Inflammasome Expression Research Articles

Epigallocatechin‐3‐Gallate Ameliorates Diabetic Kidney Disease by Inhibiting the TXNIP/NLRP3/IL‐1β Signaling Pathway

ABSTRACTRecent research indicates that the activation of the NLRP3 inflammasome is crucial in the development of diabetic kidney disease (DKD). Epigallocatechin‐3‐gallate (EGCG), the predominant catechin in green tea, has been noted for its anti‐inflammatory properties in DKD. However, the specific mechanisms are not yet fully understood. In this study, our objective was to explore the effects of EGCG on podocytes and in diabetic kidney disease (DKD) mice and investigate how EGCG modulates the TXNIP/NLRP3/IL‐1β signaling pathway in DKD, both in podocytes and animal models. In vitro, we co‐cultured podocytes with EGCG and detected the viability, apoptosis, inflammation and the TXNIP/NLRP3/IL‐1β signaling pathway. In vivo, DKD mice were given EGCG via oral gavage, followed by evaluations of renal function, inflammation, and the aforementioned signaling pathway. Our findings revealed that oxidative stress, inflammatory cytokines, and the TXNIP/NLRP3/IL‐1β pathway were upregulated in podocytes exposed to high glucose (HG) and in the kidneys of DKD mice. However, EGCG treatment reduced the expression of the NLRP3 inflammasome and its associated proteins, including TXNIP, ASC, caspase‐1, and IL‐1β, as well as the levels of ROS and inflammatory factors such as TNF‐α, IL‐6, and IL‐18. Furthermore, in vivo, EGCG improved kidney function, reduced albuminuria and body weight, and alleviated renal pathological damage. In summary, our study suggests that EGCG mitigates inflammation in podocytes and DKD through the TXNIP/NLRP3/IL‐1β signaling pathway, indicating potential benefits of EGCG or green tea in managing DKD.

Effects of TABATA Exercise Volume and Royal Jelly Supplementation on NLRP3 Inflammasome and lncRNA-H19 Expression in Obese Men

Background: Both coding and long non-coding RNAs (lncRNAs) have emerged as vital regulators in almost every cellular process, and their expression can be modulated by external stimuli, such as physical exercise. Objectives: The current research aimed to investigate the effects of different volumes of TABATA-high-intensity interval training (HIIT) exercises combined with royal jelly (RJ) supplementation on the NLRP3 inflammasome and lncRNA-H19 expression in obese males. Methods: Forty-two healthy men [Body Mass Index (BMI) = 30 kg/m², waist-to-hip ratio = 0.95, age range: 40 - 60 years] volunteered to participate in the study. The individuals were randomly divided into five experimental groups (N = 35) and one control + placebo group (N = 7). The high-volume (HV) or low-volume (LV) TABATA exercise programs were performed twice a week for 8 weeks. Participants in the RJ supplementation groups received a 1000 mg capsule once a day for 8 weeks. The expression of NLRP3 and lncRNA-H19 genes was evaluated using the real-time PCR method. Results: The NLRP3 gene expression in the Bruce test, measured before and after the 8-week exercise interventions and RJ supplementation, showed insignificant changes across the different groups. However, the H19 gene expression in the Bruce test showed a significant reduction in the HV-TABATA HIIT intervention groups, which was more pronounced than in the LV groups after 8 weeks: HV group (P = 0.004), RJ group (P = 0.001), HV + RJ group (P = 0.007), and LV + RJ group (P = 0.002). After 8 weeks of non-pharmacological interventions involving exercise training and supplementation, a significant decrease in NLRP3 and a significant increase in H19 gene expression were detected in the HV group compared to the LV group (P = 0.05 and P = 0.010). Significant improvement was also found in the resting H19 levels between the RJ and LV groups (P = 0.011) and the LV + RJ group (P = 0.44). Moreover, a significant reduction in resting NLRP3 gene expression was observed between the RJ + LV and LV groups (P = 0.038). Conclusions: Chronic HV TABATA HIIT exercise, when combined with RJ supplementation, is effective in attenuating inflammatory responses to acute stress.

Comparison of Different Keratinocyte Cell Line Models for Analysis of NLRP1 Inflammasome Activation.

The NLRP1 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-1) inflammasome is the most important inflammasome in human keratinocytes. It plays a crucial role in regulating innate immunity in the skin. This study aimed to evaluate NLRP1 inflammasome activation and the corresponding levels of detection in different keratinocyte cell lines to identify a suitable in vitro model for analyzing inflammasome activation in keratinocytes. We compared NLRP1 inflammasome activation, expression, and cell death among primary keratinocytes and immortalized keratinocyte cell lines HaCaT, HaSKpw, and SVTERT upon stimulation with ultraviolet B (UVB) irradiation or talabostat. The effects of both NLRP1 inducers on cell death and the modification of NLRP1 molecules were examined using fluorescence-activated cell sorting analysis, Western blotting, and an enzyme-linked immunosorbent assay. The key inflammasome components had varied expression levels among the keratinocyte cell models, with the highest expression observed in primary keratinocytes. Moreover, our data showed that both UVB and talabostat triggered cell death, and NLRP1 inflammasome activation was readily detected in primary keratinocytes but not in the analyzed immortalized keratinocyte cell lines. Therefore, we do not recommend the use of the immortalized keratinocyte cell lines HaCaT, HaSKpw, and SVTERT for analyzing inflammasome activation in keratinocytes; we strongly recommend the use of primary keratinocytes for these studies.

TXNIP regulates pulmonary inflammation induced by Asian sand dust

Asian sand dust (ASD), a seasonal dust storm originating from the deserts of China and Mongolia, affects Korea and Japan during the spring, carrying soil particles and a variety of biochemical components. Exposure to ASD has been associated with the onset and exacerbation of respiratory disorders, although the underlying mechanisms remain unclear. This study investigates ASD-induced pulmonary toxicity and its mechanistic pathways, focusing on the role of thioredoxin-interacting protein (TXNIP). Using TXNIP knock-out (KO) mice and adeno-associated virus (AAV)-mediated TXNIP overexpression transgenic mice, we explored how TXNIP modulates ASD-induced pulmonary inflammation. Mice were exposed to ASD via intranasal administration on days 1, 3, and 5 to induce inflammation. ASD exposure led to significant pulmonary inflammation, evidenced by increased inflammatory cell counts and elevated cytokine levels in bronchoalveolar lavage fluid, as well as heightened protein expression of the TXNIP/NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. TXNIP KO mice exhibited attenuated airway inflammation and downregulation of the NLRP3 inflammasome compared to wild-type controls, while AAV-mediated TXNIP overexpression mice showed exacerbated inflammatory responses, including elevated NLRP3 inflammasome expression, compared to AAV-GFP controls. These findings suggest that TXNIP is a key regulator of ASD-induced pulmonary inflammation.

Involvement of inflammasomes in the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with a long preclinical and prodromal stage near 20 years. The neuropathological hallmarks of AD include amyloid plaques, neurofibrillary tangles, and neuroinflammation, those lead to neuronal and synaptic loss. Important fact, oxidative stress participates in the AD development by promoting amyloid-β deposition, tau hyperphosphorylation. However, the inflammatory response and pyroptotic death are mediated by the aberrant expression of NLRP inflammasome activated caspase-1, which leads to cleavage pro-inflammatory cytokines such as pro-interleukin-1β and pro-IL-18. IL-1β, TNF-α, and IL-6 which amplify the neuroinflammation loop, are produce by activated microglia and astrocytes, that can serve as early diagnostic markers or therapeutic targets in AD. In this review, we summarize our current understanding of the role of inflammasome in the pathogenesis of AD, highlighting key issues that need to be addressed to improve the development of new therapies.

BA6b9, a novel sk4 K + channel blocker, attenuates atrial fibrillation substrate in rats with reduced ejection fraction

Abstract Background Atrial fibrillation (AF), the most common cardiac arrhythmia, is strongly associated with several comorbidities including heart failure (HF). AF in general, and specifically in the context of HF, is progressive in nature and associated with poor clinical outcomes. Current therapies for AF are limited in number and efficacy and do not target the underlying causes of atrial remodeling such as inflammation or fibrosis. We previously identified the calcium-activated SK4 K+ channels, which are preferentially expressed in the atria relative to the ventricles in both rat and human hearts, as novel druggable targets for efforts to treat AF. Methods and Findings We examined the ability of BA6b9, a novel allosteric inhibitor of SK4 channels that targets the specific calmodulin-PIP2 binding domain, to alter AF susceptibility and atrial remodeling in a systolic HF rat post-myocardial infarction (post-MI) model. Daily BA6b9 injection (20 mg/kg/day) for 3 weeks starting 1-week post-MI prolonged the atrial effective refractory period, reduced AF induction and duration, and dramatically prevented atrial structural remodeling. In the post-MI left atrium (LA), pronounced upregulation of the SK4 K+ channel was observed, with corresponding increases in collagen deposition, α-SMA levels, and NLRP3 inflammasome expression. Strikingly, BA6b9 treatment reversed these changes while also significantly reducing the lateralization of the atrial connexin Cx43 in the LA of post-MI rats. Interpretation Our findings indicate that the blockade of SK4 K+ channels using BA6b9 not only favors rhythm control but also remarkably reduces atrial structural remodeling, a property that is highly desirable for novel AF therapies, particularly in patients with comorbid HF.

Pinocembrin alleviates LPS-induced depressive-like behavior in mice via the NLRP3/DCC signaling pathway

ObjectiveDepression, a prevalent and severe mental disorder, continues to be a significant area of research concerning its pathogenesis and therapeutic approaches. Conventional antidepressants are often limited by delayed therapeutic effects and notable adverse reactions, necessitating the development of innovative and efficacious treatment modalities. Multiple lines of evidence suggest that peripheral and central inflammation play a role in depression, and that anti-inflammatory drugs can ameliorate depressive symptoms in patients with inflammation-related depression. Pinocembrin (PB), a natural bioactive compound, is renowned for its anti-inflammatory and antioxidant properties, while the effect and mechanism of PB are still unclear. Consequently, this study employs PB as an intervention to investigate its effects on depression in mice model, with the objective of establishing a novel therapeutic strategy and foundational data for the treatment of depression. Methods(1) The acute inflammation model used lipopolysaccharide (LPS) to induce depression-like behavior in mice by injecting LPS intraperitoneally at a dose of 0.83 mg/kg. The effects of PB (20 mg/kg, i.p.) and the NLRP3 inflammasome inhibitor MCC950 (10 mg/kg, i.p.) on improving depression behavior in mice were evaluated. (2) To explore the specific mechanism of PB in improving depression-like behavior in LPS mice by regulating NLRP3 and Netrin-1/DCC pathway. ResultsThe results showed that after intraperitoneal injection of LPS, the mice exhibited a significant decrease in body weight, sucrose preference score, and a significant increase in tail suspension immobility time. Treatment with PB and MCC950 increased the sucrose preference score and decreased the tail suspension immobility time. Besides, PB and MCC950 could inhibit the expression of NLRP3 related neuroinflammation, down-regulated the Netrin-1/DCC signaling pathway, and improved hippocampal neuroplasticity in mice. ConclusionIn conclusion, PB significantly improved LPS-induced depression-like behavior in mice by reducing the expression of hippocampal NLRP3 inflammasome and down-regulating the Netrin-1/DCC signaling pathway. Additionally, PB was found to regulate α-amino-3-hydroxy-5-methyl-4 isoxazole receptor (AMPAR) and postsynaptic density 95 (PSD95), protecting excitatory synaptic transmission and enhancing synaptic plasticity. This study demonstrates the effectiveness of PB in improving depressive symptoms induced by LPS and provides a new strategy for the clinical treatment of depression.

Discovery of novel substituted (Z)-N′-hydroxy-3-(3-phenylureido)benzimidamide derivatives as multifunctional molecules targeting pathological hallmarks of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder marked by significant loss of central cholinergic neurons. This progressive deterioration leads to cognitive dysfunction and impaired motor activity, culminating in the brain cell's death at the later stages of the disease. The approved drugs for AD are limited to providing symptomatic relief for an initial period due to the multifaceted etiology of the disease. Several studies have demonstrated that rivastigmine (RIV) is a selectively potent inhibitor of butyrylcholinesterase and devoid of antioxidant, Aβ, and tau protein aggregation inhibition and anti-inflammatory properties. Therefore, to address these issues associated with RIV, novel rivastigmine-based molecules were rationally designed, synthesized, and evaluated in various in-vitro and in-vivo AD models. In in-vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition studies revealed that 3q &6e as promising leads (AChE, IC50 1.72 ± 0.15, 0.91 ± 0.016 μM, BChE, IC50 6.69 ± 0.28 μM, 1.19 ± 0.026 μM, for 3q &6e, respectively). The computational studies (molecular docking and dynamics) further corroborated the in-vitro studies. Further, 3q and 6e were found to be potent antioxidants in the DPPH assay (IC50 16.15 ± 1.05 & 15.17 ± 0.07 μM, for 3q &6e, respectively). Interestingly, 3q, and 6e could effectively inhibit self-induced full-length tau and Aβ1-42 aggregation. Treatment with 3q &6e inhibited microglial activation by attenuating ROS release and mitochondrial damage. Further, 3q &6e also suppressed NLRP3 inflammasome and NF-κB expression levels in microglial cells and halted the release of pro-inflammatory cytokines in human microglial cells. Finally, 3q &6e were found to be efficacious in reversing the scopolamine-induced memory impairment in the Morris water maze test. The expression of various neuroprotection markers, such as BDNF and TRKB, was significantly overexpressed compared to the disease control group.

Inhibition of BCAT1 expression improves recurrent miscarriage by regulating cellular dysfunction and inflammation of trophoblasts.

Sustained or chronic inflammation in the placenta can result in placental insufficiency, leading to adverse reproductive outcomes such as pregnancy loss. Branched-chain amino acid transaminase 1 (BCAT1) expresses in the placenta and is involved in the pathological inflammatory response, but its role in recurrent miscarriage (RM) has not been fully investigated. In the present study, we delved into the effects of BCAT1 on trophoblast inflammation induced by lipopolysaccharide (LPS) and a mouse model of pregnancy loss induced by LPS. In vitro, after the HTR-8/SVneo cells were treated with LPS and BCATc inhibitor 2 (a selective BCAT inhibitor), the cell apoptosis was verified by TUNEL assay, and the activity of caspase-3 and caspase-9 was detected. Real-time PCR, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence (IF) were used to determine the expression of inflammatory cytokines (TNF-α, IL-6, and IL-1β) and inflammasomes (NLRP3 and ASC) in LPS-treated trophoblast cells. Western blot analysis was performed to verify the expression of phospho-IκBα (p-IκBα) in cells and NF-κB p65 in the nuclei. IF staining was used to detect the nuclear translocation of NF-κB p65. The DNA binding activity of NF-κB was detected by an electrophoretic mobility shift assay (EMSA). The results demonstrated that inhibition of BCAT1 reduced trophoblast apoptosis, suppressed the release of proinflammatory cytokines, and prevented NLRP3 inflammasome activation in response to LPS. Additionally, BCAT1 inhibition blocked the activation of the NF-κB pathway in trophoblasts. This study highlights the potential therapeutic role of targeting BCAT1 in preventing adverse reproductive outcomes associated with chronic placental inflammation.

Expression of the Aim2 Inflammasome in Skeletal is Modulated by Surgical Bypass And is a Target to Reduce Ischemic Myopathy in Pad

Expression of the Aim2 Inflammasome in Skeletal is Modulated by Surgical Bypass And is a Target to Reduce Ischemic Myopathy in Pad

Application of a modified multifunctional short peptide in the treatment of periodontitis

Periodontitis is a chronic inflammatory disease involving plaque biofilm as a pathogenic factor. Potassium ion plays an important role in cellular homeostasis; a large outflow of potassium may lead to local inflammation progression. In this work, the multifunctional short peptide molecule BmKTX-33 was designed by modifying the BmKTX, a Kv1.3 potassium channel inhibitor. This was to explore its antibacterial properties, capability of maintaining cell ion homeostasis, and bone-forming capacity. The results showed that BmKTX-33 had inhibitory effects on S. gordonii, F. nucleatum, and P. gingivalis. Moreover, BmKTX-33 also inhibited excessive potassium outflow in inflammatory environments. Finally, BmKTX-33 promoted MC3T3-E1 early osteogenesis while suppressing the NLRP3 inflammasome's production. In conclusion, BmKTX-33 not only has antibacterial properties, but also can inhibit the expression of NLRP3 inflammasome and play an anti-inflammatory role.

A carbamazepine metabolite activates NLRP3 and controls skin homing of CD8+ T-cells in SJS/TEN

BackgroundStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse drug reactions with extensive keratinocyte death. Carbamazepine (CBZ), the most commonly implicated drug in SJS/TEN, is metabolized by the cytochrome P450 enzyme 3A4 (CYP3A4) into carbamazepine-10,11-epoxide (CBZE) in the liver. While CD8+ cytotoxic T cells play an important role in SJS/TEN, the underlying mechanism of exuberant immune response by CD8+ T cells in these conditions remains incompletely understood. ObjectivesTo examine the expression of NLRP3 inflammasome and their skin migration in CBZE-induced SJS/TEN. MethodsThe expression of the NLRP3 inflammasome complex in skin lesions, sera, and blister fluids of SJS/TEN patients were analyzed by immunohistochemistry and enzyme-linked immunosorbent assay. NLRP3 formation and CD8+ T cell activation status and their functions were examined by immunoblotting, immunofluorescence, and chemotaxis assays. ResultsThe expression of the NLRP3 inflammasome complex was greatly increased in skin lesions of SJS/TEN patients. Moreover, IL-1β and IL-18 levels in sera and blister fluids of SJS/TEN patients were approximately 3-fold higher than those in healthy individuals, with a linear correlation between IL-1β levels and disease activity. CBZE induced NLRP3 inflammasome formation, upregulated CXCL9/CXCL10 levels, and activated CD8+ cytotoxic T cell functions via IL-1β/IL-1R or IL-18/IL-18R signaling in SJS/TEN keratinocytes, which promoted CD8+ cytotoxic T cell migration in SJS/TEN patients. ConclusionThis study showed that CBZE promoted NLRP3 inflammasome formation and strengthened the activation and function of CD8+ cytotoxic T cells in the skin, which contributed to the initiation and progression of SJS/TEN.

Inhibiting endoplasmic reticulum stress alleviates perioperative neurocognitive disorders by reducing neuroinflammation mediated by NLRP3 inflammasome activation.

The aim of this study is to explore the key mechanisms of perioperative neurocognitive dysfunction (PND) after anesthesia/surgery (A/S) by screening hub genes. Transcriptome sequencing was conducted on hippocampal samples obtained from 18-month-old C57BL/6 mice assigned to control (Ctrl) and A/S groups. The functionality of differentially expressed genes (DEGs) was investigated using Metascape. Hub genes associated with changes between the two groups were screened by combining weighted gene coexpression network analysis within CytoHubba. Reverse transcription PCR and western blotting were used to validate changes in mRNA and protein expression, respectively. NLRP3 inflammasome activation was detected by western blotting and ELISA. Tauroursodeoxycholic acid (TUDCA), an inhibitor of endoplasmic reticulum (ER) stress, was administrated preoperatively to explore its effects on the occurrence of PND. Immunofluorescence analysis was performed to evaluate the activation of astrocytes and microglia in the hippocampus, and hippocampus-dependent learning and memory were assessed using behavioral experiments. In total, 521 DEGs were detected between the control and A/S groups. These DEGs were significantly enriched in biological processes related to metabolic processes and their regulation. Four hub genes (Hspa5, Igf1r, Sfpq, and Xbp1) were identified. Animal experiments have shown that mice in the A/S group exhibited cognitive impairments accompanied by increased Hspa5 and Xbp1 expression, ER stress, and activation of NLRP3 inflammasome. Inhibiting ER stress alleviated cognitive impairment in A/S mice; particularly, ER stress induced by A/S results in NLRP3 inflammasome activation and neuroinflammation. Moreover, the preoperative administration of TUDCA inhibited ER stress, NLRP3 inflammasome activation, and neuroinflammation.

The impact of alternate-day fasting on the salivary gland stem cell compartments in non-obese diabetic mice with newly established Sjögren's syndrome.

Intermittent fasting exerts a profound beneficial influence on a spectrum of diseases through various mechanisms including regulation of immune responses, elimination of senescent- and pathogenic cells and improvement of stem cell-based tissue regeneration in a disease- and tissue-dependent manner. Our previous study demonstrated that alternate-day fasting (ADF) led to alleviation of xerostomia and sialadenitis in non-obese diabetic (NOD) mice, a well-defined model of Sjögren's syndrome (SS). This present study delved into the previously unexplored impacts of ADF in this disease setting and revealed that ADF increases the proportion of salivary gland stem cells (SGSCs), defined as the EpCAMhi cell population among the lineage marker negative submandibular gland (SMG) cells. Furthermore, ADF downregulated the expression of p16INK4a, a cellular senescence marker, which was concomitant with increased apoptosis and decreased expression and activity of NLRP3 inflammasomes in the SMGs, particularly in the SGSC-residing ductal compartments. RNA-sequencing analysis of purified SGSCs from NOD mice revealed that the significantly downregulated genes by ADF were mainly associated with sugar metabolism, amino acid biosynthetic process and MAPK signaling pathway, whereas the significantly upregulated genes related to fatty acid metabolic processes, among others. Collectively, these findings indicate that ADF increases the SGSC proportion, accompanied by a modulation of the SGSC property and a switch from sugar- to fatty acid-based metabolism. These findings lay the foundation for further investigation into the functionality of SGSCs influenced by ADF and shed light on the cellular and molecular mechanisms by which ADF exerts beneficial actions on salivary gland restoration in SS.

The AGEs/RAGE Signaling Pathway Regulates NLRP3-Mediated Neuronal Pyroptosis After MCAO Injury in Lepr-/- Obese Rats.

Obesity is recognized as a primary risk factor for cerebral ischemia, which has shown a significant increase in its incidence among obese patients. The exact mechanism by which obesity exacerbates cerebral ischemic injury is not fully understood though. The present study validated the hypothesis that obesity mediates pyroptosis by the AGEs/RAGE signaling pathway to exacerbate cerebral ischemic injury. Leptin receptor knockout (Lepr-/- ) rats were used in this study to construct an obesity model, and the middle cerebral artery occlusion (MCAO) models of ischemic stroke were established in Lepr-/- obese rats and their wild-type (WT) littermates respectively. Zea-Longa score, TTC and H&E staining were utilized to evaluate the neurological impairment. Western Blot, immunohistochemistry, and immunofluorescence were used to detect protein expressions. Transmission electron microscopy was used to observe the pores in the neuronal cell membrane in the ischemic penumbra cortex. Compared with WT littermates, Lepr-/- obese rats exhibited exacerbated neuronal injury after MCAO, with higher expressions of NLRP3 inflammasome and pyroptosis-related proteins in the cortical tissue of the penumbra. Moreover, more GSDMD pores were observed on the neuronal cell membranes of Lepr-/- obese rats according to the electron microscopy. Inhibition of NLRP3 inflammasome expression with MCC950 inhibited neuronal pyroptosis after cerebral ischemia in Lepr-/- obese rats, thus reducing neuronal injury. We also found that compared with WT littermates, the levels of AGEs and RAGE in the cortex of Lepr-/- obese rats are significantly higher, with further increase after cerebral ischemia. Inhibition of AGEs/RAGE signaling pathway with FPS-ZM1 reduced the NLRP3 inflammasome-mediated neuronal pyroptosis in Lepr-/- obese rats, thereby mitigating the neuronal damage after cerebral ischemia. The AGEs/RAGE signaling pathway is involved in the exacerbation of cerebral ischemic injury in Lepr-/- obese rats via regulating NLRP3-mediated neuronal pyroptosis.

Regulation of NLRP3 Inflammasome Expression through Inhibition of Podocyte-Specific Lysyl Oxidase-Like 2 as a New Therapeutic Target for AKI on CKD

Regulation of NLRP3 Inflammasome Expression through Inhibition of Podocyte-Specific Lysyl Oxidase-Like 2 as a New Therapeutic Target for AKI on CKD

Plasma Zinc Levels in Patients with Diabetic Nephropathy: Is there a Relationship with NLRP3 Inflammasome Activation and Renal Prognosis?

Zinc is an essential trace element, and impaired zinc homeostasis may be associated with inflammation in patients with diabetic nephropathy (DN). We investigated the influence of zinc level on nod-like receptor nucleotide-binding domain and leucine-rich repeat pyrin-3 domain (NLRP3) inflammasome expression and renal prognosis in patients with DN. We recruited 90 patients definitively diagnosed with DN by renal biopsy and 40 healthy controls. Zinc, NLRP3, interleukin (IL)-1β, and IL-18 levels were detected in blood samples, and the correlations between these parameters were assessed. Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) evaluated the predictive value of zinc and the NLRP3 inflammasome for DN. Furthermore, patients with DN were divided into low- and normal-zinc groups to observe differences in clinical indicators and identify expression of inflammatory-related factors in renal tissue. Kaplan-Meier survival curves predicted the impact of zinc levels on renal prognosis. We found thatthe plasma zinc concentration in patients with DN was lower, while NLRP3, IL-1β, and IL-18 levels were higher than were those in patients without DN (P < 0.05). Zinc level was negatively correlated with NLRP3, IL-1β, and IL-18 levels (P < 0.01). Zinc and the NLRP3 inflammasome were predictive of DN, but their combination improved the diagnostic value. The DCA curve demonstrated a good positive net benefit in the combined model. Compared to patients with low zinc levels, patients with normal zinc levels had lower expression of NLRP3 inflammasome and a better prognosis. Zinc has a protective effect on DN and may affect NLRP3 inflammasome activation.

Acetate attenuates hypothalamic pyroptosis in experimentally induced polycystic ovarian syndrome

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.

PM2.5 Induces Pyroptosis via Activation of the ROS/NF-κB Signaling Pathway in Bronchial Epithelial Cells.

Background and Objectives: Fine particulate matter, PM2.5, is becoming a major threat to human health, particularly in terms of respiratory diseases. Pyroptosis is a recently discovered and distinct form of cell death, characterized by pore formation in the cell membrane and secretions of proinflammatory cytokines. There has been little research on the effect of PM2.5 on pyroptosis, especially in airway epithelium. We investigated whether PM2.5-related oxidative stress induces pyroptosis in bronchial epithelial cells and defined the underlying mechanisms. Materials and Methods: After exposure of a BEAS-2B cell line to PM2.5 concentration of 20 µg/mL, reactive oxygen species (ROS) levels, parameters related to pyroptosis, and NF-κB signaling were measured by Western blotting, immunofluorescence, and ELISA (Enzyme-linked immunosorbent assay). Results: PM2.5 induced pyroptotic cell death, accompanied by LDH (Lactate dehydrogenase) release and increased uptake of propidium iodide in a dose-dependent manner. PM2.5 activated the NLRP3-casp1-gasdermin D pathway, with resulting secretions of the proinflammatory cytokines IL-1β and IL-18. The pyroptosis activated by PM2.5 was alleviated significantly by NLRP3 inhibitor. In PM2.5-exposed BEAS-2B cells, levels of intracellular ROS and NF-κB p65 increased. ROS scavenger inhibited the expression of the NLRP3 inflammasome, and the NF-κB inhibitor attenuated pyroptotic cell death triggered by PM2.5 exposure, indicating that the ROS/NF-κB pathway is involved in PM2.5-induced pyroptosis. Conclusions: These findings show that PM2.5 exposure can cause cell injury by NLRP3-inflammasome-mediated pyroptosis by upregulating the ROS/NF-κB pathway in airway epithelium.

Ferulic acid reduces inflammatory response induced by radiation through Sirt1-NLRP3 pathway

Objective: A model of inflammatory damage was induced by radiation to investigate whether ferulic acid (FA) can reduce the inflammatory response through the Sirt1-NLRP3 inflammatory pathway. This will help discover radiation-protective drugs and elucidate the molecular mechanisms related to radiation-induced inflammatory damage. Methods: A mouse model of radiation-induced immunoinflammatory injury was established to verify the anti-inflammatory effects of FA in vivo. C57BL/6J mice were randomly divided into six groups, and 5 Gy whole-body irradiation was used for modeling. Mice were administered a gastric solvent, amifostine, or 25, 50, or 100 mg/kg FA daily for 12 days, consecutively, before irradiation. The serum of mice was collected 24 hour after irradiation to observe the content of inflammatory factors interleukin (IL)-1β, IL-18, IL-6, and tumor necrosis factor (TNF)-α. The spleen and thymus tissues of mice were weighed and the organ index was calculated for pathological testing and immunofluorescence detection. Results: FA reduced the radiation-induced decrease in the spleen and thymus indices. FA significantly reduced the secretion of inflammatory factors in the serum and reversed the radiation-induced reduction in lymphocytes in the spleen and thymus of mice. FA activated Sirt1 and inhibited the expression of the NLRP3 inflammasome to alleviate the inflammatory response. Conclusions: FA reduced radiation-induced inflammation in animals, possibly by activating Sirt1 and reducing nucleotide oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome expression, thereby reducing the secretion of inflammatory factors.