Alzheimer's disease (AD) is the most debilitating form of dementia, characterized by amyloid-β (Aβ)-related toxic mechanisms such as oxidative stress, neuroinflammation, and mitochondrial dysfunction. The development of AD is influenced by environmental factors linked to lifestyle, including physical and mental inactivity, diet, and smoking, all of which have been associated with the severity of the disease and Aβ-related pathology. In this study, we used differentiated SH-SY5Y neuroblastoma and C6 glioma cells to investigate the neuroprotective and anti-inflammatory effects of daidzein, a naturally occurring isoflavone, in the context of Aβ oligomer-related toxicity. We observed that pre-treatment with daidzein prevented Aβ-induced cell viability loss, increased oxidative stress, and mitochondrial membrane potential decline in both SH-SY5Y and C6 cells. Furthermore, daidzein application reduced elevated levels of MAPK pathway proteins, pro-inflammatory molecules (cyclooxygenase-2 and IL-1β), and pyroptosis markers, including caspase-1 and gasdermin D, all of which were increased by Aβ exposure. These findings strongly suggest that daidzein alleviates inflammation and toxicity caused by Aβ oligomers. Our results indicate that daidzein could be a potential therapeutic agent for AD and other Aβ-related neurodegenerative diseases.
- MeSH
- Amyloid beta-Peptides * toxicity MeSH
- Anti-Inflammatory Agents * pharmacology MeSH
- Glioma * pathology metabolism drug therapy MeSH
- Isoflavones * pharmacology MeSH
- Rats MeSH
- Humans MeSH
- Membrane Potential, Mitochondrial drug effects MeSH
- Cell Line, Tumor MeSH
- Neuroblastoma * pathology metabolism drug therapy MeSH
- Neuroprotective Agents * pharmacology MeSH
- Oxidative Stress drug effects MeSH
- Pyroptosis drug effects MeSH
- Cell Survival drug effects MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The biotransformation of nanoparticles plays a crucial role in determining their biological fate and responses. Although a few engineering strategies (e.g., surface functionalization and shape control) have been employed to regulate the fate of nanoparticles, the genetic control of nanoparticle biotransformation remains an unexplored avenue. Herein, we utilized a CRISPR-based genome-scale knockout approach to identify genes involved in the biotransformation of rare earth oxide (REO) nanoparticles. We found that the biotransformation of REOs in lysosomes could be genetically controlled via SMPD1. Specifically, suppression of SMPD1 inhibited the transformation of La2O3 into sea urchin-shaped structures, thereby protecting against lysosomal damage, proinflammatory cytokine release, pyroptosis and RE-induced pneumoconiosis. Overall, our study provides insight into how to control the biological fate of nanomaterials.
- MeSH
- Biotransformation genetics MeSH
- CRISPR-Cas Systems MeSH
- Sea Urchins metabolism MeSH
- Metal Nanoparticles * chemistry MeSH
- Metals, Rare Earth * metabolism chemistry MeSH
- Humans MeSH
- Lysosomes metabolism MeSH
- Mice MeSH
- Nanoparticles * metabolism chemistry MeSH
- Pyroptosis MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Since cell dying in heart failure (HF) may vary based on the aetiology, we examined the main forms of regulated necrosis, such as necroptosis and pyroptosis, in the hearts damaged due to myocardial infarction (MI) or pressure overload. We also investigated the effects of a drug inhibiting RIP3, a proposed convergent point for both these necrosis-like cell death modes. In rat hearts, left ventricular function, remodelling, pro-cell death, and pro-inflammatory events were investigated, and the pharmacodynamic action of RIP3 inhibitor (GSK'872) was assessed. Regardless of the HF aetiology, the heart cells were dying due to necroptosis, albeit the upstream signals may be different. Pyroptosis was observed only in post-MI HF. The dysregulated miRNAs in post-MI hearts were accompanied by higher levels of a predicted target, HMGB1, its receptors (TLRs), as well as the exacerbation of inflammation likely originating from macrophages. The RIP3 inhibitor suppressed necroptosis, unlike pyroptosis, normalised the dysregulated miRNAs and tended to decrease collagen content and affect macrophage infiltration without affecting cardiac function or structure. The drug also mitigated the local heart inflammation and normalised the higher circulating HMGB1 in rats with post-MI HF. Elevated serum levels of HMGB1 were also detected in HF patients and positively correlated with C-reactive protein, highlighting pro-inflammatory axis. In conclusion, in MI-, but not pressure overload-induced HF, both necroptosis and pyroptosis operate and might underlie HF pathogenesis. The RIP3-targeting pharmacological intervention might protect the heart by preventing pro-death and pro-inflammatory mechanisms, however, additional strategies targeting multiple pro-death pathways may exhibit greater cardioprotection.
- MeSH
- Ventricular Function, Left drug effects MeSH
- Protein Kinase Inhibitors * pharmacology MeSH
- Myocytes, Cardiac * drug effects pathology enzymology MeSH
- Rats MeSH
- MicroRNAs metabolism genetics MeSH
- Disease Models, Animal MeSH
- Necroptosis * drug effects MeSH
- Necrosis MeSH
- Rats, Sprague-Dawley MeSH
- Pyroptosis * drug effects MeSH
- Ventricular Remodeling drug effects MeSH
- Receptor-Interacting Protein Serine-Threonine Kinases * antagonists & inhibitors metabolism MeSH
- Heart Failure * pathology enzymology physiopathology drug therapy etiology genetics MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
This study aimed to establish a rat model of chronic wounds to observe the effects of hyperbaric oxygen (HBO) on chronic wound repair and pyroptosis and explore the potential role of pyroptosis in the pathogenesis of chronic wounds. Sprague-Dawley (SD) rats were randomly divided into acute wound group (control group), chronic wound group (model group), chronic wound + HBO treatment group (HBO group), and chronic wound + VX-765 (IL-converting enzyme/Caspase-1 inhibitor) treatment group (VX-765 group). After 7 days of respective interventions, the wound healing status was observed, and wound tissue specimens were collected. Hematoxylin and eosin (HE) staining was used to observe the pathological changes in wound tissues. Transmission electron microscopy was used to observe the changes in cellular ultrastructure. Immunofluorescence was used to observe the expression and localization of vascular endothelial growth factor A (VEGF-A) and the N-terminal domain of gasdermin D (GSDMD-N). Western blot was conducted to detect the expression of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), cysteine-requiring aspartate protease-1 (Caspase-1), VEGF-A, and GSDMD-N proteins in wound tissues. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of NLRP3, Caspase-1, and GSDMD genes. Enzyme-linked immunosorbent assay (ELISA) was performed to observe the expression of the inflammatory cytokines interleukin-1 beta (IL-1beta) and IL-18. The results showed that the HBO group had a faster wound healing rate and better pathology improvement compared to the model group. The expression level of VEGF-A was higher in the HBO group compared to the model group, while the expression levels of NLRP3, Caspase-1, GSDMD, IL-1beta, and IL-18 were lower than those in the model group. HBO can effectively promote the healing of chronic wounds, and the regulation of pyroptosis may be one of its mechanisms of action. Keywords: Hyperbaric oxygen, Pyroptosis, Chronic wounds, Inflammatory.
- MeSH
- Chronic Disease MeSH
- Gasdermins MeSH
- Wound Healing * physiology MeSH
- Hyperbaric Oxygenation * methods MeSH
- Rats MeSH
- Rats, Sprague-Dawley * MeSH
- NLR Family, Pyrin Domain-Containing 3 Protein metabolism MeSH
- Phosphate-Binding Proteins metabolism MeSH
- Pyroptosis * physiology MeSH
- Vascular Endothelial Growth Factor A metabolism genetics MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
This study hypothesized that SCFA, acetate impacts positively on hypothalamic pyroptosis and its related abnormalities in experimentally induced PCOS rat model, possibly through NrF2/HIF1-α modulation. Eight-week-old female Wister rats were divided into groups (n = 5), namely control, PCOS, acetate and PCOS + acetate groups. Induction of PCOS was performed by administering 1 mg/kg body weight of letrozole for 21 days. After PCOS confirmation, the animals were treated with 200 mg/kg of acetate for 6 weeks. Rats with PCOS were characterized with insulin resistance, leptin resistance, increased plasma testosterone as well as degenerated ovarian follicles. There was also a significant increase in hypothalamic triglyceride level, triglyceride-glucose index, inflammatory biomarkers (SDF-1 and NF-kB) and caspase-6 as well as plasma LH and triglyceride. A decrease was observed in plasma adiponectin, GnRH, FSH, and hypothalamic GABA with severe inflammasome expression in PCOS rats. These were accompanied by decreased level of NrF2/HIF1-α, and the alterations were reversed when treated with acetate. Collectively, the present results suggest the therapeutic impact of acetate on hypothalamic pyroptosis and its related comorbidity in PCOS, a beneficial effect that is accompanied by modulation of NrF2/HIF1-α.
- MeSH
- Adiponectin metabolism blood MeSH
- Hypoxia-Inducible Factor 1, alpha Subunit * metabolism MeSH
- NF-E2-Related Factor 2 metabolism MeSH
- Follicle Stimulating Hormone blood MeSH
- gamma-Aminobutyric Acid metabolism MeSH
- Gonadotropin-Releasing Hormone metabolism MeSH
- Hypothalamus * metabolism drug effects pathology MeSH
- Insulin Resistance MeSH
- Rats MeSH
- Leptin blood metabolism MeSH
- Letrozole pharmacology MeSH
- Luteinizing Hormone blood MeSH
- Disease Models, Animal MeSH
- Rats, Wistar * MeSH
- Pyroptosis * drug effects MeSH
- Polycystic Ovary Syndrome * chemically induced metabolism drug therapy pathology MeSH
- Testosterone blood MeSH
- Triglycerides blood metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Cell death is one of the most important mechanisms of maintaining homeostasis in our body. Ferroptosis and pyroptosis are forms of necrosis-like cell death. These cell death modalities play key roles in the pathophysiology of cancer, cardiovascular, neurological diseases, and other pathologies. Transition metals are abundant group of elements in all living organisms. This paper presents a summary of ferroptosis and pyroptosis pathways and their connection to significant transition metals, namely zinc (Zn), copper (Cu), molybdenum (Mo), lead (Pb), cobalt (Co), iron (Fe), cadmium (Cd), nickel (Ni), mercury (Hg), uranium (U), platinum (Pt), and one crucial element, selenium (Se). Authors aim to summarize the up-to-date knowledge of this topic.In this review, there are categorized and highlighted the most common patterns in the alterations of ferroptosis and pyroptosis by transition metals. Special attention is given to zinc since collected data support its dual nature of action in both ferroptosis and pyroptosis. All findings are presented together with a brief description of major biochemical pathways involving mentioned metals and are visualized in attached comprehensive figures.This work concludes that the majority of disruptions in the studied metals' homeostasis impacts cell fate, influencing both death and survival of cells in the complex system of altered pathways. Therefore, this summary opens up the space for further research.
- Publication type
- Journal Article MeSH
- Review MeSH
Plasmonic photothermal therapy (PPTT) employing plasmonic gold nanorods (GNRs) presents a potent strategy for eradication of tumors including aggressive brain gliomas. Despite its promise, there is a pressing need for a more comprehensive evaluation of PPTT using sophisticated in vitro models that closely resemble tumor tissues, thereby facilitating the elucidation of therapeutic mechanisms. In this study, we exposed 3D glioma spheroids (tumoroids) to (16-mercaptohexadecyl)trimethylammonium bromide-functionalized gold nanorods (MTAB-GNRs) and a near-infrared (NIR) laser. We demonstrate that the photothermal effect can be fine-tuned by adjusting the nanoparticle concentration and laser power. Depending on the selected parameters, the laser can trigger either regulated or non-regulated cell death (necrosis) in both mouse GL261 and human U-87 MG glioma cell lines, accompanied by translocation of phosphatidylserine in the membrane. Our investigation into the mechanism of regulated cell death induced by PPTT revealed an absence of markers associated with classical apoptosis pathways, such as cleaved caspase 3. Instead, we observed the presence of cleaved caspase 1, gasdermin D, and elevated levels of NLRP3 in NIR-irradiated tumoroids, indicating the activation of pyroptosis. This finding correlates with previous observations of lysosomal accumulation of MTAB-GNRs and the known lysosomal pathway of pyroptosis activation. We further confirmed the absence of toxic breakdown products of GNRs using electron microscopy, which showed no melting or fragmentation of gold nanoparticles under the conditions causing regulated cell death. In conclusion, PPTT using coated gold nanorods offers significant potential for glioma cell elimination occurring through the activation of pyroptosis rather than classical apoptosis pathways.
- MeSH
- Spheroids, Cellular drug effects pathology MeSH
- Photothermal Therapy MeSH
- Glioma * pathology drug therapy metabolism MeSH
- Cations chemistry pharmacology MeSH
- Metal Nanoparticles chemistry MeSH
- Quaternary Ammonium Compounds chemistry pharmacology MeSH
- Humans MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Tumor Cells, Cultured MeSH
- Nanotubes * chemistry MeSH
- Pyroptosis * drug effects MeSH
- Cell Survival drug effects MeSH
- Gold * chemistry pharmacology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Current diabetic retinopathy (DR) treatment involves blood glucose regulation combined with laser photocoagulation or intravitreal injection of vascular endothelial growth factor (VEGF) antibodies. However, due to the complex pathogenesis and cross-interference of multiple biochemical pathways, these interventions cannot block disease progression. Recognizing the critical role of the retinal microenvironment (RME) in DR, it is hypothesized that reshaping the RME by simultaneously inhibiting primary and secondary blood-retinal barrier (BRB) injury can attenuate DR. For this, a glucose-responsive hydrogel named Cu-PEI/siMyD88@GEMA-Con A (CSGC) is developed that effectively delivers Cu-PEI/siMyD88 nanoparticles (NPs) to the retinal pigment epithelium (RPE). The Cu-PEI NPs act as antioxidant enzymes, scavenging ROS and inhibiting RPE pyroptosis, ultimately blocking primary BRB injury by reducing microglial activation and Th1 differentiation. Simultaneously, MyD88 expression silence in combination with the Cu-PEI NPs decreases IL-18 production, synergistically reduces VEGF levels, and enhances tight junction proteins expression, thus blocking secondary BRB injury. In summary, via remodeling the RME, the CSGC hydrogel has the potential to disrupt the detrimental cycle of cross-interference between primary and secondary BRB injury, providing a promising therapeutic strategy for DR.
- MeSH
- Cellular Microenvironment drug effects MeSH
- Diabetic Retinopathy * drug therapy metabolism MeSH
- Glucose * metabolism MeSH
- Blood-Retinal Barrier * metabolism drug effects MeSH
- Hydrogels * pharmacology MeSH
- Disease Models, Animal MeSH
- Mice MeSH
- Nanoparticles MeSH
- Retina drug effects metabolism MeSH
- Retinal Pigment Epithelium metabolism drug effects MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Netrin-1 (NTN-1) plays a vital role in the progress of nervous system development and inflammatory diseases. However, the role and underlying mechanism of NTN-1 in inflammatory pain (IP) are unclear. BV2 microglia were treated with LPS to mimic the cell status under IP. Adeno-associated virus carrying the NTN-1 gene (AAV-NTN-1) was used to overexpress NTN-1. Complete Freund's Adjuvant (CFA)-induced mouse was recruited as an in vivo model. MTT and commercial kits were utilized to evaluate cell viability and cell death of BV2 cells. The mRNA expressions and secretions of cytokines were measured using the ELISA method. Also, the pyroptosis and activation of BV2 cells were investigated based on western blotting. To verify the role of Rac1/NF-kappaB signaling, isochamaejasmin (ISO) and AAV-Rac1 were presented. The results showed that NTN-1 expression was decreased in LPS-treated BV2 microglia and spinal cord tissues of CFA-injected mice. Overexpressing NTN-1 dramatically reversed cell viability and decreased cell death rate of BV2 microglia under lipopolysaccharide (LPS) stimulation, while the level of pyroptosis was inhibited. Besides, AAV-NTN-1 rescued the activation of microglia and inflammatory injury induced by LPS, decreasing IBA-1 expression, as well as iNOS, IL-1beta and IL-6 secretions. Meanwhile AAV-NTN-1 promoted the anti-inflammation response, including increases in Arg-1, IL-4 and IL-10 levels. In addition, the LPS-induced activation of Rac1/NF-kappaB signaling was depressed by NTN-1 overexpression. The same results were verified in a CFA-induced mouse model. In conclusion, NTN-1 alleviated IP by suppressing pyroptosis and promoting M2 type activation of microglia via inhibiting Rac1/NF-?B signaling, suggesting the protective role of NTN-1 in IP. Keywords: Netrin-1, Inflammatory pain, Pyroptosis, Microglia M2 activation, Rac1/NF-kappaB.
- MeSH
- Pain metabolism MeSH
- Cell Line MeSH
- Lipopolysaccharides MeSH
- Microglia * metabolism MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Netrin-1 * metabolism MeSH
- Neuropeptides * MeSH
- NF-kappa B * metabolism MeSH
- Pyroptosis * physiology drug effects MeSH
- rac1 GTP-Binding Protein * metabolism MeSH
- Signal Transduction * MeSH
- Inflammation * metabolism pathology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The review proposes a model of the etiology of celiac disease. It describes how an enteroviral attack by a lytic virus leads to hyper-extracellular Transglutaminase 2, Tg2, evident at all stages of the disease by the presence of anti-tTG. The demand for Tg2 is supplied by both the cell and the lytic virus. The demand leads to excess Tg2 passing through the cell wall, excess ingress of Ca2+ , the destruction of the mitochondria by Ca 2+ , and pyroptosis of the cell. The increase in extracellular Tg2 during the cell's life and following pyroptosis has two effects. First, it binds a C1r inhibitor to the vascular wall, preventing C1r-LP from converting prehaptoglobin (zonulin) into haptoglobin, causing the weakening of the tight junctions among the epithelial cells and allowing the entry of extraneous luminal materials and particularly the access of Tg2 arterial and luminal, as it is now open directly to the lumen and the mesenchyme structure. It is this Tg2 that damages the villus structure as the Tg2 binds fibronectin into the mesenchyme, causing scarring, shrinkage, and turning the villi into the rigid scarred structures characteristic of CD. The model suggests why CD is a chronic lifelong disease reactivated upon the resumption of gluten consumption. A discussion of refractory CD follows. The paper explains how extracellular transglutaminase causes zonulin and damages the extracellular membrane. Thus, zonulin is a symptom, not a cause. Notably, the paper demonstrates that the basic tenet of autoimmune diseases that the cells destroy themselves is incorrect, at least for CD. Applying this etiology to other conditions may be relevant because of the almost universal glutaminolysis in cells and the substantial amount of Gluten in modern diets.
