expression of gut–microbial–inflammasome components may be an important trigger for subsequent downstream activation of inflammatory and potentially cytotoxic mediators, and gastrointestinal NLRP3 may promote NLRP3 inflammasome-mediated neuroinflammation. Thus, modulation of the gut microbiota may be a potential strategy for the treatment of AD-related neurological disorders in genetically susceptible hosts.

scholarly journals A post mortem assessment of a 25-year-old man with ascending aortic dissection and a novel MYLK variant

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Katelyn Hodge ◽  
Katherine G. Spoonamore ◽  
Christopher B. Griffith ◽  
David D. Weaver ◽  
Patricia B.S. Celestino-Soper ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Aortic Aneurysm ◽  
Aortic Dissection ◽  
Thoracic Aortic Aneurysm ◽  
Aortic Rupture ◽  
Clinical Consequence ◽  
Post Mortem ◽  
Variant Of Uncertain Significance ◽  
Pathogenic Variants ◽  
Aortic Aneurysm And Dissection

We report on the process of <em>post mortem</em> evaluation and genetic testing following the death of a 25-year-old man due to ascending aortic dissection leading to aortic rupture. Following the negative clinical testing of a 12- gene thoracic aortic aneurysm and dissection panel, research testing revealed a novel c.5732A&gt;T (p.E1911V) variant in exon 34 of the MYLK gene (NM_053025). Two likely pathogenic variants in this gene have been reported previously in individuals with familial thoracic aortic aneurysm and dissection. Given the unclear clinical consequence of the variant found in our proband, we have classified this change as a variant of uncertain significance. In addition to discussing the complexity involved in variant interpretation, we recognize the need for additional research for more accurate <em>MYLK</em> interpretation. Finally, we comment on the unique challenges of <em>post mortem</em> genetic testing.

Thoracic aortic-aneurysm and dissection in association with significant mitral valve disease caused by mutations in TGFB2

2013 ◽  
Vol 165 (3) ◽  
pp. 584-587 ◽  
Author(s):  
Marjolijn Renard ◽  
Bert Callewaert ◽  
Fransiska Malfait ◽  
Laurence Campens ◽  
Saba Sharif ◽  
...  
Keyword(s):  
Mitral Valve ◽  
Aortic Aneurysm ◽  
Mitral Valve Disease ◽  
Thoracic Aortic Aneurysm ◽  
Valve Disease ◽  
Aortic Aneurysm And Dissection

scholarly journals Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2019 Update and Clinical Implications

Aorta ◽  
2019 ◽  
Vol 07 (04) ◽  
pp. 099-107 ◽  
Author(s):  
Thais Faggion Vinholo ◽  
Adam J. Brownstein ◽  
Bulat A. Ziganshin ◽  
Mohammad A. Zafar ◽  
Helena Kuivaniemi ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Natural History ◽  
Molecular Genetics ◽  
Thoracic Aortic Aneurysm ◽  
Surgical Intervention ◽  
Pathogenic Mutation ◽  
Clinical Implications ◽  
Aortic Aneurysm And Dissection

AbstractThoracic aortic aneurysm is a typically silent disease characterized by a lethal natural history. Since the discovery of the familial nature of thoracic aortic aneurysm and dissection (TAAD) almost 2 decades ago, our understanding of the genetics of this disorder has undergone a transformative amplification. To date, at least 37 TAAD-causing genes have been identified and an estimated 30% of the patients with familial nonsyndromic TAAD harbor a pathogenic mutation in one of these genes. In this review, we present our yearly update summarizing the genes associated with TAAD and the ensuing clinical implications for surgical intervention. Molecular genetics will continue to bolster this burgeoning catalog of culprit genes, enabling the provision of personalized aortic care.

scholarly journals Protective Role of Shiitake Mushroom-Derived Exosome-Like Nanoparticles in D-Galactosamine and Lipopolysaccharide-Induced Acute Liver Injury in Mice

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 477 ◽  
Author(s):  
Baolong Liu ◽  
Yizhu Lu ◽  
Xingyi Chen ◽  
Philma Glora Muthuraj ◽  
Xingzhi Li ◽  
...  
Keyword(s):  
Liver Injury ◽  
Nlrp3 Inflammasome ◽  
Acute Liver Injury ◽  
Therapeutic Potential ◽  
Disease Model ◽  
Protective Role ◽  
Therapeutic Interventions ◽  
Inflammasome Activation ◽  
Mrna Levels ◽  
Shiitake Mushroom

Fulminant hepatic failure (FHF) is a rare, life-threatening liver disease with a poor prognosis. Administration of D-galactosamine (GalN) and lipopolysaccharide (LPS) triggers acute liver injury in mice, simulating many clinical features of FHF in humans; therefore, this disease model is often used to investigate potential therapeutic interventions to treat FHF. Recently, suppression of the nucleotide-binding domain and leucine-rich repeat related (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome, was shown to alleviate the severity of GalN/LPS-induced liver damage in mice. Therefore, the goal of this study was to find dietary exosome-like nanoparticles (ELNs) with therapeutic potential in curbing FHF by suppressing the NLRP3 inflammasome. Seven commonly consumed mushrooms were used to extract ELNs. These mushrooms were found to contain ELNs composed of RNAs, proteins, and lipids. Among these mushroom-derived ELNs, only shiitake mushroom-derived ELNs (S-ELNs) substantially inhibited NLRP3 inflammasome activation by preventing inflammasome formation in primary macrophages. S-ELNs also suppressed the secretion of interleukin (IL)-6, as well as both protein and mRNA levels of the Il1b gene. Remarkably, pre-treatment with S-ELNs protected mice from GalN/LPS-induced acute liver injury. Therefore, S-ELNs, identified as potent new inhibitors of the NLRP3 inflammasome, represent a promising class of agents with the potential to combat FHF.

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