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Background: Intra-tumoral heterogeneity (ITH) is a distinguished hallmark of cancer, and cancer stem cells (CSCs) contribute to this malignant characteristic. Therefore, it is of great significance to investigate and even target the regulatory factors driving intra-tumoral stemness. c-Myc is a vital oncogene frequently overexpressed or amplified in various cancer types, including breast cancer. Our previous study indicated its potential association with breast cancer stem cell (BCSC) biomarkers. Methods: In this research, we performed immunohistochemical (IHC) staining on sixty breast cancer surgical specimens for c-Myc, CD44, CD24, CD133 and ALDH1A1. Then, we analyzed transcriptomic atlas of 1533 patients with breast cancer from public database. Results: IHC staining indicated the positive correlation between c-Myc and BCSC phenotype. Then, we used bioinformatic analysis to interrogate transcriptomics data of 1533 breast cancer specimens and identified an intriguing link among c-Myc, cancer stemness and copper-induced cell death (also known as "cuproptosis"). We screened out cuproptosis-related characteristics that predicts poor clinical outcomes and found that the pro-tumoral cuproptosis-based features were putatively enriched in MYC-targets and showed a significantly positive correlation with cancer stemness. Conclusion: In addition to previous reports on its oncogenic roles, c-Myc showed significant correlation to stemness phenotype and copper-induced cell toxicity in breast cancer tissues. Moreover, transcriptomics data demonstrated that pro-tumoral cuproptosis biomarkers had putative positive association with cancer stemness. This research combined clinical samples with large-scale bioinformatic analysis, covered description and deduction, bridged classic oncogenic mechanisms to innovative opportunities, and inspired the development of copper-based nanomaterials in targeting highly heterogeneous tumors. [ABSTRACT FROM AUTHOR]

Background: Lung cancer remains a major cause of cancer-related mortality throughout the world at present. Repositioning of existing drugs for other diseases is a promising strategy for cancer therapies, which may rapidly advance potentially promising agents into clinical trials and cut down the cost of drug development. Ciclopirox (CPX), an iron chelator commonly used to treat fungal infections, which has recently been shown to have antitumor activity against a variety of cancers including both solid tumors and hematological malignancies in vitro and in vivo. However, the effect of CPX on non-small cell lung cancer (NSCLC) and the underlying mechanism is still unclear. Methods: CCK-8, clonal formation test and cell cycle detection were used to observe the effect of inhibitor on the proliferation ability of NSCLC cells. The effects of CPX on the metastasis ability of NSCLC cells were analyzed by Transwell assays. Apoptosis assay was used to observe the level of cells apoptosis. The role of CPX in energy metabolism of NSCLC cells was investigated by reactive oxygen species (ROS) detection, glucose uptake, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) experiments. Western blot was used to examine the protein changes. Results: We report that CPX inhibits NSCLC cell migration and invasion abilities through inhibiting the epithelial-mesenchymal transition, impairing cellular bioenergetics, and promoting reactive oxygen species to activate endoplasmic reticulum (ER) stress-induced apoptotic cell death. Moreover, CPX intraperitoneal injection can significantly inhibit NSCLC growth in vivo in a xenograft model. Conclusions: Our study revealed that CPX targets cellular bioenergetics and activates unfolded protein response in ER to drive apoptosis in NSCLC cells, indicating that CPX may be a potential therapeutic drug for the treatment of NSCLC. 8ygDyd_B2wN4YvZP6nTer7 Video Abstract [ABSTRACT FROM AUTHOR]

Myocardial infarction is the most common form of acute coronary syndrome. Blockage of a coronary artery due to blood clotting leads to ischemia and subsequent cell death in the form of necrosis, apoptosis, necroptosis and ferroptosis. Revascularization by coronary artery bypass graft surgery or non-surgical percutaneous coronary intervention combined with pharmacotherapy is effective in relieving symptoms and decreasing mortality. However, reactive oxygen species (ROS) are generated from damaged mitochondria, NADPH oxidases, xanthine oxidase, and inflammation. Impairment of mitochondria is shown as decreased metabolic activity, increased ROS production, membrane permeability transition, and release of mitochondrial proteins into the cytoplasm. Oxidative stress activates Nrf2 transcription factor, which in turn mediates the expression of mitofusin 2 (Mfn 2) and proteasomal genes. Increased expression of Mfn2 and inhibition of mitochondrial fission due to decreased Drp1 protein by proteasomal degradation contribute to mitochondrial hyperfusion. Damaged mitochondria can be removed by mitophagy via Parkin or p62 mediated ubiquitination. Mitochondrial biogenesis compensates for the loss of mitochondria, but requires mitochondrial DNA replication and initiation of transcription or translation of mitochondrial genes. Experimental evidence supports a role of Nrf2 in mitophagy, via up-regulation of PINK1 or p62 gene expression; and in mitochondrial biogenesis, by influencing the expression of PGC-1α, NResF1, NResF2, TFAM and mitochondrial genes. Oxidative stress causes Nrf2 activation via Keap1 dissociation, de novo protein translation, and nuclear translocation related to inactivation of GSK3β. The mechanism of Keap 1 mediated Nrf2 activation has been hijacked for Nrf2 activation by small molecules derived from natural products, some of which have been shown capable of mitochondrial protection. Multiple lines of evidence support the importance of Nrf2 in protecting mitochondria and preserving or renewing energy metabolism following tissue injury. [Display omitted] • Myocardial ischemia and reperfusion produce ROS via mitochondria and oxidases. • ROS activates Nrf2 transcript factor by protein translation or protein stabilization. • Nrf2 increases Mfn2, PINK1, p62, PGC-1α, NResF1 and mitochondrial gene expression. • Nrf2 aids in regulation of mitochondrial hyerfusion, mitophagy and biogenesis. • Nrf2 inducers show mitochondrial protection in animal models of cardiac injury. [ABSTRACT FROM AUTHOR]

Diverse pathogen effectors convergently target conserved components in plant immunity guarded by intracellular nucleotide‐binding domain leucine‐rich repeat receptors (NLRs) and activate effector‐triggered immunity (ETI), often causing cell death. Little is known of the differences underlying ETI in different plants triggered by the same effector. In this study, we demonstrated that effector RipAW triggers ETI on Nicotiana benthamiana and Nicotiana tabacum. Both the first 107 amino acids (N1‐107) and RipAW E3‐ligase activity are required but not sufficient for triggering ETI on N. benthamiana. However, on N. tabacum, the N1‐107 fragment is essential and sufficient for inducing cell death. The first 60 amino acids of the protein are not essential for RipAW‐triggered cell death on either N. benthamiana or N. tabacum. Furthermore, simultaneous mutation of both R75 and R78 disrupts RipAW‐triggered ETI on N. tabacum, but not on N. benthamiana. In addition, N. tabacum recognizes more RipAW orthologs than N. benthamiana. These data showcase the commonalities and specificities of RipAW‐activated ETI in two evolutionally related species, suggesting Nicotiana species have acquired different abilities to perceive RipAW and activate plant defences during plant–pathogen co‐evolution. [ABSTRACT FROM AUTHOR]

Myocardial ischemia or reperfusion increases the generation of reactive oxygen species (ROS) from damaged mitochondria, NADPH oxidases, xanthine oxidase, and inflammation. ROS can be removed by eight endogenous antioxidant and redox systems, many components of which are expressed under the influence of the activated Nrf2 transcription factor. Transcriptomic profiling, sequencing of Nrf2-bound DNA, and Nrf2 gene knockout studies have revealed the power of Nrf2 beyond the antioxidant and detoxification response, from tissue recovery, repair, and remodeling, mitochondrial turnover, and metabolic reprogramming to the suppression of proinflammatory cytokines. Multifaceted regulatory mechanisms for Nrf2 protein levels or activity have been mapped to its functional domains, Nrf2-ECH homology (Neh)1–7. Oxidative stress activates Nrf2 via nuclear translocation, de novo protein translation, and increased protein stability due to removal of the Kelch-like ECH-associated protein 1 (Keap1) checkpoint, or the inactivation of β-transducin repeat-containing protein (β-TrCP), or Hmg-CoA reductase degradation protein 1 (Hrd1). The promise of small-molecule Nrf2 inducers from natural products or derivatives is discussed here. Experimental evidence is presented to support Nrf2 as a lead target for drug development to further improve the treatment outcome for myocardial infarction (MI). Myocardial ischemic reperfusion leads to increased oxidative stress and cell death by necrosis, apoptosis, and necroptosis. During oxidative stress, the activity of Nrf2 as a transcription factor is regulated by protein stability, translation, nuclear localization, and protein–protein interactions. The Nrf2 transcription factor controls the expression of key components in eight antioxidant and redox systems for the removal of reactive oxygen species. The genes under the influence of Nrf2 status suggest its involvement in mitochondrial turnover, tissue recovery, repair, or remodeling, metabolic reprogramming, and the limitation of proinflammatory cytokines. Small-molecule Nrf2 inducers have shown promise in eliciting cardiac protection and inhibiting inflammation in experimental animals, suggesting a future direction for the development of nontoxic Nrf2 inducers using modern technologies. [ABSTRACT FROM AUTHOR]

To assess the effect of cluster of differentiation (CD47) downregulation on autophagy in hypoxia/reoxygenation (H/R)-treated H9c2 cardiomyocytes. H9c2 cells were maintained in normoxic conditions (95% air, 5% CO2, 37°C) without CD47 antibodies, Si-CD47 or chloroquine (CQ) treatment; H9c2 cells in the H/R group were subjected to 24 h of hypoxia (1% O2, 94% N2, 5% CO2, 37°C) followed by 12 h of reoxygenation (95% air, 5% CO2, 37°C). All assays were controlled, triplicated and repeated on three separately initiated cultures. The biochemical parameters in the medium supernatant were measured to evaluate the oxidative stress in cardiomyocytes. The Annexin V-fluorescein isothiocyanate assay was used to detect the apoptotic rate in the H9c2 cells. Transmission electron microscope, immunofluorescent staining and western blot analysis were performed to detect the effect of the CD47 antibody on autophagic flux in H/R-treated H9c2 cardiomyocytes. The cardiomyocytic oxidative stress and apoptotic rate decreased and autophagic clearance increased after CD47 downregulation. H/R triggered cell autophagy, autophagosome accumulation and apoptosis in H9c2 cell lines. However, these effects can be attenuated by CD47 downregulation. This study demonstrates its clinical implications in ischemia/reperfusion injury treatment. [ABSTRACT FROM AUTHOR]

The wide use of disinfectants has prompted resistance from the microbiome which will in turn reduce the bactericidal effect of disinfectants. Hence, glutaraldehyde (GA) and didecyldimethylammonium bromide (DDAB) were used to develop a combination disinfectant with high stability and antimicrobial effects, which was named GA-DDAB combination disinfectant (GD). The bactericidal mechanism against Escherichia coli was studied in our earlier work. In this study, we focused on GD’s bactericidal efficacy in both the laboratory and environment, the genetic toxicity to mouse lymphoma L5178Y TK+/− cells, acute peroral toxicity in mice, and its metal corrosion properties with a view to providing theoretical support for developing a high-efficiency, low toxicity, and weakly corrosive disinfectant for general use. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) contamination in soils has become a serious issue of sustainable crop production and food safety. Here, HvVPE3 , a γ-type VPE (vacuolar processing enzyme) gene, is firstly reported to regulate Cd uptake/tolerance. We isolated and functionally characterized HvVPE3 using genetic transformation coupled with physio-biochemical assay of Cd tolerance in barley. HvVPE3 was mainly expressed in leaves and being inducible by Cd stress. Subcellular localization verified that HvVPE3 is localized in the endoplasmic reticulum (ER). Silencing of HvVPE3 by RNA interfering (RNAi) significantly decreased Cd concentration in barley and improved tolerance to Cd stress, whereas HvVPE3 overexpression resulted in increased Cd concentration and hypersensitivity to Cd stress. Compared with the transformation-free wild-type (WT), HvVPE3- RNAi lines recorded significantly higher plant height and shoot biomass after two weeks 10 μM Cd exposure, but exhibited inhibited root net Cd2+ influx, suppressed Cd-induced increase in caspase-1, -8-like activities, and enhanced anti-oxidative activities such as catalase (CAT), peroxidase (POD), glutathione reductase (GR) and ascorbic acid oxidase (APX) thus mitigated Cd-induced oxidative stress and programmed cell death (PCD) to improve Cd tolerance in barley. Evolutionary bioinformatic confirms that VPE3s are highly conserved in green plants and may have evolved from the Order of Huperzia in Lycophytes. Our findings reveal a promising functional gene for breeding in developing barley varieties with low Cd accumulation and high Cd tolerance. • First report a γ-type VPE gene HvVPE3 regulates Cd uptake/tolerance. • VPE3 are evolved from the Order of Huperzia in Lycophytes. • HvVPE3 -RNAi curbed root net Cd2+ influx and Cd accumulation in barley. • HvVPE3 -RNAi suppressed Cd-induced PCD and ROS accumulation. • Novel genetic resource for Cd-tolerance/accumulation was verified. [ABSTRACT FROM AUTHOR]

Flap endonuclease 1 (FEN1), a structure-specific endo- and exonuclease, has multiple functions that determine essential biological processes, such as cell proliferation and cell death. As such, the enzyme must be precisely regulated to execute each of its functions with the right timing and in a specific subcellular location. Here we report that FEN1 is methylated at arginine residues, primarily at Arg192. The methylation suppresses FEN1 phosphorylation at Ser187. The methylated form, but not the phosphorylated form, of FEN1 strongly interacts with proliferating cell nuclear antigen (PCNA), ensuring the 'on' and 'off' timing of its reaction. Mutations of FEN1 disrupting arginine methylation and PCNA interaction result in unscheduled phosphorylation and a failure to localize to DNA replication or repair foci. This consequently leads to a defect in Okazaki fragment maturation, a delay in cell cycle progression, impairment of DNA repair and a high frequency of genome-wide mutations. [ABSTRACT FROM AUTHOR]

Presents a study which tested the hypothesis that inactivating tumor suppressor p53 protein with E6 gene delays cell death and studied the mechanism related to p53 independent cell death. Role of cell death in tissue homeostasis; Forms of cell death observed after injury or toxic stress; Background on apoptosis.

Abstract: Doxorubicin (Dox) is an indispensable chemotherapeutic agent for the treatment of various forms of neoplasia such as lung, breast, ovarian, and bladder cancers. Cardiotoxicity is a major concern for patients receiving Dox therapy. Previous work from our laboratory indicated that glucocorticoids (GCs) alleviate Dox-induced apoptosis in cardiomyocytes. Here we have found Glucocorticoid-Induced Leucine Zipper (GILZ) to be a mediator of GC-induced cytoprotection. GILZ was found to be induced in cardiomyocytes by GC treatment. Knocking down of GILZ using siRNA resulted in cancelation of GC-induced cytoprotection against apoptosis by Dox treatment. Overexpressing GILZ by transfection was able to protect cells from apoptosis induced by Dox as measured by caspase activation, Annexin V binding and morphologic changes. Western blot analyses indicate that GILZ overexpression prevented cytochrome c release from mitochondria and cleavage of caspase-3. When bcl-2 family proteins were examined, we found that GILZ overexpression causes induction of the pro-survival protein Bcl-xL. Since siRNA against Bcl-xL reverses GC induced cytoprotection, Bcl-xL induction represents an important event in GILZ-induced cytoprotection. Our data suggest that GILZ functions as a cytoprotective gene in cardiomyocytes. [Copyright &y& Elsevier]

The objective of this study was to investigate the cardioprotective effects of a dodecafluoropentane (DDFP)-based perfluorocarbon emulsion (DDFPe) as an artificial carrier for oxygen delivery to ischemic myocardium, using 99mTc-duramycin SPECT imaging. Rat hearts with Ischemia-reperfusion (I/R) was prepared by coronary ligation for 45-min followed by reperfusion. The feasibility of 99mTc-duramycin in detecting myocardial I/R injury and its kinetic profile were first verified in the ischemic hearts with 2-h reperfusion (n = 6). DDFPe (0.6 mL/kg) was intravenously administered at 10 min after coronary ligation in fifteen rats and saline was given in thirteen rats as controls. 99mTc-duramycin SPECT images were acquired in the DDFPe-treated hearts and saline controls at 2-h (DDFPe-2 h, n = 7 and Saline-2 h, n = 6) or 24-h (DDFPe-24 h, n = 8 and Saline-24 h, n = 7) of reperfusion. SPECT images, showing "hot-spot" 99mTc-duramycin uptake in the ischemic myocardium, exhibited significantly lower radioactive retention and smaller hot-spot size in the DDFPe-2 h and DDFPe-24 h hearts compared to controls. The infarcts in the Saline-24 h hearts extended significantly relative to measurements in the Saline-2 h. The extension of infarct size did not reach a statistical difference between the DDFPe-2 h and DDFPe-24 h hearts. Ex vivo measurement of 99mTc-duramycin activity (%ID/g) was lower in the ischemic area of DDFPe-2 h and DDFPe-24 h than that of the Saline-2 h and Saline-24 h hearts (P < 0.05). The area of injured myocardium, delineated by the uptake of 99mTc-duramycin, extended more substantially outside the infarct zone in the controls. Significant reduction in myocardial I/R injury, as assessed by 99mTc-duramycin cell death imaging and histopathological analysis, was induced by DDFPe treatment after acute myocardial ischemia. 99mTc-duramycin imaging can reveal myocardial cell death in ischemic hearts and may provide a tool for the non-invasive assessment of cardioprotective interventions. [ABSTRACT FROM AUTHOR]

Nrf2 encodes a transcription factor best known for regulating the expression of antioxidant and detoxification genes. Recent evidence suggested that Nrf2 mediates metabolic reprogramming in cancer cells. However, the role of Nrf2 in the biochemical metabolism of cardiac cells has not been studied. Using LC-MS/MS-based metabolomics, we addressed whether knocking out the Nrf2 gene in AC16 human cardiomyocytes affects metabolic reprogramming by oxidative stress. Profiling the basal level metabolites showed an elevated pentose phosphate pathway and increased levels of sugar alcohols, sorbitol, L-arabitol, xylitol and xylonic acid, in Nrf2 KO cells. With sublethal levels of oxidative stress, depletion of NAD, an increase of GDP and elevation of sugar alcohols, sorbitol and dulcitol, were detected in parent wild type (WT) cells. Knocking out Nrf2 did not affect these changes. Biochemical assays confirmed depletion of NAD in WT and Nrf2 KO cells due to H 2 O 2 treatment. These data support that although Nrf2 deficiency caused baseline activation of the pentose phosphate pathway and sugar alcohol synthesis, a brief exposure to none-lethal doses of H 2 O 2 caused NAD depletion in an Nrf2 independent manner. Loss of NAD may contribute to oxidative stress associated cell degeneration as observed with aging, diabetes and heart failure. • Nrf2 effect on metabolic reprogramming by oxidants was determined via metabolomics. • Oxidant causes NAD decrease but increased sugar alcohols in AC16 cardiomyocytes. • Nrf2 knockout did not affect these metabolic reprogramming by oxidative stress. • Nrf2 knockout caused a baseline increase of pentose phosphate pathway. [ABSTRACT FROM AUTHOR]

Poor immunogenicity and compromised T cell infiltration impede the application of immune-checkpoint blockade (ICB) immunotherapy for osteosarcoma (OS). Although autophagy is involved in enhancing the immune response, the synergistic role of autophagy in ICB immunotherapy and the accurate control of autophagy levels in OS remain elusive and challenging. Here, we designed a pH-sensitive autophagy-controlling nanocarrier, CUR-BMS1166@ZIF-8@PEG-FA (CBZP), loading a natural derivative, curcumin (CUR), to boost the immunotherapeutic response of PD-1/PD-L1 blockade by activating immunogenic cell death (ICD) via autophagic cell death, and BMS1166 to inhibit the PD-1/PD-L1 interaction simultaneously, enhancing the tumor immunogenicity and sensitizing the antitumor T cell immunity. After entering tumor cells, the pH-sensitive nanoparticles induced autophagy and decreased the intracellular pH, which in turn further facilitated the release of CUR to enhance autophagic activity. Transferring CBZP to orthotopic OS tumor-bearing mice showed powerful antitumor effects and established long-term immunity against tumor recurrence, accompanied by enhanced dendritic cell maturation and tumor infiltration of CD8+ T lymphocytes. Collectively, CBZP exhibited synergistic effects in treating OS by combining ICD induction with checkpoint blockade, thereby shedding light on the use of autophagy control as a potential clinical therapy for OS. [ABSTRACT FROM AUTHOR]