China
Africa
Explore chapters and articles related to this topic
Precision medicine in myelodysplastic syndromes
Published in Debmalya Barh, 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
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Madhuvika Murugan, Long-Jun Wu
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).
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.
Pyroptosis in neurodegenerative diseases: What lies beneath the tip of the iceberg?
Published in International Reviews of Immunology, 2023
Mengli Yue, Li Xiao, Rui Yan, Xinyi Li, Wei Yang
Since researchers found that glycolysis pathways could be exploited for cancer therapeutic purposes, the in-depth exploration of the key molecules in this pathway has never stopped [39]. α-Ketoglutarate (α-KG) serves as an essential metabolite in many physiological processes such as tricarboxylic acid (TCA) cycle, lipid biosynthesis, oxidative stress reduction, protein modification, cell death and so on. Recent study has uncovered its novel role in pyroptosis. Dimethyl α-Ketoglutarate (DM-α KG), a cell-permeable analog of α-KG, can penetrate the cell membrane and effectively induce tumor cell pyroptosis through DM-α-KG/L-2 hydroxyglutarate (L-2HG)/Reactive Oxygen Species (ROS)/Death Receptor-6 (DR6)/Caspase-8/GSDMC axis. In physiological state, metabolic enzyme malate dehydrogenase 1 (MDH1) has no function. While in an acidic environment, it can transform α-KG to L-2HG, which triggers the increase of ROS level in cells and induces the oxidative polymerization of DR6 on cell membrane. Then endocytosis occurs with receptosomes. Endocytic DR6 is activated through the recruitment of pro-caspase-8 to receptosomes mediated by Fas associated via death domain(FADD). At the same time, GSDMC is also recruited and cleaved by activated caspase-8 on receptosomes. Finally, the N-terminal GSDMC targets the cell membrane and leads to cell death by pore-formation [40].
Inhibition of Caspase-11-Mediated Pyroptosis Alleviates Acute Kidney Injury Associated with Severe Acute Pancreatitis in Rats
Published in Journal of Investigative Surgery, 2023
Yang Shao, Chang Li, Yingjian Jiang, Hongbo Li, Xuefei Tang, Zhaoyu Gao, Dianliang Zhang
Pyroptosis is essentially an intrinsic immune reaction and contributes to the clearance of exogenous invasion by causing local inflammatory reactions [20]. However, severe pyroptosis may lead to an uncontrolled local inflammatory reaction, which may cause tissue damage and even organ failure. Caspase-11 can trigger the non-canonical pyroptosis pathway when activated by lipopolysaccharide [22]. Recent studies have proved that caspase-11-mediated pyroptosis involves cisplatin, contrast, or sepsis-induced renal injury [14, 15, 23]. A significant increase in caspase-11 and caspase-11 P20 protein in the renal tissue of the SAP rat model was observed in the current study. GSDMD, a crucial downstream target of caspase-11, is involved in pyroptosis and causes rapid lytic cell death by promoting cell pore formation [24]. Here, we also observed the upregulation of GSDMD as well as GSDMD-N expressions in the renal tissue of SAP rats. In summary, these observations revealed that caspase-11-mediated pyroptosis occurs in the renal injury induced by SAP. Furthermore, it is hypothesized that pyroptosis occurs mostly in renal tubular epithelia because GSDMD and caspase-11 were highly expressed in renal tubular epithelia.