AML cell-derived exosomes suppress the activation and cytotoxicity of NK cells in AML via PD-1/PD-L1 pathway.

Exosomes are bilayer lipid bodies and contain a variety of bioactive molecules such as proteins, lipids, and nucleic acids, and so forth. Exosomes derived from solid tumors may play critical roles in tumor development and immune evasion. However, the underlying effects of tumor-derived exosomes on immune function in modulating intercellular crosstalk within the bone marrow niche during acute myeloid leukemia (AML) development and immune evasion remain largely elusive. In this study, we aimed to explore the role of AML-exos in AML immune evasion. First, we isolated tumor-derived exosomes from AML cells (AML-exos) and revealed the presence of programmed cell death ligand-1 (PD-L1) protein in AML-exos. Next, we demonstrated that AML-exos can directly suppress the activation of natural killer (NK) cells and inhibit the cytotoxicity of NK cells, probably through activating the programmed cell death-1 (PD-1)/PD-L1 pathway. Furthermore, the inhibitory effect of AML-exos on NK cells could be alleviated by either PD-L1 inhibitor or antagonist. In summary, we demonstrated that AML-exos possess a PD-L1-dependent tumor-promoting effect which may contribute to immune tolerance in antitumor therapy, but blocking the PD-1/PD-L1 pathway may alleviate the tumor immunosuppression induced by AML-exos. Our findings in this study may offer a new immunotherapy strategy to cure AML.

[Application of LU-tarjet congruent-arc technique in treatment of recurrent shoulder dislocation with huge glenoid defect].

Objective: To investigate the early effectiveness of the limited unique coracoid osteotomy suture button fixation Latarjet (LU-tarjet)-congruent-arc (CA) technique (LU-tarjet-CA) in treating recurrent shoulder dislocations with huge glenoid defect. Methods: The clinical data of 12 patients with recurrent shoulder dislocation and huge glenoid defect who met the selection criteria and treated with arthroscopic LU-tarjet-CA between January 2021 and December 2023 were retrospectively analyzed. The cohort included 8 males and 4 females, aged 20-40 years with an average age of 30.4 years. The range of glenoid bone loss was 30%-40%, with an average of 35.5%. The time from symptom onset to hospital admission ranged from 1 to 36 months, with an average of 18.5 months. The University of California Los Angeles (UCLA) score, American Association for Shoulder and Elbow Surgery (ASES) score, Walch-Duplay score, and Rowe score were used to evaluate shoulder function preoperatively and at 3, 6, and 12 months postoperatively. CT three-dimensional (3D) reconstruction was used to assess coracoid healing and plasticity at 3, 6, and 12 months postoperatively. Subjective satisfaction of patient was recorded at last follow-up. Results: All incisions healed by first intention, with no incision infection or nerve injury. All 12 patients were followed up 12 months. One patient developed Propionibacterium acnes infection within the joint postoperatively and recovered after initial arthroscopic debridement and anti-inflammatory treatment. At 3 months after operation, CT 3D-reconstruction showed 1 case of complete coracoid absorption; neither of these two patients experienced redislocation. The remaining patients exhibited partial coracoid absorption but displayed local reshaping, filling the preoperative defect area, and bony fusion between the coracoid and the glenoid. At last follow-up, 9 patients (75%) were very satisfied with the outcome, and 3 patients (25%) were satisfied; the satisfied patients experienced postoperative shoulder stiffness caused by suboptimal functional exercise but did not have impaired daily life activities. The UCLA score, ASES score, Walch-Duplay score, and Rowe score at 3, 6, and 12 months postoperatively were significantly better than preoperative scores, and each score improved further over time postoperatively, with significant differences between different time points ( P<0.05). Conclusion: The arthroscopic LU-tarjet-CA technique for treating recurrent shoulder dislocations with huge glenoid defect can achieve the surgical objective of bony blockade and filling bone defects to prevent shoulder dislocation, thereby improving patients' quality of life and shoulder joint function and stability.

Exploring the Mechanism of Isoforskolin against Asthma Based on Network Pharmacology and Experimental Verification.

In this study, network pharmacology combined with biological experimental verification was utilized to screen the targets of isoforskolin (ISOF) and investigate the potential underlying mechanism of ISOF against asthma. Asthma-related targets were screened from the Genecards and DisGeNET databases. SEA and Super-PRED databases were used to obtain the targets of ISOF. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were employed to identify enriched regulatory pathways of key targets in ISOF acting on asthma. Then, a protein-protein interaction (PPI) network was constructed via STRING database and hub genes of ISOF against asthma were further screened using molecular docking. Finally, CCK-8, qPCR, and Western blotting were performed to confirm the targets of ISOF in treating asthma. A total of 96 drug potential therapeutic targets from the relevant databases were screened out. KEGG pathway enrichment analysis predicted that the target genes might be involved in the PI3K-Akt pathway. The core targets of ISOF in treating asthma were identified by the PPI network and molecular docking, including MAPK1, mTOR, and NFKB1. Consistently, in vitro experiments showed that ISOF acting on asthma was involved in inflammatory response by reducing the expression of MAPK1, mTOR, and NFKB1. The present study reveals that MAPK1, mTOR, and NFKB1 might be key targets of ISOF in asthma treatment and the anti-asthma effect might be related to the PI3K-AKT signaling pathway.

Constructing immune and prognostic features associated with ADCP in hepatocellular carcinoma and pan-cancer based on scRNA-seq and bulk RNA-seq.

Aim: Despite the significant therapeutic outcomes achieved in systemic treatments for liver hepatocellular carcinoma (LIHC), it is an objective reality that only a low proportion of patients exhibit an improved objective response rate (ORR) to current immunotherapies. Antibody-dependent cellular phagocytosis (ADCP) immunotherapy is considered the new engine for precision immunotherapy. Based on this, we aim to develop an ADCP-based LIHC risk stratification system and screen for relevant targets. Method: Utilizing a combination of single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq data, we screened for ADCP modulating factors in LIHC and identified differentially expressed genes along with their involved functional pathways. A risk scoring model was established by identifying ADCP-related genes with prognostic value through LASSO Cox regression analysis. The risk scoring model was then subjected to evaluations of immune infiltration and immunotherapy relevance, with pan-cancer analysis and in vitro experimental studies conducted on key targets. Results: Building on the research by Kamber RA et al., we identified GYPA, CLDN18, and IRX5 as potential key target genes regulating ADCP in LIHC. These genes demonstrated significant correlations with immune infiltration cells, such as M1-type macrophages, and the effectiveness of immunotherapy in LIHC, as well as a close association with clinical pathological staging and patient prognosis. Pan-cancer analysis revealed that CLDN18 was prognostically and immunologically relevant across multiple types of cancer. Validation through tissue and cell samples confirmed that GYPA and CLDN18 were upregulated in liver cancer tissues and cells. Furthermore, in vitro knockdown of CLDN18 inhibited the malignancy capabilities of liver cancer cells. Conclusion: We have identified an ADCP signature in LIHC comprising three genes. Analysis based on a risk scoring model derived from these three genes, coupled with subsequent experimental validation, confirmed the pivotal role of M1-type macrophages in ADCP within LIHC, establishing CLDN18 as a critical ADCP regulatory target in LIHC.

Role and Mechanism of Growth Differentiation Factor 15 in Chronic Kidney Disease.

GDF-15 is an essential member of the transforming growth factor-beta superfamily. Its functions mainly involve in tissue injury, inflammation, fibrosis, regulation of appetite and weight, development of tumor, and cardiovascular disease. GDF-15 is involved in various signaling pathways, such as MAPK pathway, PI3K/AKT pathway, STAT3 pathway, RET pathway, and SMAD pathway. In addition, several factors such as p53, ROS, and TNF-α participate the regulation of GDF-15. However, the specific mechanism of these factors regulating GDF-15 is still unclear and more research is needed to explore them. GDF-15 mainly improves the function of kidneys in CKD and plays an important role in the prediction of CKD progression and cardiovascular complications. In addition, the role of GDF-15 in the kidney may be related to the SMAD and MAPK pathways. However, the specific mechanism of these pathways remains unclear. Accordingly, more research on the specific mechanism of GDF-15 affecting kidney disease is needed in the future. In conclusion, GDF-15 may be a therapeutic target for kidney disease.

Exosome may be the next generation of promising cell-free vaccines.

Traditional vaccines have limits against some persistent infections and pathogens. The development of novel vaccine technologies is particularly critical for the future. Exosomes play an important role in physiological and pathological processes. Exosomes present many advantages, such as inherent capacity being biocompatible, non-toxic, which make them a more desirable candidate for vaccines. However, research on exosomes are in their infancy and the barriers of low yield, low purity, and weak targeting of exosomes limit their applications in vaccines. Accordingly, further exploration is necessary to improve these problems and subsequently facilitate the functional studies of exosomes. In this study, we reviewed the origin, classification, functions, modifications, separation and purification, and characterization methods of exosomes. Meanwhile, we focused on the role and mechanism of exosomes for cancer and COVID-19 vaccines.

NLRP3 Inflammasome Triggers Inflammation of Obstructive Sleep Apnea.

Obstructive sleep apnea [OSA] is widespread in the population and affects as many as one billion people worldwide. OSA is associated with dysfunction of the brain system that controls breathing, which leads to intermittent hypoxia [IH], hypercapnia, and oxidative stress [OS]. The number of NOD-like receptor family pyrin domain-containing [NLRP3] inflammasome was increased after IH, hypercapnia, and OS. NLRP3 inflammasome is closely related to inflammation. NLRP3 inflammasome causes a series of inflammatory diseases by activating IL-1ß and IL-18. Subsequently, NLRP3 inflammasome plays an important role in the complications of OSA, including Type 2 diabetes [T2DM], coronary heart disease [CHD], hypertension, neuroinflammation, and depression. This review will introduce the basic composition and structure of the NLRP3 inflammasome and focus on the relationship between the NLRP3 inflammasome and OSA and OSA complications. We can deeply understand how NLRP3 inflammasome is strongly associated with OSA and OSA complications.

Identification of ferroptosis-related key genes associated with immune infiltration in sepsis by bioinformatics analysis and in vivo validation.

OBJECTIVES: Sepsis is a life-threatening infectious disease in which an immune inflammatory response is triggered. The potential effect of ferroptosis-related genes (FRGs) in inflammation of sepsis remained unclear. We focused on identifying and validating core FRGs and their association with immune infiltration in blood from currently all patients with sepsis. METHODS: All current raw data of septic blood were obtained from Gene Expression Omnibus. After removing the batch effect merging into a complete dataset and obtaining Diferentially expressed genes (DEGs). Common cross-talk genes were identified from DEGs and FRGs. WGCNA, GO, KEGG, PPI, GESA, ROC curves, and LASSO regression analysis were performed to indentify and validate key genes based on external septic datasets. Infiltrated immune cells in 2 hub genes (MAPK14 and ACSL4) were conducted using CIBERSORT algorithm and Spearman correlation analysis. Further, the expressions of 2 core FRGs were verified in the LPS-induced ALI and cardiac injury sepsis mice. RESULTS: MAPK14 and ACSL4 were identified, mostly enriched in T cell infiltration through NOD-like receptor signaling pathway according to the high or low 2 hub genes expression. The upregulated 2 ferroptosis-related genes were validated in LPS-induced ALI and cardiac injury mice, accompanied by upregulation of the NLRP3 pathway. CONCLUSION: MAPK14 and ACSL4 could become robustly reliable and promising biomarkers for sepsis by regulating ferroptosis through the NLRP3 pathway, which is mainly associated with T-cell infiltration.

Identification and experimental validation of PYCARD as a crucial PANoptosis-related gene for immune response and inflammation in COPD.

Chronic inflammatory and immune responses play key roles in the development and progression of chronic obstructive pulmonary disease (COPD). PANoptosis, as a unique inflammatory cell death modality, is involved in the pathogenesis of many inflammatory diseases. We aim to identify critical PANoptosis-related biomarkers and explore their potential effects on respiratory tract diseases and immune infiltration landscapes in COPD. Total microarray data consisting of peripheral blood and lung tissue datasets associated with COPD were obtained from the GEO database. PANoptosis-associated genes in COPD were identified by intersecting differentially expressed genes (DEGs) with genes involved in pyroptosis, apoptosis, and necroptosis after normalizing and removing the batch effect. Furthermore, GO, KEGG, PPI network, WGCNA, LASSO-COX, and ROC curves analysis were conducted to screen and verify hub genes, and the correlation between PYCARD and infiltrated immune cells was analyzed. The effect of PYCARD on respiratory tract diseases and the potential small-molecule agents for the treatment of COPD were identified. PYCARD expression was verified in the lung tissue of CS/LPS-induced COPD mice. PYCARD was a critical PANoptosis-related gene in all COPD patients. PYCARD was positively related to NOD-like receptor signaling pathway and promoted immune cell infiltration. Moreover, PYCARD was significantly activated in COPD mice mainly by targeting PANoptosis. PANoptosis-related gene PYCARD is a potential biomarker for COPD diagnosis and treatment.

Guiding bar motif of thioredoxin reductase 1 modulates enzymatic activity and inhibitor binding by communicating with the co-factor FAD and regulating the flexible C-terminal redox motif.

Thioredoxin reductase (TXNRD) is a selenoprotein that plays a crucial role in cellular antioxidant defense. Previously, a distinctive guiding bar motif was identified in TXNRD1, which influences the transfer of electrons. In this study, utilizing single amino acid substitution and Excitation-Emission Matrix (EEM) fluorescence spectrum analysis, we discovered that the guiding bar communicates with the FAD and modulates the electron flow of the enzyme. Differential Scanning Fluorimetry (DSF) analysis demonstrated that the aromatic amino acid in guiding bar is a stabilizer for TXNRD1. Kinetic analysis revealed that the guiding bar is vital for the disulfide reductase activity but hinders the selenocysteine-independent reduction activity of TXNRD1. Meanwhile, the guiding bar shields the selenocysteine residue of TXNRD1 from the attack of electrophilic reagents. We also found that the inhibition of TXNRD1 by caveolin-1 scaffolding domain (CSD) peptides and compound LCS3 did not bind to the guiding bar motif. In summary, the obtained results highlight new aspects of the guiding bar that restrict the flexibility of the C-terminal redox motif and govern the transition from antioxidant to pro-oxidant.

A Double-ligand Chelating Strategy to Iron Complex Anolytes with Ultrahigh Cyclability for Aqueous Iron Flow Batteries.

Aqueous all-iron flow batteries (AIFBs) are attractive for large-scale and long-term energy storage due to their extremely low cost and safety features. To accelerate commercial application, a long cyclable and reversible iron anolyte is expected to address the critical barriers, namely iron dendrite growth and hydrogen evolution reaction (HER). Herein, we report a robust iron complex with triethanolamine (TEA) and 2-methylimidazole (MM) double ligands. By introducing two ligands into one iron center, the binding energy of the complex increases, making it more stable in the charge-discharge reactions. The Fe(TEA)MM complex achieves reversible and stable redox between Fe3+ and Fe2+ , without metallic iron growth and HER. AIFBs based on this anolyte perform a high energy efficiency of 80.5 % at 80 mA cm-2 and exhibit a record durability among reported AIFBs. The efficiency and capacity retain nearly 100 % after 1,400 cycles. The capital cost of this AIFB is $ 33.2 kWh-1 (e.g., 20 h duration), cheaper than Li-ion battery and vanadium flow battery. This double-ligand chelating strategy not only solves the current problems faced by AIFBs, but also provides an insight for further improving the cycling stability of other flow batteries.

Synergistic Enhancement of Isoforskolin and Dexamethasone Against Sepsis and Acute Lung Injury Mouse Models.

Background: Sepsis is initiated by the dysfunctional response of the host immune system to infection. Septic shock and acute lung injury (ALI) are the main etiology of death caused by sepsis. Glucocorticoids, which are commonly used in clinic to antagonize the inflammatory response of sepsis, may cause serious side effects. Isoforskolin (ISOF) from the plant Coleus forskohlii stimulates adenylyl cyclase, increases the cAMP level and inhibits inflammatory response. The aim of this study was to investigate the synergistic effect of ISOF with dexamethasone (DEX) to prevent and ameliorate septic inflammation. Methods: Lipopolysaccharide (LPS) of 30 and 5 mg/kg (iv.) was used to induce sepsis and ALI mice model respectively in vivo. BEAS-2B cells stimulated by LPS were applied as cell model in vitro. The cumulative survival of mice with LPS-induced sepsis and the histopathological changes of lungs in mice with acute lung injury were observed, and the secretion of pro-inflammatory cytokines was analyzed by ELISA. The expression of RGS2 in BEAS-2B cells was detected by immunoblotting assay and PCR. Results: In the sepsis mice model, ISOF (10 mg/kg) combined with DEX (10 mg/kg.) (ip.) pretreatment significantly increased mice survival rate from 33.3% to 58.3%, which was significantly higher than that of ISOF or DEX treated alone. In the ALI mice model, ISOF, DEX pretreatment alone and combined application attenuated pulmonary pathological changes in ALI mice. Furthermore, ISOF, DEX alone or combined administration decreased MPO, MDA, IL-6, and IL-8 levels, while significantly synergistic effects were observed in the combined treatment group compared with ISOF or DEX alone. In BEAS-2B cells, combined pretreatment with ISOF and DEX significantly decreased the expression of IL-8 and increased the expression of RGS2. Conclusion: The results indicated that ISOF in combination with DEX synergistically improves survival rate and attenuates ALI in mice model through anti-inflammatory and antioxidant effects.

High-mobility group box 1 emerges as a therapeutic target for asthma.

High-mobility group box 1 (HMGB1) is a highly conserved nonhistone nuclear protein found in the calf thymus and participates in a variety of intracellular processes such as DNA transcription, replication and repair. In the cytoplasm, HMGB1 promotes mitochondrial autophagy and is involved in in cellular stress response. Once released into the extracellular, HMGB1 becomes an inflammatory factor that triggers inflammatory responses and a variety of immune responses. In addition, HMGB1 binding with the corresponding receptor can activate the downstream substrate to carry out several biological effects. Meanwhile, HMGB1 is involved in various signaling pathways, such as the HMGB1/RAGE pathway, HMGB1/NF-κB pathway, and HMGB1/JAK/STAT pathway, which ultimately promote inflammation. Moreover, HMGB1 may be involved in the pathogenesis of asthma by regulating downstream signaling pathways through corresponding receptors and mediates a number of signaling pathways in asthma, such as HMGB1/TLR4/NF-κB, HMGB1/RAGE, HMGB1/TGF-ß, and so forth. Accordingly, HMGB1 emerges as a therapeutic target for asthma.

Ferroptosis triggers airway inflammation in asthma.

Ferroptosis is a regulatory cell death characterized by intracellular iron accumulation and lipid peroxidation that leads to oxidative stress. Many signaling pathways such as iron metabolism, lipid metabolism, and amino acid metabolism precisely regulate the process of ferroptosis. Ferroptosis is involved in a variety of lung diseases, such as acute lung injury, chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis. Increasing studies suggest that ferroptosis is involved in the development of asthma. Ferroptosis plays an important role in asthma. Iron metabolism disorders, lipid peroxidation, amino acid metabolism disorders lead to the occurrence of ferroptosis in airway epithelial cells, and then aggravate clinical symptoms in asthmatic patients. Moreover, several regulators of ferroptosis are involved in the pathogenesis of asthma, such as Nrf2, heme oxygenase-1, mevalonate pathway, and ferroptosis inhibitor protein 1. Importantly, ferroptosis inhibitors improve asthma. Thus, the pathogenesis of ferroptosis and its contribution to the pathogenesis of asthma help us better understand the occurrence and development of asthma, and provide new directions in asthma treatment. This article aimed to review the role and mechanism of ferroptosis in asthma, describing the relationship between ferroptosis and asthma based on signaling pathways and related regulatory factors. At the same time, we summarized current observations of ferroptosis in eosinophils, airway epithelial cells, and airway smooth muscle cells in asthmatic patients.

MST1/2 in inflammation and immunity.

The mammalian Sterile 20-like kinase 1/2 (MST1/2) belongs to the serine/threonine (GC) protein kinase superfamily. Collective studies confirm the vital role MST1/2 in inflammation and immunity. MST1/2 is closely related to the progress of inflammation. Generally, MST1/2 aggravates the inflammatory injury through MST1-JNK, MST1-mROS, MST1-Foxo3, and NF-κB pathways, as well as several regulatory factors such as tumor necrosis factor-α (TNF-α), mitochondrial extension factor 1 (MIEF1), and lipopolysaccharide (LPS). Moreover, MST1/2 is also involved in the regulation of immunity to balance immune activation and tolerance by regulating MST1/2-Rac, MST1-Akt1/c-myc, MST1-Foxos, MST1-STAT, Btk pathways, and lymphocyte function-related antigen 1 (LFA-1), which subsequently prevents immunodeficiency syndrome and autoimmune diseases. This article reviews the effects of MST1/2 on inflammation and immunity.

Analysis of characteristics related to interstitial lung disease or pulmonary hypertension in patients with dermatomyositis.

INTRODUCTION: Dermatomyositis (DM) is often associated with interstitial lung disease (ILD) or pulmonary hypertension (PH). The aim of this study was to investigate the clinical characteristics of DM patients with ILD or PH. METHODS: This study retrospectively analysed the clinical characteristics of 372 patients with DM, including cytokines, lymphocyte subsets, immunoglobulin and complement. The DM patients were divided into different groups according to whether complicated with ILD, PH or anti-melanoma differentiation-associated gene 5 antibodies (MDA5). A qualitative and quantitative data analysis was performed. RESULTS: IgG, IgA and IgM in the DM-associated ILD (ILD-DM) were higher than that of the DM non-complicating ILD (Non-ILD-DM) (p = 0.022, 0.002 and 0.029, respectively). Meanwhile, IL-6 (p = 0.008) and IL-10 (p = 0.001) were increased in the DM-associated PH (PH-DM) than in the DM non-complicating PH (Non-PH-DM), while IL-17 (p = 0.004), double positive (DP) cell ratio and B lymphocyte ratio were reduced in the PH-DM. Moreover, the incidence of ILD and levels of C4 were higher in the DM with MDA5 (MDA5+ DM) than that of the DM without MDA5. CONCLUSION: ILD-DM has higher IgG, IgA and IgM than that of Non-ILD-DM. PH-DM has higher IL-6, IL-10 and lower IL-17, DP cell ratio and B lymphocyte ratio than that of Non-PH-DM.

Role and mechanism of ferroptosis in acute lung injury.

Ferroptosis is a new non-apoptotic cell death caused by the accumulation of dysregulated metabolism of ferric iron, amino acids or lipid peroxidation. Increasing studies suggest that ferroptosis is involved in the acute lung injury (ALI). This article aims to review the role of ferroptosis in ALI. ALI is a common respiratory disease and presents a high mortality rate. Inhibiting cell ferroptosis of lung improves the ALI. In addition, several signaling pathways are related to ferroptosis in ALI, involving in iron homeostasis, lipid peroxidation, and amino acid metabolism. Moreover, there are various key factors to regulate the occurrence of ferroptosis in ALI, such as ACSL4, NRF2, and P53. The ACSL4 promotes the ferroptosis, while the NRF2 alleviates the ferroptosis in ALI. The main effect of P53 is to promote ferroptosis. Accordingly, ferroptosis is involved in ALI and may be an important therapeutic target for ALI.

Benzophenanthridine Alkaloid Chelerythrine Elicits Necroptosis of Gastric Cancer Cells via Selective Conjugation at the Redox Hyperreactive C-Terminal Sec498 Residue of Cytosolic Selenoprotein Thioredoxin Reductase.

Targeting thioredoxin reductase (TXNRD) with low-weight molecules is emerging as a high-efficacy anti-cancer strategy in chemotherapy. Sanguinarine has been reported to inhibit the activity of TXNRD1, indicating that benzophenanthridine alkaloid is a fascinating chemical entity in the field of TXNRD1 inhibitors. In this study, the inhibition of three benzophenanthridine alkaloids, including chelerythrine, sanguinarine, and nitidine, on recombinant TXNRD1 was investigated, and their anti-cancer mechanisms were revealed using three gastric cancer cell lines. Chelerythrine and sanguinarine are more potent inhibitors of TXNRD1 than nitidine, and the inhibitory effects take place in a dose- and time-dependent manner. Site-directed mutagenesis of TXNRD1 and in vitro inhibition analysis proved that chelerythrine or sanguinarine is primarily bound to the Sec498 residue of the enzyme, but the neighboring Cys497 and remaining N-terminal redox-active cysteines could also be modified after the conjugation of Sec498. With high similarity to sanguinarine, chelerythrine exhibited cytotoxic effects on multiple gastric cancer cell lines and suppressed the proliferation of tumor spheroids derived from NCI-N87 cells. Chelerythrine elevated cellular levels of reactive oxygen species (ROS) and induced endoplasmic reticulum (ER) stress. Moreover, the ROS induced by chelerythrine could be completely suppressed by the addition of N-acetyl-L-cysteine (NAC), and the same is true for sanguinarine. Notably, Nec-1, an RIPK1 inhibitor, rescued the chelerythrine-induced rapid cell death, indicating that chelerythrine triggers necroptosis in gastric cancer cells. Taken together, this study demonstrates that chelerythrine is a novel inhibitor of TXNRD1 by targeting Sec498 and possessing high anti-tumor properties on multiple gastric cancer cell lines by eliciting necroptosis.

Advanced oxidation protein products induce Paneth cells defects by endoplasmic reticulum stress in Crohn's disease.

Paneth cells (PC) play a key role in the innate immune response of intestine epithelium, and PC defects contribute to the pathogenesis of Crohn's disease (CD). In this study, we utilized active CD tissues and advanced oxidation protein products (AOPP)-challenged C57BL/6 mouse model to investigate the effect of AOPP on PC defects in CD. We found that AOPP accumulated in active CD tissues and was negatively associated with lysozyme expression, while positively correlated with the presence of ER stress markers. Furthermore, AOPP treatment induced PC defects mainly through excessive ER stress in vivo, and AOPP also caused mitochondria-associated ER membranes formation and mitochondrial dysfunction. In addition, the effects of AOPP could be attenuated by the administration of ER stress inhibitor, TUDCA. These findings suggest a pathogenic role of AOPP contributing to PC defects and may provide the basis for developing new strategies to managing CD.

The Mechanisms of Ferroptosis Under Hypoxia.

Ferroptosis is a new form of programmed cell death, which is characterized by the iron-dependent accumulation of lipid peroxidation and increase of ROS, resulting in oxidative stress and cell death. Iron, lipid, and multiple signaling pathways precisely control the occurrence and implementation of ferroptosis. The pathways mainly include Nrf2/HO-1 signaling pathway, p62/Keap1/Nrf2 signaling pathway. Activating p62/Keap1/Nrf2 signaling pathway inhibits ferroptosis. Nrf2/HO-1 signaling pathway promotes ferroptosis. Furthermore, some factors also participate in the occurrence of ferroptosis under hypoxia, such as HIF-1, NCOA4, DMT1. Meanwhile, ferroptosis is related with hypoxia-related diseases, such as MIRI, cancers, and AKI. Accordingly, ferroptosis appears to be a therapeutic target for hypoxia-related diseases.