Programmed Cell Death Research Articles

The link between amyloid β and ferroptosis pathway in Alzheimer’s disease progression

Alzheimer’s disease (AD) affects millions of people worldwide and represents the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Here we evaluate if Aβ is associated with ferroptosis pathways in post-mortem human brain tissue and whether ferroptosis inhibition could attenuate Aβ-related effects in human brain organoids. Performing positive pixel density scoring on immunohistochemically stained post-mortem Brodmann Area 17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 and glutathione peroxidase 4 in the grey matter. Differentiating between white and grey matter, allowed for a more precise understanding of the disease’s impact on different brain regions. In addition, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids at day 50 of differentiation. Differential gene expression analysis of RNAseq of AD organoids compared to isogenic controls indicated activation of the ferroptotic pathway. This was also supported by results from untargeted proteomic analysis revealing significant changes between AD and isogenic brain organoids. Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.

Companion diagnostics and predictive biomarkers for PD-1/PD-L1 immune checkpoint inhibitors therapy in malignant melanoma

Programmed cell death receptor 1 (PD-1), when bound to the ligand programmed death-ligand 1 (PD-L1), can suppress cellular immunity and play a critical role in the initiation and development of cancer. Immune drugs targeting these two sites have been developed for different cancers, including malignant melanoma. The accompanying diagnostic method has been approved by the FDA to guide patient medication. However, the method of immunohistochemical staining, which varies widely due to the antibody and staining cut-off values, has certain limitations in application and does not benefit all patients. Increasing researches begin to focus on new biomarkers to improve objective response rates and survival in cancer patients. In this article, we enumerated three major groups, including tumour microenvironment, peripheral circulation, and gene mutation, which covered the current main research directions. In the future, we hope those biomarkers may be used to guide the treatment of patients with malignant melanoma.

Oxct1 regulates cardiomyocyte PANoptosis in acute myocardial infarction via succinylating Tfam

Abstract Background Myocardial ischemia leads to various forms of programmed cell death in cardiomyocytes, resulting in acute myocardial infarction (AMI) and the development of heart failure in the long term. PANoptosis is a unique cell death regulatory mechanism orchestrated by the PANoptosome complex, which regulates and intersects multiple forms of programmed cell death. Oxct1 has been demonstrated to play crucial roles in tumors, pressure-overloaded hearts, and cardiac endothelial cells. However, whether Oxct1 is involved in the regulation of PANoptosis and correlated mechanisms during AMI remains unclear. Purpose To elucidate the role of Oxct1 in cardiomyocytes during AMI and uncover the potential mechanisms. Methods The myocardial infarction model induced by anterior descending branch ligation and the primary cardiomyocytes hypoxia model were employed in our experiments. Small interfering RNA (siRNA) and adenovirus were constructed to knock down and overexpress Oxct1 for altering its expression in cardiomyocytes in vitro. Cardiomyocyte-specific knockout mice were constructed to alter Oxct1 expression in vivo. PANoptosis characteristic measurement, including Z-DNA binding protein 1(Zbp1), pyroptosis markers, apoptosis markers, necroptosis markers, ROS, and mitochondrial morphology, were performed to verify the ability of Oxct1 to regulate the PANoptosis of cardiomyocytes. Cardiac morphological, structural, and functional changes were measured to assess the effect of Oxct1 on AMI. RNA sequencing was performed to identify downstream pathways. Immunoprecipitation +Mass spectrometry and co-immunoprecipitation were performed to identify the specific binding factors of Oxct1. Results We found that the expression of Oxct1 was significantly elevated after AMI. Besides, gain- and loss-of-function experiments were constructed both in vitro and in vivo. Functionally, Oxct1 knockdown significantly enhanced cardiomyocyte vitality, reduced ROS production and mtDNA cytoplasmic release in hypoxic cardiomyocytes. In vivo, Oxct1cko mice manifested reduced infarct size, improved cardiac function and alleviated cardiac fibrosis by mitigating PANoptosis. However, Oxct1 overexpression resulted in the opposite effects. Afterwards, RNA-seq analysis results showed that cytosolic DNA-sensing pathway was significantly enriched in Oxct1 knockdown cardiomyocytes. Mechanistically, Oxct1 could bind to mitochondrial transcription factor A(Tfam) and increased its succinylation, promoting Tfam degradation. Downregulation of Tfam resulted in ROS production and mtDNA damage, while mtDNA released into cytoplasm could activate Zbp1 and induce cascade reaction of PANoptosis. Conclusion This study demonstrates that Oxct1 promotes Tfam degradation through succinylation, exacerbating ROS production, mtDNA damage and cytoplasmic release, ultimately leading to cardiomyocyte PANoptosis in AMI.

Molecular characterization of PANoptosis-related genes in chronic kidney disease.

Chronic kidney disease (CKD) is characterized by fibrosis and inflammation in renal tissues. Several types of cell death have been implicated in CKD onset and progression. Unlike traditional forms of cell death, PANoptosis is characterized by the crosstalk among programmed cell death pathways. However, the interaction between PANoptosis and CKD remains unclear. Here, we used bioinformatics methods to identify differentially expressed genes and differentially expressed PANoptosis-related genes (DE-PRGs) using data from the GSE37171 dataset. Following this, we further performed gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and gene set enrichment analysis using the data. We adopted a combined approach to select hub genes, using the STRING database and CytoHubba plug-in, and we used the GSE66494 as a validation dataset. In addition, we constructed ceRNA, transcription factor (TF)-gene, and drug-gene networks using Cytoscape. Lastly, we conducted immunohistochemical analysis and western blotting to validate the hub genes. We identified 57 PANoptosis-associated genes as DE-PRGs. We screened nine hub genes from the 57 DE-PRGs. We identified two hub genes (FOS and PTGS2) using the GSE66494 database, Nephroseq, immunohistochemistry, and western blotting. A common miRNA (Hsa-miR-101-3p) and three TFs (CREB1, E2F1, and RELA) may play a crucial role in the onset and progression of PANoptosis-related CKD. In our analysis of the drug-gene network, we identified eight drugs targeting FOS and 52 drugs targeting PTGS2.

The Role and Interactive Mechanism of Endoplasmic Reticulum Stress and Ferroptosis in Musculoskeletal Disorders

Endoplasmic reticulum (ER) stress is a cellular phenomenon that arises in response to the accumulation of misfolded proteins within the ER. This process triggers the activation of a signalling pathway known as the unfolded protein response (UPR), which aims to restore ER homeostasis by reducing protein synthesis, increasing protein degradation, and promoting proper protein folding. However, excessive ER stress can perturb regular cellular function and contribute to the development of diverse pathological conditions. As is well known, ferroptosis is a kind of programmed cell death characterized by the accumulation of lipid peroxides and iron-dependent reactive oxygen species (ROS), resulting in oxidative harm to cellular structures. In recent years, there has been increasing evidence indicating that ferroptosis occurs in musculoskeletal disorders (MSDs), with emerging recognition of the complex relationship between ER stress and ferroptosis. This review presents a summary of ER stress and the ferroptosis pathway. Most importantly, it delves into the significance of ER stress in the ferroptosis process within diverse skeletal or muscle cell types. Furthermore, we highlight the potential benefits of targeting the correlation between ER stress and ferroptosis in treating degenerative MSDs.

One‐Pot Synthesis of [(l‐GluA)‐b‐(PCL)]‐Based Diblock Copolymer and Solvent‐Assisted Multifaceted Capsules as Potential Cargo Payload for Nanomedicines

Abstract This study shows that the synthesis of di‐BCP between amino acid l‐glutamic acid (l‐GluA) and hydrophobic polycaprolactone (PCL) leads to multifunctional and multifaceted capsule formation with different dispersion solvents. Successful synthesis of [(l‐GluA)‐b‐(PCL)] was confirmed by using FTIR and 1H NMR characterizations. For morphological studies, synthesized di‐BCP of [(l‐GluA)‐b‐(PCL)] was dispersed in four different solvents such as acetone, DMSO, IPA, and ethanol and was used for sample preparation for SEM imaging. Interestingly, smooth‐surfaced NPs (defined as type I NPs), rough‐surfaced NPs (type II NPs), porous NPs (type III NPs), and football‐type deep excavation having NPs (defined as type IV NPs). Furthermore, these NPs were characterized through BET, AFM, and DLS for particle size and ζ potential of NPs. LC for types III and IV NPs was calculated to be 1.96% ± 0.01% and 1.92% ± 0.01%, respectively. EE of types III and IV NPs was calculated to be 91% ± 1.5% and 94% ± 1.2%. We used K562 (leukemia blood cancer) and HEK293 (embryonic kidney) cells for in vitro studies. DOX@[(l‐GluA)‐b‐(PCL)] nanoformulation related to types III and IV NPs shows significant early apoptosis that is, 29.17%, which is a remarkable programmed cell death for these porous nanoparticles.

Combination therapy using low-dose anlotinib and immune checkpoint inhibitors for extensive-stage small cell lung cancer.

This study evaluated the efficacy and safety of low-dose anlotinib combined with immune checkpoint inhibitors as second-line or later treatment for extensive-stage small cell lung cancer (ES-SCLC). The study included 42 patients with ES-SCLC who were treated with low-dose anlotinib combined with programmed cell death protein 1/programmed cell death-ligand 1 inhibitors at Henan Cancer Hospital between March 2019 and August 2022. We retrospectively analyzed the efficacy and safety data for these patients. Indicators assessed included progression-free survival (PFS), overall survival (OS), the overall response rate (ORR), the disease control rate (DCR), and adverse events (AEs). Prognostic factors were identified in univariate and multivariate analyses. Median PFS was 11.0 months (95% CI: 7.868-14.132) and median OS was 17.3 months (95% CI: 11.517-23.083). The ORR was 28.5% and the DCR was 95.2%. Treatment-related AEs were noted in 27 patients (64.3%), the most common of which was thyroid dysfunction (26.2%). Grade 3/4 treatment-related AEs were observed in two patients (4.8%). A combination of low-dose anlotinib and immune checkpoint inhibitors as second-line or later treatment for ES-SCLC may achieve longer PFS and OS and have manageable AEs.

A bibliometric and visualization analysis of entosis research from 2007 to 2024

ObjectiveIn 2007, entosis was proposed as a form of programmed cell death, distinct from apoptosis. This process involves a living cell (internalized cell) actively invading a neighboring live cell of the same type (host cell), forming a cell-in-cell structure. Recently, entosis has been increasingly associated with cancer, leading to significant advancements in research. Despite this progress, a comprehensive and unbiased review of the current state of entosis research is lacking. This study aims to evaluate the developments in the field of entosis over the past decade and highlight emerging research trends.Materials and methodsWe performed a literature search for studies published since the introduction of the entosis concept, using the Web of Science Core Collection database. The bibliometric analysis was conducted using VOSviewer, CiteSpace, Microsoft Excel, and the Bibliometrix R package.ResultsA total of 196 articles from 39 countries and 346 institutions were included. Between 2007 and 2024, research on entosis has seen rapid growth, with most publications originating from China and the United States. The United States also leads in total citations, with Memorial Sloan Kettering Cancer Center emerging as the top research institution. Sun Qiang is the most prolific author in this field, while Overholtzer M has the highest number of citations. Current Molecular Medicine has published the most articles related to entosis. Frequently occurring keywords include “entosis,” “cannibalism,” “autophagy,” and “apoptosis.” In recent years, keywords such as “phagocytosis,” “drug resistance,” and “human cancers” have surged, indicating a growing focus on understanding the role of entosis in tumor progression and exploring its potential as a therapeutic target for cancer treatment.ConclusionsThis study provides the first bibliometric analysis of entosis, detailing its evolution over the last decade. It highlights critical areas of interest, including the development of inhibitors targeting entosis and their potential clinical applications. This research aims to guide future investigations and serve as a valuable resource for scholars exploring entosis in cancer biology.

Effects of empagliflozin on myocardial transcriptome in rats with aortic stenosis-induced heart failure

Abstract Introduction Aortic stenosis (AS) represents one of the most prevalent valvular heart diseases and an important cause of heart failure. Currently, no medical therapies influence the natural history of aortic stenosis. Although sodium glucose co-transporter 2 inhibitors (SGLT2i) have improved cardiovascular outcomes in heart failure patients with both reduced and preserved ejection fraction, their action mechanisms are not clear. Transcriptome analysis present great potential to identify biomarkers of disease and to gain insight into disease pathophysiology. In this study, we analyzed myocardial mRNA profile in aortic stenosis rats treated with empagliflozin. Methods Eighteen weeks after supra-aortic banding surgery, male Wistar rats were divided into 3 groups: Sham (n=15); aortic stenosis (AS, n=27); AS+empagliflozin (AS-EMP, n=27). Empagliflozin (10 mg/kg/day) was added to rat chow for 8 weeks. Transcriptome of left ventricle (LV) myocardium was studied by RNA-sequencing (sample size: 5 per group). Differential gene expression was analyzed in R environment using the DESeq2 package. Genes were considered differentially expressed (DEG) when they exhibited a log2 fold change (log2FC) higher than 1 (upregulated) or lower than -1 (downregulated), coupled with an adjusted p-value below 0.05. Functional enrichment analysis using gene ontology was performed by the online tool Enrich. Statistical analysis: ANOVA and Tukey. Results AS-EMP had lower LV diastolic diameter (Sham 8.39±0.57; AS 9.80±0.53*; AS-EMP 9.08±0.87# mm; p<0.05: * vs Sham; # vs AS), left atrium diameter (Sham 5.68±0.40; AS 9.67±1.00*; AS-EMP 8.97±1.36*# mm; p<0.05: * vs Sham; # vs AS), and LV mass (Sham 0.85±0.11; AS 2.19±0.27*; AS-EMP 1.76±0.34*# g; p<0.05: * vs Sham; # vs AS) than AS. A total of 1246 differentially expressed genes were identified, comprising 663 upregulated genes (70 genes in AS vs SHAM; 593 in AS-EMP vs AS) and 583 downregulated genes (35 genes in AS vs SHAM; 548 in AS-EMP vs AS). Most of the differentially expressed genes were enriched in processes such as extracellular matrix and structure organization, signal transduction regulation, and substrate-dependent cell migration (AS vs SHAM), as well as myocardial contraction, negative regulation of programmed cell death, and mitochondrial membrane organization (AS-EMP vs AS). The main upregulated genes were Loxl1, Mfap4, Postn, Col8a1, Pi16, and Nppa in AS vs SHAM; and Mxra8, Zfta, Pnisr, Thoc1, and Ralbp1 in AS-EMP vs AS comparison. The main downregulated genes were Mxra8, Ralbp1, and Tubgcp6 in AS vs SHAM; and Itgb5, Ltbp2, Tmem109, Plec, and Rorc in AS-EMP vs AS comparison. Conclusion We identified myocardial genes and biological processes that are potentially involved in aortic stenosis-induced heart failure. Empagliflozin attenuates cardiac remodeling and modulates myocardial genes involved with myocyte contraction, apoptosis, and mitochondrial organization in aortic stenosis rats.

Advances in immunotherapy for hepatitis B virus associated hepatocellular carcinoma patients.

Hepatitis B virus (HBV) infection plays an important role in the occurrence and development of hepatocellular carcinoma (HCC), and the rate of HBV infection in liver cancer patients in China is as high as 92.05%. Due to long-term exposure to chronic antigens from the gut, the liver needs to maintain a certain level of immune tolerance, both to avoid severe inflammation caused by non-pathogenic antigens and to maintain the possibility of rapid and violent responses to infection and tumors. Therefore, HBV infection interacts with the tumor microenvironment (TME) through a highly complex and intertwined signaling pathway, which results in a special TME in HCC. Due to changes in the TME, tumor cells can evade immune surveillance by inhibiting tumor-specific T cell function through cytotoxic T-lymphocy-associated protein-4 (CTLA-4) and programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1). Interferons, as a class of immune factors with strong biological activity, can improve the TME of HBV-HCC through various pathways. In recent years, the systematic treatment of HCC has gradually come out of the dilemma. In addition to the continuous emergence of new multi-target anti-vascular tyrosine kinase inhibitor drugs, immune checkpoint inhibitors have opened up a new avenue for the systematic treatment of HCC. At present, immunotherapy based on PD-1/L1 inhibitors has gradually become a new direction of systematic treatment for HCC, and the disease characteristics of patients included in global clinical studies are different from those of Chinese patients. Therefore, whether a group of HCC patients with HBV background and poor prognosis in China can also benefit from immunotherapy is an issue of wide concern. This review aims to elucidate the advances of immunotherapy for HBV related HCC patients with regard to: (1) Immunotherapy based on interferons; (2) Immunotherapy based on PD-1/L1 inhibitors; (3) Immunotherapy based on CTLA4 inhibitors; (4) Adoptive cell transfer; (5) Combination immunotherapy strategy; and (6) Shortcomings of immunotherapy.

Sensing of endogenous retroviruses-derived RNA by ZBP1 triggers PANoptosis in DNA damage and contributes to toxic side effects of chemotherapy

Excessive DNA damage triggers various types of programmed cell death (PCD), yet the regulatory mechanism of DNA damage-induced cell death is not fully understood. Here, we report that PANoptosis, a coordinated PCD pathway, including pyroptosis, apoptosis and necroptosis, is activated by DNA damage. The Z-DNA binding protein 1 (ZBP1) is the apical sensor of PANoptosis and essential for PANoptosome assembly in response to DNA damage. We find endogenous retroviruses (ERVs) are activated by DNA damage and act as ligands for ZBP1 to trigger PANoptosis. By using ZBP1 knock-out and knock-in mice disrupting ZBP1 nucleic acid-binding activity, we demonstrate that ZBP1-mediated PANoptosis contributes to the toxic effects of chemotherapeutic drugs, which is dependent on ZBP1 nucleic acid-binding activity. We found that ZBP1 expression is downregulated in tumor tissue. Furthermore, in colorectal cancer patients, dsRNA is induced by chemotherapy and sensed by ZBP1 in normal colonic tissues, suggesting ZBP1-mediated PANoptosis is activated by chemotherapy in normal tissues. Our findings indicate that ZBP1-mediated PANoptosis is activated by DNA damage and contributes to the toxic side effects of DNA-damage-based chemotherapy. These data suggest that ZBP1 could be a promising therapeutic target to alleviate chemotherapy-related side effects.

High Mitophagy and Low Glycolysis Predict Better Clinical Outcomes in Acute Myeloid Leukemias

Acute myeloid leukemia (AML) emerges as one of the most common and fatal leukemias. Treatment of the disease remains highly challenging owing to profound metabolic rewiring mechanisms that confer plasticity to AML cells, ultimately resulting in therapy resistance. Autophagy, a highly conserved lysosomal-driven catabolic process devoted to macromolecular turnover, displays a dichotomous role in AML by suppressing or promoting disease development and progression. Glycolytic metabolism represents a pivotal strategy for AML cells to sustain increasing energy needs related to uncontrolled growth during disease progression. In this study, we tested the hypothesis that a high glycolytic rate and low autophagy flux could represent an advantage for AML cell proliferation and thus be detrimental for patient’s prognosis, and vice versa. TCGA in silico analysis of the AML cohort shows that the high expression of MAP1LC3B (along with that of BECN1 and with low expression of p62/SQSTM1) and the high expression of BNIP3 (along with that of PRKN and of MAP1LC3B), which together are indicative of increased autophagy and mitophagy, correlate with better prognosis. On the other hand, the high expression of glycolytic markers HK2, PFKM, and PKM correlates with poor prognosis. Most importantly, the association of a low expression of glycolytic markers with a high expression of autophagy–mitophagy markers conferred the longest overall survival for AML patients. Transcriptomic analysis showed that this combined signature correlates with the downregulation of a subset of genes required for the differentiation of myeloid cells, lactate/pyruvate transporters, and cell cycle progression, in parallel with the upregulation of genes involved in autophagy/lysosomal trafficking and proteolysis, anti-tumor responses like beta-interferon production, and positive regulation of programmed cell death. Taken together, our data support the view that enhanced autophagy-mitophagy flux together with low glycolytic rate predisposes AML patients to a better clinical outcome, suggesting that autophagy inducers and glucose restrictors may hold potential as adjuvant therapeutics for improving AML management.

Immune checkpoint inhibitor-associated bullous pemphigoid: Aretrospective and real-world study based on the United States Food and Drug Administration adverse event reporting system.

This study aimed to describe bullous pemphigoid (BP) associated with immune checkpoint inhibitors (ICIs) reported in the United States Food and Drug Administration adverse event reporting system (FAERS). We obtained reports of ICI-associated BP from the first quarter of 2011 to the first quarter of 2024 in the FAERS database. The reporting odds ratio (ROR) method of the disproportionality analysis was performed to assess the potential risk for ICI-associated BP. We also described the clinical characteristics of ICI-associated BP and evaluated the time to onset (TTO) of BP developed after treatment with ICIs. Eight hundred and six cases of ICI-associated BP were gathered, in which 56.58% of the patients were aged 65 years or older. The majority of patients were male, accounting for 68.49% of all cases. The prevalent potential cancer type was skin cancer (31.64%). The results of the disproportionality analysis showed that males (ROR = 2.10 [1.78-2.49]), patients aged 65 or older (ROR = 2.13 [1.79-2.55]), and patients with skin cancer (ROR = 2.08 [1.80-2.43]) were more likely to develop ICI-associated BP. In comparison to cytotoxic T-lymphocyte-associated antigen 4 inhibitor and programmed cell death ligand 1 inhibitor, programmed cell death 1 inhibitor-associated BP has a higher risk of development (ROR = 24.45 [22.52-26.56]). ICI-associated BP had a median TTO of 204 days (interquartile range 57-426 days). ICI-associated BP is a rare but important immune-related adverse event. Our study provided helpful information to help medical professionals further understand ICI-associated BP.

Genetic profile of ferroptosis in non-small cell lung carcinoma and pharmaceutical options for ferroptosis induction.

Lung cancer (LC) is the leading cause of cancer-related deaths and the second most commonly diagnosed malignancy worldwide. Lung adenocarcinoma (LUAD) and lung squamous cell LC (LUSCC) are the most common subtypes of non-small cell LC (NSCLC). Early diagnosis of LC can be challenging due to a lack of biomarkers. The overall survival (OS) of patients with NSCLC is still poor despite the enormous efforts that have been made to develop novel treatments. Understanding fundamental molecular and genetic mechanisms is necessary to develop new therapeutic approaches for NSCLC. A recently identified type of programmed cell death known as ferroptosis is one potential approach. Ferroptosis causes oxidative damage and the death of cancerous cells by peroxidizing unsaturated phospholipids and accumulating reactive oxygen species (ROS) in an iron-dependent manner. Ferroptosis-related gene (FRG) signatures have recently been evaluated for their ability to predict patient OS and prognosis. These analyses show FRGs are involved in cancer progression, and may serve as promising biomarkers for tumor diagnosis and therapy. Moreover, we summarize the current pharmaceutical options of ferroptosis induction and their underlying molecular mechanism in LC. Therefore, this review aims to provide a comprehensive summary of FRG-based prognostic models, their associated metabolic and signaling pathways, and promising therapeutic options for ferroptosis induction in NSCLC.

Molecular insights into Solanum sisymbriifolium’s resistance against Globodera pallida via RNA-seq

BackgroundThe presence of potato cyst nematodes (PCN) causes a significant risk to potato crops globally, leading to reduced yields and economic losses. While the plant Solanum sisymbriifolium is known for its resistance to PCN and can be used as a trap crop, the molecular mechanisms behind this resistance remain poorly understood. In this study, genes differentially expressed were identified in control and infected plants during the early stages of the S. sisymbriifolium - G. pallida interaction.ResultsGene expression profiles were characterized for two S. sisymbriifolium cultivars, Melody and Sis6001, uninfected and infected by G. pallida. The comparative transcriptome analysis revealed a total of 4,087 and 2,043 differentially expressed genes (DEGs) in response to nematode infection in the cultivars Melody and Sis6001, respectively. Gene ontology (GO) enrichment analysis provided insights into the response of the plant to nematode infection, indicating an activation of the plant metabolism, oxidative stress leading to defence mechanism activation, and modification of the plant cell wall. Genes associated with the jasmonic and salicylic acid pathways were also found to be differentially expressed, suggesting their involvement in the plant’s defence response. In addition, the analysis of NBS-LRR domain-containing transcripts that play an important role in hypersensitive response and programmed cell death led to the identification of ten transcripts that had no annotations from the databases, with emphasis on TRINITY_DN52667_C1_G1, found to be upregulated in both cultivars.ConclusionsThese findings represent an important step towards understanding the molecular basis underlying plant resistance to nematodes and facilitating the development of more effective control strategies against PCN.

Cytochalasin H enhances sensitivity to gefitinib in non-small-cell lung cancer cells through inhibiting EGFR activation and PD-L1 expression

In our previous study, we have isolated cytochalasin H (CyH) from endophytic fungus derived from mangrove plant and found that CyH inhibited the proliferation of non-small cell lung cancer (NSCLC) cells. Recently, epidermal growth factor receptor (EGFR) activation and programmed cell death 1 ligand (PD-L1) expression have been demonstrated to mediate NSCLC resistance to gefitinib, first-generation EGFR tyrosine kinase inhibitor (EGFR-TKI). Here, we further investigated the effect of CyH on EGFR activation, PD-L1 expression, and gefitinib sensitivity in NSCLC cell lines, A549 (wild-type EGFR), HCC827 (EGFR mutation), and NCI-H1975 (dual EGFR mutations and acquired gefitinib resistance) and animal model. Our results showed that CyH significantly inhibited EGFR activation and PD-L1 expression in NSCLC cells. Additionally, CyH dramatically promoted the inhibitory effect of gefitinib on the proliferation of A549 and HCC827 cells, and enhanced the sensitivity to gefitinib in NCI-H1975 cells. Moreover, CyH increased the inhibitory effect of gefitinib on EGFR activation and PD-L1 expression in HCC827 and NCI-H1975 cells. Animal experiments further demonstrated that CyH significantly promoted the inhibitory effect of gefitinib on the growth of NSCLC and the expression of Ki-67, p-EGFR, and PD-L1 in NCI-H1975 NSCLC xenograft tumors of nude mice. Furthermore, CyH inhibited the activation of JAK3/STAT signaling pathway. Taken together, our findings suggest that CyH promotes the sensitivity to gefitinib in NSCLC cells through the inhibition of EGFR activation and PD-L1 expression.

In vivo imaging of ferroptosis through nanodynamic changes in lipid membranes.

Ferroptosis emerged as a cell death modality for drug resistant cancer cells, but there are currently no available biomarkers for imaging ferroptosis based therapies. To address this gab, we evaluated the nanodynamic changes in lipid membranes occurring during cell death to explore potential targeting opportunities to image cell death. We nano-sized gaps at late stages of ferroptosis can serve as entry points for dyes that can bind to cellular structures. These changes were accompanied with cellular signaling components similar to platelet activation, with phosphatidyl serine emerging on the surface of the cells and therefore as a potential target for imaging of programed cell death, including ferroptosis. Taking advantage of these changes in cell membrane dynamics, we employed a novel tumor-seeking dye CJ215 that can label apoptotic cells as recently described by us. We show that CJ215 accumulates in ferroptotic cells both in vitro and in vivo by binding to phosphatidyl serine, a process that is prevented by inhibition of ferroptosis. Since phosphatidyl serine exposure also occurs during apoptosis, CJ215 can serve to image both apoptosis and ferroptosis based therapy.

High PD-1 and CTLA-4 expression correlates with host immune suppression in patients and a mouse model infected with Echinococcus multilocularis

BackgroundAlveolar echinococcosis (AE), a fatal disease caused by Echinococcus multilocularis, often affects the liver, with tumor-like growth. However, the mechanism by which E. multilocularis evades host immune surveillance remains unclear.MethodsWe collected liver specimens from hepatic alveolar echinococcosis (HAE) patients and established a mouse model of E. multilocularis infection. Immunofluorescence staining and flow cytometry were performed to analyze programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte associated antigen 4 (CTLA-4) expression in human samples, while flow cytometry and quantitative real-time polymerase chain reaction (PCR) were performed for similar analyses in mouse samples. Cell proliferation and protoscolex (PSC) killing assays were designed to explore how E. multilocularis induces host immunosuppression.ResultsAn inflammatory reaction band with high PD-1 and CTLA-4 expression was found in close liver tissue (CLT). The ratio of regulatory T cells (Tregs) was higher in CLT than in distant liver tissue (DLT), and Tregs in CLT tended to express higher levels of PD-1 and CTLA-4 than those in DLT from HAE patients. Echinococcus multilocularis-infected mice showed significantly elevated expression of PD-1 and CTLA-4 on splenocytes and peritoneal cells. PD-1/PD-L1 or CTLA-4 pathway blockade could relieve the immunosuppressive effects of Tregs from infected mice and enhance PSC killing by mouse splenocytes.ConclusionsE. multilocularis regulated the function of T cells via the PD-1/PD-L1- and CTLA-4-dependent pathways and subsequently evaded host immune attacks. These findings provide insights for investigating the pathogenic mechanism of AE.Graphical

A Narrative Review of the Clinical, Humanistic, and Economic Value of Pembrolizumab-Based Immunotherapy for the Treatment of Breast and Gynecologic Cancers.

Breast and gynecologic cancers are common across the world and are associated with substantial societal and economic burden. Pembrolizumab was among the first immune checkpoint inhibitors targeting programmed cell death protein1 to be approved for the treatment of patients with triple-negative breast cancer, cervical cancer, and endometrial cancer. Recent clinical trials have established pembrolizumab regimens as a standard of care treatment for these tumor types. Clinical data are further supported by patient-reported outcome, cost-effectiveness, and real-world evidence. Pembrolizumab monotherapy and combination regimens do not negatively influence health-related quality of life and are cost-effective relative to comparators. Ongoing phase3 studies with pembrolizumab will expand the current understanding of its use in breast and gynecologic cancers. Several of these studies are in patients with early-stage disease with the hope of curing patients. The main objective of this review is to summarize the clinical, humanistic, and economic value of pembrolizumab in these settings and to describe the future challenges for patients, caregivers, clinicians, and payers.

T-Cell Phenotypes and Systemic Cytokine Profiles of People Living with HIV Admitted to Hospital with COVID-19

Whether SARS-CoV-2 infection leads to a higher mortality and morbidity in people living with HIV (PLWH) in Africa remains inconclusive. In this study, we explored the differences in the T-cell phenotypes between people with and without HIV on the day of admission (V1) and ±7 days later (V2), as well as their cytokine/chemokine profiles on V1. Patients admitted with COVID-19 were recruited between May 2020 and December 2021 from the Steve Biko Academic and Tshwane District Hospitals in Pretoria, South Africa. Of 174 patients, 37 (21%) were PLWH. T-cell profiles were determined by flow cytometry, and cytokine levels were determined using a multiplex suspension bead array. PLWH were significantly younger than those without HIV, and were more likely to be female. In an adjusted analysis, PLWH had higher percentages of CD4+ central memory (CM) programmed cell death protein 1 (PD-1)+, CD8+ effector memory (EM)2, and CD8+ EM4 CD57+ cells, as well as higher concentrations of interleukin (IL)-35 at admission. PLWH with CD4+ T-cell counts of >200 cells/mm3 had altered CD4+ and CD8+ T-cell profiles, lower levels of systemic inflammation measured by plasma ferritin and PCT levels, and less severe disease. PLWH with CD4+ T-cell counts of <200 cells/mm3 on admission had higher concentrations of IL-6 and lower levels of IL-29. At V2, the percentages of CD4+ CM PD-1+ T-cells and CD8+ EM4 T-cells co-expressing CD57 and PD-1 remained higher in PLWH, while all other CD8+ EM populations were lower. Fewer CD8+ EM T-cells after ±7 days of admission may be indicative of mechanisms inhibiting EM T-cell survival, as indicated by the higher expression of IL-35 and the T-cell maturation arrest observed in PLWH. This profile was not observed in PLWH with severe immunodeficiency, highlighting the need for differentiated care in the broader PLWH population.