Cell Death Discovery最新文献

Traumatic brain injury (TBI) is one of the leading causes of disability and mortality, which was classified as low-altitude TBI and high-altitude TBI. A large amount of literature shows that high-altitude TBI is associated with more severe neurological impairments and higher mortality rates compared to low-altitude TBI, due to the special environment of high-altitude hypoxia. However, the role of high-altitude hypoxia in the pathogenesis of TBI remains unclear. In order to deeply investigate this scientific issue, we constructed a high-altitude hypoxic TBI model at different altitudes and used animal behavioral assessments (Modified neurological severity score, rotarod test, elevated plus maze test) as well as histopathological analyses (brain gross specimens, brain water content, Evans blue content, hypoxia inducible factor-1α, Hematoxylin-Eosin staining and ROS detection) to reveal its underlying principles and characteristics. We found that with higher altitude, TBI-induced neurological deficits were more severe and the associated histopathological changes were more significant. Single-nuclear RNA sequencing was subsequently employed to further reveal differential gene expression profiles in high-altitude TBI. We found a significant increase in ferroptosis of astrocytes in cases of high-altitude TBI compared to those at low-altitude TBI. Analyzing transcription factors in depth, we found that Bach1 plays a crucial role in regulating key molecules that induce ferroptosis in astrocytes following high-altitude TBI. Down-regulation of Bach1 can effectively alleviate high-altitude TBI-induced neurological deficits and histopathological changes in mice. In conclusion, high-altitude hypoxia may significantly enhance the ferroptosis of astrocytes and aggravate TBI by up-regulating Bach1 expression. Our study provides a theoretical foundation for further understanding of the mechanism of high-altitude hypoxic TBI and targeted intervention therapy.

RelA, also known as nuclear factor kappa B p65, plays a crucial role in the pathogenesis of various liver diseases. However, the specific role of RelA in hepatocytes during the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) is not well understood. This study explored the relationship between impaired RelA signaling and lipid metabolism disorders in hepatocytes, and how they synergistically contribute to the advancement of MASLD. We assessed the changes, regulatory relationships, and impacts of RelA signaling and lipid metabolism remodeling on disease progression both in vitro and in vivo. During MASLD, there was a decrease in the expression of RelA and hepatocyte nuclear factor 1 alpha (HNF1α), with both factors showing mutual enhancement of each other's expression under normal conditions. This synergistic effect was absent during hepatocyte steatosis. RelA or HNF1α depletion in hepatocytes intensified MASLD symptoms, whereas overexpression of RELA or treatment with necrostatin-1 (a necroptosis inhibitor) or Z-VAD (a caspase inhibitor) significantly mitigated these effects. Mechanistically, during hepatic steatosis, altered lipid profiles exhibited lipotoxicity, inducing hepatocyte apoptosis and necroptosis, whereas endoplasmic reticulum (ER) stress triggered lipid remodeling processes similar to those observed in MASLD. RelA signaling upregulated the expression of activating transcription factor 4 and glucose-regulated protein 78, thereby alleviating ER stress. Impaired RelA signaling remodeled the ER stress response and lipid metabolism, and enhanced lipid accumulation and lipid toxicity. In conclusion, impaired RelA signaling and disrupted lipid metabolism form a detrimental feedback loop in hepatocytes that promotes MASLD progression. Lipid accumulation suppresses RelA signaling, remodeling the ER stress response and exacerbating lipid metabolism disorder, ultimately leading to hepatocyte apoptosis and necroptosis.

With the development of public health, female diseases have become the focus of current concern. The unique reproductive anatomy of women leads to the development of gynecological diseases gradually become an important part of the socio-economic burden. Epigenetics plays an irreplaceable role in gynecologic diseases. As an important mRNA modification, m6A is involved in the maturation of ovum cells and maternal-fetal microenvironment. At present, researchers have found that m6A is involved in the regulation of gestational diabetes and other reproductive system diseases, but the specific mechanism is not clear. In this manuscript, we summarize the components of m6A, the biological function of m6A, the progression of m6A in the maternal-fetal microenvironment and a variety of gynecological diseases as well as the progression of targeted m6A treatment-related diseases, providing a new perspective for clinical treatment-related diseases.

The persistence of HIV-1 latency reservoirs in CD4⁺ T cells is a significant obstacle for curing HIV-1. Shock-and-kill strategies, which aim to reactivate latent HIV-1 followed by cytotoxic clearance, have shown limited success in vivo due to insufficient efficacy of latency reversal agents (LRAs) and off-target effects. Natural killer (NK) cells, with their ability to mediate cytotoxicity independent of antigen specificity, offer a promising avenue for enhancing the shock-and-kill approach. Previously, we observed that pan-caspase inhibitors induce NK cells to secrete an LRA in vitro. Here, we aimed to identify this LRA using a targeted proteomic approach. We identified lymphotoxin-α (LTα) as the key LRA secreted by NK cells following pan-caspase inhibitor treatment. LTα was shown to significantly induce HIV-1 LTR promoter activity, a hallmark of viral reactivation. Neutralization of LTα effectively abolished the observed LRA activity, confirming its central role. Moreover, cytokine-primed but not resting human primary NK cells exhibited LRA activity that could be neutralized with LTα neutralizing antibodies. Finally, pan-caspase inhibitor treatment did not decrease the ability of the cytokine-primed NK cells to kill target cells. These findings demonstrate that cytokine-primed NK cells, through LTα secretion, can effectively reactivate latent HIV-1 following pan-caspase inhibitor treatment, without compromising NK cell cytotoxicity. This highlights a potential enhancement strategy utilizing NK cells for shock-and-kill approaches in HIV-1 cure research.

In tumors, cancer cells are frequently exposed to adverse environmental conditions that result in endoplasmic reticulum (ER) stress. Mechanical signals emerging from extracellular matrix (ECM) rigidity and cell shape regulate the activity of transcriptional co-activators Yes-associated protein (YAP) and its paralog Transcriptional Coactivator with PDZ-binding motif (TAZ). However, the role of ECM rigidity and YAP/TAZ in tumor cell fate decisions under ER stress remains relatively unexplored. Our results suggest that the YAP/TAZ system plays an important role in the control of ER stress-induced cell death by mechanical signaling arising from ECM stiffness in tumor cells. Mechanistically, YAP/TAZ regulates apoptosis induced by ER stress in tumor cells by controlling the activation of the TRAIL-R2/DR5-mediated extrinsic apoptotic pathway through a dual mechanism. On the one hand, the YAP/TAZ system prevents intracellular TRAIL-R2/DR5 clustering in tumor cells. On the other hand, it inhibits cFLIP down-regulation in tumor cells experiencing ER stress. In addition, YAP/TAZ controls the expression of pro-inflammatory interleukin-8 (IL-8/CXCL8) in tumor cells undergoing ER stress by a TRAIL-R2/DR5/caspase-8-dependent mechanism. Although other mechanisms may also be involved in controlling cell death and inflammation in tumor cells facing environmental stress, our results support a model in which regulation of the subcellular localization and activity of the YAP/TAZ transcriptional co-activators could contribute to the microenvironmental control of cell fate decisions in tumor cells undergoing ER stress.

Chronic inflammatory pain is often caused by peripheral tissue damage and persistent inflammation. This disease substantially affects patients' physical and social well-being. We investigated the role of metallothionein-3 (MT3) in modulating complete Freund's adjuvant (CFA)-induced intracellular Zn²⁺ activity in an MT3 knockout mouse model of inflammatory pain in the hind paw. The results demonstrated that increasing intracellular Zn²⁺ levels ameliorate deficits in motor behavior, as well as inflammation in the paw, spleen, and thymus. Furthermore, intracellular Zn²⁺ was crucial in regulating oxidative stress markers (glutathione, superoxide dismutase, catalase, and malondialdehyde) and inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, in MT3 knockout mice induced with CFA. This study highlights the critical role of MT3 in coordinating the intracellular interaction with Zn²⁺, which is vital for the immune systems's protective functions. These interactions are fundamental for maintaining metal ion homeostasis and regulating the synthesis of various biomolecules in the body.

Plasma membrane macromolecular complexes function as signaling hubs that regulate cell behavior, which is particularly relevant in cancer. Our study provides evidence that the complex formed by the hERG1 potassium channel and the β1 subunit of integrin receptors preferentially localizes in Lipid Rafts (LRs) in Pancreatic Ductal Adenocarcinoma (PDAC) cell lines and primary samples. The complex recruits the p85 subunit of phosphatidyl-inositol-3-kinase (PI3K), activating phosphoinositide metabolism and triggering an intracellular signaling pathway centered on Akt. This pathway ultimately affects cancer cell proliferation through cyclins and p21, and cell migration through the small GTPase Rac-1 and f-actin organization. The hERG1/β1 integrin complex in LRs can be dissociated and the downstream signaling pathway can be inhibited by either disrupting LRs through methyl-beta-cyclodextrin (MβCD) or inhibiting cholesterol synthesis by statins. Treatment with a single chain bispecific antibody-scDb-hERG1-β1-specifically targeting the complex significantly potentiates the effects of both MβCD and statins on intracellular signaling. Consequently, these treatments decrease PDAC cell proliferation and motility in vitro. From a pharmacological perspective, different statins produce anti-neoplastic effects in synergy with scDb-hERG1-β1. Such combination also enhances tumor sensitivity to chemotherapeutic drugs, such as gemcitabine and oxaliplatin. The efficacy of these combination treatments depends on the amount of the hERG1/β1 integrin complex present on the plasma membrane of cancer cells. Finally, the combined treatment with statins and scDb-hERG1-β1 significantly reduces tumor growth and improves survival in vivo, in a preclinical mouse model. These results suggest that the combination of scDb-hERG1-β1 and statins represent a potential novel strategy for treating PDAC patients.

A sort of major malignant disease, cancer can compromise human health wherever. Some mechanisms of the occurrence and evolution of cancer still seem elusive even now. Consequently, the therapeutic strategies for cancer must continually evolve. The hedgehog signaling pathway, a critical mediator in the normal development of numerous organs and the pathogenesis of cancer, is typically quiescent but is aberrantly activated in several malignancies. Extensive research has delineated that the aberrant activity of the hedgehog signaling pathway, whether autocrine or paracrine, is implicated in the initiation and progression of various neoplasms, including medulloblastoma (MB), basal cell carcinoma (BCC) and so on. Thus, notably Smo inhibitors, the opening of inhibitors of the hedgehog signaling pathway has become a topic of research attention. This review aims to summarize four aberrant activation pathways and the influence of hedgehog signaling pathway associated chemicals on tumor formation and development. Additionally, it will explore the therapeutic potential of targeted interventions in the hedgehog signaling pathway for cancer treatment.

N⁶-methyladenosine (m⁶A) mRNA modification is the most common mRNA internal modification in eukaryotes, which participates in a variety of biological processes. However, the role of m⁶A methylation in regulating autophagy induced by ischemia and hypoxia remains to be widely investigated. Here, we investigated the impact of METTL3, a key m⁶A methyltransferase, on the autophagy regulation in ischemic and hypoxic cardiomyocytes, as well as in mice following acute myocardial infarction (AMI). METTL3 negatively regulated autophagy in cardiomyocytes under ischemia and hypoxia conditions. Silencing METTL3 enhanced autophagy and mitigated cardiomyocyte injury, whereas overexpression of METTL3 exerted the opposite effect. Mechanistically, METTL3 methylated ATG7 mRNA, a crucial autophagy-related gene, leads to the recruitment of the m⁶A-binding protein YTHDF2. Subsequently, YTHDF2 facilitated the degradation of ATG7 mRNA, consequently inhibiting autophagy and exacerbating cellular damage. Our study shed light on the pivotal role of METTL3-mediated m⁶A modification in the regulation of autophagy during AMI, providing novel insights into the functional significance of m⁶A methylation and its regulatory mechanisms.