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Pyroptotic cell death. Canonical and non-canonical pathways are schematically shown in this figure. PAMPs or DAMPs molecules are required to activate the canonical pathway. Afterward, the inflammasome complex is assembled and mediates pro-caspase-1 autocatalysis. Subsequently, active caspase-1 processes pro-IL-1β and pro-IL-18 through its proteolytic activities. Pro-inflammatory cytokine release, particularly IL-1β has been shown to increase neuronal hyperexcitability. Transcription of inactive precursor of IL-1β and also some inflammasome components, like NLRP3, is mediated through NF-κB activation in the priming step. Activation of NF-κB occurs via TLRs, TNFR, and IL-1R stimulation. Caspase-1 activation can also promote GSDMD cleavage, and then GSDMD-N oligomerizes and creates GSDMD pores in the plasma membrane, mediating IL-1β and IL-18 release and cell death. In the non-canonical pathway, GBPs bind to the intracellular LPS and promote caspase4/5/11 recruitment and auto-activation. These activated caspases cleave GSDMD, and then GSDMD-N oligomerizes and forms plasma membrane pores that facilitate K⁺ efflux. Transcription of caspase-11 during the priming step is also needed before activation of the non-canonical pathway. Biorender software (biorender.com) was used to draw the figure of this manuscript. PAMPs pathogen-associated molecular patterns, DAMPs damage-associated molecular patterns, IL-1β interleukin-1β, IL-18 interleukin-18, NLRP3 NLR family pyrin domain-containing 3, NF-κB nuclear factor-kappa B, TLRs toll-like receptors, TNFR tumor necrosis factor receptor, IL-1R interleukin-1β receptor, GSDMD gasdermin, GSDMD-N GSDMD n-terminal, GBPs guanylate-binding proteins, LPS lipopolysaccharide
Source publication
Epilepsy is one of the most common serious brain diseases worldwide. Programmed cell death (PCD), a cellular self-destruction phenomenon, has been greatly documented in neurodegenerative diseases. Pyroptosis is a well-known pro-inflammatory PCD, and its involvement in epilepsy has been reported in animal models of epilepsy and also epileptic patien...
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It is well-known that viruses activate various inflammasomes, which can initiate the programmed cell death pathway known as pyroptosis, subsequently leading to cell lysis and release of inflammatory cytokines IL-1 and IL-18. This pathway can be triggered by various sensors, including, but not limited to, NLRP3, AIM2, IFI16, RIG-I, and NLRC4. Many v...
Citations
... Pyroptosis is involved in the pathophysiology of various central nervous system disorders, such as intracerebral hemorrhage, Alzheimer's disease, and Parkinson's disease, and interventions targeting it may improve the prognosis of these diseases 22,23 . NLRP3 may be involved in the development of refractory temporal lobe epilepsy and pyroptosis has also been mentioned in epilepsy research [24][25][26] . However, the exact relationship between these processes and mitophagy remains unclear. ...
... In our epileptic rat model, we also observed the release of these two cytokines, further emphasizing the significant role of NLRP3 inflammasome-mediated pyroptosis in epilepsy. Previous studies have demonstrated its involvement in the pathophysiology of epilepsy 24,25 . Therefore, NLRP3 inflammasome-mediated pyroptosis holds great potential as a target for the development of innovative therapies for epilepsy. ...
Epilepsy is a neurological disorder involving mitochondrial dysfunction and neuroinflammation. This study examines the relationship between NLRP3 inflammasome activation and mitophagy in the temporal lobe epilepsy, which has not been reported before. A pilocarpine-induced epileptic rat model was used to assess seizure activity and neuronal loss. Pyroptosis markers (NLRP3, cleaved Gasdermin D, IL-1β/IL-18), and autophagy/mitophagy activity (LC3B-II/I, BNIP3, TOMM20/LC3B colocalization) were analyzed via immunofluorescence, Western blot, and transmission electron microscopy. NLRP3 inhibitors and anti-IL-1β antibodies were administered to evaluate therapeutic effects. Epileptic rats exhibited progressive neuronal loss and seizure aggravation, correlating with NLRP3 inflammasome activation and pyroptosis. While general autophagy was upregulated, mitophagy was selectively impaired in the hippocampus. NLRP3 activation promoted IL-1β release, which suppressed mitophagy via PPTC7 upregulation. NLRP3 activation inhibitor (MCC950) and anti-IL-1β treatment restored mitophagy and reduced seizures. NLRP3 inflammasome-driven pyroptosis exacerbates epilepsy by impairing mitophagy activity via IL-1β/PPTC7. Targeted NLRP3 inhibition mitigates this cascade, offering a promising strategy for refractory epilepsy.
... In addition, inflammatory processes, such as the generation of inflammatory factors and related molecules, have been noted to increases the risk of acquired epilepsy in humans and relevant animal models [2]. Numerous cytokines, including IL-1β and IL-6, have been shown to be associated with epilepsy [3,4]. Disruption of glial-neuronal networks may play a crucial role in epilepsy, particularly by causing the activation of microglia [5]. ...
Background
Epilepsy is a neurological disorder characterized by recurrent seizures, tightly associated with neuroinflammation. Activation of inflammatory cells and molecules in damaged nervous tissues plays a pivotal role in epilepsy. Caffeic acid, one of the most abundant polyphenols in coffee, has shown potent protective effects as a phytomedicine in various neurological disorders. However, the direct protein targets and exact molecular mechanisms of caffeic acid in epilepsy, remain largely elusive.
Purpose
This study aimed to explore the protective effects of caffeic acid in epilepsy and elucidate its underlying mechanism.
Methods
In this study, we established pentylenetetrazol-induced acute and kindling models of seizures. Additionally, a BV2 microglial cellular inflammation model was established by lipopolysaccharide stimulation. The potential direct protein targets of caffeic acid in BV2 cells were analyzed using an activity-based protein profiling (ABPP) with a caffeic acid probe. Various methods such as pull-down assay, immunofluorescence and cellular heat transfer assays were used for experimental validation. The anti-inflammatory effects of caffeic acid in LPS-activated BV2 cells was proved by knocking down the target protein.
Results
Here, we found that caffeic acid exhibits antiepileptic effects in pentylenetetrazol-induced epilepsy mice and exerts anti-neuroinflammation effect in vivo and in vitro. Besides, we discovered that caffeic acid directly binds to aconitate decarboxylase 1 and influenced its enzymatic activity. Moreover, we indicated that caffeic acid exhibits anti-neuroinflammation effect through aconitate decarboxylase 1 mediated PERK-NF-κB pathway in vitro.
Conclusion
In summary, this study elucidates, for the first time, the potential antiepileptic targets and mechanism of action of caffeic acid using the ABPP strategy. Our study provides evidence supporting the utilization of caffeic acid as a promising therapeutic agent for treating epilepsy and neuroinflammation-related disorders.
... Although a controlled immune response is beneficial, it can become detrimental when the response is too intense or the inflammatory process persists for an extended period of time. Key pro-inflammatory cytokines, including IL-1, IL-6, IL-18, IFN-γ, and TNF-α, are implicated in diseases such as epilepsy [40]. Excessive production and release of these pro-inflammatory cytokines are believed to have local and systemic cytotoxic effects. ...
... Molecular mechanisms include but are not limited to promoting chemotaxis of neutrophils and other immune cells, activating Toll-like receptors and Th1 signaling pathway, and so on. However, the specific mechanism by which STING activates the NF-κB signaling pathway remains controversial, primarily regarding whether the phosphorylation of IKKβ by TBK1 is essential in this process [40,41]. In the present work, we demonstrated the activation of NF-κB by cGAS-STING signaling pathway in granulosa cells treated with T, which is associated with increased apoptosis of these cells in PCOS. ...
Background
Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. The ketogenic diet (KD), a diet high in fat and low in carbohydrates, has been applied clinically for the treatment of obese women with PCOS. We have previously demonstrated that KD improved the reproductive phenotype in an androgen-induced PCOS mouse model, yet the underlying molecular mechanisms remain largely unclear. The aim of the present study was to investigate the effect of KD on the reproductive phenotype of a letrozole-induced PCOS mouse model.
Methods
Female C57BL/6N mice were divided into three groups, designated control, letrozole, and letrozole + KD groups. Mice of control and letrozole groups were fed the control diet, whereas letrozole + KD mice were fed a KD with 89.9% (kcal) fat for 3 weeks after the PCOS mouse model was generated. β-hydroxybutyrate (BHB), the most abundant ketone body in the body, was used to treat KGN cells with testosterone (T) to simulate the KD effect on PCOS mouse ovaries in vitro.
Results
Our data showed that KD treatment significantly increased blood ketone levels and reduced body weight. Ovarian functions were improved in some letrozole + KD mice. Results from in vitro experiments indicated mitochondrial damage owing to high T levels, which resulted in the leakage of cytochrome C and mitochondrial DNA into the cytosol and thus induced the activation of the intracellular caspase cascade and the cGAS-STING-NF-κB pathway, leading to granulosa cell inflammation and apoptosis. BHB exhibited certain protective effects on mitochondria of T-treated KGN cells via inhibiting the cGAS-STING pathway. Moreover, the cGAS-STING pathway was activated in ovaries of letrozole mice and was down-regulated in letrozole + KD mice.
Conclusion
These findings, for the first time, revealed that hyperandrogenism induced ovarian dysfunction possibly through activation of the cGAS-STING pathway, which could be partially inhibited by ketone bodies produced from KD administration.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12964-024-01939-6.
... The mature IL-1b and IL-18 are then released extracellularly, further amplifying the inflammatory response (24). In the Caspase-1-independent pathway of pyroptosis, exposure to lipopolysaccharides (LPS) results in the direct activation of human Caspase-4 and Caspase-5, as well as mouse Caspase-11 (25). These caspases bind to LPS, leading to their activation and subsequent cleavage of GSDMD. ...
Sepsis represents a severe condition characterized by organ dysfunction resulting from a dysregulated host response to infection. Among the organs affected, the kidneys are particularly vulnerable, with significant functional impairment that markedly elevates mortality rates. Previous researches have highlighted that both inflammatory response dysregulation and metabolic reprogramming are crucial in the onset and progression of sepsis associated acute kidney injury (SA-AKI), making these processes potential targets for innovative therapies. This study aims to elucidate the pathophysiological mechanisms of renal injury in sepsis by perspective of inflammatory response dysregulation, with particular emphasis on pyroptosis, necroptosis, autophagy, and ferroptosis. Furthermore, it will incorporate insights into metabolic reprogramming to provide a detailed analysis of the mechanisms driving SA-AKI and explore potential targeted therapeutic strategies, providing solid theoretical framework for the development of targeted therapies for SA-AKI.
... These changes cellular osmotic pressure and cell membrane pore formation, which distends until the cell membrane ruptures. 9 Gasdermin D (GSDMD) and Gasdermin E (GSDME) are two commonly described molecules that can be cleaved by caspases and exert a pyroptosis effect. 10 GSDMD is cleaved by inflammatory caspase-1/4/5/11, whereas GSDME is cleaved by apoptotic caspase3, which mediates cell pyroptosis. ...
Background
The incidence of papillary thyroid cancer (PTC) has been increasing annually; however, early diagnosis can improve patient outcomes. Pyroptosis is a programmed cell death modality that has received considerable attention recently. However, no studies have reported using pyroptosis-related genes in PTC diagnosis.
Methods
Analyzed 33 pyroptosis-related genes in PTC transcriptome data from the Gene Expression Omnibus database. Subsequently, used the Least Absolute Shrinkage and Selection Operator (LASSO) model to construct a PTC molecular diagnostic model. Furthermore, confirmed differences in the expression of five genes between PTC and non-tumor tissues using immunohistochemistry. Collected 338 PTC and control samples to construct a five-gene PTC diagnostic model, which was then validated using a training set and underwent correlation analysis with immune cell infiltration. Additionally, validated the biological functions of the core gene NOD1 in vitro.
Results
The five-gene PTC diagnostic model demonstrated good diagnostic value for PTC. Moreover, identified three reliable subtypes of pyroptosis and found that NOD1 is involved in tumor-suppressive microenvironment formation. Notably, patients with high NOD1 expression had lower Progression-Free Survival (PFS). Additionally, NOD1 expression was positively correlated with immune markers such as CD47, CD68, CD3, and CD8. Lastly, inhibiting NOD1 showed significant anti-PTC activity in vitro.
Conclusion
Our results suggest that pyroptosis-related genes can be used for PTC diagnosis, and NOD1 could be a promising therapeutic target.
... These receptors have the capability to recognize both pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Upon activation of PRRs, downstream signaling pathways are initiated, leading to the generation of type I interferons and the release of pro-inflammatory cytokines [36,37]. ...
Pyroptosis, as a lytic-inflammatory type of programmed cell death, has garnered considerable attention due to its role in cancer chemotherapy and many inflammatory diseases. This review will discuss the biochemical classification of pyroptotic inducers according to their chemical structure, pyroptotic mechanism, and cancer type of these targets. A structure-activity relationship study on pyroptotic inducers is revealed based on the surveyed pyroptotic inducer chemotherapeutics. The shared features in the chemical structures of current pyroptotic inducer agents were displayed, including an essential cyclic head, a vital linker, and a hydrophilic tail that is significant for π-π interactions and hydrogen bonding. The presented structural features will open the way to design new hybridized classes or scaffolds as potent pyroptotic inducers in the future, which may represent a solution to the apoptotic-resistance dilemma along with synergistic chemotherapeutic advantage.
Graphical Abstract
... Similarly, the biomarker protein for microgliosis, IBA-1, was significantly elevated in 5xFAD mice compared to WT controls , and this increase was also abolished by intranasal LiCl in RFV (Fig. 7B). Pathological elevation of cytotoxic cytokines plays a critical role on programmed death by pyroptosis [78,82]. We have determined changes of critical neurotoxic (IL-6, TNF-α) and neuroprotective (IL-10) cytokines in the brains of aged 5xFAD mice, both with or without intranasal LiCl in RFV treatments. ...
Background
Alzheimer’s disease (AD) is a devastating neurodegenerative disease (AD) and has no treatment that can cure or halt the disease progression. This study explored the therapeutic potential of lithium salt dissolved in Ryanodex formulation vehicle (RFV) and delivered to the brain by intranasal application. We first compared lithium concentrations in the brain and blood of wild-type mice following intranasal or oral administration of lithium chloride (LiCl) dissolved in either RFV or water. The beneficial and side effects of intranasal versus oral LiCl in RFV in these mice were assessed and potential mechanisms underlying the efficacy of anti-inflammation and anti-pyroptosis in the brains were also investigated in both wild-type (WT) and 5XFAD Alzheimer’s Disease (AD) mice brains.
Methods
For the study of brain versus blood lithium concentrations, WT B6SJLF1/J mice at 2 months of age were treated with intranasal or oral LiCl (3 mmol/kg) dissolved in RFV or in water. Brain and blood lithium concentrations were measured at various times after drugs administration. Brain/blood lithium concentration ratios were then determined. For studying therapeutic efficacy versus side effects and their underlying mechanisms, 5XFAD and WT B6SJLF1/J mice were treated with intranasal LiCl (3 mmol/kg) daily, Monday to Friday each week, in RFV beginning at 2 or 9 months of age with a 12-week treatment duration. Animal behaviors were assessed for depression (tail suspension), cognition (fear conditioning and Y maze), olfaction (buried food test), and motor functions (rotarod) at the age of 5 and 12 months. Blood and brain tissue were harvested from these mice at 13 months. Blood biomarkers for the functions of thyroid (thyroid stimulating hormone, TSH) and kidney (creatinine) were measured using ELISA. Changes in protein expression levels of the endoplasmic reticulum Ca ²⁺ release channels type 1 InsP 3 receptors (InsP 3 R-1), malondialdehyde (MDA)-modified proteins and 4-hydroxy-2-nonenal (4-HNE), pyroptosis regulatory proteins (NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1, N-terminal of Gasdermin D (GSDMD)), cytotoxic (IL-1β, IL-18, IL-6, TNF-α) and cytoprotective (IL-10) cytokines and synapse proteins (PSD-95, synapsin-1) were determined using immunoblotting. Mouse body weights were monitored regularly.
Results
Compared to oral LiCl in RFV nanoparticles, intranasal treatment of WT mice with LiCl in RFV markedly decreased blood concentrations at the time frame of 30-120 minutes. The ratio of brain/blood lithium concentration after Intranasal lithium chloride in RFV significantly increased, in comparison to those after oral administration lithium chloride in RFV or intranasal administration of lithium chloride in water. Intranasal lithium chloride in RFV inhibited both memory loss and depressive behavior in adult and aged 5XFAD mice. Additionally intranasal treatment of aged 5XFAD mice with LiCl in RFV effectively suppressed the increases in InsP 3 R-1, intracellular oxidative stress markers (4-HNE-bound and MDA-modified proteins), pyroptosis activation proteins (NLRP3, cleaved caspase-1, N-terminal GSDMD) and cytotoxic cytokines (IL-1β, IL-6, TNF-α), but reversed the down-regulation of cytoprotective cytokine IL-10. Intranasal LiCl in RFV also alleviated the loss of the postsynaptic synapse protein PSD-95, but not synapsin-1, in aged 5XFAD mice. Blood level of the kidney function marker creatinine was significantly increased in 5XFAD than in WT mice in an age-dependent manner and this elevation was abolished by intranasal delivery of LiCl in RFV. Intranasal LiCl in RFV for 12 weeks in both WT or 5XFAD mice did not affect blood biomarkers for thyroid function, nor did it affect smell or muscle function or body weight.
Conclusion
Intranasal administration of LiCl in RFV significantly decreased lithium blood concentrations and increased brain/blood lithium concentration ratio, in comparison to its oral administration. Intranasal administration of LiCl in RFV robustly protected against both memory loss and depressive-like behavior, while had no side effects concerning thyroid and kidney toxicity in 5XFAD mice. These lithium-induced beneficial effects were strongly associated with lithium’s suppression of InsP 3 R-1 Ca ²⁺ channel receptor increase, pathological neuroinflammation and activation of the pyroptosis pathway, as well as the loss of some synaptic proteins. Intranasal delivery of lithium salt in RFV could become an effective and potent inhibitor of pathological inflammation/pyroptosis in the CNS and serve as a new treatment for both AD-associated dementia and depression with minimal unwanted side effects including peripheral organ toxicity.
... In adult tissues, apoptosis acts as a quality control mechanism, removing aged or malfunctioning cells to prevent the accumulation of cellular debris and maintain overall tissue health [7]. Apart from apoptosis, a subset of the caspase family participates in the inflammatory type of cell death known as pyroptosis, where they act as pro-cytokine activators [8]. This mode of cell death differs morphologically from apoptosis, which is characterized by cell shrinkage, membrane blebbing, and DNA fragmentation, leading to the formation of apoptotic bodies that are phagocytosed without inducing inflammation [9]. ...
Introduction:
Caspases are a family of protease enzymes that play a crucial role in apoptosis. Dysregulation of caspase activity has been implicated in various pathological conditions, making caspases an important focus of research in understanding cell death mechanisms and developing therapeutic strategies for diseases associated with abnormal apoptosis.
Areas covered:
It is a comprehensive review of caspase inhibitors that have been comprising recently granted patents from 2016 to 2023. It includes peptide and non-peptide caspase inhibitors with their application for different diseases.
Expert opinion:
This review categorizes and analyses recently patented caspase inhibitors on various diseases. Diseases linked to caspase dysregulation, including neurodegenerative disorders, and autoimmune conditions, are highlighted to accentuate the therapeutic relevance of the patented caspase inhibitors. This paper serves as a valuable resource for researchers, clinicians, and pharmaceutical developers seeking an up-to-date understanding of recently patented caspase inhibitors. The integration of recent patented compounds, structural insights, and mechanistic details provides a holistic view of the progress in caspase inhibitor research and its potential impact on addressing various diseases.
... To determine the viability of ICT-treated HepG2, MHCC97H, HCCLM3, Huh7, and LO2 cells, we treated HepG2, MHCC97H, HCCLM3, and Huh7 cells with diverse concentrations of ICT (0, 5,10,15,20,25,30,40,50, 60 µM) for 24 and 48 h, respectively. LO2 cells were exposed to ICT (0, 5, 10, 20, 40, 60, 80, and 100 µM). ...
Icaritin (ICT), a natural compound extracted from the dried leaves of the genus Epimedium, possesses antitumor and immunomodulatory properties. However, the mechanisms through which ICT modulates pyroptosis and immune response in hepatocellular carcinoma (HCC) remain unclear. This study demonstrated that ICT exhibits pyroptosis-inducing and anti-hepatocarcinoma effects. Specifically, the caspase1-GSDMD and caspase3-GSDME pathways were found to be involved in ICT-triggered pyroptosis. Furthermore, ICT promoted pyroptosis in co-cultivation of HepG2 cells and macrophages, regulating the release of inflammatory cytokines and the transformation of macrophages into a proinflammatory phenotype. In the Hepa1-6+Luc liver cancer model, ICT treatment significantly increased the expression of cleaved-caspase1, cleaved-caspase3, and granzyme B, modulated cytokine secretion, and stimulated CD8⁺ T cell infiltration, resulting in a reduction in tumor growth. In conclusion, the findings in this research suggested that ICT may modulate cell pyroptosis in HCC and subsequently regulate the immune microenvironment of the tumor. These observations may expand the understanding of the pharmacological mechanism of ICT, as well as the therapy of liver cancer.
... Recent studies show that when NLRP1 is activated, it triggers the creation of an inflammasome containing active caspase-1, which starts a proinflammatory form of cell death called pyroptosis. This process is significant in the development of neurological diseases [67]. Pyroptosis is a form of regulated cell death characterized by inflammation, which can be categorized into classical and non-classical signaling pathways. ...
The development and progression of temporal lobe epilepsy (TLE) are heavily influenced by inflammation, excessive activation of glial cells, and neuronal cell death. This study aimed to investigate the effects of treatment with alpha-pinene (APN) on pro-and anti-inflammatory cytokine levels, astrogliosis, pyroptosis, and autophagy markers in the hippocampus in a rat model of TLE induced by kainic acid (KA). Male Wistar rats were employed, and TLE was induced by intracerebroventricular injection of KA. APN (50 mg/kg) was intraperitoneally administered for 19 days, including two weeks before and five days after the administration of KA. After full recovery from anesthesia and KA injection, the seizure-related behavioral expressions were evaluated. On day 19, the hippocampal levels of IL-1β, TNF-α, progranulin, IL-10, ERK1/2, phospho-ERK1/2, NF-κB, GFAP, S100-B, NLRP1, NLRP3, caspase-1, and becline-1 were examined. The results revealed that treatment with APN significantly diminished the heightened levels of IL-1β, TNF-α, progranulin, ERK1/2, and NF-κB and reversed the reduced levels of the anti-inflammatory cytokine, IL-10, in the hippocampus caused by KA. Furthermore, administration of APN significantly reduced the levels of astrogliosis, pyroptosis, and autophagy markers in the hippocampus that were elevated by KA. It can be concluded that treatment with APN for 19 days alleviated neuroinflammation by inhibiting ERK1/2 and NF-κB signaling pathways and prevented increases in astrogliosis, pyroptosis, and autophagy markers in the hippocampus in a rat model of TLE.
