Neuroinflammation is a pivotal factor in the progression of both age-related and acute neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Mitochondria, essential for neuronal health due to their roles in energy production, calcium buffering, and oxidative stress regulation, become increasingly susceptible to dysfunction under conditions of metabolic stress, aging, or injury. Impaired mitophagy in aged or injured neurons leads to the accumulation of dysfunctional mitochondria, which release mitochondrial-derived damage-associated molecular patterns (mtDAMPs). These mtDAMPs act as immune checkpoints, activating pattern recognition receptors (PRRs) and triggering innate immune signaling pathways. This activation initiates inflammatory responses in neurons and brain-resident immune cells, releasing cytokines and chemokines that damage adjacent healthy neurons and recruit peripheral immune cells, further amplifying neuroinflammation and neurodegeneration. Long-term mitochondrial dysfunction perpetuates a chronic inflammatory state, exacerbating neuronal injury and contributing additional immunogenic components to the extracellular environment. Emerging evidence highlights the critical role of mtDAMPs in initiating and sustaining neuroinflammation, with circulating levels of these molecules potentially serving as biomarkers for disease progression. This review explores the mechanisms of mtDAMP release due to mitochondrial dysfunction, their interaction with PRRs, and the subsequent activation of inflammatory pathways. We also discuss the role of mtDAMP-triggered innate immune responses in exacerbating both acute and chronic neuroinflammation and neurodegeneration. Targeting dysfunctional mitochondria and mtDAMPs with pharmacological agents presents a promising strategy for mitigating the initiation and progression of neuropathological conditions.

Obstetric antiphospholipid syndrome (OAPS) is a pregnancy-related complication characterized by trophoblast pyroptosis and placental injury induced by antiphospholipid antibodies (aPLs). M2-polarized macrophage-derived exosomes (M2-exos) exert anti-inflammatory, immunomodulatory, and growth-promoting effects in various autoimmune diseases and tumors. However, their role in OAPS is not yet clear. Therefore, in this study, we isolated M2-exos from M2 macrophages and investigated their effects on trophoblast proliferation, death, migration, invasion, and pyroptosis following stimulation using aPLs.

First, we established an animal model of OAPS and thereafter treated the OAPS mice with exogenous M2-exos via injection through the tail vein. Then to clarify the roles of miR-20a-5p and thioredoxin-interacting protein (TXNIP) in OAPS, we performed gain- or loss-of-function assays, and used GraphPad Prism software to analyze the collected data with statistical significance set at P < 0.05.

MicroRNAs (miRNAs) sequencing revealed the enrichment of miR-20a-5p in M2-exos, and these M2-exos significantly alleviated aPLs-induced trophoblast dysfunction. Our results also indicated that M2-exos delivered miR-20a-5p to trophoblast cells directly targeted thioredoxin-interacting protein (TXNIP), and thus suppressed the TXNIP/NLRP3 pathway, reduced pyroptosis and inflammation in trophoblast cells, and improved placental function and fetal development.

M2-exos improve pregnancy outcomes in OAPS via the miR-20a-5p/TXNIP/NLRP3 axis, and thus represent as a novel therapeutic approach for aPLs-induced OAPS.

As a traditional Chinese medicine, ginseng has many benefits, including regulating blood sugar, blood pressure and so on. Ginsenoside Rg1 is the main active component of ginseng and has been found to significantly improve renal pathological injury in type 2 diabetes mellitus (T2DM) mice. However, the effects and mechanisms of Rg1 in attenuating T2DM are not fully understood.

This study aims to investigate the role of Rg1 in the treatment of renal damage and fibrosis induced by T2DM and its molecular mechanism.

T2DM models were constructed on mice and cells respectively and were administered with corresponding drugs. SA-β-Gal and Oil Red O were used to observe cell senescence and lipid droplet deposition; H&E and PAS were used to observe pathological changes in the kidney; masson and sirius red were used to evaluate the level of renal fibrosis. Immunohistochemistry, immunofluorescence and Western blotting were performed to analyze the relevant indexes which resulted in the detection of ROS levels in vitro and in vivo. Calcium imaging was used to test the level of [Ca2+]i.

Rg1 and Trpc6 knockout could significantly improve kidney dysfunction, attenuate renal injury and fibrosis and also decrease the expression levels of TRPC6, CaN, TXNIP, ChREBP, p-ASK1 and NLRP3 inflammasome. Meanwhile, Rg1 and Trpc6 knockout significantly inhibited mitochondrial damage and apoptosis protein release. Additionally, Rg1 treatment has been shown to markedly reduce lipid deposition and ROS accumulation in T2DM, while Trpc6 knockout exhibited no effect on these parameters.

Rg1 treatment can inhibit the TRPC6-ChREBP-TXNIP pathway, thereby improving chronic T2DM-induced renal injury and fibrosis.

Sodium-glucose transport protein-2 (SGLT2) inhibitors, initially developed for glycemic control in type 2 diabetes mellitus (T2DM), have emerged as potential cardioprotective agents, reducing cardiovascular mortality and improving heart failure outcomes. Recent evidence suggests that SGLT2 inhibitors exert anti-inflammatory effects, particularly through modulating the inflammasome pathway. This review explores the role of the inflammasome in acute myocardial infarction (AMI) in T2DM and discusses the mechanisms by which SGLT2 inhibitors influence this pathway. We evaluate current studies on the impact of SGLT2 inhibitors on key inflammatory mediators, particularly the NLRP3 inflammasome, and discuss their potential therapeutic implications for reducing inflammation and myocardial injury in patients with T2DM experiencing AMI. In summary, the key novelties in this review lie in its focused mechanistic approach on the inflammasome pathway, its integration of diabetes and cardiovascular research, and its potential to influence future therapeutic strategies for AMI in T2DM patients. It offers a novel angle by tying together molecular mechanisms of inflammation with clinical implications in a specific patient population that faces high cardiovascular risk.

Ventilator-induced diaphragm dysfunction (VIDD) is one of the main causes of weaning from mechanical ventilation (MV). The forkhead box O3 (Foxo3) has been identified as being involved in regulating the contractile function of skeletal muscle. This study aimed to figure out the regulatory role and mechanism of Foxo3 on VIDD. The mouse myoblast C2C12 cells were stimulated using different intensities of stress to mimic the in-vitro VIDD model. 3- (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and TdT-mediated dUTP nick end labeling (TUNEL) assays were applied to check cell viability and apoptosis, respectively. Cellular inflammation and oxidative stress levels were evaluated by measuring cellular inflammatory factors (IL-1β and TNF-α) and oxidative stress markers (SOD and MDA). The release of oxygen species (ROS) was assayed by cellular immunofluorescence. The expression of apoptosis-associated proteins (Bax and Bcl-2), Gpx4, Slc7a11, Ptgs2, Foxo3, Txnip, Murf1, Atrogin-1, Nlrp3, Asc, and Caspase1 was gauged using Western blot. The rats with or without MV therapy were treated with the Foxo3 inhibitor Carbenoxolone (CBX) to characterize the impact of Foxo3 on VIDD. Stress stimulation dampened myogenic cell viability, boosted apoptosis, inflammation, oxidative stress, and ROS release, and activated the expression of Foxo3 and Txnip pathways. Overexpression of Txnip or Murf1 lessened the protective effect of FOxO3 inhibition on myoblasts. Downregulation of Txnip or Murf1 mitigated myoblasts dysfunction that was induced by Foxo3 overexpression. In vivo, inhibition of Foxo3 mitigated MV-induced diaphragmatic atrophy and reduced contractility, inflammation, and oxidative stress in rats. Inhibition of Foxo3 eased VIDD by downregulating Txnip and Murf1.

Intervertebral disc degeneration (IDD) is a predominant risk factor for low back pain (LBP). However, the mechanisms underlying IDD progression remain unclear.

The protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with various chronic inflammatory and autoimmune conditions. However, its role in the progression of IDD remains obscure. This investigation delves into the function of PTPN22 within IDD and examines its molecular mechanisms.

The expression levels of PTPN22 in human and rat degenerative nucleus pulposus (NP) cells were analyzed using Western blot and immunohistochemistry. Following PTPN22 knockdown via lentiviral transfection, pyroptosis, extracellular matrix (ECM) degradation, mitophagy, and mitochondrial function were assessed using Western blot, immunofluorescence, Calcein-AM/PI staining, qPCR, Seahorse, JC-1, and MitoSOX assays. The roles of autophagy and the PI3K/AKT/mTOR pathway were further investigated using the autophagy inhibitor 3-MA, Baf-A1, and the PI3K agonist 740Y-P. A puncture-induced rat model was established, and the effects of LV-shPTPN22 on IDD were evaluated through imaging and histological analyses.

We noted an upregulation of PTPN22 in degenerative NP cells. A deficiency in PTPN22 was found to enhance mitophagy, thereby alleviating hydrogen peroxide (H2O2)-induced mitochondrial dysfunction and consequently mitigating NP cell pyroptosis and ECM degradation. Inhibition of the PI3K/AKT/mTOR pathway appears to play a pivotal role in the protective effects of PTPN22 deficiency against IDD. Experiments conducted in vivo revealed that PTPN22 knockdown significantly curtails the progression of IDD.

In summary, PTPN22 knockdown alleviates IDD progression by reducing pyroptosis and ECM degradation through enhanced mitophagy. This highlights PTPN22 as a critical contributor to IDD and a promising therapeutic target.

There is a large body of evidence implicating mitochondrial reactive oxygen species (ROS) overproduction and oxidative stress in the development of diabetic kidney disease and the deficiency of mitochondrial antioxidant systems in the kidney, such as manganese superoxide dismutase (MnSOD/SOD2) have been identified. The proximal tubules of the kidney are densely packed with mitochondria thereby providing energy via oxidative phosphorylation in order to drive active transport for proximal tubular reabsorption of solutes from the glomerular filtrate. We hypothesized that maintenance of MnSOD function in the proximal tubules would be critical to maintain kidney health in diabetes. Here, we induced targeted deletion of SOD2 in the proximal tubules of the kidney in Ins2Akita diabetic mice (SODptKO mice) and show that 20 weeks of SOD2 deletion leads to no major impairment of kidney function and structure, despite these mice displaying enhanced albuminuria and kidney lipid peroxidation (8-isoprostanes). Plasma cystatin C, which is a surrogate marker of glomerular filtration was not altered in SODptKO diabetic mice and histological assessment of the kidney cortex revealed no change in kidney fibrosis. Thus, our findings suggest that deletion of SOD2 in the proximal tubular compartment of the kidney induces a more subtle phenotype than expected, shedding light on the involvement of SOD2 and the proximal tubular compartment in the pathogenesis of diabetic kidney disease.

To investigate the effects of astragaloside IV (AS-IV) on podocyte injury of diabetic nephropathy (DN) and reveal its potential mechanism.

In in vitro experiment, podocytes were divided into 4 groups, normal, high glucose (HG), inositol-requiring enzyme 1 (IRE-1) α activator (HG+thapsigargin 1 µmol/L), and IRE-1α inhibitor (HG+STF-083010, 20 µmol/L) groups. Additionally, podocytes were divided into 4 groups, including normal, HG, AS-IV (HG+AS-IV 20 µmol/L), and IRE-1α inhibitor (HG+STF-083010, 20 µmol/L) groups, respectively. After 24 h treatment, the morphology of podocytes and endoplasmic reticulum (ER) was observed by electron microscopy. The expressions of glucose-regulated protein 78 (GRP78) and IRE-1α were detected by cellular immunofluorescence. In in vivo experiment, DN rat model was established via a consecutive 3-day intraperitoneal streptozotocin (STZ) injections. A total of 40 rats were assigned into the normal, DN, AS-IV [AS-IV 40 mg/(kg·d)], and IRE-1α inhibitor [STF-083010, 10 mg/(kg·d)] groups (n=10), respectively. The general condition, 24-h urine volume, random blood glucose, urinary protein excretion rate (UAER), urea nitrogen (BUN), and serum creatinine (SCr) levels of rats were measured after 8 weeks of intervention. Pathological changes in the renal tissue were observed by hematoxylin and eosin (HE) staining. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) and Western blot were used to detect the expressions of GRP78, IRE-1α, nuclear factor kappa Bp65 (NF-κBp65), interleukin (IL)-1β, NLR family pyrin domain containing 3 (NLRP3), caspase-1, gasdermin D-N (GSDMD-N), and nephrin at the mRNA and protein levels in vivo and in vitro, respectively.

Cytoplasmic vacuolation and ER swelling were observed in the HG and IRE-1α activator groups. Podocyte morphology and ER expansion were improved in AS-IV and IRE-1α inhibitor groups compared with HG group. Cellular immunofluorescence showed that compared with the normal group, the fluorescence intensity of GRP78 and IRE-1α in the HG and IRE-1α activator groups were significantly increased whereas decreased in AS-IV and IRE-1α inhibitor groups (P<0.05). Compared with the normal group, the mRNA and protein expressions of GRP78, IRE-1α, NF-κ Bp65, IL-1β, NLRP3, caspase-1 and GSDMD-N in the HG group was increased (P<0.05). Compared with HG group, the expression of above indices was decreased in the AS-IV and IRE-1α inhibitor groups, and the expression in the IRE-1α activator group was increased (P<0.05). The expression of nephrin was decreased in the HG group, and increased in AS-IV and IRE-1α inhibitor groups (P<0.05). The in vivo experiment results revealed that compared to the normal group, the levels of blood glucose, triglyceride, total cholesterol, BUN, blood creatinine and urinary protein in the DN group were higher (P<0.05). Compared with DN group, the above indices in AS-IV and IRE-1α inhibitor groups were decreased (P<0.05). HE staining revealed glomerular hypertrophy, mesangial widening and mesangial cell proliferation in the renal tissue of the DN group. Compared with the DN group, the above pathological changes in renal tissue of AS-IV and IRE-1α inhibitor groups were alleviated. Quantitative RT-PCR and Western blot results of GRP78, IRE-1α, NF-κ Bp65, IL-1β, NLRP3, caspase-1 and GSDMD-N were consistent with immunofluorescence analysis.

AS-IV could reduce ERS and inflammation, improve podocyte pyroptosis, thus exerting a podocyte-protective effect in DN, through regulating IRE-1α/NF-κ B/NLRP3 signaling pathway.

To examine the association between uric acid (UA) to high-density lipoprotein cholesterol (HDL-C) ratio (UHR) and chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM) patients in China.

The investigation stems from a survey conducted in the eastern Chinese province of Zhejiang, spanning from March to November 2018. A multivariable logistic regression model was employed to assess the relationship between UHR and CKD, while restricted cubic spline (RCS) analysis was used to evaluate the dose-response relationship. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal UHR cut-off value and assess its diagnostic performance for CKD. Model performance was further evaluated using net reclassification improvement (NRI) and integrated discrimination improvement (IDI) metrics. Sensitivity analyses, including propensity score matching (PSM) and k-means clustering, were conducted to enhance the robustness of the findings. Subgroup analyses were performed across various demographic and clinical categories to examine the consistency of the UHR-CKD association.

This cross-sectional study included 1,756 Chinese patients with T2DM, among whom 485 (27.62%) were identified with CKD. Multivariable logistic regression analysis revealed a significant positive association between UHR and CKD. Per standard deviation (SD) increase in UHR was associated with a 40% higher odds of CKD (OR = 1.40, 95% CI: 1.23-1.60) after adjusting for potential covariates. When analyzed categorically, participants in the highest UHR tertile (T3) had 1.82-fold higher odds of CKD compared to the lowest tertile (T1) (95% CI: 1.32-2.50). RCS analysis demonstrated a consistent linear dose-response relationship between UHR and CKD across all models (all p for nonlinearity >0.05). ROC curve analysis identified an optimal UHR cut-off value of 12.28 for CKD prediction, with an area under the curve (AUC) of 0.710 (95% CI: 0.683-0.737) in the fully adjusted model. Subgroup analyses confirmed the robustness of the UHR-CKD association across most demographic and clinical variables, except for younger age groups (18-44 and 45-59 years) and smokers. Notably, BMI significantly modified the UHR-CKD relationship, with a nonlinear association observed in individuals with lower BMI (<24 kg/m2) and a linear association in those with higher BMI (≥24 kg/m2).

This study demonstrates a significant dose-response relationship between the UHR and CKD in Chinese patients with T2DM, highlighting UHR as a promising biomarker for CKD risk assessment. The identified UHR cut-off of 12.28 offers a practical threshold for early renal monitoring and targeted interventions. Future research should explore UHR-targeted therapies and its integration into personalized risk stratification models to improve CKD management in T2DM.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. The etiology of UC is multifaceted, and the underlying pathogenesis remains incompletely understood. Pyroptosis, programmed cell death mediated by the gasdermins, is a pivotal driver of UC pathology due to its dual role in epithelial barrier disruption and inflammatory amplification. We previously showed that phenethyl isothiocyanate (PEITC), an isothiocyanate derived from cruciferous vegetables, alleviated acute liver injury in mice by suppressing hepatocyte pyroptosis. In this study we evaluated the therapeutic potential of PEITC in the treatment of UC and the underlying mechanisms. UC mouse models were established by administration of 2.5% (w/v) dextran sulfate sodium (DSS) daily for 7 days. PEITC (5, 10, or 20 mg·kg-1·d-1, i.g.) was given 2 days before the start of modeling, and the dosing lasted for a total of 10 days. We showed that during the progression of DSS-induced UC, the pyroptosis pathway was activated accompanied by elevated expression levels of thioredoxin-interacting protein (TXNIP) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3), as well as the activation of caspase-1, gasdermin D (GSDMD) and interleukin-1β (IL-1β). Treatment with PEITC dose-dependently reduced TXNIP and NLRP3 expression while inhibiting the cleavage of proteins associated with the pyroptosis pathway such as caspase-1, GSDMD, and IL-1β. We confirmed the inhibitory effect of PEITC on colonocyte pyroptosis in an in vitro model established in HT29 cells, where PEITC (0.2, 1, 5 µM) dose-dependently inhibited TXNIP and NLRP3 expression and the activation of pro-caspase-1, GSDMD and pro-IL-1β. We revealed that PEITC is directly bound to TXNIP and disrupted the interaction between TXNIP and NLRP3, leading to diminished cellular inflammation and oxidative stress levels. In conclusion, this study demonstrates that PEITC disrupts the interaction of TXNIP and NLRP3 by binding to TXNIP, inhibits NLRP3 activation and colonocyte pyroptosis, and thus effectively alleviates UC symptoms in mice. This study offers novel drug targets along with potential therapeutic candidates for the clinical prevention and treatment of UC.

Oxidation and reduction are vital for keeping life through several prime mechanisms, including respiration, metabolism, and other energy supplies. Mitochondria are considered the cell's powerhouse and use nutrients to produce redox potential and generate ATP and H2O through the process of oxidative phosphorylation by operating electron transfer and proton pumping. Simultaneously, mitochondria also produce oxygen free radicals, called superoxide (O2 -), non-enzymatically, which interacts with other moieties and generate reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), peroxynitrite (ONOO-), and hydroxyl radical (OH-). These reactive oxygen species modify nucleic acids, proteins, and carbohydrates and ultimately cause damage to organs. The nutrient-sensing kinases, such as AMPK and mTOR, function as a key regulator of cellular ROS levels, as loss of AMPK or aberrant activation of mTOR signaling causes ROS production and compromises the cell's oxidant status, resulting in various cellular injuries. The increased ROS not only directly damages DNA, proteins, and lipids but also alters cellular signaling pathways, such as the activation of MAPK or PI3K, the accumulation of HIF-1α in the nucleus, and NFkB-mediated transcription of pro-inflammatory cytokines. These factors cause mesenchymal activation in renal endothelial cells. Here, we discuss the biology of redox signaling that underlies the pathophysiology of diabetic renal endothelial cells.

Gasdermins (GSDMs), functioning as membrane perforating proteins, can be activated by canonical inflammasomes, noncanonical inflammasomes, as well as non-inflammasomes, leading to cell pyroptosis and the subsequent release of inflammatory mediators. Increasing evidence has implicated that GSDMs are associated with chronic kidney disease (CKD), including diabetes nephropathy, lupus nephritis, obstructive nephropathy, and crystalline nephropathy. This review centers on the role of GSDMs-mediated pyroptosis in the pathogenesis of CKD, providing novel ideas for enhancing the prognosis and therapeutic strategies of CKD.

The pathophysiology of diabetic kidney disease (DKD) is complex. Interfering with the processes of pyroptosis and fibrosis is an effective strategy for slowing DKD progression. Previous studies have revealed that nuclear receptor subfamily 4 group A member 1 (NR4A1) may serve as a novel pathogenic element in DKD; however, the specific mechanism by which it contributes to pyroptosis and fibrosis in DKD is unknown.

To investigate the role of NR4A1 in renal pyroptosis and fibrosis in DKD and possible molecular mechanisms.

Streptozotocin 60 mg/kg was injected intraperitoneally to establish a rat model of DKD. Typically, 45 mmol/L glucose [high glucose (HG)] was used to activate HK-2 cells to mimic the DKD model in vitro. HK-2 cells were transfected with NR4A1 siRNA to silence NR4A1.

NR4A1 was elevated in renal tissues of DKD rats and HG-stimulated HK-2 cells. Concurrently, NOD-like receptor protein 3 (NLRP3) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathways were triggered, and pyroptosis and expression of fibrosis-linked elements was increased in vivo and in vitro. These alterations were significantly reversed via NR4A1 silencing.

Inhibition of NR4A1 mitigated pyroptosis and fibrosis via suppressing NLRP3 activation and the PI3K/AKT pathway in HG-activated HK-2 cells.

The activation of inflammasomes (NLRP3 and NLRP1) is central to the pathogenesis of inflammatory bowel disease (IBD). Here we examined the protective effects of a thioredoxin-mimetic peptide CB13 (TXM-CB13), known for its antioxidative stress and anti-inflammatory properties. We examined the effects of TXM-CB13 on dextran sulfate sodium (DSS)-induced colitis and lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation in RAW264.7 macrophages. TXM-CB13 appeared to alleviate symptoms of DSS-induced colitis and to significantly suppress the protein and mRNA levels of NLRP3, Mlck, and IL-1β in colonic tissues. Additionally, TXM-CB13 treatment increased the levels of the intestinal barrier proteins Occludin, ZO-1, and NLRP1, as shown through immunohistochemistry and Western blot analysis. In vitro, TXM-CB13 inhibited LPS-induced TLR4 signaling, reducing MyD88 levels and consequently attenuating the activation of the NF-κB pathways, including p-IκB-α/IκB-α and p-NF-κB-p65/NF-κB-p65. This inhibition further reduced the activation of the NLRP3 inflammasome components, NLRP3, ASC, Caspase-1, GSDMD, and IL-1β. In addition, TXM-CB13 prevented the ROS-mediated dissociation of TXNIP from TRX, inhibiting NLRP3 activation. These findings suggest that TXM-CB13 is a potential therapeutic candidate for IBD through its modulation of the TLR4/MyD88/NF-κB/NLRP3 and ROS/TXNIP/TRX/NLRP3 pathways.

The role of ER stress in the pathogenesis of diabetic kidney diseases (DKD) remains unclear. We employed bioinformatics to identify the UPR pathway activation, inflammation, and programmed cell death patterns in diabetic tubules. Levels of IRE1α/sXBP1 signaling, NLRP3 inflammasome activity and pyroptosis in tubular cells under high glucose conditions were measured. IRE1α knockdown was used to determine its role in glucose-triggered activation of the NLRP3 inflammasome and pyroptosis. PDIA4 overexpression and silencing were used to assess its impact on the IRE1α/sXBP1 pathway. The dynamic interaction among PDIA4, GRP78, and IRE1α under high glucose were analyzed using immunoprecipitation and crosslinking assays. In STZ-induced and db/db mouse models of DKD, the regulatory role of PDIA4 on IRE1α/sXBP1 signaling and diabetic tubular inflammation and injury were evaluated. Our study showed that IRE1α/sXBP1, NLRP3 inflammasome, and pyroptosis are activated in the renal tubules of DKD patients. Induction of IRE1α pathway mediated the glucose-triggered activation of the NLRP3 inflammasome and pyroptosis. Moreover, overexpression of PDIA4 decreased the activation of IRE1α/sXBP1 under high glucose conditions. High glucose leads to the release of GRP78 from IRE1α and an increased interaction between IRE1α and PDIA4. In mouse models of DKD, overexpressing PDIA4 mitigated diabetic tubular injury and inflammation, marked by decreased IRE1α/sXBP1 and NLRP3 inflammasome. In conclusion, our findings demonstrate that high glucose triggers NLRP3 inflammasome and pyroptosis via the IRE1α/sXBP1 pathway in renal tubular cells. Overexpression of PDIA4 suppresses IRE1α signaling by binding to its oligomeric form, implying a promising therapeutic intervention for DKD.

Cardiovascular disease (CVD) continues to be the leading cause of mortality worldwide. The nucleotide oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing protein 3 (NLRP3) inflammasome is involved in numerous types of CVD. As part of innate immunity, the NLRP3 inflammasome plays a vital role, requiring priming and activation signals to trigger inflammation. The NLRP3 inflammasome leads both to the release of IL-1 family cytokines and to a distinct form of programmed cell death called pyroptosis. Inflammation related to CVD has been extensively investigated in relation to the NLRP3 inflammasome. In this review, we describe the pathways triggering NLRP3 priming and activation and discuss its pathogenic effects on CVD. This study also provides an overview of potential therapeutic approaches targeting the NLRP3 inflammasome.

This study aims to investigate the role of hypercalciuria and pyroptosis in the formation of calcium oxalate kidney stones. Bioinformatics analysis was performed to compare the correlation of pyroptosis scores and cell adhesion scores between Randall's plaques and normal tissues from kidney stone patients. For the in vitro experiments, we investigated the effects of high concentrations of Ca2+ on the pyroptosis and adhesion levels of renal tubular epithelial cells and examined the adhesion levels and crystal aggregation of the cells in high Ca2+ concentrations environment by knockdown and overexpression of the key pyroptosis gene, GSDMD, and we verified the effects of Ca2+ concentration on pyroptosis and adhesion levels, kidney injury, and crystal deposition by in vivo experiments. Bioinformatic results showed that the scores of pyroptosis and cell adhesion in Randall's plaques of patients with kidney stones were significantly higher than those in normal tissues, and pyroptosis was highly positively correlated with cell adhesion. In vitro and in vivo experiments showed that high concentrations of Ca2+ activated the NLRP3/Caspase-1/GSDMD pathway of pyroptosis through ROS and up-regulated the expression of adhesion-related proteins, and GSDMD could regulate the adhesion level of renal tubular epithelial cells by mediating the level of pyroptosis, thereby affecting the adhesion and deposition of calcium oxalate crystals. Our findings reveal that the Ca2+-induced classical pyroptosis pathway may be a potential mechanism to promote calcium oxalate kidney stone formation, which provides new insights into the etiology of kidney stones.

Spinal cord injury (SCI) remains a severe condition with an extremely high disability rate and complex pathophysiologic mechanisms. Pyroptosis, an inflammatory form of cell death triggered by certain inflammasomes, has a key role in a variety of inflammatory diseases, including SCI. However, it is unclear whether microRNAs (miRNAs), novel regulators in the SCI, are involved in SCI-induced pyroptosis.

Two GEO miRNA expression profiles (GSE158195 and GSE90452) were downloaded, and the differentially expressed miRNAs were analyzed by bioinformatics methods. An in vivo animal model and an in vitro cellular model of SCI were constructed in female C57BL/6 mice and BV-2 cells for studying the possible roles of FOXO3, miR-128-3p and NLRP3-mediated pyroptosis in SCI. Markers of ROS, cell pyroptosis and inflammation were measured by RT-qPCR, Western blotting, immunofluorescence, flow cytometry, and enzyme-linked immunosorbent assays. Histopathological changes in spinal cord tissue were detected using hematoxylin and eosin and immunohistochemical. The Basso-Beattie-Bresnahan (BBB) score was used to evaluate the motor function of mice in each group.

Bioinformatics analysis of GSE158195 and GSE90452 datasets revealed a significant downregulation of miR-128-3p, a phenomenon that was consistently observed in the SCI mice model. Functionally, miR-128-3p upregulation improved functional behavioral recovery, relieved pathological injury, repressed oxidative stress, and alleviated pyroptosis and inflammation in the mouse SCI models. We also confirmed that Thioredoxin-interacting protein (TXNIP) was the target gene of miR-128-3p, and overexpression of TXNIP can effectively reverse the improvement of miR-128-3p in SCI cell model. Moreover, we found that transcription factor FOXO3 facilitated miR-128-3p expression, and its overexpression resulted in similar effects of miR-128-3p in the SCI cell model.

To the best of our knowledge, this is the first report demonstrating miR-128-3p improved secondary injury in SCI through the modulation of cell pyroptosis pathway. Our results suggest that FOXO3/miR-128-3p/TXNIP/NLRP3-mediated pyroptosis axis may be a potential therapeutic target for SCI.

Diabetic nephropathy (DN) is a microvascular complication of type 2 diabetes mellitus (T2DM) that develops after years of T2DM and affects approximately one in four diabetic patients. Thioredoxin (TXN), thioredoxin reductase (TXNRD), and thioredoxin-interacting protein (TXNIP) are part of the thioredoxin antioxidant system, which is involved in DN. We included 897 Slovenian patients with T2DM lasting more than 10 years in our preliminary study. In total, 344 patients with DN were included in our case group, while 553 without DN comprised our control group. The genotypes of TXN2 rs8140110, TXNRD2 rs1548357, and TXNIP rs7212 were determined for all participants using real-time PCR. We found a statistically significant association between the T allele of the TXN2 rs8140110 polymorphism and DN (p < 0.001; OR: 0.52; 95% CI: 0.36-0.74). The TT and TC genotypes were also significantly less likely to develop DN in comparison to the CC genotype according to the dominant model of inheritance (p < 0.001; OR: 0.51; 95 CI: 0.34-0.75). We did not find a statistically significant association between rs1548357 or rs7212 and DN. To conclude, the rs8140110 polymorphism in the TXN2 gene is associated with DN in Slovenian patients with T2DM.

The NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome may play an important role in diabetic kidney disease (DKD). However, the exact link remains unclear.

To investigate the role of the NLRP3 inflammasome in DKD.

Using datasets from the Gene Expression Omnibus database, 30 NLRP3 inflammasome-related genes were identified. Differentially expressed genes were selected using differential expression analysis, whereas intersecting genes were selected based on overlapping differentially expressed genes and NLRP3 inflammasome-related genes. Subsequently, three machine learning algorithms were used to screen genes, and biomarkers were identified by overlapping the genes from the three algorithms. Potential biomarkers were validated by western blotting in a db/db mouse model of diabetes.

Two biomarkers, sirtuin 2 (SIRT2) and caspase 1 (CASP1), involved in the Leishmania infection pathway were identified. Both biomarkers were expressed in endothelial cells. Pseudo-temporal analysis based on endothelial cells showed that DKD mostly occurs during the mid-differentiation stage. Western blotting results showed that CASP1 expression was higher in the DKD group than in the control group (P < 0.05), and SIRT2 content decreased (P < 0.05).

SIRT2 and CASP1 provide a potential theoretical basis for DKD treatment.

Low-temperature preservation of yak semen during transportation and conservation is crucial to accelerate yak breeding. The effects of low-temperature cooling on yak semen quality, however, are poorly understood. This study aimed to determine the dose-dependent effect of mitochondria-targeted antioxidant "MitoQ" on the motility, oxidative status, and mitochondrial function of yak semen during low-temperature preservation. Semen samples were collected from six adult healthy Maiwa yaks and preserved at 4 ℃ in semen extender containing 0, 50, 100, 200, and 400 nM MitoQ, respectively. Firstly, the motility, membrane integrity, acrosome integrity, and abnormity index of yak spermatozoa were evaluated to determine the optimal MitoQ concentration. Next, the effect of MitoQ at the optimal concentration on spermatozoa antioxidant capacity, including reactive oxygen species (ROS) and malondialdehyde (MDA) contents, total antioxidant capacity (T-AOC), and superoxide dismutase content (SOD) levels, as well as mitochondrial membrane potential were analyzed. Up to 96 h of low-temperature storage, 200 nM MitoQ showed the most optimal effect on motility, membrane integrity, and acrosome integrity (P < 0.05) but not on sperm morphology (P > 0.05). Also, 200 nM MitoQ markedly reduced yak spermatozoa ROS and MDA contents for up to 48 h of low-temperature storage (P < 0.05). Finally, 200 nM MitoQ significantly improved T-AOC, SOD, and mitochondrial membrane potential for up to 24, 48, and 72 h of low-temperature storage, respectively (P < 0.05). In summary, semen extender supplementation with 200 nM MitoQ is beneficial for low-temperature yak semen preservation via improving the oxidative status.

This study investigated the role of fibrin on neutrophil extracellular traps (NETs) formation from neutrophils and to elucidate the involvement of mitochondria in NETs formation during periodontitis.

Plasminogen-deficient (Plg-/-) mice were employed to evaluate the effects of fibrin deposition on inflammation, bone resorption, and neutrophil infiltration in periodontal tissues. In addition, in vitro tests evaluated fibrin's impact on neutrophil-driven inflammation. Mitochondrial reactive oxygen species (mtROS) levels within neutrophils were quantified utilizing flow cytometry and immunofluorescence in vitro. Furthermore, the anti-inflammatory properties of the mtROS scavenger, Mito-TEMPO, were confirmed to regulate the NET formation in vitro and in vivo.

Plasminogen deficiency resulted in increased fibrin deposition, neutrophil infiltration, inflammatory factors concentration, and alveolar bone resorption in periodontal tissues. After neutrophils were treated by fibrin in vitro, the expression of inflammatory factors, the formation of mtROS, and NETs enriched in mitochondrial DNA (mtDNA) were upregulated, which were reversed by Mito-TEMPO in vitro. Moreover, Mito-TEMPO alleviated inflammation in Plg-/- mice.

This study showed that fibrin deposition in gingiva induced the NET formation in Plg-/- mice, in which the DNA in NETs was from mitochondria depending on increasing mtROS.

Prolonged spaceflight is known to cause vascular deconditioning and remodeling. Tail suspension, a widely used spaceflight analog, is reported to result in vascular remodeling of rats. However, little is known about the cellular atlas of the heterogeneous cells of CA and FA from hindlimb-unloaded rats.

Firstly, we leveraged scRNA-seq to perform clustering analysis to identify diverse cell populations and sub-clusters within CA and FA from rats subjected to 3 months of hindlimb unloading. The dysregulated genes specific for artery types and cell types in HU group compared to Con were unraveled. Then R package "Cellchat" was used to reveal ligand-receptor cellular communication. At last, the TF network analysis was performed using the SCENIC R package to predict the pivotal TFs in rat artery remodeling induced by hindlimb unloading.

Clustering analysis identified ECs, SMCs, fibroblasts, and a spectrum of immune cells, as well as neuronal and stem cells. Notably, an increased percentage of ECs in the CA and a diminished proportion of SMCs in both CA and FA were observed following tail suspension. Intersection of dysregulated genes specific for artery type and cell type after tail suspension revealed several gene sets involved in ECM remodeling, inflammation, vasoconstriction, etc. Fibroblasts, in particular, exhibited the most significant gene expression variability, highlighting their plasticity. Subclustering within ECs, SMCs and fibroblasts revealed specialized subsets engaged in processes such as EndoMT and cell cycle checkpoint regulation. Additionally, enhanced intercellular interactions among major cell types, especially between SMC and fibroblast, underscored the importance of cell communication in vascular remodeling. Several TFs were identified as potentially influential in the vascular remodeling process under simulated microgravity conditions.

This study presents the first cellular atlas of the conductive arteries in hindlimb-unloaded rats, revealing a spectrum of dysregulated gene profiles. The identification of the subclusters of ECs, SMCs and fibroblasts, cellular communication analysis and transcription factors prediction are also included in this work. The findings provide a reference for future research on vascular deconditioning following long-duration spaceflight.

Autophagy and mitophagy are critical cellular processes that maintain homeostasis by removing damaged organelles and promoting cellular survival under stress conditions. In the context of diabetic kidney disease, these mechanisms play essential roles in mitigating cellular damage. This review provides an in-depth analysis of the recent literature on the relationship between autophagy, mitophagy, and diabetic kidney disease, highlighting the current state of knowledge, existing research gaps, and potential areas for future investigations. Diabetic nephropathy (DN) is traditionally defined as a specific form of kidney disease caused by long-standing diabetes, characterized by the classic histological lesions in the kidney, including mesangial expansion, glomerular basement membrane thickening, nodular glomerulosclerosis (Kimmelstiel-Wilson nodules), and podocyte injury. Clinical markers for DN are albuminuria and the gradual decline in glomerular filtration rate (GFR). Diabetic kidney disease (DKD) is a broader and more inclusive term, for all forms of chronic kidney disease (CKD) in individuals with diabetes, regardless of the underlying pathology. This includes patients who may have diabetes-associated kidney damage without the typical histological findings of diabetic nephropathy. It also accounts for patients with other coexisting kidney diseases (e.g., hypertensive nephrosclerosis, ischemic nephropathy, tubulointerstitial nephropathies), even in the absence of albuminuria, such as a reduction in GFR.

Bone homeostasis between osteoclast bone resorption and osteoblastic bone formation is tightly regulated by a series of factors such as the receptor activator of nuclear factor-κB ligand (RANKL). Denosumab that neutralizes RANKL is effective and widely applied in the treatment of postmenopausal osteoporosis. However, factors that participated in the RANKL-related bone remodeling process in primary and secondary osteoporosis are less known.

Revealing the novel transcriptional regulatory mechanism of RANKL is of great significance for the treatment of osteoporosis.

After differential expression genes (DEGs) intersection and screening, we generated Thioredoxin-interacting protein (Txnip) bone marrow-derived mesenchymal stromal cells (BMSCs) genetic knockout mice and performed bone histomorphometry and histological analysis. RNA-Sequencing, Western blotting and immunofluorescence staining verified Rankl downregulation. Co-immunoprecipitation and immunofluorescence staining were used for Rankl regulation mechanism exploration. A specific inhibitor was selected for treatment effect verification.

Txnip knockout in BMSCs impaired its osteogenic differentiation, suppressed Rankl expression and subsequent osteoclast formation and thus led to increased bone mass. The regulatory function of Txnip on Rankl expression was revealed for the first time through the novel transcription-related Ecdysoneless (Ecd)-P300 axis. Pharmacological inhibition of Txnip can effectively prevent bilateral ovariectomy (OVX)-induced osteoporosis.

Inhibition of Txnip is an alternative way to suppress Rankl-mediated osteoblast and osteoclast crosstalk. This interesting finding rendered Txnip an ideal therapeutic target for the treatment of both ovariectomy-induced and diabetes-induced osteoporosis.

Vascular endothelial dysfunction (VED) is one of the main pathogenic events in pulmonary arterial hypertension (PAH). Previous studies have demonstrated that the ginsenoside Rg1 (Rg1) can ameliorate PAH, but the mechanism by which Rg1 affects pulmonary VED in hypoxia-induced PAH remains unclear.

Network pharmacology, molecular docking and other experiments were used to explore the mechanisms by which Rg1 affects PAH. A PAH mouse model was established via hypoxia combined with the vascular endothelial growth factor (VEGFR) inhibitor su5416 (SuHx), and a cell model was established via hypoxia. The functions of Rg1 in VED, oxidative stress, inflammation, mitophagy, and TXNIP and NLRP3 expression were examined.

In hypoxia-induced VED, progressive exacerbation of oxidative stress, inflammation, and mitophagy were observed, and were associated with elevated TXNIP and NLRP3 expression in vivo and in vitro. Rg1 improved hypoxia-induced impaired endothelium-dependent vasodilation and increased nitric oxide (NO) and endothelial NO synthase (eNOS) expression. Rg1, SRI37330 (a TXNIP inhibitor), MCC950 (an NLRP3 inhibitor), and Liensinine (a mitophagy inhibitor) attenuated oxidative stress, inflammation, and mitophagy by reducing the expression of TXNIP and NLRP3 in mice and cells. Furthermore, the combination of SB203580 (a mitophagy agonist) with Rg1 disrupted the protective effect of Rg1 on hypoxia-induced pulmonary artery and human pulmonary artery endothelial cells (HPAECs).

Rg1 improves hypoxia-induced pulmonary vascular endothelial dysfunction through TXNIP/NLRP3 pathway-modulated oxidative stress, inflammation and mitophagy.

Chronic low-grade inflammation is a characteristic of diabetes, which often culminates in cardiovascular events including myocardial damage, thereby increasing the risk of debilitating cardiac complications. The mitochondria-derived peptide MOTS-c regulates glucose and lipid metabolism while improving insulin resistance, making it a potential candidate for the treatment of diabetes and cardiovascular diseases. We investigated the impact of MOTS-c on cardiac structure and inflammation in diabetic rats induced by a high-sugar-fat diet combined with low-dose streptozotocin (30 mg/kg, i.p.). Our results confirm that high glucose levels activate the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and increase reactive oxygen species (ROS), ultimately leading to myocardial injury. Furthermore, treatment with MOTS-c (0.5 mg/kg/day, i.p.) for 8 weeks reduced the expression of ROS/TXNIP/NLRP3 pathway proteins to inhibit the diabetic myocardial inflammatory response. These findings suggested that MOTS-c alleviates myocardial damage by inhibiting the ROS/TXNIP/NLRP3 pathway.

Hyperuricemia (HUA) is an important factor leading to chronic kidney disease (CKD). The kidney tubular inflammatory response is activated in HUA. This study aimed to investigate whether lactate dehydrogenase A (LDHA) is involved in mediating uric acid-induced kidney tubular inflammatory response.

In vivo, an HUA mouse model was established by continuous intraperitoneal injection of potassium oxonate (PO) for one week. A total of 18 C57BL/6J male adult mice were divided into three groups: control group, HUA group, and HUA+oxamate group, with six mice in each group. Oxamate was intraperitoneally injected into the mice one hour after PO injection. In vitro, an HUA model was simulated by stimulating HK-2 cells with uric acid. Oxamate and tempol inhibited LDHA and reactive oxygen species (ROS) in HK-2 cells.

In HUA mice, blood uric acid levels were significantly elevated. LDHA in kidney tubular cells was significantly increased in both in vivo and in vitro HUA models, accompanied by an increase in kidney tubular inflammation and ROS. Mechanistically, LDHA mediates uric acid-induced inflammation to kidney tubular cells through the ROS/NLRP3 pathway. Pharmacologic inhibition of LDHA or ROS in kidney tubular cells can significantly ameliorate inflammation response caused by uric acid.

LDHA in kidney tubular cells significantly was increased in HUA models. LDHA mediates kidney inflammation response induced by uric acid through the ROS/NLRP3 pathway. This study may provide a new intervention target for preventing kidney tubular inflammation caused by uric acid.

Isodeoxyelephantopin (IDET), a sesquiterpene lactone compound isolated from the Asteraceae plant Inula helenium, has been demonstrated to possess excellent antimicrobial, antidiabetic, hepatoprotective, wound healing, anti-inflammatory, and anticancer activities. However, the underlying mechanisms of IDET's anti-inflammatory properties remain unclear. In this study, we investigated the anti-inflammatory effects and mechanisms of IDET using both in vitro and in vivo models. Our findings revealed that IDET dose-dependently inhibited the upregulation of inflammatory cytokines (IL-1β, IL-6, TNF-α) and pro-inflammatory chemokines (MCP-1, CCL20) induced by Lipopolysaccharide (LPS). IDET suppressed the activation of cyclooxygenase-2 (COX-2) and the NLRP3 inflammasome. Subsequent mechanistic investigations demonstrated that IDET inhibited the mRNA and protein levels of Txnip, FOXO1, and EFhd2 in THP-1 cells in a time- and concentration-dependent manner. Furthermore, in an LPS-induced acute peritonitis mouse model, IDET effectively ameliorated symptoms, preserved ileal tissue integrity, attenuated immune cell infiltration, and reduced the expression of inflammatory cytokines in mouse serum. Notably, IDET exhibited an improvement in acute peritonitis by inhibiting the activation of NLRP3 inflammasome. Overall, our study highlights the significant anti-inflammatory activity of IDET, providing valuable insights into its therapeutic potential for acute peritonitis.

Among all the diabetes complications brought on by persistent inflammation is diabetic kidney disease (DKD). One essential method of the inflammatory response's programmed cell death is anthrax. One of the main causes of diabetic renal disease progression in a high-glycemic environment is the lysis of renal resident cells.

This investigation sought to determine whether Astragaloside IV (AS-IV)'s anti-pyroptosis action provides a protective function for the kidneys. For 12 weeks, db/db mice received 40 mg/kg of AS-IV by transgastric gavage. To validate the possible in vitro mechanism, mouse podocytes were cultivated for additional experiments.

In vitro, AS-IV led to a significant reduction in blood urea nitrogen (BUN), urine albumen-to-creatinine ratio (UACR), serum creatinine (CREA), and hyperglycemia in db/db mice and lessen the pathological alterations in the kidney. Moreover, pyrin structural domain of the NLR family pyrin domain containing 3 (NLRP3), cleaved-caspase-1, gasdermin D (GSDMD), IL-18, and IL-1β were down-expressed and podocyte markers podocin and nphs1 were up-regulated following AS-IV intervention. By silencing GSDMD, we demonstrated in vitro that HG-stimulated podocytes undergo pyroptosis. We also discovered that AS-IV can mitigate this pyroptosis. To confirm that AS-IV prevented the NLRP3 inflammasome from activating, the NLRP3 inhibitor CY-09 was employed. It was also discovered that AS-IV prevents the expression of TXNIP and NLRP3 as well as their interaction. GSDMD expression was significantly downregulated following TXNIP-siRNA treatment, whereas GSDMD expression was upregulated in TXNIP overexpression cells; this upregulation could be undone with AS-IV.

The anti-pyroptosis effect of AS-IV via the TXNIP-NLRP3-GSDMD axis improves the renal function and podocyte damage of db/db mice and delays the onset of DKD, according to in vivo and in vitro experimental data.

Diabetes induces a pro-aging state characterized by an increased abundance of senescent cells in various tissues, heightened chronic inflammation, reduced substance and energy metabolism, and a significant increase in intracellular reactive oxygen species (ROS) levels. This condition leads to mitochondrial dysfunction, including elevated oxidative stress, the accumulation of mitochondrial DNA (mtDNA) damage, mitophagy defects, dysregulation of mitochondrial dynamics, and abnormal energy metabolism. These dysfunctions result in intracellular calcium ion (Ca2+) homeostasis disorders, telomere shortening, immune cell damage, and exacerbated inflammation, accelerating the aging of diabetic cells or tissues. Hydrogen sulfide (H2S), a novel gaseous signaling molecule, plays a crucial role in maintaining mitochondrial function and mitigating the aging process in diabetic cells. This article systematically explores the specific mechanisms by which H2S regulates diabetes-induced mitochondrial dysfunction to delay cellular senescence, offering a promising new strategy for improving diabetes and its complications.

Recent 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.

Asthma poses a major threat to human health. The aim of this study was to identify genetic markers of severe asthma and analyze the relationship between key genes and immune infiltration. Differentially expressed genes (DEGs) were first screened by downloading the training set GSE69683 and validation set GSE137268 from the GEO dataset. SVM-RFE analysis and the LASSO regression model were used to screen key genes, and CIBERSORT was used to assess immune infiltration in the samples. A total of 20 DEGs were identified in this study, mainly enriched for lymph node-like receptors, b-cell receptors, and neutrophil extracellular trap pathway. Comparative validation set GSE137268 identified thioredoxin (TXN) and coagulation factor V (F5) were identified as diagnostic markers of severe asthma. CIBERSORT analysis revealed that TXN and F5 are associated with multiple immune cell infiltrates. In addition, we identified miRNA and TF at the transcriptional level that may regulate F5 and TXN, and found that several commonly used drugs may exert therapeutic effects by targeting F5 and TXN. Taken together, TXN and F5 may be key genes in the development of severe asthma and are associated with immune infiltration. Our study can help to better understand the pathogenesis of asthma and provide new ideas for clinical treatment.

The virulent bacteria-induced host immune response dominates the occurrence and progression of periodontal diseases because of the roles of individual virulence factors from these pathogens in the initiation and spread of inflammation. Outer membrane vesicles (OMVs) as a pathogenic entity have recently attracted great attention as messenger bridges between bacteria and host tissues. Herein, the novel role of OMVs derived from Fusobacterium nucleatum in the occurrence of periodontitis is dissected. In a rat periodontitis model, it is found that OMVs derived from F. nucleatum caused deterioration of periodontitis by enhancing inflammation of the periodontium and absorption of alveolar bone, which is almost equivalent to the effect of F. nucleatum itself. Furthermore, that OMVs can independently induce periodontitis is shown. The pathogenicity of OMVs is attributed to multiple pathogenic components identified by omics. After entering human periodontal ligament stem cells (hPDLSCs) by endocytosis, OMVs activated NLRP3 inflammasomes and impaired the mineralization of hPDLSCs through NF-κB (p65) signaling, leading to the final injury of the periodontium and damage of alveolar bone in periodontitis. These results provide a new understanding of OMVs derived from pathogens and cues for the prevention of periodontitis.

Renal tubule cells act as a primary site of injury in diabetic kidney disease (DKD), with dysfunctional mitochondrial quality control (MQC) closely associated with progressive kidney dysfunction in this context. Our investigation delves into the observed inactivation of yes-associated protein 1 (YAP1) and consequential dysregulation of MQC within renal tubule cells among DKD subjects through bioinformatic analysis of transcriptomics data from the Gene Expression Omnibus (GEO) dataset. Receiver operating characteristic curve analysis unequivocally underscores the robust diagnostic accuracy of YAP1 and MQC-related genes for DKD. Furthermore, we observed YAP1 inactivation, accompanied by perturbed MQC, within cultured tubule cells exposed to high glucose (HG) and palmitic acid (PA). This pattern was also evident in the tubulointerstitial compartment of kidney sections from biopsy-approved DKD patients. Additionally, renal tubule cell-specific Yap1 deletion exacerbated kidney injury in diabetic mice. Mechanistically, Yap1 deletion disrupted MQC, leading to mitochondrial aberrations in mitobiogenesis and mitophagy within tubule cells, ultimately culminating in histologic tubular injury. Notably, Yap1 deletion-induced renal tubule injury promoted the secretion of C-X-C motif chemokine ligand 1 (CXCL1), potentially augmenting M1 macrophage infiltration within the renal microenvironment. These multifaceted events were significantly ameliorated by administrating the YAP1 activator XMU-MP-1 in DKD mice. Consistently, bioinformatic analysis of transcriptomics data from the GEO dataset revealed a noteworthy upregulation of tubule cells-derived chemokine CXCL1 associated with macrophage infiltration among DKD patients. Crucially, overexpression of YAP1 via adenovirus transfection sustained mitochondrial membrane potential, mtDNA copy number, oxygen consumption rate, and activity of mitochondrial respiratory chain complex, but attenuated mitochondrial ROS production, thereby maintaining MQC and subsequently suppressing CXCL1 generation within cultured tubule cells exposed to HG and PA. Collectively, our study establishes a pivotal role of tubule YAP1 inactivation-mediated MQC dysfunction in driving DKD progression, at least in part, facilitated by promoting M1 macrophage polarization through a paracrine-dependent mechanism.