Overexpression of low-density lipoprotein receptor prevents neurotoxic polarization of astrocytes via inhibiting NLRP3 inflammasome activation in experimental ischemic stroke.

JOURNAL/nrgr/04.03/01300535-202502000-00027/figure1/v/2024-05-28T214302Z/r/image-tiff Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury. Low-density lipoprotein receptor, a classic cholesterol regulatory receptor, has been found to inhibit NLR family pyrin domain containing protein 3 (NLRP3) inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer's disease. However, little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke. To address this issue in the present study, we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models. First, we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis. We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation. Second, we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus. Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype. Finally, we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin, an NLRP3 agonist, restored the neurotoxic astrocyte phenotype. These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.

Polystyrene microplastics exacerbated the toxicity of okadaic acid to the small intestine in mice.

Microplastics (MPs) and okadaic acid (OA) are known to coexist in marine organisms, potentially impacting humans through food chain. However, the combined toxicity of OA and MPs remains unknown. In this study, mice were orally administered OA at 200 µg/kg bw and MPs at 2 mg/kg bw. The co-exposure group showed a significant increase in malondialdehyde (MDA) content and significant decreases in superoxide dismutase (SOD) activity and glutathione (GSH) level compared to the control, MPs and OA groups (p < 0.05). Additionally, the co-exposure group exhibited significantly higher levels of IL-1ß and IL-18 compared to other groups (p < 0.05). These results demonstrated that co-exposure to MPs and OA induces oxidative stress and exacerbates inflammation. Histological and cellular ultrastructure analyses suggested that this combined exposure may enhance gut damage and compromise barrier integrity. Consequently, the concentration of OA in the small intestine of the co-exposure group was significantly higher than that in the OA group. Furthermore, MPs were observed in the lamina propria of the gut in the co-exposure group. Transcriptomic analysis revealed that the co-exposure led to increased expression of certain genes related to the NF-κB/NLRP3 pathway compared to the OA and MPs groups. Overall, this combined exposure may disrupt the intestinal barrier, and promote inflammation through the NF-κB/NLRP3 pathway. These findings provide precious information for the understanding of health risks associated with MPs and phycotoxins.

Generation and transcriptomic characterization of MIR137 knockout miniature pig model for neurodevelopmental disorders.

BACKGROUND: Neurodevelopmental disorders (NDD), such as autism spectrum disorders (ASD) and intellectual disorders (ID), are highly debilitating childhood psychiatric conditions. Genetic factors are recognized as playing a major role in NDD, with a multitude of genes and genomic regions implicated. While the functional validation of NDD-associated genes has predominantly been carried out using mouse models, the significant differences in brain structure and gene function between mice and humans have limited the effectiveness of mouse models in exploring the underlying mechanisms of NDD. Therefore, it is important to establish alternative animal models that are more evolutionarily aligned with humans. RESULTS: In this study, we employed CRISPR/Cas9 and somatic cell nuclear transplantation technologies to successfully generate a knockout miniature pig model of the MIR137 gene, which encodes the neuropsychiatric disorder-associated microRNA miR-137. The homozygous knockout of MIR137 (MIR137-/-) effectively suppressed the expression of mature miR-137 and led to the birth of stillborn or short-lived piglets. Transcriptomic analysis revealed significant changes in genes associated with neurodevelopment and synaptic signaling in the brains of MIR137-/- miniature pig, mirroring findings from human ASD transcriptomic data. In comparison to miR-137-deficient mouse and human induced pluripotent stem cell (hiPSC)-derived neuron models, the miniature pig model exhibited more consistent changes in critical neuronal genes relevant to humans following the loss of miR-137. Furthermore, a comparative analysis identified differentially expressed genes associated with ASD and ID risk genes in both miniature pig and hiPSC-derived neurons. Notably, human-specific miR-137 targets, such as CAMK2A, known to be linked to cognitive impairments and NDD, exhibited dysregulation in MIR137-/- miniature pigs. These findings suggest that the loss of miR-137 in miniature pigs affects genes crucial for neurodevelopment, potentially contributing to the development of NDD. CONCLUSIONS: Our study highlights the impact of miR-137 loss on critical genes involved in neurodevelopment and related disorders in MIR137-/- miniature pigs. It establishes the miniature pig model as a valuable tool for investigating neurodevelopmental disorders, providing valuable insights for potential applications in human research.

Jnk1 and downstream signalling hubs regulate anxiety-like behaviours in a zebrafish larvae phenotypic screen.

Current treatments for anxiety and depression show limited efficacy in many patients, indicating the need for further research into the underlying mechanisms. JNK1 has been shown to regulate anxiety- and depressive-like behaviours in mice, however the effectors downstream of JNK1 are not known. Here we compare the phosphoproteomes from wild-type and Jnk1-/- mouse brains and identify JNK1-regulated signalling hubs. We next employ a zebrafish (Danio rerio) larvae behavioural assay to identify an antidepressant- and anxiolytic-like (AA) phenotype based on 2759 measured stereotypic responses to clinically proven antidepressant and anxiolytic (AA) drugs. Employing machine learning, we classify an AA phenotype from extracted features measured during and after a startle battery in fish exposed to AA drugs. Using this classifier, we demonstrate that structurally independent JNK inhibitors replicate the AA phenotype with high accuracy, consistent with findings in mice. Furthermore, pharmacological targeting of JNK1-regulated signalling hubs identifies AKT, GSK-3, 14-3-3 ζ/ε and PKCε as downstream hubs that phenocopy clinically proven AA drugs. This study identifies AKT and related signalling molecules as mediators of JNK1-regulated antidepressant- and anxiolytic-like behaviours. Moreover, the assay shows promise for early phase screening of compounds with anti-stress-axis properties and for mode of action analysis.

Clinical study on treatment of cervical spondylotic radiculopathy (Qi stagnation and blood stasis syndrome) with Gao's nape needle and Shentong Zhuyu decoction.

BACKGROUND: Cervical spondylotic radiculopathy is currently one of the common orthopedic diseases, mainly characterized by neck pain, stiffness, limited mobility, and related symptoms of nerve root compression, which seriously troubles people's work and life. METHODS: Ninety cases of cervical spondylotic radiculopathy (Qi stagnation and blood stasis syndrome) were randomly divided into treatment group and control group, 45 cases in each group. The control group was treated with western medicine (nerve nutrition, pain relief, and circulation improvement drugs), and the treatment group was treated with Gao's nape needle combined with modified Shentong Zhuyu decoction on the basis of the control group. Before and after 2 weeks, TCM syndrome score, TCM curative effect, visual analogue scale score, numbness score, neck disability index score, related serum inflammatory factors (interleukin-10 [IL-10], interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α]), related hemorheological indexes (plasma viscosity, high shear whole blood viscosity, low shear whole blood viscosity level) were used as evaluation indexes to evaluate the effect. RESULTS: After treatment, the total effective rate of the treatment group was 91.11%, which was better than that of the control group (78.78%), and the TCM syndrome scores of the 2 groups were decreased, the treatment group was better than that of the control group, and the differences were statistically significant (P < .05). After treatment, the visual analogue scale score, numbness score, and neck disability index score were decreased in both groups, and the decrease in the treatment group was more significant than that in the control group, and the differences were statistically significant (P < .05). After treatment, the related serum inflammatory factors (IL-10, IL-6, TNF-α) and related hemorheological indexes (plasma viscosity, high-shear whole blood viscosity, low-shear whole blood viscosity) were decreased in both groups, and the decrease in the treatment group was more significant than that in the control group, and the differences were statistically significant (P < .05). CONCLUSION: The treatment of cervical spondylotic radiculopathy (Qi stagnation and blood stasis syndrome) with Gao's nape needle and modified Shentong Zhuyu decoction can improve the curative effect of traditional Chinese medicine, improve the related discomfort symptoms (neck tenderness, adverse activity, numbness, etc), improve the neck function, reduce IL-10, IL-6, TNF-α, and other related serum inflammatory factors, and improve hemorheological indicators.

Investigating the impact of protein S-sulfhydration modification on vascular diseases: A comprehensive review.

The post-translational modification of cysteine through redox reactions, especially S-sulfhydration, plays a critical role in regulating protein activity, interactions, and spatial arrangement. This review focuses on the impact of protein S-sulfhydration on vascular function and its implications in vascular diseases. Dysregulated S-sulfhydration has been linked to the development of vascular pathologies, including aortic aneurysms and dissections, atherosclerosis, and thrombotic diseases. The H2S signaling pathway and the enzyme cystathionine γ-lyase (CSE), which is responsible for H2S generation, are identified as key regulators of vascular function. Additionally, potential therapeutic targets for the treatment of vascular diseases, such as the H2S donor GYY4137 and the HDAC inhibitor entinostat, are discussed. The review also emphasizes the antithrombotic effects of H2S in regulating platelet aggregation and thrombosis. The aim of this review is to enhance our understanding of the function and mechanism of protein S-sulfhydration modification in vascular diseases, and to provide new insights into the clinical application of this modification.

Mechanistic insights into the effects of diuron exposure on Alexandrium pacificum.

Diuron (N-(3,4-dichlorophenyl)-N,N­dimethylurea, DCMU), a ureic herbicide, is extensively used in agriculture to boost crop productivity; however, its extensive application culminates in notable environmental pollution, especially in aquatic habitats. Therefore, the present study investigated the effect of diuron on the dinoflagellate Alexandrium pacificum, which is known to induce harmful algal blooms (HAB), and its potential to biodegrade DCMU. Following a four-day DCMU exposure, our results revealed that A. pacificum proficiently assimilated DCMU at concentrations of 0.05 mg/L and 0.1 mg/L in seawater, attaining a complete reduction (100 % efficiency) after 96 h for both concentrations. Moreover, evaluations of paralytic shellfish toxins content indicated that cells subjected to higher DCMU concentrations (0.1 mg/L) exhibited reductions of 73.4 %, 86.7 %, and 75 % in GTX1, GTX4, and NEO, respectively. Exposure to DCMU led to a notable decrease in A. pacificum's photosynthetic efficacy, accompanied by increased levels of reactive oxygen species (ROS) and suppressed cell growth, with a growth inhibition rate of 41.1 % at 72 h. Proteomic investigations pinpointed the diminished expression levels of specific proteins like SxtV and SxtW, linked to paralytic shellfish toxins (PSTs) synthesis, as well as key proteins associated with Photosystem II, namely PsbA, PsbD, PsbO, and PsbU. Conversely, proteins central to the cysteine biosynthesis pathways exhibited enhanced expression. In summary, our results preliminarily resolved the molecular mechanisms underlying the response of A. pacificum to DCMU and revealed that DCMU affected the synthesis of PSTs. Meanwhile, our data suggested that A. pacificum has great potential in scavenging DCMU.

The dual HDAC and PI3K inhibitor, CUDC­907, inhibits tumor growth and stem­like properties by suppressing PTX3 in neuroblastoma.

Neuroblastoma (NB) is one of the common solid tumors in childhood and poses a threat to the lives of children. Patients with advanced­stage or recurrent NB have a poor prognosis. CUDC­907, as a novel dual­target inhibitor of histone deacetylase (HDAC) and phosphatidylinositol­3­kinase (PI3K), has been proven to play an antitumor role in several types of tumors. However, the exact role of CUDC­907 in NB remains unclear. In the present study, in vivo and in vitro assays were performed to investigate the anti­NB activity of CUDC­907. Pentraxin 3 (PTX3) small interfering RNA (siRNA) and PTX3 overexpression plasmid were transfected into cells to define the underlying mechanisms of CUDC­907. Tumor tissues and clinical information were collected and immunohistochemistry (IHC) was conducted to analyze the association between the expression of HDAC1, HDAC2, HDAC3 and CD44, and the prognosis of patients with NB. The results indicated that CUDC­907 significantly inhibited the proliferation and migration, and induced the apoptosis of NB cells, downregulating the expression level of MYCN, and suppressing the PI3K/AKT and MAPK/ERK pathways. Furthermore, CUDC­907 suppressed the stem­like properties of NB cells by inhibiting PTX3, a ligand and upstream protein of CD44. IHC revealed that the high expression of HDAC1, 2, 3 and CD44 was associated with a poor prognosis of patients with NB. On the whole, these findings indicate that CUDC­907 may be developed into a possible therapeutic approach for patients with NB.

PD-L1-expressing natural killer cells predict favorable prognosis and response to PD-1/PD-L1 blockade in neuroblastoma.

T/NK cell-based immunotherapy has achieved remarkable success in adult cancers but has limited efficacy in pediatric malignancies including high-risk neuroblastoma (NB). Immune defects of NB tumor microenvironment are poorly understood compared with adults. Here, we described the unique characteristics of NB immune contexture and determined the phenotype signatures of PD-L1-expressing CD8+ T and NK cells in NB tumors by systemically analyzing the spatial distribution of T and NK cells and the distinct expression of programmed death 1 (PD-1) and its ligand (PD-L1) in patients with NB. We found that PD-L1-expressing CD8+ T and NK cells in NB tumors were highly activated and functionally competent and associated with better clinical outcomes. Intratumoral NK cells were a favorable prognostic biomarker independent of CD8+ T cells, PD-1/PD-L1 expression, tumor stage, MYCN amplification, and risk classification. NK cells combined with anti-PD-1/PD-L1 antibodies showed potent antitumor activity against both MYCN-amplified and non-amplified NBs in vitro and in vivo, and PD-L1-expressing NK cells associated with improved antitumor efficacy. Collectively, we raise novel insights into the role of PD-L1 expression on CD8+ T-cell and NK-cell activation. We highlight the great potential of intratumoral NK cells in better defining risk stratification, and predicting survival and response to anti-PD-1/PD-L1 therapy in NB. These findings explain why single anti-PD-1/PD-L1 therapy may not be successful in NB, suggesting its combination with NK cell-adoptive cellular therapy as a promising strategy for relapsing/refractory NB. This study provides a potential prospect that patients with PD-L1-expressing NK cells may respond to anti-PD-1/PD-L1 therapy.

BLCA prognostic model creation and validation based on immune gene-metabolic gene combination.

BACKGROUND: Bladder cancer (BLCA) is a prevalent urinary system malignancy. Understanding the interplay of immunological and metabolic genes in BLCA is crucial for prognosis and treatment. METHODS: Immune/metabolism genes were extracted, their expression profiles analyzed. NMF clustering found prognostic genes. Immunocyte infiltration and tumor microenvironment were examined. Risk prognostic signature using Cox/LASSO methods was developed. Immunological Microenvironment and functional enrichment analysis explored. Immunotherapy response and somatic mutations evaluated. RT-qPCR validated gene expression. RESULTS: We investigated these genes in 614 BLCA samples, identifying relevant prognostic genes. We developed a predictive feature and signature comprising 7 genes (POLE2, AHNAK, SHMT2, NR2F1, TFRC, OAS1, CHKB). This immune and metabolism-related gene (IMRG) signature showed superior predictive performance across multiple datasets and was independent of clinical indicators. Immunotherapy response and immune cell infiltration correlated with the risk score. Functional enrichment analysis revealed distinct biological pathways between low- and high-risk groups. The signature demonstrated higher prediction accuracy than other signatures. qRT-PCR confirmed differential gene expression and immunotherapy response. CONCLUSIONS: The model in our work is a novel assessment tool to measure immunotherapy's effectiveness and anticipate BLCA patients' prognosis, offering new avenues for immunological biomarkers and targeted treatments.

Assessment of the Adverse Health Effects of Aflatoxin Exposure from Unpackaged Peanut Oil in Guangdong, China.

Aflatoxins are liver carcinogens and are common contaminants in unpackaged peanut (UPP) oil. However, the health risks associated with consuming aflatoxins in UPP oil remain unclear. In this study, aflatoxin contamination in 143 UPP oil samples from Guangdong Province were assessed via liquid chromatography-tandem mass spectrometry (LC-MS). We also recruited 168 human subjects, who consumed this oil, to measure their liver functions and lipid metabolism status. Aflatoxin B1 (AFB1) was detected in 79.72% of the UPP oil samples, with levels ranging from 0.02 to 174.13 µg/kg. The average daily human intake of AFB1 from UPP oil was 3.14 ng/kg·bw/day; therefore, the incidence of liver cancer, caused by intake of 1 ng/kg·bw/day AFB1, was estimated to be 5.32 cases out of every 100,000 persons per year. Meanwhile, Hepatitis B virus (HBV) infection and AFB1 exposure exerted a synergistic effect to cause liver dysfunction. In addition, the triglycerides (TG) abnormal rate was statistically significant when using AFB1 to estimate daily intake (EDI) quartile spacing grouping (p = 0.011). In conclusion, high aflatoxin exposure may exacerbate the harmful effects of HBV infection on liver function. Contamination of UPP oil with aflatoxins in Guangdong urgently requires more attention, and public health management of the consumer population is urgently required.

Systematic dissection of genomic features determining the vast diversity of conotoxins.

BACKGROUND: Conus, a highly diverse species of venomous predators, has attracted significant attention in neuroscience and new drug development due to their rich collection of neuroactive peptides called conotoxins. Recent advancements in transcriptome, proteome, and genome analyses have facilitated the identification of conotoxins within Conus' venom glands, providing insights into the genetic features and evolutionary patterns of conotoxin genes. However, the underlying mechanism behind the extraordinary hypervariability of conotoxins remains largely unknown. RESULTS: We analyzed the transcriptomes of 34 Conus species, examining various tissues such as the venom duct, venom bulb, and salivary gland, leading to the identification of conotoxin genes. Genetic variation analysis revealed that a subset of these genes (15.78% of the total) in Conus species underwent positive selection (Ka/Ks > 1, p < 0.01). Additionally, we reassembled and annotated the genome of C. betulinus, uncovering 221 conotoxin-encoding genes. These genes primarily consisted of three exons, with a significant portion showing high transcriptional activity in the venom ducts. Importantly, the flanking regions and adjacent introns of conotoxin genes exhibited a higher prevalence of transposon elements, suggesting their potential contribution to the extensive variability observed in conotoxins. Furthermore, we detected genome duplication in C. betulinus, which likely contributed to the expansion of conotoxin gene numbers. Interestingly, our study also provided evidence of introgression among Conus species, indicating that interspecies hybridization may have played a role in shaping the evolution of diverse conotoxin genes. CONCLUSIONS: This study highlights the impact of adaptive evolution and introgressive hybridization on the genetic diversity of conotoxin genes and the evolution of Conus. We also propose a hypothesis suggesting that transposable elements might significantly contribute to the remarkable diversity observed in conotoxins. These findings not only enhance our understanding of peptide genetic diversity but also present a novel approach for peptide bioengineering.

Glioblastoma cellular MAP4K1 facilitates tumor growth and disrupts T effector cell infiltration.

MAP4K1 has been identified as a cancer immunotherapy target. Whether and how cancer cell-intrinsic MAP4K1 contributes to glioblastoma multiforme (GBM) progression remains unclear. We found that MAP4K1 was highly expressed in the glioma cells of human GBM specimens. High levels of MAP4K1 mRNA were prevalent in IDH-WT and 1p/19q non-codeletion gliomas and correlated with poor prognosis of patients. MAP4K1 silencing inhibited GBM cell proliferation and glioma growth. Transcriptome analysis of GBM cells and patient samples showed that MAP4K1 modulated cytokine‒cytokine receptor interactions and chemokine signaling pathway, including IL-18R and IL-6R Importantly, MAP4K1 loss down-regulated membrane-bound IL-18R/IL-6R by inhibiting the PI3K-AKT pathway, whereas MAP4K1 restoration rescued this phenotype and therefore GBM cell proliferation. MAP4K1 deficiency abolished GBM cell pro-proliferation responses to IL-18, suggesting an oncogenic role of MAP4K1 via the intrinsic IL-18/IL-18R pathway. In addition, GBM cell-derived MAP4K1 impaired T-cell migration and reduced CD8+ T-cell infiltration in mouse glioma models. Together, our findings provide novel insight into the pathological significance of GBM cell-intrinsic MAP4K1 in driving tumor growth and immune evasion by remodeling cytokine-chemokine networks.

Caenorhabditis elegans NSE3 homolog (MAGE-1) is involved in genome stability and acts in inter-sister recombination during meiosis.

Melanoma antigen (MAGE) genes encode for a family of proteins that share a common MAGE homology domain. These genes are conserved in eukaryotes and have been linked to a variety of cellular and developmental processes including ubiquitination and oncogenesis in cancer. Current knowledge on the MAGE family of proteins mainly comes from the analysis of yeast and human cell lines, and their functions have not been reported at an organismal level in animals. Caenorhabditis elegans only encodes 1 known MAGE gene member, mage-1 (NSE3 in yeast), forming part of the SMC-5/6 complex. Here, we characterize the role of mage-1/nse-3 in mitosis and meiosis in C. elegans. mage-1/nse-3 has a role in inter-sister recombination repair during meiotic recombination and for preserving chromosomal integrity upon treatment with a variety of DNA-damaging agents. MAGE-1 directly interacts with NSE-1 and NSE-4. In contrast to smc-5, smc-6, and nse-4 mutants which cause the loss of NSE-1 nuclear localization and strong cytoplasmic accumulation, mage-1/nse-3 mutants have a reduced level of NSE-1::GFP, remnant NSE-1::GFP being partially nuclear but largely cytoplasmic. Our data suggest that MAGE-1 is essential for NSE-1 stability and the proper functioning of the SMC-5/6 complex.

Downregulation of DNA methylation enhances differentiation of THP-1 cells and induces M1 polarization of differentiated macrophages.

DNA methylation is an epigenetic modification that regulates gene expression and plays an essential role in hematopoiesis. UHRF1 and DNMT1 are both crucial for regulating genome-wide maintenance of DNA methylation. Specifically, it is well known that hypermethylation is crucial characteristic of acute myeloid leukemia (AML). However, the mechanism underlying how DNA methylation regulates the differentiation of AML cells, including THP-1 is not fully elucidated. In this study, we report that UHRF1 or DNMT1 depletion enhances the phorbol-12-myristate-13-acetate (PMA)-induced differentiation of THP-1 cells. Transcriptome analysis and genome-wide methylation array results showed that depleting UHRF1 or DNMT1 induced changes that made THP-1 cells highly sensitive to PMA. Furthermore, knockdown of UHRF1 or DNMT1 impeded solid tumor formation in xenograft mouse model. These findings suggest that UHRF1 and DNMT1 play a pivotal role in regulating differentiation and proliferation of THP-1 cells and targeting these proteins may improve the efficiency of differentiation therapy in AML patients.

Nickel-Ion Activating Discarded COVID-19 Medical Surgical Masks for Forming Carbon-Nickel Composite Nanowires and Using as a High-Performance Lithium Battery Anode.

With the prevalence of COVID-19, wearing medical surgical masks has become a requisite measure to protect against the invasion of the virus. Therefore, a huge amount of discarded medical surgical masks will be produced, which will become a potential hazard to pollute the environment and endanger the health of organisms without our awareness. Herein, a green and cost-effective way for the reasonable disposal of waste masks becomes necessary. In this work, we realized the transformation from waste medical surgical masks into high-quality carbon-nickel composite nanowires, which not only benefit the protection of the environment and ecosystem but also contribute to the realization of economic value. The obtained composite carbon-based materials demonstrate 70 S m-1 conductivity, 5.2 nm average pore diameters, 234 m2 g-1 surface areas, and proper graphitization degree. As an anode material for lithium-ion batteries, the prepared carbon composite materials demonstrate a specific capacity of 420 mA h g-1 after 800 cycles at a current density of 0.2 A g-1. It also displays good rate performance and decent cycling stability. Therefore, this study provides an approach to converting the discarded medical surgical masks into high-quality carbon nanowire anode materials to turn waste into treasure.

Silencing of FAM111B inhibited proliferation, migration and invasion of hepatoma cells through activating p53 pathway.

BACKGROUND: The function of Family with sequence similarity 111 member B (FAM111B) has been reported in multiple malignancies, but its involvement in occurrence and development of hepatocellular carcinoma (HCC) is still unclear. PURPOSE: To investigate the role of FAM111B in HCC and explore the potential molecular mechanism. METHODS: We examined the mRNA level of FAM111B via qPCR and protein level via immunohistochemistry in human HCC tissues. siRNA was used to construct a FAM111B-knockdown model in HCC cell lines. CCK-8, colony formation, transwell, and wound healing assays were performed to investigate the effect of FAM111B on proliferation, migration and invasion of HCC cell. Gene Set Enrichment Analysis, western blotting, and flow cytometry were carried out to find the related molecular mechanism. RESULTS: Human HCC tumor tissues exhibited higher expression of FAM111B, and high FAM111B expression was associated with poor prognosis. Vitro assays demonstrated that knockdown of FAM111B greatly repressed proliferation, migration and invasion of HCC cells. Furthermore, silencing of FAM111B significantly resulted in cell cycle arrest at G0/G1 and downregulation of epithelial-mesenchymal transition (EMT)-related proteins MMP7 and MMP9 via activation of p53 pathway. CONCLUSION: FAM111B played an essential role in promoting HCC development by regulation of p53 pathway.

A Pan-Cancer Analysis of Prognostic and Immunological Roles for Cell Death Genes.

The dysregulation of cell death is closely associated with the development, progression, tumor microenvironment (TME), and prognosis of cancer. However, there is no study that comprehensively explores the prognostic and immunological role of cell death in human pan-cancer. We used published human pan-cancer RNA-sequencing and clinical data to explore the prognostic and immunological roles of programmed cell death, which included apoptosis, autophagy, ferroptosis, necroptosis, and pyroptosis. A total of 9925 patients were included for bioinformatic analysis, with 6949 and 2976 patients in the training cohort and validation cohort, respectively. Five-hundred and ninety-nine genes were defined as programmed-cell-death-related genes. In the training cohort, 75 genes were identified to define PAGscore by survival analysis. According to the median value of PAGscore, patients were divided into high- and low-risk groups, and subsequent analyses demonstrated that the high-risk group had a higher level of genomic mutation frequency, hypoxia score, immuneScore, expression of immune genes, activity of malignant signaling pathways, and cancer immunity cycle. Most anti-tumor and pro-tumor components of the TME showed greater activity in high-risk patients. Scores of malignant cell properties were also higher in high-risk patients. These findings were confirmed in the validation cohort and external cohort. Our study constructed a reliable gene signature to distinguish prognosis-favorable and prognosis-unfavorable patients and demonstrated that cell death was significantly associated with cancer prognosis and the TME.

Lipocalin-2-mediated astrocyte pyroptosis promotes neuroinflammatory injury via NLRP3 inflammasome activation in cerebral ischemia/reperfusion injury.

BACKGROUND: Neuroinflammation is a vital pathophysiological process during ischemic stroke. Activated astrocytes play a major role in inflammation. Lipocalin-2 (LCN2), secreted by activated astrocytes, promotes neuroinflammation. Pyroptosis is a pro-inflammatory form of programmed cell death that has emerged as a new area of research in stroke. Nevertheless, the potential role of LCN2 in astrocyte pyroptosis remains unclear. METHODS: An ischemic stroke model was established by middle cerebral artery occlusion (MCAO) in vivo. In this study, in vitro, oxygen-glucose deprivation and reoxygenation (O/R) were applied to cultured astrocytes. 24p3R (the LCN2 receptor) was inhibited by astrocyte-specific adeno-associated virus (AAV-GFAP-24p3Ri). MCC950 and Nigericin sodium salt (Nig) were used to inhibit or promote the activation of NLRP3 inflammasome pharmacologically, respectively. Histological and biochemical analyses were performed to assess astrocyte and neuron death. Additionally, the neurological deficits of mice were evaluated. RESULTS: LCN2 expression was significantly induced in astrocytes 24 h after stroke onset in the mouse MCAO model. Lcn2 knockout (Lcn2-/-) mice exhibited reduced infarct volume and improved neurological and cognitive functions after MCAO. LCN2 and its receptor 24p3R were colocalized in astrocytes. Mechanistically, suppression of 24p3R by AAV-GFAP-24p3Ri alleviated pyroptosis-related pore formation and the secretion of pro-inflammatory cytokines via LCN2, which was then reversed by Nig-induced NLRP3 inflammasome activation. Astrocyte pyroptosis was exacerbated in Lcn2-/- mice by intracerebroventricular administration of recombinant LCN2 (rLCN2), while this aggravation was restricted by blocking 24p3R or inhibiting NLRP3 inflammasome activation with MCC950. CONCLUSION: LCN2/24p3R mediates astrocyte pyroptosis via NLRP3 inflammasome activation following cerebral ischemia/reperfusion injury.