Expression Of NLRP3 Research Articles

Molecular mechanism of Rolupram reducing neuroinflammation in noise induced tinnitus mice through TLR4/NF kB/NLRP3 protein/caspase-1/IL-1 β signaling pathway

Noisy tinnitus is a common auditory system disease characterized by persistent tinnitus symptoms. The TLR4/NF - κ B/NLRP3 signaling pathway plays an important role in neuroinflammatory response. Select 6 control and 6 noise exposed mice for transcriptome sequencing analysis in the hippocampus, conduct high-throughput data analysis, identify differentially expressed genes, and screen for pathways. Auditory brainstem response (ABR) detection was performed to understand the hearing changes, and the modeling effect was evaluated using the GPIAS% inhibition experiment of auditory startle reflex. Morphological observation of the basement membrane was performed to determine whether the inner hair cells were damaged. Immunohistochemistry and immunofluorescence were used to determine the activation of microglia in the hippocampus of noise induced tinnitus mice. Finally, qPCR and Western Blot were used to detect the expression of TLR4, NF kB, NLRP3, caspase-1, and IL-1 β in the hippocampus of each group of mice. Through high-throughput data analysis, it was found that there was no significant difference in the auditory threshold of the three groups of mice; After 2 h of exposure to 100 dB SPL noise, the GPIAS% of mice decreased significantly compared to before exposure, and membrane construction was successful. After 7 days, the GPIAS% of the drug intervention group increased. After noise exposure, mice developed tinnitus, and hippocampus neuroinflammation. Roflupram can inhibit neuroinflammation and improve tinnitus through the TLR4/NF kB/NLRP3/caspase-1/IL-1 β signaling pathway.

NLRP12 c.1382dup promotes the development of Crohn’s disease through the ERK/NLRP3/ IL-1β pathway

Whole-genome sequencing was used to identify a dominant inherited NLRP12 c.1382dup mutation in refractory familial Crohn’s disease (CD) patients. Additionally, we observed a T insertion at position 1382 in the third exon of NLRP12, leading to a frameshift mutation. Isolation of peripheral blood from mutation carriers and subsequent experiments demonstrated increased interleukin (IL)-1β in CD patients with the NLRP12 c.1382dup mutation. However, the mechanisms by which the NLRP12 c.1382dup mutation mediates IL-1β remain unclear. Our research findings reveal a close correlation between elevated p-ERK levels and increased expression of NLRP3 and IL-1β in the presence of the NLRP12 c.1382dup mutation. Further experiments demonstrate that inhibiting p-ERK with PD98059 effectively reduces the production of NLRP3 and IL-1β. This discovery provides new insights into the pathogenesis of CD, highlighting the significant role of the ERK/NLRP3/IL-1β pathway in the progression of CD. Not only does this offer novel therapeutic targets for treating CD, but it also lays the groundwork for the development of treatment strategies targeting this pathway.

NLRP3 inflammasome inhibition decreases Schistosomiasis japonica-induced granulomatous inflammation and fibrosis in BALB/c mice.

To research the role of the NLRP3 inflammasome in Schistosoma japonicum-induced granuloma formation and liver fibrosis. In in vivo tests, BALB/c mice were used. shNLRP3 plasmid based on adeno-associated virus serotype 8 (AAV8-shNLRP3) was injected to block NLRP3 inflammasome via tail vein. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were detected to assess liver injury. H&E staining was used for routine histopathological assessment; Masson's trichrome staining was used to detect fibrous tissues and collagen fibers. Hepatic expression of NLRP3, procaspase-1, bioactive caspase-1, collagen-1, tissue inhibitor of metalloproteinases-1 (TIMP-1), and α-smooth muscle actin (α-SMA) were detected by western blot. Serum levels of IL-1β were detected by enzyme-linked immunosorbent assay (ELISA). The inflammatory cell infiltration and hepatic expression of IL-1β around the granuloma were detected by immunohistochemistry staining. Treatment of S. japonicum infected mice with AAV8-shNLRP3 significantly reduced the hepatic levels of bioactive caspase-1 and IL-1β, as well as circulating IL-1β concentrations, while reducing the amounts of myeloperoxidase (MPO) and F4/80 positive cells around the granuloma. Moreover, collagen deposition, TIMP-1, and α-SMA, which are markers of hepatic stellate cell (HSC) activation, were reduced around the liver granuloma. These findings highlight a therapeutic potential of AAV8-shNLRP3 in schistosomiasis cirrhosis.

Isoorientin ameliorated ulcerative colitis by inhibiting the Galectin-3/NLRP3/IL-1β signaling pathway

Isoorientin (Iso) is a natural flavonoid present in the human diet, known for its anti-inflammatory, antioxidant, and antiviral properties. The purpose of this research was to illustrate the anti-inflammatory potential of Iso in ulcerative colitis (UC) mice and elucidate potential mechanisms. The mice model of UC was induced by cyclic intervention with Dextran Sulfate Sodium (DSS). We evaluated the efficacy of Iso in the treatment of UC, detected the expression of proteins related to the Galectin-3/NLRP3/IL-1β signaling pathway, and assessed the intestinal mucosa barrier function of colon tissue. Our findings demonstrated that Iso could improve colon length, the index of colonic weight, pathological damage to the colon, and serum cytokine secretion of UC mice. Most importantly, Iso could competitively bind Galectin-3, inhibit the interaction of Galectin-3 with NLRP3 and the expression of Galectin-3, NLRP3, ASC, caspase-1, IL-1β, and IL-18, increase the expression of MUC2, Occludin, and ZO-1. In summary, Iso had a therapeutic effect on UC mice, and its mechanism may be to inhibit the inflammatory response and improve the intestinal mucosa barrier by binding Galectin-3 and inhibiting the Galectin-3/NLRP3/IL-1β signaling pathway.

Hesperetin protects against rotenone-induced motor disability and neurotoxicity via the regulation of SIRT1/NLRP3 signaling

Rotenone is a pesticide that causes complex I inhibition and is widely known to induce motor disability and experimental Parkinson’s disease (PD) in rodents. Evidence suggests a crucial role for sirtuin/nuclear factor-kappaB/nod-like receptor family, pyrin domain-containing 3 (SIRT1/NFκB/NLRP3) signaling and inflammation in PD and rotenone neurotoxicity. Hesperetin (C16H14O6) is a citrus flavonoid with documented anti-inflammatory activity. We investigated the value of hesperetin in delaying rotenone-induced PD in mice and the possible modulation of inflammatory burden. PD was induced in mice via rotenone injections. Groups were assigned as a vehicle, PD, or PD + hesperetin (50 or 100 mg/kg) and compared for the motor function, protein level (by ELISA), and gene expression (by real-time PCR) of the target proteins, histopathology, and immunohistochemistry for tyrosine hydroxylase enzyme. Hesperetin (50 or 100 mg/kg) alleviated the motor disability and the striatal dopamine level and decreased the expression of NLRP3 and NF-κB but increased SIRT1 expression (p < 0.05). Further, it enhanced the neural viability and significantly decreased neural degeneration in the substantia nigra, hippocampus, and cerebral cortex (p < 0.05). Taken together, we propose that hesperetin mediates its neuroprotective function via alleviating modulation of the SIRT1/NFκB/NLRP3 pathway. Therefore, hesperetin might delay the PD progression.

Vascular endothelial dysfunction improvements in patients with uraemia using pentoxifylline-suppressing NLRP3 expressions and HMGB1 release.

This study aimed to investigate the protective effect of pentoxifylline (PTX) on vascular endothelial dysfunction in uraemia. The human aortic endothelial cells (HAECs) required for the experiments were all obtained from the National Collection of Authenticated Cell Cultures (Salisbury, UK). The permeability of HAECs was assessed. Each group had six samples. Compared with the healthy volunteer group, HAEC proliferation in the 20% uraemia group was significantly inhibited after 72 h (p < 0.001), co-localisation of nucleotide-binding domain, leucine-rich repeat-containing receptor family pyrin domain-containing 3 (NLRP3) and apoptosis-associated speck-like (ASC) protein induced by uremic serum was enhanced (p < 0.01) and high mobility group box 1 (HMGB1) release was increased (0.594 ± 0.057, p = 0.03). The co-immunoprecipitation of NLRP3, ASC and HMGB1 induced by uremic toxin was also enhanced (p < 0.01), and PTX inhibited this phenomenon. The expression of NLRP3 (0.810 ± 0.032, p = 0.02) and caspase-1 (0.580 ± 0.041, p = 0.03) was increased, whereas the expression of ZO-1 (0.255 ± 0.038, p = 0.03) and VE-cadherin (0.0546 ± 0.053, p = 0.02) was decreased in the uraemia group; compared with the healthy volunteer group, treated with PTX (NLRP3, 0.298 ± 0.042, p = 0.03; caspase-1, 0.310 ± 0.021, p = 0.03; ZO-1, 0.412 ± 0.028, p = 0.02; VE-cadherin, 0.150 ± 0.034, p = 0.02) and MCC950 (NLRP3, 0.432 ± 0.022, p = 0.03; caspase-1, 0.067 ± 0.031, p > 0.05; ZO-1, 0.457 ± 0.026, p = 0.03; VE-cadherin, 0.286 ± 0.017, p = 0.03) lessened this trend. Pentoxifylline promoted the HAEC permeability mediated by uremic toxins (1.507 ± 0.012, p = 0.02). In conclusion, PTX enhances the release of HMGB1, which is dependent on NLRP3 activation, and consequently exerts positive effects on interconnecting proteins, ultimately leading to an improvement in vascular permeability.

NLRP3 Inflammasome Activation Mediates Hepatitis E Virus-Induced Neuroinflammation.

Hepatitis E virus (HEV) is a foodborne zoonotic pathogen that is supposed to be one of the most common causes of acute viral hepatitis. However, HEV infection has been recently associated with a wide spectrum of extrahepatic manifestations, particularly neurological disorders. Previous studies have shown that HEV is able to cross the blood-brain barrier (BBB) and induce inflammatory response of the central nervous system. However, the pathogenesis of HEV-induced neuroinflammation and tissue injury of the central nervous system have yet to be fully elucidated. In this study, activation of NLRP3 inflammasome following HEV infection were investigated. In a gerbil model infected by HEV, brain histopathological changes including gliosis, neuronophagia and neuron injury were observed and expression of NLRP3, caspase-1, IL-1β and IL-18 were elevated. Brain microvascular endothelial cells (BMECs) are key components of the BBB that protects the brain from various challenges. Following HEV infection, virus-like particles range from 30 to 40 nm in diameter were observed in human BMECs (hBMECs). Enhanced expression levels of NLRP3 and subsequent ASC, caspase-1, IL-1β and IL-18 were detected in infected cells. Treatment with MCC950 alleviated HEV infection induced activation of NLRP3 inflammasome, mitochondrial damage and VE-cadherin degradation. The findings provide new insights into HEV-associated neuroinflammation. Moreover, targeting NLRP3 inflammasome signalling is a promising therapeutic in HEV-induced neurological disorder.

Macrophages regulate plaque progression in diabetic Apoe−/− mice dependent on Pi4p/Nlrp3 signaling pathway

Background and aimsAtherosclerotic cardiovascular disease complicated by diabetes mellitus (DM) is the leading cause of death in diabetic patients, and it is strongly associated with macrophages and inflammasomes. It has been found that activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome is closely associated with phosphatidylinositol 4-phosphate (PI4P) on the trans-Golgi. However, how PI4P and NLRP3 regulate macrophage function and its role in diabetic atherosclerotic plaques is unclear. MethodsThe expression of Pi4p and Nlrp3-inflammasome-related proteins in atherosclerosis in apolipoprotein E-deficient (Apoe−/−) and Apoe−/− DM mice was investigated. Then, Pi4p levels were affected by shRNA-Pi4kb or cDNA-Sac1 plasmid to investigate the effects of changes in Pi4p-related metabolic enzymes on macrophage function. Finally, genetically modified macrophages were injected into diabetic Apoe−/− mice to explore the effects on atherosclerosis. ResultsDM promoted plaque progression in atherosclerotic mice and increased expression of Pi4p and Nlrp3 in plaques. In addition, impaired macrophage function induced by high glucose was reversed by transfected shRNA-Pi4kb or cDNA-Sac1 plasmid. Furthermore, decreased levels of Pi4p reduced plaque area in diabetic Apoe−/− mice. ConclusionsOur data suggests that Pi4p/Nlrp3 in macrophages play an important role in the exacerbation of atherosclerosis in diabetic mice. Pi4p-related metabolizing enzymes (PI4KB and SAC1) may be a potential therapeutic strategy for diabetic atherosclerosis, and macrophage therapy is also a potential treatment.

Docosahexaenoic acid eliminates endoplasmic reticulum stress and inflammatory pathways in diabetic rat keratopathy

Diabetic keratopathy, characterized by corneal structural changes, is a common complication of diabetes mellitus (DM). Docosahexaenoic acid (DHA), an omega-3 fatty acid, has shown potential therapeutic benefits in various diabetic complications. This study aimed to investigate the protective effect of DHA on corneal tissue in streptozotocin (STZ)-induced type 2 DM in rats. Forty male Sprague–Dawley rats were randomly assigned to four groups (n = 10 per group): Control, DHA, DM, and DM + DHA. The DHA group received DHA by oral gavage at a dose of 100 mg/kg daily for 10 days. In the DM group, diabetes was induced by a single intraperitoneal injection of STZ at 50 mg/kg. Confirmation of diabetes induction was based on monitoring fasting blood glucose levels on the third day post-injection. The DM + DHA group underwent the same diabetes induction protocol with STZ and received DHA at 100 mg/kg daily via oral gavage for 10 consecutive days. Corneal tissue samples were collected at the end of the study period for histopathological, immunohistochemical, qRT-PCR, and ELISA analyses. Histopathological analysis showed significant edema, angiogenesis, and degeneration in the DM group compared to the control (p < 0.001). DHA treatment significantly mitigated these changes, approaching control levels (p < 0.01). Immunohistochemistry showed increased VEGFR2 and iNOS expression in the DM group, which was significantly reduced in the DM + DHA group (p < 0.01). qRT-PCR results indicated a significant decrease in Bcl-2 expression (p < 0.001) and an increase in ATF-6, IRE1, NF-κB, TNF-α, IL-1β, NLRP3, Bax, and Caspase-3 expressions in the DM group (p < 0.001). ELISA analyses revealed significantly elevated levels of inflammatory markers NF-κB, TNF-α, IL-1β, and IL-6 in the DM group compared to the control (p < 0.001). DHA treatment significantly upregulated Bcl-2 and downregulated apoptotic and inflammatory markers (p < 0.01). DHA demonstrated significant protective effects against STZ-induced corneal damage in diabetic rats by modulating apoptotic and inflammatory pathways. These findings suggest that DHA may be a promising therapeutic agent for preventing diabetic keratopathy.

Knockdown of KCNQ1OT1 Alleviates the Activation of NLRP3 Inflammasome Through miR-17-5p/TXNIP Axis in Retinal Müller Cells

Purpose Diabetic retinopathy (DR) is one of the most severe and common complications caused by diabetic mellites. Inhibiting NLRP3 inflammasome activation displays a crucial therapeutic value in DR. Studies have shown that KCNQ1OT1 plays a critical role in regulating NLRP3 inflammasome activation and participates in the pathogenesis of diabetic complications. The present study aims to explore the role, and the potential mechanism of KCNQ1OT1 in regulating the activation of NLRP3 inflammasome in DR. Methods qRT-PCR was used to detect the expression of KCNQ1OT1, miR-17-5p, TXNIP, NLRP3, ASC, caspase-1 and IL-1β. Western blot was performed to detect the expression of NLRP3, ASC, caspase-1, IL-1β and TXNIP. Immunohistochemistry and immunostaining were performed to detect the expression of caspase-1. The levels of the inflammatory cytokine IL-1β were determined by ELISA assay. FISH was used to detect the subcellular localisation of KCNQ1OT1. Bioinformatic analysis, luciferase reporter assay and in vitro studies were performed to elucidate the mechanism of KCNQ1OT1-mediated dysfunction. Results The expression of KCNQ1OT1 and the activation of NLRP3 inflammasome were increased in experimental DR models. KCNQ1OT1 knockdown alleviated NLRP3 inflammasome-associated molecules expression. In addition, KCNQ1OT1 was found to be localized mainly in the cytoplasm of Müller cells and facilitated TXNIP expression by acting as a miR-17-5p sponge. KCNQ1OT1 promoted the activation of NLRP3 inflammasome through miR-17-5p/TXNIP axis. Conclusions In conclusion, it was found in this study that KCNQ1OT1 promoted the activation of NLRP3 inflammasome both in vitro and in vivo, which was mediated by miR-17-5p/TXNIP axis. KCNQ1OT1 might be an effective interference target for the prevention and treatment of DR.

LincRNA-p21/AIF-1/CMPK2/NLRP3 pathway promoted inflammation, autophagy and apoptosis of human tubular epithelial cell induced by urate via exosomes

Urate nephropathy, a common complication of hyperuricemia, has garnered increasing attention worldwide. However, the exact pathogenesis of this condition remains unclear. Currently, inflammation is widely accepted as the key factor in urate nephropathy. Therefore, the aim of this study was to elucidate the interaction of lincRNA-p21/AIF-1/CMPK2/NLRP3 via exosomes in urate nephropathy. This study evaluated the effect of lincRNA-p21/AIF-1/CMPK2/NLRP3 using clinical data collected from patients with urate nephropathy and human renal tubular epithelial cells (HK2) cultured with different concentrations of urate. In clinical research section, the level of lincRNA-p21/AIF-1 in exosomes of urine in patients with hyperuricemia or urate nephropathy was found to be increased, particularly in patients with urate nephropathy. In vitro study section, the level of exosomes, inflammation, autophagy, and apoptosis was increased in HK2 cells induced by urate. Additionally, the expression of lincRNA-p21, AIF-1, CMPK2, and NLRP3 was upregulated in exosomes and HK2 cells. Furthermore, manipulating the activity of lincRNA-p21, AIF-1, CMPK2, and NLRP3 through overexpression or interference vectors regulated the level of inflammation, autophagy, and apoptosis in HK2 cells. In conclusion, the pathway of lincRNA-p21/AIF-1/CMPK2/NLRP3 contributed to inflammation, autophagy, and apoptosis of human renal tubular epithelial cell induced by urate via exosomes. Additionally, the specific exosomes in urine might serve as novel biomarkers for urate nephropathy.

Hypoxia activates macrophage-NLRP3 inflammasome promoting atherosclerosis via PFKFB3-driven glycolysis.

The onset and progression of atherosclerosis are closely linked to the involvement of macrophages. While the contribution of NLRP3 inflammasome activation to the creation of a local highly inflammatory microenvironment is well recognized, the precise triggers remain unclear. In this study, we aimed to investigate the regulatory mechanism of NLRP3 inflammasome activation in response to hypoxia-induced glycolysis involving PFKFB3 in the development of atherosclerosis. To develop an atherosclerosis model, we selected ApoE knockout mice treated with a high-fat western diet. We then quantified the expression of HIF-1α, PFKFB3, and NLRP3. In addition, we administered the PFKFB3 inhibitor PFK158 during atherosclerosis modeling. The glycolytic activity was subsequently determined through 18F-FDG micro-PET/CT, exvivo glucose uptake, and ECAR analysis. Furthermore, we employed lipopolysaccharide (LPS) and TNF-α to induce the differentiation of bone marrow-derived macrophages (BMDMs) into M1-like phenotypes under both hypoxic and normoxic conditions. Our histological analyses revealed the accumulation of PFKFB3 in human atherosclerotic plaques, demonstrating colocalization with NLRP3 expression and macrophages. Treatment with PFK158 reduced glycolytic activity and NLRP3 inflammasome activation, thereby mitigating the occurrence of atherosclerosis. Mechanistically, hypoxia promoted glycolytic reprogramming and NLRP3 inflammasome activation in BMDMs. Subsequent blocking of either HIF-1α or PFKFB3 downregulated the NLRP3/Caspase-1/IL-1β pathway in hypoxic BMDMs. Our study demonstrated that the HIF-1α/PFKFB3/NLRP3 axis serves as a crucial mechanism for macrophage inflammation activation in the emergence of atherosclerosis. The therapeutic potential of PFKFB3 inhibition may represent a promising strategy for atheroprotection.

Network pharmacology and in vivo experimental studies reveal the protective effects of 6-hydroxygenistein against hypobaric hypoxia-induced brain injury

Hypobaric hypoxia-induced brain injury (HHBI) is a progressive neurodegenerative disease that has still not been effectively treated. There are several different mechanisms involved in HHBI. Among them, oxidative stress and inflammation response predominate. 6-hydroxygenistein (4′,5,6,7-tetrahydroxyisoflavone, 6-OHG) is a hydroxylated derivative of genistein with excellent antioxidant activity, however, the protective effects and underlying mechanisms against HHBI have not been clarified. In the present study, we aimed to explore the mechanisms of action of 6-OHG on HHBI using network pharmacology and experimental validation. Network pharmacology analysis revealed 186 candidate targets through the intersection of the targets of 6-OHG and related genes in HHBI, which were mainly enriched in oxidative stress and inflammation response. Moreover, key targets of 6-OHG against HHBI, namely Nrf2 and NF-κB, were screened and found to be closely related to oxidative stress and inflammation response. Subsequent in vivo experiments revealed that 6-OHG treatment attenuated oxidative stress and inflammation response, prevented energy disorder and apoptosis as well as maintained the BBB integrity in HHBI mice. In addition, 6-OHG administration up-regulated the expressions of Nrf2 and HO-1 and down-regulated the expressions of NF-κB and NLRP3, thereby inhibiting oxidative stress and inflammation response. Hence, the present study demonstrates that 6-OHG protects against HHBI by stimulating the Nrf2/HO-1 signaling pathway and suppressing the NF-κB/NLRP3 signaling pathway.

Anti-inflammatory Properties of Tongfeng Li'an Granules in an Acute Gouty Arthritis Rat Model.

To examine the anti-inflammatory properties and underlying mechanisms of Tongfeng Li'an Granules (TFLA), a traditional medicine, in acute gouty arthritis using a rat model. We identified 55 major compounds in TFLA via ultrahigh-performance liquid chromatography connected to quadrupole time-of-flight mass spectrometry (UPLC-TQF-MS/MS). Databases were employed for the prediction of potential targets, followed by PPI network construction as well as GO and KEGG analyses. After network-pharmacology-based analysis, a rat gouty arthritis model was used to validate the anti-inflammatory mechanism of TFLA. UPLC-TQF-MS/MS and network pharmacology analyses revealed 55 active ingredients and 160 targets of TFLA associated with gouty arthritis, forming an ingredient-target-disease network. The PPI network identified 20 core targets, including TLR2, TLR4, IL6, NFκB, etc. Functional enrichment analyses highlighted the Toll-like receptor signaling pathway as significantly enriched by multiple targets, validated in in vivo experiments. Animal experiments demonstrated that TFLA improved pathological changes in gouty joint synovium, with decreased ankle joint circumference, serum IL6, IL10, and TNFα levels, as well as reduced protein and mRNA expression of NLRP3, TLR2, and TLR4 in ankle joint synovial tissue observed in the middle- and high-dose TFLA and positive control groups compared to the model group (p < 0.05). This research elucidated the pharmacological mechanisms of TFLA against gouty arthritis, implicating various ingredients, targets, and signaling pathways. Animal experiments confirmed TFLA's efficacy in alleviating inflammation in acute gouty arthritis by modulating Toll-like receptor signaling and NLRP3 expression.

Particulate Matter Induces NLRP3 Inflammasome-Mediated Pyroptosis in Human Nasal Epithelial Cells

Background and Objectives: Air pollution, particularly particulate matter (PM), has a variety of adverse effects on human health. PM is known to induce cell death through various pathways, including pyroptosis. Despite its significance, research on PM-induced pyroptosis in nasal epithelial cells remains limited. This study aimed to explore PM-induced pyroptosis in cultured human nasal epithelial cells.Methods: For the in vitro experiments, human nasal epithelial cells were cultured. Cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while cell death was evaluated through propidium iodide (PI) staining and lactate dehydrogenase (LDH) release measurement. Protein expression levels related to pyroptosis were examined via western blot using antibodies against NOD-like receptor family, pyrin domain containing 3 (NLRP3), cleaved caspase-1 (CASP1 P20), gasdermin D (GSDMD)-N, and glyceraldehyde phosphate dehydrogenase. Immunofluorescent staining with a CASP1 P20 antibody was conducted to visualize cellular localization. Enzyme-linked immunosorbent assay was utilized to quantify interleukin (IL)-1β and IL-18 protein levels.Results: Treatment with PM resulted in decreased cell viability, elevated LDH release, and intensified PI staining, indicating cell death. Pyroptosis was confirmed by the elevated expression of NLRP3, CASP1 P20, and GSDMD-N, along with increased levels of IL-1β and IL-18. Inhibiting the NLRP3 inflammasome with MCC950 reduced the PM-induced effects on protein expression and cytokine release, highlighting the role of the NLRP3 inflammasome in PM-triggered pyroptosis in human nasal epithelial cells.Conclusion: We showed that PM triggers pyroptosis in human nasal epithelial cells, driven by NLRP3 inflammasome-dependent signaling pathways.

Intranuclear Irradiation Inhibits Solid Tumor Growth by Upregulating Caspase8 and Activating Apoptosis.

Radioimmunotherapy (RIT) is a novel and promising cancer treatment method, with ongoing research focusing on RIT antibody selection, radionuclides, treatment options, and benefited patient groups. As we dive into the mechanisms of tumor biology, a deeper exploration of how RIT affects tumor tissue is needed to provide new ways to improve clinical treatment outcome and patient prognosis. We labeled the anti-PD-L1 monoclonal antibody atezolizumab with iodine-131 (131I), separated and purified the labeled mAb with Sephadex G-25 medium gel filtration resin, and tested product stability. We detected the in vivo activity of 131I-PD-L1 mAb by analyzing its in vivo biodistribution and performing SPECT imaging and then set different treatment groups to study the effect of 131I-atezolizumab on the survival of tumor-bearing mice. Western blot, real-time quantitative PCR, and immunohistochemistry were used to detect the expression level of Caspase8 and Nlrp3 in tumor. TUNEL fluorescence staining was used to detect the apoptosis in the tumor. The radiopharmaceutical molecular probe 131I-atezolizumab showed high stability and in vivo biological activity. The treatment regimen adopted had a positive effect on the survival of tumor-bearing mice. 131I internal irradiation upregulated Caspase8 in tumor and ultimately inhibited solid tumor growth by activating apoptosis pathways. We also found a significant increase in the expression of NLRP3, which plays an important role in the pyroptosis pathway, in tumor. In summary, our data demonstrated that radiopharmaceuticals combined with immunotherapy affected tumor tissue by modulating relevant biological pathways, thereby achieving better antitumor effects compared with single therapy and providing new insights for promoting better patient prognosis and combination treatment strategies.

Assessment of the role of high-density lipoproteins and their immunomodulatory activity in systemic lupus erythematosus immunopathology

ObjectiveTo explore the potential associations between high-density lipoprotein (HDL) levels and inflammasome components in the context of systemic lupus erythematosus (SLE).MethodsA cross-sectional study was conducted. A group of 50 patients...

Re-positioning of low dose paclitaxel against depressive-like behavior and neuroinflammation induced by lipopolysaccharide in rats: Crosstalk between NLRP3/caspase-1/IL-1β and Sphk1/S1P/ NF-κB signaling pathways

AimsDepression is a potentially fatal illness affecting millions of individuals worldwide, across all age groups. Neuroinflammation is a key factor in depression development. Paclitaxel (PXL), a well-known chemotherapeutic agent has been used as therapy for several types of cancer. This study aims to evaluate the ameliorative effect of low-dose PXL against lipopolysaccharide (LPS)-induced depression in rats. Materials and methodsAdult male Sprague-Dawley rats were administrated a single dose of LPS (5 mg/kg, i.p.); 2 h later, rats received PXL (0.3 mg/kg, i.p. three times/week) for one week. Key findingsLow-dose PXL alleviated LPS-induced depressive-like behavior in rats as evidenced by significantly improving behavioral changes in both forced swim test (FST) and open field test (OFT), successfully mitigated depletion of monoamines (serotonin, norepinephrine, and dopamine), in addition to markedly decreasing lipid peroxidation with antioxidant levels elevation in brain tissues. Low-dose PXL substantially decreased inflammation triggered by LPS in brain tissue via repressing the expression of NLRP3 and its downstream markers level, caspase-1 and IL-1β jointly with a corresponding decrease in proinflammatory cytokine levels (TNF-α). Furthermore, low-dose PXL remarkably down-regulated Sphk1/S1P signaling pathway. Concurrent with these biochemical findings, there was a noticeable improvement in the brain tissue's histological changes. SignificanceThese findings prove the role of low-dose PXL in treatment of LPS-induced neuroinflammation and depressive-like behavior through their anti-depressant, antioxidant and anti-inflammatory actions. The suggested molecular mechanism may entail focusing the interconnection among Sphk1/S1P, and NLRP3/caspase-1/IL-1β signaling pathways. Hence PXL could be used as a novel treatment against LPS-induced depression.

In-vitro and in-vivo studies of two-drug cocktail therapy targeting chemobrain via the Nrf2/NF-κB signaling pathway.

Today, we critically need alternative therapeutic options for chemotherapy-induced cognitive impairment (CICI), often known as chemo brain. Mitochondrial dysfunction and oxidative stress are two of the primary processes that contribute to the development of chemobrain. Therefore, the purpose of this study was to investigate how CoQ10 and berberine shield neurons from chemotherapy-induced damage in in-vitro studies and memory loss in vivo studies. For the in-vitro investigation, we employed SH-SY5Y cell lines, and for the in-vivo study, we used female Swiss albino mice divided into seven different groups. Data from in-vitro studies revealed that treatment with coenzyme Q10 (CoQ10) and berberine improved chemotherapy-induced toxicity by reducing mitochondrial and total cellular ROS, as well as apoptosis-elicited markers (caspase 3 and 9). CoQ10 and berberine therapy inhibited the nuclear translocation of NF-κB and, consequently, the subsequent expressions of NLRP3 and IL-1β, implying the prevention of inflammasome formation. Furthermore, CoQ10 and berberine therapy boosted Nrf2 levels. This is a regulator for cellular resistance to oxidants. The in vivo results showed that treatment with CoQ10 (40mg/kg) and berberine (200mg/kg) improved the behavioral alterations induced by CAF (40/4/25mg/kg) in both the Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests. Furthermore, biochemical and molecular evidence revealed the antioxidant, mitochondrial restorative, and anti-inflammatory potential of CoQ10 (40mg/kg) and berberine (200mg/kg) against CAF (40/4/25mg/kg) subjected mice. In addition, the histological analysis using H&E staining and transmission electron microscopy (for mitochondrial morphology) showed that mice treated with the cocktails had an increased number of healthy neurons with intact mitochondria and a reduced presence of autophagic vacuoles in the hippocampal region of the brain. These findings back up our theory about this novel cocktail method for CAF-induced cognitive impairment.

Liraglutide ameliorates high glucose-induced vascular endothelial injury through TRIB3/NF-κB signaling pathway.

As one of the most commonly used antidiabetic medications clinically, liraglutide is involved in the protection of vascular endothelium, and whether it can relieve high glucose-induced vascular endothelial damage was unknown. This study aims to address the response of liraglutide (LIRA) on human umbilical vein endothelial cells, as well as to elucidate its possible underlying mechanism. We established a vascular endothelial cell injury model by exposing human umbilical vein endothelial cells (HUVECs) to high glucose, and used LIRA pretreatment before HG treatment to address the endothelial protective effect of LIRA. Our results suggest that LIRA prevented HG-induced HUVEC apoptosis, oxidative stress, inflammasome activation, and pyroptosis. Furthermore, silencing of tribbles homolog 3 (TRIB3) could markedly reduce HG-induced HUVEC apoptosis, ROS level, the expressions of TXNIP, cleaved caspase3, NLRP3, and caspase1, indicating TRIB3 inhibition protected HUVECs against HG-induced vascular endothelial injury. In addition, LIRA restrained NF-κB/IκB-α signaling pathway activation in HUVECs. Thus, LIRA appears to mitigate HG-induced apoptosis, oxidative stress, inflammasome activation, and pyroptosis in HUVECs via regulating the TRIB3/NF-κB/IκB-α signaling pathway. Our study provides new insight into the mechanisms underlying the protective activity of LIRA against the vascular endothelial injury in diabetic vascular complication.