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Necroptosis refers to a regulated form of cell death induced by a variety of stimuli. Although it has been implicated in the pathogenesis of many diseases, there is evidence to support that necroptosis is not purely a detrimental process. We propose that necroptosis is a “double-edged sword” in terms of physiology and pathology. On the one hand, necroptosis can trigger an uncontrolled inflammatory cascade response, resulting in severe tissue injury, disease chronicity, and even tumor progression. On the other hand, necroptosis functions as a host defense mechanism, exerting antipathogenic and antitumor effects through its powerful pro-inflammatory properties. Moreover, necroptosis plays an important role during both development and regeneration. Misestimation of the multifaceted features of necroptosis may influence the development of therapeutic approaches targeting necroptosis. In this review, we summarize current knowledge of the pathways involved in necroptosis as well as five important steps that determine its occurrence. The dual role of necroptosis in a variety of physiological and pathological conditions is also highlighted. Future studies and the development of therapeutic strategies targeting necroptosis should fully consider the complicated properties of this type of regulated cell death.

Background Cardiovascular-kidney-metabolic (CKM) syndrome and systemic inflammation significantly contribute to mortality. However, the joint associations of CKM stages and systemic inflammation with all-cause and cardiovascular disease (CVD) mortality remain unclear. This study aimed to evaluate the independent and joint associations of CKM stages and systemic inflammation with all-cause and CVD mortality in a representative cohort of United States adults. Methods We analyzed data from 29,459 adults aged ≥ 20 years from the National Health and Nutrition Examination Survey (1999–2018). CKM stages were classified based on metabolic risk factors, CVD, and chronic kidney disease. Systemic inflammation was assessed using multiple indicators, and time-dependent ROC analysis identified the systemic inflammatory response index (SIRI) as the most effective inflammatory marker. The associations of CKM stages and SIRI with mortality were evaluated. Results Over a median follow-up of 109 months, 5,583 all-cause deaths and 1,843 CVD-specific deaths occurred. Both advanced CKM stages and elevated SIRI were associated with higher risks of all-cause and CVD mortality. Individuals with advanced CKM stages (Stages 3–4) and elevated SIRI (> 0.81) had the highest risks of all-cause (HR: 1.84, 95% CI: 1.65–2.05) and CVD mortality (HR: 2.50, 95% CI: 2.00–3.12). These associations were particularly pronounced in adults aged < 60 years ( P  for interaction < 0.001). Conclusions Advanced CKM stages and elevated SIRI are associated with increased risks of all-cause and CVD mortality, particularly in younger adults. These findings highlight the significance of targeted interventions to address systemic inflammation and CKM progression, potentially improving long-term outcomes in high-risk populations.

In rolling bearing fault diagnosis, weak features are often masked by complex environmental conditions, blurring the original fault signals and reducing diagnostic accuracy. To address this issue, we propose the VMD/FFT-Quadratic-BiGRU diagnostic model. First, the original vibration signals are processed with variational mode decomposition (VMD) and fast Fourier transform (FFT) and then stacked as quadratic neural network inputs. Next, a Bidirectional Gated Recurrent Unit (BiGRU) module is introduced to capture the temporal characteristics of the feature signals. An attention mechanism is then applied to assign weights to the hidden layers of the BiGRU network. Finally, fault diagnosis is performed using a fully connected layer and softmax classifier. Experimental results demonstrate that this model significantly enhances the ability to capture weak fault features in complex environments. The fault diagnosis accuracy reaches 100% on both datasets, showing improvements of 2.68% and 1.58% over models without the quadratic network. Additionally, comparisons with other models in noisy environments show that the proposed model exhibits superior noise suppression capabilities, further highlighting its robustness and diagnostic accuracy.

Renal tubular cell (RTC) death and inflammation contribute to the progression of obstructive nephropathy, but its underlying mechanisms have not been fully elucidated. Here, we showed that Gasdermin E (GSDME) expression level and GSDME-N domain generation determined the RTC fate response to TNFα under the condition of oxygen-glucose-serum deprivation. Deletion of Caspase-3 (Casp3) or Gsdme alleviated renal tubule damage and inflammation and finally prevented the development of hydronephrosis and kidney fibrosis after ureteral obstruction. Using bone marrow transplantation and cell type-specific Casp3 knockout mice, we demonstrated that Casp3/GSDME-mediated pyroptosis in renal parenchymal cells, but not in hematopoietic cells, played predominant roles in this process. We further showed that HMGB1 released from pyroptotic RTCs amplified inflammatory responses, which critically contributed to renal fibrogenesis. Specific deletion of Hmgb1 in RTCs alleviated caspase11 and IL-1β activation in macrophages. Collectively, our results uncovered that TNFα/Casp3/GSDME-mediated pyroptosis is responsible for the initiation of ureteral obstruction-induced renal tubule injury, which subsequentially contributes to the late-stage progression of hydronephrosis, inflammation, and fibrosis. This novel mechanism will provide valuable therapeutic insights for the treatment of obstructive nephropathy.

Sepsis is a systemic inflammatory disease causing life-threatening multi-organ dysfunction. Accumulating evidences suggest that two forms of programmed necrosis, necroptosis and pyroptosis triggered by the pathogen component lipopolysaccharide (LPS) and inflammatory cytokines, play important roles in the development of bacterial sepsis-induced shock and tissue injury. Sepsis-induced shock and tissue injury required receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) phosphorylation, caspase11 activation and gasdermin D (GSDMD) cleavage. However, the synergistic effect of necroptosis and pyroptosis in the pathological progress of sepsis remains elusive. In this study, we found that blockage of both necroptosis and pyroptosis (double deletion of Ripk3 / Gsdmd or Mlkl / Gsdmd ) resulted in accumulative protection against septic shock, systemic blood clotting and multi-organ injury in mice. Bone marrow transplantation confirmed that necroptosis and pyroptosis in both myeloid and nonmyeloid cells are indispensable in the progression of sepsis-induced multi-organ injury. Both RIPK3 and GSDMD signaling collaborated to amplify necroinflammation and tissue factor release in macrophages and endothelial cells, which led to tissue injury. Furthermore, cell death induced by inflammatory cytokines and high-mobility group box 1 could be prevented by double ablation of Ripk3/Gsdmd or Mlkl/Gsdmd , suggesting that a positive feedback loop interconnecting RIPK3/MLKL and GSDMD machinery and inflammation facilitated sepsis progression. Collectively, our findings demonstrated that RIPK3-mediated necroptosis and GSDMD-mediated pyroptosis collaborated to amply inflammatory signaling and enhance tissue injury in the process of sepsis, which may shed new light on two potential targets of combined therapeutic interventions for this highly lethal disorder.

In this study, the effect of packing density, oil type and temperature on the sorption kinetics behavior of cattail fiber was investigated based on Washburn theory by capillary rise test. It was found that higher packing density resulted in lower oil sorption capacity due to the less available space among fibers. The sorption coefficient to different oils which represented the sorption rate exhibited large difference with various packing densities. The results illustrated that when the packing density was 0.04 g/cm3, the cattail fiber showed higher oil sorption capacity and faster oil sorption rate. With regards to the temperature, results revealed that at the packing density of 0.06 g/cm3, the oil sorption capacity of cattail fiber showed little difference when the temperature ranged from 20 to 80 °C. However, the sorption coefficient depicted almost linear enhancement when higher temperature was applied. Moreover, the wetting characteristics of single cattail fiber to three test oils were performed by drop-on-fiber test. It was concluded that three test oils all displayed barrel-shaped droplets on single fiber with the smallest size for diesel oil and the largest for engine oil. Oil drops of vegetable oil and engine oil on single cattail fiber presented a dynamic flow process where smaller droplets converge into large ones. The unique wetting characteristic of cattail fiber was supposed to result from the open-cavity surface structure of cattail fiber.

Renal fibrosis is a common consequence of various progressive nephropathies, including obstructive nephropathy, and ultimately leads to kidney failure. Infiltration of inflammatory cells is a prominent feature of renal injury after draining blockages from the kidney, and correlates closely with the development of renal fibrosis. However, the underlying molecular mechanism behind the promotion of renal fibrosis by inflammatory cells remains unclear. Herein, we showed that unilateral ureteral obstruction (UUO) induced Gasdermin D (GSDMD) activation in neutrophils, abundant neutrophil extracellular traps (NETs) formation and macrophage-to-myofibroblast transition (MMT) characterized by α-smooth muscle actin (α-SMA) expression in macrophages. Gsdmd deletion significantly reduced infiltration of inflammatory cells in the kidneys and inhibited NETs formation, MMT and thereby renal fibrosis. Chimera studies confirmed that Gsdmd deletion in bone marrow-derived cells, instead of renal parenchymal cells, provided protection against renal fibrosis. Further, specific deletion of Gsdmd in neutrophils instead of macrophages protected the kidney from undergoing fibrosis after UUO. Single-cell RNA sequencing identified robust crosstalk between neutrophils and macrophages. In vitro, GSDMD-dependent NETs triggered p65 translocation to the nucleus, which boosted the production of inflammatory cytokines and α-SMA expression in macrophages by activating TGF-β1/Smad pathway. In addition, we demonstrated that caspase-11, that could cleave GSDMD, was required for NETs formation and renal fibrosis after UUO. Collectively, our findings demonstrate that caspase-11/GSDMD-dependent NETs promote renal fibrosis by facilitating inflammation and MMT, therefore highlighting the role and mechanisms of NETs in renal fibrosis.

Homogeneity and heterogeneity of the cytopathological mechanisms in different etiology-induced acute kidney injury (AKI) are poorly understood. Here, we performed single-cell sequencing (scRNA) on mouse kidneys with five common AKI etiologies (CP-Cisplatin, IRI-Ischemia-reperfusion injury, UUO-Unilateral ureteral obstruction, FA-Folic acid, and SO-Sodium oxalate). We constructed a potent multi-model AKI scRNA atlas containing 20 celltypes with 80,689 high-quality cells. The data suggest that compared to IRI and CP-AKI, FA- and SO-AKI exhibit injury characteristics more similar to UUO-AKI, which may due to tiny crystal-induced intrarenal obstruction. Through scRNA atlas, 7 different functional proximal tubular cell (PTC) subtypes were identified, we found that Maladaptive PTCs and classical Havcr1 PTCs but not novel Krt20 PTCs affect the pro-inflammatory and pro-fibrotic levels in different AKI models. And cell death and cytoskeletal remodeling events are widespread patterns of injury in PTCs. Moreover, we found that programmed cell death predominated in PTCs, whereas apoptosis and autophagy prevailed in the remaining renal tubules. We also identified S100a6 as a novel AKI-endothelial injury biomarker. Furthermore, we revealed that the dynamic and active immune (especially Arg1 Macro_2 cells) -parenchymal cell interactions are important features of AKI. Taken together, our study provides a potent resource for understanding the pathogenesis of AKI and early intervention in AKI progression at single-cell resolution.

Necroptosis predominates functionally over apoptosis in the pathophysiology of renal ischemia-reperfusion injury (IRI). Inhibition of the core components of the necroptotic pathway—receptor-interacting protein kinase 1 (RIPK1), RIPK3 or mixed lineage kinase domain-like protein (MLKL) reduced renal injury after ischemia/reperfusion (IR). Necrosis can initiate inflammation, which enhances necrosis in a positive feedback loop, subsequently leading to triggering more inflammation, termed as necroinflammation. However, the mechanisms underlying necroinflammation driven by renal tubular cell necroptosis in progression of AKI to CKD are still largely unknown. Here we showed that the upregulated expression and interactions between RIPK3 and MLKL induced necroptosis of renal proximal tubular cells and contributed to NLRP3 inflammasome activation under the conditions of IRI. Gene deletion of Ripk3 or Mlkl ameliorated renal tubular cell necroptosis, macrophage infiltration and NLRP3 inflammasome activation with a reduction in caspase-1 activation and maturation of IL-1β, and then finally reduced interstitial fibrogenesis in the long term after IRI. Bone marrow chimeras confirmed that RIPK3-MLKL-dependent necroptosis is responsible for the initiation of the early renal injury after IRI, and then necroptosis triggered NLRP3 inflammasome activation, which subsequently accelerates necroptosis and triggers more inflammation in an auto-amplification loop. These data indicate that necroinflammation driven by RIPK3-MLKL-dependent necroptosis plays a crucial role in the progression of IRI to CKD.

Immunonephropathy, encompassing disorders such as anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), and membranous nephropathy (MN), is characterized by immune-mediated glomerular injury leading to progressive renal dysfunction. Despite advances in clinical characterization, the precise molecular mechanisms underlying glomerular damage remain poorly understood. Gene expression profiles from the Gene Expression Omnibus (GEO) database were analyzed to identify plasma membrane homeostasis-related genes differentially expressed between immunonephropathy and healthy controls. Functional enrichment analyses were performed to investigate the biological pathways involved in disease progression. Least absolute shrinkage and selection operator (LASSO) regression and support vector machine (SVM) algorithms were used to identify diagnostic signature genes. Immune infiltration analysis and correlation analyses were further conducted to evaluate the associations between characteristic genes and clinical parameters, including estimated glomerular filtration rate (eGFR), proteinuria, and serum creatinine. Differentially expressed plasma membrane homeostasis-related genes were identified in immunonephropathy. Functional enrichment analyses revealed significant enrichment of immune- and metabolism-related pathways. An eight-gene diagnostic signature consisting of IPMK, TP53, SLC40A1, NCOA4, SLC39A7, KEAP1, TNIP1, and SAT1 demonstrated high diagnostic accuracy. Immune infiltration analysis further revealed disease-specific immune profiles. Correlation analyses showed that KEAP1 and SLC40A1 were positively associated with proteinuria, whereas TNIP1 and TP53 were significantly associated with impaired renal function. Necroptosis, pyroptosis, and ferroptosis may be involved in glomerular injury in immunonephropathy. The identified characteristic genes provide insight into the molecular landscape of immunonephropathy and may serve as potential biomarkers for disease characterization.