Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

Chitosan modified with PAP as a promising delivery system for melatonin in the treatment of osteoporosis: targeting the divalent metal transporter 1.

The demands for novel and efficient therapies have gradually increased with the rising concerns of osteoporosis (OP). The most popular method in promoting bone regeneration during osteoporotic conditions consists of loading bioactive materials with different drugs to treat osteoporotic bones by either promoting the process of osteogenesis, or by inhibiting the activity of osteoclasts. By analyzing single cell sequencing results, we found that divalent metal transporter 1 (DMT1) played a role in OP. Based on our previous results, we found that melatonin (MT) suppressed expression of DMT1 induced by high glucose during OP, so we determined the efficacy of MT for the treatment of OP. However, the clinical effects of MT on OP were unsatisfactory. To enhance its biological efficacy, we combined MT with porous gelatin chitosan (chitosan) and the conductive material, PLA-b-AP-b-PLA (PAP), then determined how MT incorporation in chitosan@PAP nanoparticles affected the ability to promote MC3T3-E1 osteogenesis and mineralization, both in vitro and in vivo. The results confirmed the effect of MT on DMT1. We then prepared and characterized composites prepared as nanofibers, and determined the efficacy of MT combined with chitosan-PAP modified hydrogels as a slow-release system in a femur model of osteoporosis mice, with associated properties suitable for bone tissue engineering. The results indicated that MT-loaded chitosan@PAP nanospheres showed favorable osteogenic functions, both in vivo and in vitro, providing a practical solution for bone regeneration for OP patients.

Freezing pre-treatment improves radio frequency explosion puffing (RFEP) quality by altering the cellular structure of purple sweet potato [Ipomoea batatas (L) Lam.].

Radio frequency explosion puffing (RFEP) is a novel oil-free puffing technique used to produce crispy textured and nutritious puffed snacks. This study aimed to investigate the effects of freezing at different temperatures (-20 °C, -40 °C, -80 °C) for14 h and freezing times (1 and 2 times) on the cellular structure of purple sweet potato and the quality of RFEP chips. The analysis of cell microstructure, conductivity, and rheology revealed that higher freezing temperatures and more freezing times resulted in increased damage to the cellular structure, leading to greater cell membrane permeability and decreased cell wall stiffness. However, excessive damage to cellular structure caused tissue structure to collapse. Compared with the control group (4 °C), the RFEP sample pre-frozen once at -40 °C had a 47.13 % increase in puffing ratio and a 61.93 % increase in crispness, while hardness decreased by 23.44 % (p < 0.05). There was no significant change in anthocyanin retention or color difference. X-ray microtomography demonstrated that the RFEP sample pre-frozen once at -40 °C exhibited a more homogeneous morphology and uniform pore distribution, resulting in the highest overall acceptability. In conclusion, freezing pre-treatment before RFEP can significantly enhance the puffing quality, making this an effective method for preparing oil-free puffing products for fruits and vegetables.

PPP2R1A silencing suppresses LUAD progression by sensitizing cells to nelfinavir-induced apoptosis and pyroptosis.

Lung adenocarcinoma is a major public health problem with the low 5-year survival rate (15%) among cancers. Aberrant alterations of meiotic genes, which have gained increased attention recently, might contribute to elevated tumor risks. However, systematic and comprehensive studies based on the relationship between meiotic genes and LUAD recurrence and treatment response are still lacking. In this manuscript, we first confirmed that the meiosis related prognostic model (MRPM) was strongly related to LUAD progression via LASSO-Cox regression analyses. Furthermore, we identified the role of PPP2R1A in LUAD, which showed more contributions to LUAD process compared with other meiotic genes in our prognostic model. Additionally, repression of PPP2R1A enhances cellular susceptibility to nelfinavir-induced apoptosis and pyroptosis. Collectively, our findings indicated that meiosis-related genes might be therapeutic targets in LUAD and provided crucial guidelines for LUAD clinical intervention.

Proteomic analysis of ferroptosis pathways reveals a role of CEPT1 in suppressing ferroptosis.

Ferroptosis has been recognized as a unique cell death modality driven by excessive lipid peroxidation and unbalanced cellular metabolism. In this study, we established a protein interaction landscape for ferroptosis pathways through proteomic analyses, and identified choline/ethanolamine phosphotransferase 1 (CEPT1) as a lysophosphatidylcholine acyltransferase 3 (LPCAT3)-interacting protein that regulates LPCAT3 protein stability. In contrast to its known role in promoting phospholipid synthesis, we showed that CEPT1 suppresses ferroptosis potentially by interacting with phospholipases and breaking down certain pro-ferroptotic polyunsaturated fatty acid (PUFA)-containing phospholipids. Together, our study reveals a previously unrecognized role of CEPT1 in suppressing ferroptosis.

Metabolic cell death in cancer: Ferroptosis, cuproptosis, disulfidptosis, and beyond.

Cell death resistance represents a hallmark of cancer. Recent studies have identified metabolic cell death as unique forms of regulated cell death resulting from an imbalance in the cellular metabolism. This review discusses the mechanisms of metabolic cell death-ferroptosis, cuproptosis, disulfidptosis, lysozincrosis, and alkaliptosis-and explores their potential in cancer therapy. Our review underscores the complexity of the metabolic cell death pathways and offers insights into innovative therapeutic avenues for cancer treatment.

BRCA1-mediated dual regulation of ferroptosis exposes a vulnerability to GPX4 and PARP co-inhibition in BRCA1-deficient cancers.

Resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) limits the therapeutic efficacy of PARP inhibition in treating breast cancer susceptibility gene 1 (BRCA1)-deficient cancers. Here we reveal that BRCA1 has a dual role in regulating ferroptosis. BRCA1 promotes the transcription of voltage-dependent anion channel 3 (VDAC3) and glutathione peroxidase 4 (GPX4); consequently, BRCA1 deficiency promotes cellular resistance to erastin-induced ferroptosis but sensitizes cancer cells to ferroptosis induced by GPX4 inhibitors (GPX4i). In addition, nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and defective GPX4 induction unleash potent ferroptosis in BRCA1-deficient cancer cells upon PARPi and GPX4i co-treatment. Finally, we show that xenograft tumors derived from BRCA1-mutant breast cancer patients with PARPi resistance exhibit decreased GPX4 expression and high sensitivity to PARP and GPX4 co-inhibition. Our results show that BRCA1 deficiency induces a ferroptosis vulnerability to PARP and GPX4 co-inhibition and inform a therapeutic strategy for overcoming PARPi resistance in BRCA1-deficient cancers.

Epigenetic modifications in obesity-associated diseases.

The global prevalence of obesity has reached epidemic levels, significantly elevating the susceptibility to various cardiometabolic conditions and certain types of cancer. In addition to causing metabolic abnormalities such as insulin resistance (IR), elevated blood glucose and lipids, and ectopic fat deposition, obesity can also damage pancreatic islet cells, endothelial cells, and cardiomyocytes through chronic inflammation, and even promote the development of a microenvironment conducive to cancer initiation. Improper dietary habits and lack of physical exercise are important behavioral factors that increase the risk of obesity, which can affect gene expression through epigenetic modifications. Epigenetic alterations can occur in early stage of obesity, some of which are reversible, while others persist over time and lead to obesity-related complications. Therefore, the dynamic adjustability of epigenetic modifications can be leveraged to reverse the development of obesity-associated diseases through behavioral interventions, drugs, and bariatric surgery. This review provides a comprehensive summary of the impact of epigenetic regulation on the initiation and development of obesity-associated cancers, type 2 diabetes, and cardiovascular diseases, establishing a theoretical basis for prevention, diagnosis, and treatment of these conditions.

Pyruvate maintains and enhances the pro-inflammatory response of microglia caused by glucose deficiency in early stroke.

Pro-inflammatory microglia mainly rely on glycolysis to maintain cytokine production during ischemia, accompanied by an increase in inducible nitric oxide synthase (iNOS) and monocarboxylate transporter 1 (MCT1). The role of energy metabolism in the pro-inflammatory response of microglia is currently unclear. In this study, we tested the response of microglia in mice after cerebral ischemia and simulated an energy environment in vitro using low glucose culture medium. The research results indicate that the expression levels of iNOS and arginase 1 (ARG1) increase in the ischemic mouse brain, but the upregulation of MCT1 expression is mainly present in iNOS positive microglia. In microglia exposed to low glucose conditions, iNOS and MCT1 levels increased, while ARG1 levels decreased. Under the same conditions, knocking down MCT1 in microglia leads to a decrease in iNOS levels, while overexpression of MCT1 leads to the opposite result. The use of NF-κB inhibitors reduced the expression levels of iNOS and MCT1 in microglia. In summary, our data indicate that pyruvate maintains and enhances the NF-κB regulated pro-inflammatory response of microglia induced by low glucose.

Are latent working memory items retrieved from long-term memory?

Switching one's focus of attention between to-be-remembered items in working memory (WM) is critical for cognition, but the mechanisms by which this is accomplished are unclear. A long-term memory (LTM) account suggests that switching attention away from an item, and passively retaining and reactivating such "latent" items back into the focus of attention involves episodic LTM retrieval processes, even for delays of only a few seconds. We tested this hypothesis using a two-item, double-retrocue WM task that requires participants to switch attention away from and reactivate items followed by subsequent LTM tests for reactivated items from the initial WM task (vs. continuously retained or untested control items). We compared performance on these tests between older adults (a population with LTM deficits) and young adults with either full (Experiment 1) or divided (Experiment 2) attention during the WM delay periods. The effects of reactivating latent items, as well as ageing and divided attention, had significant effects on WM performance, but did not interact with or systematically affect subsequent LTM for reactivated versus control items on item-, location-, or associative-recognition memory judgements made with either high or low confidence. Experiment 3 confirmed that these effects did not depend on whether or not young participants were warned about the subsequent LTM tests before performing the WM task. These dissociations between WM and LTM are inconsistent with the LTM account of latent WM; they are more consistent with the dynamic processing model of WM (Current Directions in Psychological Science).

LINC02774 inhibits glycolysis in glioma to destabilize HIF-1α dependent on transcription factor RP58.

Glioma, the most common of malignant tumors in the brain, is responsible for the majority of deaths from primary brain tumors. The regulation of long noncoding RNAs (lncRNAs) in HIF-1α-driven tumor development remains unclear. LINC02774 is a nuclear lncRNA and that it is being reported for the first time in this study. We found the downregulation of LINC02774 in glioma and decreased with the degree of malignant, with its expression showing a negative correlation with the relative index of enhanced magnetic resonance (RIEMR). RIEMR-associated LINC02774 was found to inhibit glycolysis by modulating the hypoxia pathway rather than the hypoxia response itself. LINC02774 interacted with its neighboring gene, RP58 (ZBTB18), to enhance the expression of PHD3, which catalyzed HIF-1α hydroxylase and ubiquitination, leading to the downregulation of HIF-1α expression. We also found that the function of LINC02774, dependent on PHD3, was diminished upon RP58 depletion. Notably, higher expression of RIEMR-associated LINC02774 was associated with a favorable prognosis. In conclusion, these findings reveal the role of RIEMR-associated LINC02774, which relies on its neighbor gene, RP58, to regulate the hypoxia pathway as a novel tumor suppressor, suggesting its potential to be a prognostic marker and a molecular target for the therapy of glioma.

The DUBA-SLC7A11-c-Myc axis is critical for stemness and ferroptosis.

Ferroptosis is characterized by the accumulation of lipid peroxidation as a unique iron-dependent cell death. However, the interplay between stemness and ferroptosis remains unknown. Here, we demonstrate that undifferentiated cells are more sensitive to ferroptosis than differentiated cells, and cystine transporter SLC7A11 protein is highly up-regulated by deubiquitinase DUBA in differentiated cells. Additionally, DUBA promotes stemness by deubiquitinating SLC7A11. Moreover, SLC7A11 drastically increases the expression of c-Myc through cysteine, the combination of sorafenib and c-Myc inhibitor EN4 has a synergetic effect on cancer therapy. Together, our results reveal that enhanced stemness increases the susceptibility to ferroptosis, and the DUBA-SLC7A11-c-Myc axis is pivotal for differentiated cancer stem cells (CSCs) resistant to ferroptosis, providing a promised targets to eradicate CSCs through ferroptosis.

SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells.

The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show that high overexpression of SLC7A11 promotes tumor growth but suppresses tumor metastasis, likely because metastasizing cancer cells with high expression of SLC7A11 are particularly susceptible to oxidative stress. Our findings reveal that SLC7A11 expression level dictates cancer cells' sensitivity to oxidative stress and suggests a context-dependent role for SLC7A11 in tumor biology.

Effects of warming on quantity and structure of litter-derived dissolved organic matter in subtropical natural Castanopsis kawakamii forests.

Litter-derived dissolved organic matter (DOM) is an important source of soil DOM, and the response of which to climate warming may change forest soil carbon and nitrogen dynamics, such as soil carbon and nitrogen mineralization. In this study, we conducted a field manipulative warming experiment in natural Castanopsis kawakamii forests. Combined with litter leaching solution collected in the field and ultraviolet-visible and three-dimensional fluorescence spectroscopy analyses, we explored the effects of warming on the content and structure of litter-derived DOM in subtropical evergreen broad-leaved forests. The results showed that litter-derived dissolved organic carbon and nitrogen content exhibited monthly dynamics, with the peak (in April) and the mean monthly content being 1.02 and 0.15 g·m-2, respectively. Litter-derived DOM had higher fluorescence index and lower biological index, indicating the microbial-origin of DOM from litter. The litter DOM mainly included humic-like fractions and tryptophan-like substances. Warming did not affect the content, aromaticity, hydrophobicity, molecular weight, fluorescence index, biological index and humification index of DOM, suggesting neutral effect of warming on the quantity and structure of litter DOM. Warming also did not affect the relative contribution of main components in DOM, indicating that the temperature variation exerted no effects on microbial degradation. In summary, warming did not change the quantity and quality of litter-derived DOM in subtropical evergreen broadleaved forests, indicating warming had little effect on litter-derived DOM input to soil.

Soil warming decreased dissolved organic carbon quantity and quality in subtropical forests.

Soil dissolved organic carbon (DOC) is the most active part in forest soil carbon pool, the responses of which to climate warming has profound effects on forest carbon cycling. Based on a manipulative soil warming experiment in subtropical evergreen broad-leaved forests, we collected soil solutions in situ and used ultraviolet-visible, infrared and three-dimensional fluorescence spectroscopy analyses to explore the effects of soil warming (+4 ℃, 1 year) on soil DOC quantity and quality along the soil profile. The results showed that soil DOC flux remained constant along the soil profile. Soil DOC mainly included two humic-like fractions and one microbial metabolite. Warming significantly decreased soil DOC flux and the abundance of aromatic and hydrophobic components, and increased the amount of low molecular weight carbohydrates. Furthermore, soil warming increased the relative proportion of humic-like fractions in the surface soil layer (0-10 cm) and microbial metabolite in the deep soil layer (30-40 cm), indicating that warming might accelerate microbial turnover in the deep layer. Overall, soil warming not only decreased soil DOC content, but also simplified the composition of soil DOC in subtropical evergreen broad-leaved forests.