Precision medicine in myelodysplastic syndromes
Debmalya Barh in Precision Medicine in Cancers and Non-Communicable Diseases, 2018
After failure of ESAs, lenalidomide yields red blood cell transfusion independence in 20%–30% of lower-risk non-del(5q) MDS. Indeed, several observations suggest an additive effect of ESA and lenalidomide in this situation (Komrokji et al., 2012; Toma et al., 2016). Basiorka et al. reported activation of the NLRP3 inflammasome in MDS (Basiorka et al., 2016b; Sallman et al., 2016). NRLP3 drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins. Activated NLRP3 complexes direct then activation of caspase-1, generation of interleukin-1β (IL-1β) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX) and increasing levels of reactive oxygen species (ROS). ROS initiates cation influx, cell swelling, and β-catenin activation. Knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear β-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs cause a common redox-sensitive inflammasome circuit. They are new candidates for therapeutic intervention.
Microglial Voltage-Gated Proton Channel Hv1 in Neurological Disorders
Tian-Le Xu, Long-Jun Wu in Nonclassical Ion Channels in the Nervous System, 2021
Emerging experimental evidence reveals a role for Hv1 in SCI (Murugan et al. 2020, Li, Liu, et al. 2020, Li, Yu, et al. 2020, Liet al. 2021). Hv1 deficiency was sufficient to rescue motor deficits caused by SCI. The Hv1-mediated changes in motor deficits were linked to microglial activation, IL-1β release, ROS production and neuronal loss (Murugan et al. 2020). Further, deficiency of Hv1 directly influenced microglia activation as noted by a decrease in microglial number, soma size and reduced outward rectifier K+ current density in Hv1 KO mice compared to WT mice at 7 d following SCI (Murugan et al. 2020). These results suggest that microglial Hv1 is a promising potential therapeutic target to alleviate neuronal loss and secondary damage following SCI. Interestingly, the mechanism of Hv1-mediated neuronal loss in SCI was identified to be pyroptosis (Li, Yu, et al. 2020). Contrary to apoptosis, pyroptosis is a form of inflammatory cell death requiring the activation of caspase-1 (Miao, Rajan, and Aderem 2011). Hence, the occurrence of pyroptosis was claimed based on the increased expression of nod-like receptor 3 (NLRP3) inflammasome, ASC, and caspase-1 in neurons after SCI in WT mice, which was prevented in Hv1 KO mice (Li, Yu, et al. 2020). Apart from neuronal loss, demyelination deficits and white matter damage around the injury site is believed to be the main underlying cause for motor deficits noted in SCI patients (Schucht et al. 2002). However, in Hv1 KO mice, attenuated apoptosis of oligodendrocytes, ameliorated myelin loss and a corresponding improvement in tissue repair was observed after SCI (Li, Liu, et al. 2020). Similar to this, hematoxylin and eosin staining of the lesion area at 7 d after SCI revealed enhanced myelin sparing in Hv1 KO mice compared with WT mice (Murugan et al. 2020). The prevention of myelin loss in Hv1 KO mice was prominent near the lesion epicenter and was also observed at distances up to 1500 µm rostral and caudal to the injury epicenter. Since hemorrhaging and white matter loss are key indicators of secondary tissue damage following injury (Anwar, Al Shehabi, and Eid 2016), this result strongly suggests that Hv1 deficiency can alleviate the secondary damage at the early stage following SCI (Murugan et al. 2020).
Ginsenoside Rh2 mitigates myocardial damage in acute myocardial infarction by regulating pyroptosis of cardiomyocytes
Published in Clinical and Experimental Hypertension, 2023
Hong Peng, Li Chen, Yi Deng, Xin Liao, Yi Yang
It has been established that ginsenoside Rh2 plays an important role in regulating cardiovascular, central nervous, immune, and endocrine systems, affording beneficial effects in improving myocardial ischemia, as well as anti-allergy, anti-tumor, anti-depression, and anti-inflammatory effects (20,21). Ginsenoside Rh2 can significantly inhibit the production of reactive oxygen species in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages, indicating that ginsenoside Rh2 exerts beneficial inhibitory effects on the inflammatory response induced by bacterial endotoxins (22). In addition, ginsenoside Rh2 can significantly reduce IL-6, tumor necrosis factor-α, and IL-1β released by RAW264.7 macrophages and promote the production of IL-10, which significantly inhibits LPS-induced macrophage inflammation (21). Pyroptosis differs from apoptosis and necrosis, and inflammation often accompanies pyroptosis. GSDND is the main executor of pyroptosis and relies on the stimulation of inflammation-related caspases (23,24).
Platelet-derived microparticles stimulated by anti-β2GPI/β2GPI complexes induce pyroptosis of endothelial cells in antiphospholipid syndrome
Published in Platelets, 2023
Longjiang Di, Caijun Zha, Yanhong Liu
Pyroptosis has been increasingly referred to in the context of disease development mechanisms. Pyroptosis, also known as cellular inflammatory necrosis, is different from other forms of cell death such as apoptosis [19]. Pyroptosis is cell death via NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, which manifests as swelling, lysis and perforation of cell membranes [20]. Specifically, activation of inflammasomes induces the cleavage of gasdermin D (GSDMD), which releases the N-terminal structural domain (GSDMD-N) and causes perforation of the cell membrane [21]. Inflammatory factors such as interleukin (IL)-1β and IL-18 can be released after pyroptosis [22]. NLRP3 inflammatory vesicles generate GSDMD, pro-IL-1β and pro-IL-18 by activating nuclear factor (NF)-κB, and induce GSDMD cleavage, IL-1β and IL-18 maturation by activating Caspase-1, leading to pyroptosis [23,24]. During inflammation, IC can induce increased NLRP3 in platelets. Recent studies have found that increased Caspase-1 protein expression in MPs directly activates endothelial cell pyroptosis [25]. However, the relationship between IC-PMPs and endothelial cell pyroptosis remains unclear.
Nardostachys jatamansi and levodopa combination alleviates Parkinson’s disease symptoms in rats through activation of Nrf2 and inhibition of NLRP3 signaling pathways
Published in Pharmaceutical Biology, 2023
Jiayuan Li, Jiahe Yu, Jianyou Guo, Jinfeng Liu, Guohui Wan, Xiaojia Wei, Xue Yang, Jinli Shi
In order to elucidate the anti-PD mechanism of the combination of NJ and levodopa, NLRP3 and Nrf2 signaling pathway related proteins in the ST of PD rats were detected. Previous studies have shown that NLRP3 inflammasome is closely related to the development of PD neuroinflammation (Fan et al. 2017), and involved in the entire process of PD. NLRP3 acts as a platform for caspase 1 to induce IL-1β maturation, leading to neuronal pyroptosis (Yan et al. 2018)—this is a specific pathway of caspase-1-induced programmed cell death that is dependent on a GSDMD-generated pore (Shin et al. 2015). During pyroptosis, cells divide and release more pro-inflammatory cytokines. These inflammatory cytokines are released from microglia and have toxic effects on dopaminergic neurons resulting in neuroinflammation, leading to injury and death of adjacent dopaminergic neurons (de Farias et al. 2016). There is evidence showing that NLRP3 inflammasome in PD animal models can be activated by ROT, which may be related to the failure of ROS timely clearance caused by ROT (Martinez et al. 2017). Activated NLRP3 inflammasome causes motor dysfunction and degeneration of dopaminergic neurons in PD models (Cuevas et al. 2015). Consistent with the above studies, this study found that compared with the sham group, the rats in the PD group showed a significant neuroinflammatory response, and NJ-H + levodopa-L could reduce the expression of NLRP3 pathway related proteins (caspase 1, IL-1β and IL-18) in the ST of PD rats, and alleviate the symptoms of PD rats.
Related Knowledge Centers
- Caspase
- Epithelium
- Inflammasome
- Lysis
- Programmed Cell Death
- White Blood Cell
- Apoptosis
- Cytokine
- Antimicrobial
- Damage-Associated Molecular Pattern