Explore the vast range of titles available.

Various cellular stresses including oxidative stress induce a collapse of the Ran gradient, which causes accumulation of importin α in the nucleus and a subsequent block of nuclear protein import. However, it is unknown whether accumulated importin α performs roles in the nucleus after its migration in response to stress. In this study, we found that nuclear‐retained importin α2 binds with DNase I‐sensitive nuclear component(s) and exhibits selective upregulation of mRNA encoding Serine/threonine kinase 35 ( STK35 ) by microarray analysis. Chromatin immunoprecipitation and promoter analysis demonstrated that importin α2 can access to the promoter region of STK35 and accelerate its transcription in response to hydrogen peroxide exposure. Furthermore, constitutive overexpression of STK35 proteins enhances caspase‐independent cell death under oxidative stress conditions. These results collectively reveal that nuclear‐localized importin α2 influences gene expression and contributes directly to cell fate outcomes including non‐apoptotic cell death. Importin α, responsible for nuclear translocation of cargo proteins, also has a direct role in transcriptional control, binding DNA and regulating the expression of a number of target genes.

Tumour immune microenvironment (TIME) plays an indispensable role in tumour progression, and tumour‐associated macrophages (TAMs) are the most abundant immune cells in TIME. Non‐apoptotic regulated cell death (RCD) can avoid the influence of tumour apoptosis resistance on anti‐tumour immune response. Specifically, autophagy, ferroptosis, pyroptosis and necroptosis mediate the crosstalk between TAMs and tumour cells in TIME, thus reprogram TIME and affect the progress of tumour. In addition, although some achievements have been made in immune checkpoint inhibitors (ICIs), there is still defect that ICIs are only effective for some people because non‐apoptotic RCD can bypass the apoptosis resistance of tumour. As a result, ICIs combined with targeting non‐apoptotic RCD may be a promising solution. In this paper, the basic molecular mechanism of non‐apoptotic RCD, the way in which non‐apoptotic RCD mediates crosstalk between TAMs and tumour cells to reprogram TIME, and the latest research progress in targeting non‐apoptotic RCD and ICIs are reviewed.

Programmed cell death (PCD) is now accepted as a fundamental cellular process in plants. It is involved in defence, development and response to stress, and our understanding of these processes would be greatly improved through a greater knowledge of the regulation of plant PCD. However, there may be several types of PCD that operate in plants, and PCD research findings can be confusing if they are not assigned to a specific type of PCD. The various cell-death mechanisms need therefore to be carefully described and defined. This review describes one of these plant cell-death processes, namely the apoptotic-like PCD (AL-PCD). We begin by examining the hallmark 'apoptotic-like' features (protoplast condensation, DNA degradation) of the cell's destruction that are characteristic of AL-PCD, and include examples of AL-PCD during the plant life cycle. The review explores the possible cellular 'executioners' (caspase-like molecules; mitochondria; de novo protein synthesis) that are responsible for the hallmark features of the cellular destruction. Finally, senescence is used as a case study to show that a rigorous definition of cell-death processes in plant cells can help to resolve arguments that occur in the scientific literature regarding the timing and control of plant cell death.

Within the course of a single minute, millions of cells in the human body will undergo programmed cell death in response to physiological or pathological cues. The diminished energetic capacity of an apoptotic cell renders the cell incapable of sustaining plasma membrane integrity. Under these circumstances, intracellular contents that might leak into the surrounding tissue microenvironment, a process referred to as secondary necrosis, could induce inflammation and tissue damage. Remarkably, in most cases of physiologically rendered apoptotic cell death, inflammation is avoided because a mechanism to swiftly remove apoptotic cells from the tissue prior to their secondary necrosis becomes activated. This mechanism, referred to as efferocytosis, uses phagocytes to precisely identify and engulf neighboring apoptotic cells. In doing so, efferocytosis mantains tissue homeostasis that would otherwise be disrupted by normal cellular turnover and exacerbated further when the burden of apoptotic cells becomes elevated due to disease or insult. Efferocytosis also supports the resolution of inflammation, restoring tissue homesostasis. The importance of efferocytosis in health and disease underlies the increasing research efforts to understand the mechanisms by which efferocytosis occurs, and how a failure in the efferocytic machinery contributes to diseases, or conversely, how cancers effectively use the existing efferocytic machinery to generate a tumor-tolerant, immunosuppressive tumor microenvironment. We discuss herein the molecular mechanisms of efferocytosis, how the process of efferocytosis might support a tumor ‘wound healing’ phenotype, and efforts to target efferocytosis as an adjunct to existing tumor treatments.

In concert with the increased understanding that there are many ways for cells to die, several methods have been developed to detect cell death. The classification of cell death posed some difficulties that were overcome by implementing strict selection criteria that should also apply to the detection methods. The selection of assays is based on morphological criteria and distinguishable marks of apoptotic patways. The detection of apoptosis includes methods related to membrane alterations, DNA fragmentation, cytotoxicity and cell proliferation, mitochondrial damage, immunological detection and mechanism based assays. Other less frequently used detections of apoptosis are: (a) light-scattering flow cytometry to avoid underestimating the extent and timing of apoptosis, (b) time-lapse microscopy perfusion platform to support the temporal aspects of detection, to measure cell surface area and cellular adhesion, and (c) genotoxicity specific chromatin changes. Attention is called to the advantages and limitations of various methods.

Thus far, the potential short- and long-term detrimental effects of a variety of environmental chemicals designated as endocrine-active compounds (EACs) have been found to interfere with histo- and anatomo-physiological functions of the reproductive system in humans and wildlife species. For those reasons, this study sought to examine whether selected EACs, which encompass the fungicide vinclozolin (Vnz), the androgenic anabolic steroid nandrolone (Ndn) and the immunosuppressant cyclosporin A (CsA), affect the developmental competence and molecular quality (MQ) of porcine cumulus–oocyte complexes (COCs) subjected to in vitro maturation (IVM) under 3D culture conditions. The COCs underwent 3D-IVM in the presence of Vnz, Ndn or CsA for 48 h. To explore whether the selected EACs induce internucleosomal DNA fragmentation in cumulus cells (CCs), TUNEL-assisted detection of late apoptotic cells was performed. Additionally, for the detailed evaluation of pro- and antiapoptotic pathways in COCs, apoptosis proteome profiler arrays were used. To determine changes in intracellular metabolism in COCs, comprehensive assessments of mitochondrial ultrastructure and activity were carried out. Moreover, the relative abundances (RAs) of mRNAs transcribed from genes that are involved in scavenging reactive oxygen species (ROS), such as SIRT3 and FOXO3, and intramitochondrial bioenergetic balance, such as ATP synthase subunit (ATP5A1), were ascertained. Finally, to investigate the extent of progression of oocyte maturation, the intraooplasmic levels of cAMP and the RAs of mRNA transcripts encoding regulatory and biocatalytic subunits of a heterodimeric meiosis-promoting factor, termed cyclin B1 (CCNB1) and cyclin-dependent kinase 1 (CDC2), were also estimated. The obtained results provide, for the first time, strong evidence that both Vnz and Ndn decrease the developmental competence of oocytes and stimulate apoptosis processes in CCs. The present study is also the first to highlight that Vnz accelerates the maturation process in immature oocytes due to both increased ROS production and the augmented RA of the CCNB1 gene. Furthermore, Vnz was proven to trigger proapoptotic events in CCs by prompting the activity of the FOXO3 transcription factor, which regulates the mitochondrial apoptosis pathway. In turn, Ndn was shown to inhibit oocyte maturation by inducing molecular events that ultimately lead to an increase in the intraooplasmic cAMP concentration. However, due to the simultaneous enhancement of the expression of TNF-β and HSP27 proteins in CCs, Ndn might be responsible for the onset of their neoplastic transformation. Finally, our current investigation is the first to clearly demonstrate that although CsA did not interfere with the nuclear and cytoplasmic maturation of oocytes, by inducing mitophagy in CCs, it disrupted oocyte metabolism, consequently attenuating the parameters related to the MQ of COCs. Summing up, Vnz, Ndn and CsA reduced not only the processes of growth and IVM but also the MQ of porcine COCs, which might make them unsuitable for assisted reproductive technologies (ARTs) such as in vitro fertilization by either gamete co-incubation or intracytoplasmic sperm injection (ICSI) and cloning by somatic cell nuclear transfer (SCNT).

Receptor-interacting protein (RIP) kinases promote the induction of necrotic cell death pathways. Here we investigated signaling pathways in outer hair cells (OHCs) of adult male CBA/J mice exposed to noise that causes permanent threshold shifts, with a particular focus on RIP kinase-regulated necroptosis. One hour after noise exposure, nuclei of OHCs in the basal region of the cochlea displayed both apoptotic and necrotic features. RIP1 and RIP3 protein levels increased and caspase-8 was activated. Treatment with pan-caspase inhibitor ZVAD blocked the activation of caspase-8 and reduced the number of apoptotic nuclei, while increasing levels of RIP1, RIP3, and necrotic OHCs. Conversely, treatment with necrosis inhibitor necrostatin-1 (Nec-1) or RIP3 siRNA (siRIP3) diminished noise-induced increases in RIP1 and RIP3, and decreased necrotic OHC nuclei. This treatment also increased the number of apoptotic nuclei without increasing activation of caspase-8. Consistent with the elevation of levels of RIP1 and RIP3, noise-induced active AMPK α levels increased with ZVAD treatment, but decreased with Nec-1 and siRIP3 treatment. Furthermore, treatment with siRIP3 did not alter the activation of caspase-8, but instead increased activation of caspase-9 and promoted endonuclease G translocation into OHC nuclei. Finally, auditory brainstem response functional measurements and morphological assessment of OHCs showed that ZVAD treatment reduces noise-induced deficits. This protective function is potentiated when combined with siRIP3 treatment. In conclusion, noise-induced OHC apoptosis and necrosis are modulated by caspases and RIP kinases, respectively. Inhibition of either pathway shifts the prevalence of OHC death to the alternative pathway.

The human pathogen Helicobacter pylori represents a risk factor for the development of gastric diseases including cancer. The H. pylori -induced transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is involved in the pro-inflammatory response and cell survival in the gastric mucosa, and represents a trailblazer of gastric pathophysiology. Termination of nuclear NF-κB heterodimer RelA/p50 activity is regulated by the ubiquitin-RING-ligase complex elongin-cullin-suppressor of cytokine signalling 1 (ECS SOCS1 ), which leads to K48-ubiquitinylation and degradation of RelA. We found that deubiquitinylase (DUB) ubiquitin specific protease 48 (USP48), which interacts with the COP9 signalosome (CSN) subunit CSN1, stabilises RelA by deubiquitinylation and thereby promotes the transcriptional activity of RelA to prolong de novo synthesis of DUB A20 in H. pylori infection. An important role of A20 is the suppression of caspase-8 activity and apoptotic cell death. USP48 thus enhances the activity of A20 to reduce apoptotic cell death in cells infected with H. pylori . Our results, therefore, define a synergistic mechanism by which USP48 and A20 regulate RelA and apoptotic cell death in H. pylori infection.

Purpose Curcumin (Cur), a yellow-colored dietary flavor from the plant ( Curcuma longa ), has been demonstrated to potentially resist diverse diseases, including ovarian cancer, but drug resistance becomes a major limitation of its success clinically. The key molecule or mechanism associated with curcumin resistance in ovarian cancer still remains unclear. The aim of our study was to investigate the effects of curcumin on autophagy in ovarian cancer cells and elucidate the underlying mechanism. Methods In our study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), EdU proliferation assay and colony-forming assay were used to assess cell viability. Apoptosis was detected by western blot and flow cytometric analysis of apoptosis. Autophagy was defined by both electron microscopy and immunofluorescence staining markers such as microtubule-associated protein 1 light chain 3 (LC3). Plasmid construction and shRNA transfection helped us to confirm the function of curcumin. Results Curcumin reduced cell viability and induced apoptotic cell death by MTT assay in human ovarian cancer cell lines SK-OV-3 and A2780 significantly. Electron microscopy, western blot and immunofluorescence staining proved that curcumin could induce protective autophagy. Moreover, treatment with autophagy-specific inhibitors or stable knockdown of LC3B by shRNA could markedly enhance curcumin-induced apoptosis. Finally, the cells transiently transfected with AKT1 overexpression plasmid demonstrated that autophagy had a direct relationship with the AKT/mTOR/p70S6K pathway. Conclusions Curcumin can induce protective autophagy of human ovarian cancer cells by inhibiting the AKT/mTOR/p70S6K pathway, indicating the synergistic effects of curcumin and autophagy inhibition as a possible strategy to overcome the limits of current therapies in the eradication of epithelial ovarian cancer.

Ocular surface exposure to nitrogen mustard (NM) leads to severe ocular toxicity which includes the separation of epithelial and stromal layers, loss of endothelial cells, cell death, and severe loss of tissue function. No definitive treatment for mustard gas-induced ocular surface disorders is currently available. The research was conducted to investigate the therapeutic potential of mesenchymal stem cell-conditioned media (MSC-CM) in NM-induced corneal wounds. NM was added to different types of corneal cells, the ocular surface of porcine, and the ocular surface of mice, followed by MSC-CM treatment. NM significantly induced apoptotic cell death, cellular ROS (Reactive oxygen species), and reduced cell viability, metabolic gene expression, and mitochondrial function, and, in turn, delayed wound healing. The application of MSC-CM post NM exposure partially restored mitochondrial function and decreased intracellular ROS generation which promoted cell survival. MSC-CM therapy enhanced wound healing process. MSC-CM inhibited NM-induced apoptotic cell death in murine and porcine corneal tissue. The application of MSC-CM following a chemical insult led to significant improvements in the preservation of corneal structure and wound healing. In vitro, ex vivo, and in vivo results suggest that MSC-CM can potentially provide targeted therapy for the treatment of chemical eye injuries, including mustard gas keratopathy (MGK) which presents with significant loss of vision alongside numerous corneal pathologies.