Sepsis is a life-threatening condition caused by pathogen infection and associated with pyroptosis. Pyroptosis occurs upon activation of proinflammatory caspases and their subsequent cleavage of ...gasdermin D (GSDMD), resulting in GSDMD N-terminal fragments that form membrane pores to induce cell lysis. Here, we show that antioxidant defense enzyme glutathione peroxidase 4 (GPX4) and its ability to decrease lipid peroxidation, negatively regulate macrophage pyroptosis, and septic lethality in mice. Conditional Gpx4 knockout in myeloid lineage cells increases lipid peroxidation-dependent caspase-11 activation and GSDMD cleavage. The resultant N-terminal GSDMD fragments then trigger macrophage pyroptotic cell death in a phospholipase C gamma 1 (PLCG1)-dependent fashion. Administration of the antioxidant vitamin E that reduces lipid peroxidation, chemical inhibition of PLCG1, or genetic Caspase-11 deletion or Gsdmd inactivation prevents polymicrobial sepsis in Gpx4−/− mice. Collectively, this study suggests that lipid peroxidation drives GSDMD-mediated pyroptosis and hence constitutes a potential therapeutic target for lethal infection.
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•Gpx4 deficiency in myeloid cells increases severity of polymicrobial sepsis in mice•Caspase-11-dependent pyroptosis mediates septic death in Gpx4Mye−/− mice•GPX4 decreases lipid peroxidation to block PLCG1-mediated GSDMD activity and pyroptosis•Antioxidant activity of vitamin E promotes survival during sepsis in Gpx4Mye−/− mice
Kang et al. demonstrate that glutathione peroxidase 4 (GPX4) serves a protective role in mice undergoing septic shock. Myeloid-specific deficiency of Gpx4 coordinates lipid peroxidation-dependent caspase-11 activation and gasdermin D-mediated pyroptosis during polymicrobial sepsis. Vitamin E administration reverses Gpx4Mye−/− susceptibility, thereby revealing a potential target for therapeutic intervention for lethal infection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ferroptosis is a form of regulated cell death triggered by lipid peroxidation after inhibition of the cystine/glutamate antiporter system Xc–. However, key regulators of system Xc– activity in ...ferroptosis remain undefined. Here, we show that BECN1 plays a hitherto unsuspected role in promoting ferroptosis through directly blocking system Xc– activity via binding to its core component, SLC7A11 (solute carrier family 7 member 11). Knockdown of BECN1 by shRNA inhibits ferroptosis induced by system Xc– inhibitors (e.g., erastin, sulfasalazine, and sorafenib), but not other ferroptosis inducers including RSL3, FIN56, and buthionine sulfoximine. Mechanistically, AMP-activated protein kinase (AMPK)-mediated phosphorylation of BECN1 at Ser90/93/96 is required for BECN1-SLC7A11 complex formation and lipid peroxidation. Inhibition of PRKAA/AMPKα by siRNA or compound C diminishes erastin-induced BECN1 phosphorylation at S93/96, BECN1-SLC7A11 complex formation, and subsequent ferroptosis. Accordingly, a BECN1 phosphorylation-defective mutant (S90,93,96A) reverses BECN1-induced lipid peroxidation and ferroptosis. Importantly, genetic and pharmacological activation of the BECN1 pathway by overexpression of the protein in tumor cells or by administration of the BECN1 activator peptide Tat-beclin 1, respectively, increases ferroptotic cancer cell death (but not apoptosis and necroptosis) in vitro and in vivo in subcutaneous and orthotopic tumor mouse models. Collectively, our work reveals that BECN1 plays a novel role in lipid peroxidation that could be exploited to improve anticancer therapy by the induction of ferroptosis.
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•BECN1 is required for system Xc–-inhibitor-induced ferroptosis•BECN1 inhibits system Xc– activity through directly binding to SLC7A11•AMPK is required for BECN1 phosphorylation in ferroptosis•BECN1 contributes to the anticancer activity of ferroptosis in vivo
Song et al. find that BECN1 promotes ferroptosis by directly blocking system Xc– activity via binding to its core component SLC7A11. This pathway is different from the previously identified function of BECN1 as a positive regulator of autophagy via directly activating PtdIns3K activity via binding to its core component PIK3C3.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In an effort to explore the feasibility of converting a lipase into an esterase by modifying the lid region, we designed and characterized two novel Rhizopus chinensis lipase variants by lid ...swapping. The substrate specificity of an R. chinensis lipase was successfully modified toward water-soluble substrates, that is, turned into an esterase, by replacing the hydrophobic lid with a hydrophilic lid from ferulic acid esterase from Aspergillus niger. Meanwhile, as a comparison, the lid of R. chinensis lipase was replaced by a hydrophobic lid from Rhizomucor miehei lipase, which did not alter its substrate specificity but led to a 5.4-fold higher catalytic efficiency (k*cat/K*m) toward p-nitrophenyl laurate. Based on the analysis of structure-function relationships, it suggests that the amphipathic nature of the lid is very important for the substrate specificity. This study provides new insight into the structural basis of lipase specificities and a way to tune the substrate preference of lipases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ferroptosis is a form of regulated cell death driven by oxidative injury promoting lipid peroxidation, although detailed molecular regulators are largely unknown. Here, we show that heatshock 70-kDa ...protein 5 (HSPA5) negatively regulates ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, activating transcription factor 4 (ATF4) resulted in the induction of HSPA5, which in turn bound glutathione peroxidase 4 (GPX4) and protected against GPX4 protein degradation and subsequent lipid peroxidation. Importantly, the HSPA5-GPX4 pathway mediated ferroptosis resistance, limiting the anticancer activity of gemcitabine. Genetic or pharmacologic inhibition of the HSPA5-GPX4 pathway enhanced gemcitabine sensitivity by disinhibiting ferroptosis
and in both subcutaneous and orthotopic animal models of PDAC. Collectively, these findings identify a novel role of HSPA5 in ferroptosis and suggest a potential therapeutic strategy for overcoming gemcitabine resistance.
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In this paper, the problem of sampled-data adaptive tracking control for a class of switched nonlinear systems with prescribed performance is considered. In order to guarantee the system is stable ...and achieves the prescribed performance in sampled-data control, a coordinate transformation satisfying the prescribed performance is introduced. In addition, the neural networks (NNs) used to approximate the unknown nonlinear functions and the backstepping technique are applied to design the sampled-data controller and the adaptive laws. An upper bound on the sampling period is obtained to maintain the stability of the systems. It is confirmed that the designed sampled-data scheme ensures that all signals of the closed-loop system are semi-globally uniformly ultimately bounded (SGUUB) and the tracking error is limited to the prescribed performance function. The effectiveness of the designed control scheme is demonstrated by two simulation examples.
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BFBNIB, GIS, IJS, KISLJ, NUK, PNG, UL, UM, UPUK
Due to the rising globalization of the economy, a single container transportation mode can no longer meet the requirements of global supply chain management. This article proposes a new method ...combining trapezoidal cloud and MULTIMOORA (Multi-Objective Optimization on the basis of Ratio Analysis plus full multiplicative form) for heterogeneous multi-criterion group decision-making (HMCGDM) to determine the optimal path of container multimodal transport. Firstly, in order to represent the ambiguity and uncertainty of path evaluations, this article uses heterogeneous information to represent the assessments and puts forward some new methods to convert different forms of linguistic evaluation information into trapezoidal clouds. Second, decision makers’ (DMs’) weights are determined through internal weights and external weights. Third, the similarity of trapezoidal clouds is determined by calculating the overlapping area, the criterion weights are objectively obtained by calculating the similarity of trapezoidal clouds under different situations. Fourth, based on MULTIMOORA, a new ranking index is defined to determine the optimal alternative. Thereby, the proposed method for HMCGDM is described step by step. Finally, a real case study of container multimodal transport path selection is analyzed to demonstrate the practicality of the proposed method. The findings of sensitivity and comparative analyses verify the robustness and advantages of the proposed method.
•Some new methods to convert different forms of linguistic evaluations into trapezoidal clouds.•The comprehensive weights of DMs consist of the internal weights and external weights of DMs.•The criterion weights are obtained by calculating the similarity of trapezoidal clouds.•A new ranking index of alternative is defined by extending MULTIMOORA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Liver cancer is one of the most common malignancies, with severe morbidity and mortality. While considerable progress has been made in liver cancer treatment, the 5-year overall survival (OS) of ...patients has not improved significantly. Reasons include the inadequate capability of early screening and diagnosis, a high incidence of recurrence and metastasis, a high degree of tumor heterogeneity, and an immunosuppressive tumor microenvironment. Therefore, the identification and validation of specific and robust liver cancer biomarkers are of major importance for early screening, timely diagnosis, accurate prognosis, and the prevention of tumor progression. In this review, we highlight some of the latest research progress and potential applications of liver cancer biomarkers, describing hotspots and prospective directions in biomarker discovery.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Sepsis, severe sepsis and septic shock are the main cause of mortality in non-cardiac intensive care units. Immunometabolism has been linked to sepsis; however, the precise mechanism by which ...metabolic reprogramming regulates the inflammatory response is unclear. Here we show that aerobic glycolysis contributes to sepsis by modulating inflammasome activation in macrophages. PKM2-mediated glycolysis promotes inflammasome activation by modulating EIF2AK2 phosphorylation in macrophages. Pharmacological and genetic inhibition of PKM2 or EIF2AK2 attenuates NLRP3 and AIM2 inflammasomes activation, and consequently suppresses the release of IL-1β, IL-18 and HMGB1 by macrophages. Pharmacological inhibition of the PKM2-EIF2AK2 pathway protects mice from lethal endotoxemia and polymicrobial sepsis. Moreover, conditional knockout of PKM2 in myeloid cells protects mice from septic death induced by NLRP3 and AIM2 inflammasome activation. These findings define an important role of PKM2 in immunometabolism and guide future development of therapeutic strategies to treat sepsis.
Early, express, and reliable detection of cancer can provide a favorable prognosis and decrease mortality. Tumor biomarkers have been proven to be closely related to tumor occurrence and development. ...Conventional tumor biomarker detection based on genomic, proteomic, and metabolomic methods is time and equipment-consuming and always needs a specific target marker. Surface-enhanced Raman scattering (SERS), as a non-invasive ultrasensitive and label-free vibrational spectroscopy technique, can detect cancer-related biomedical changes in biofluids. In this paper, 110 serum samples were collected from 30 healthy controls and 80 cancer patients (including 30 bladder cancer (BC), 30 adrenal cancer (AC), and 20 acute myeloid leukemia (AML)). One microliter of blood serum was mixed with 1 μl silver colloid and then was air-dried for SERS measurements. After spectral data augmentation, one-dimensional convolutional neural network (1D-CNN) was proposed for precise and rapid identification of healthy and three different cancers with high accuracy of 98.27%. After gradient-weighted class activation mapping (Grad-CAM) based spectral interpretation, the contributions of SERS peaks corresponding to biochemical substances indicated the most potential biomarkers, i.e., L-tyrosine in bladder cancer; acetoacetate and riboflavin in adrenal cancer and phospholipids, amide-I, and α-Helix in acute myeloid leukemia, which might provide an insight into the mechanism of intelligent diagnosis of different cancers based on label-free serum SERS. The integration of label-free SERS and deep learning has great potential for the rapid, reliable, and non-invasive detection of cancers, which may significantly improve the precise diagnosis in clinical practice.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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