The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence after chemotherapy and radiotherapy. Targeting BCSCs may ameliorate breast cancer ...relapse and therapy resistance. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) positively associates with breast cancer stemness and progression. Elevated TRIB3 expression supports BCSCs by interacting with AKT to interfere with the FOXO1-AKT interaction and suppress FOXO1 phosphorylation, ubiquitination, and degradation by E3 ligases SKP2 and NEDD4L. The accumulated FOXO1 promotes transcriptional expression of SOX2, a transcriptional factor for cancer stemness, which in turn, activates FOXO1 transcription and forms a positive regulatory loop. Disturbing the TRIB3-AKT interaction suppresses BCSCs by accelerating FOXO1 degradation and reducing SOX2 expression in mouse models of breast cancer. Our study provides insights into breast cancer development and confers a potential therapeutic strategy against TRIB3-overexpressed breast cancer.
Abstract
High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung ...cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, highlighting the need for therapeutics with alternative mechanisms of action. Here, we report that the elevated tribbles pseudokinase 3 (TRIB3) is positively associated with EGFR stability and NSCLC progression. TRIB3 interacts with EGFR and recruits PKCα to induce a Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream activity, and NSCLC stemness. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.
The transcription factor MYC is deregulated in almost all human cancers, especially in aggressive lymphomas, through chromosomal translocation, amplification, and transcription hyperactivation. Here, ...we report that high expression of tribbles homologue 3 (TRIB3) positively correlates with elevated MYC expression in lymphoma specimens; TRIB3 deletion attenuates the initiation and progression of MYC-driven lymphoma by reducing MYC expression. Mechanistically, TRIB3 interacts with MYC to suppress E3 ubiquitin ligase UBE3B-mediated MYC ubiquitination and degradation, which enhances MYC transcriptional activity, causing high proliferation and self-renewal of lymphoma cells. Use of a peptide to disturb the TRIB3-MYC interaction together with doxorubicin reduces the tumor burden in Myc
mice and patient-derived xenografts. The pathophysiological relevance of UBE3B, TRIB3 and MYC is further demonstrated in human lymphoma. Our study highlights a key mechanism for controlling MYC expression and a potential therapeutic option for treating lymphomas with high TRIB3-MYC expression.
This retrospective study was designed to explore whether neutrophil to lymphocyte ratio (NLR) is a prognostic factor in patients with coronavirus disease 2019 (COVID‐19). A cohort of patients with ...COVID‐19 admitted to the Tongren Hospital of Wuhan University from 11 January 2020 to 3 March 2020 was retrospectively analyzed. Patients with hematologic malignancy were excluded. The NLR was calculated by dividing the neutrophil count by the lymphocyte count. NLR values were measured at the time of admission. The primary outcome was all‐cause in‐hospital mortality. A multivariate logistic analysis was performed. A total of 1004 patients with COVID‐19 were included in this study. The mortality rate was 4.0% (40 cases). The median age of nonsurvivors (68 years) was significantly older than survivors (62 years). Male sex was more predominant in nonsurvival group (27; 67.5%) than in the survival group (466; 48.3%). NLR value of nonsurvival group (median: 49.06; interquartile range IQR: 25.71‐69.70) was higher than that of survival group (median: 4.11; IQR: 2.44‐8.12; P < .001). In multivariate logistic regression analysis, after adjusting for confounding factors, NLR more than 11.75 was significantly correlated with all‐cause in‐hospital mortality (odds ratio = 44.351; 95% confidence interval = 4.627‐425.088). These results suggest that the NLR at hospital admission is associated with in‐hospital mortality among patients with COVID‐19. Therefore, the NLR appears to be a significant prognostic biomarker of outcomes in critically ill patients with COVID‐19. However, further investigation is needed to validate this relationship with data collected prospectively.
Highlights
NLR is a significant prognostic biomarker of outcomes in critically ill patients with COVID‐19.
COVID‐19 is more likely to infected those elder men with chronic comorbidities.
NLR may also help in the early identification of older patients at higher risk of COVID‐19.
Close monitoring and timely intervention are needed for elderly patients with COVID‐19.
1,8-Naphthalimide, as one of the classical dyes and fluorophores, has been widely used in analytical chemistry, materials chemistry, and biochemistry fields because of its excellent characteristic ...photostability, good structural flexibility, high fluorescence quantum yield, and large Stokes shift. This review mainly focuses on 1,8-naphthalimide and its derivatives in ion detection, molecular recognition, material applications, and bioimaging in the past five years. Simultaneously, we hope to develop more powerful fluorescent chemosensors for broad and exciting applications in the future.
Application of the classic fluorescent dye 1,8-naphthalimide.
The laurel family within the Magnoliids has attracted attentions owing to its scents, variable inflorescences, and controversial phylogenetic position. Here, we present a chromosome-level assembly of ...the Litsea cubeba genome, together with low-coverage genomic and transcriptomic data for many other Lauraceae. Phylogenomic analyses show phylogenetic discordance at the position of Magnoliids, suggesting incomplete lineage sorting during the divergence of monocots, eudicots, and Magnoliids. An ancient whole-genome duplication (WGD) event occurred just before the divergence of Laurales and Magnoliales; subsequently, independent WGDs occurred almost simultaneously in the three Lauralean lineages. The phylogenetic relationships within Lauraceae correspond to the divergence of inflorescences, as evidenced by the phylogeny of FUWA, a conserved gene involved in determining panicle architecture in Lauraceae. Monoterpene synthases responsible for production of specific volatile compounds in Lauraceae are functionally verified. Our work sheds light on the evolution of the Lauraceae, the genetic basis for floral evolution and specific scents.
Although the electrochemical catalytic conversion process is effective in increasing the reversible capacity of lithium‐ion batteries, the low contact efficiency between metal catalyst and substrate ...and pulverization of the solid electrolyte interface (SEI) film without protection are not beneficial for the electrochemical reactions. Herein, Fe7S8 nanoparticles are confined by both reduced graphene oxide (RGO) and in‐situ‐formed amorphous carbon (C) to form dual‐carbon‐confined Fe7S8 as a lithium‐ion anode. The dual‐carbon‐confined structure provides a confined space to prevent pulverization of the SEI film and increases the local concentration of intermediate phases, which could be electrocatalytically decomposed by Fe nanoparticles formed in situ to increase the reversibility of the electrochemical reactions and gain high reversible capacity. In addition, the dual‐carbon‐confined structure ensures fast transfer of electrons and boosts transport of lithium ions due to the highly conductive dual‐carbon shell. Thus, the Fe7S8/C/RGO anode delivers an excellent rate performance and long cycling stability. At current densities of 2000 and 5000 mA g−1, the reversible capacities are 520 mA h g−1 over 1500 cycles and 294 mA h g−1 over 2000 cycles, respectively.
Dual confinement: Fe7S8 nanoparticles dually confined by both reduced graphene oxide (RGO) and in‐situ‐formed amorphous carbon (C) were fabricated as Li‐ion battery anodes (see figure). The dual‐carbon‐confined structure prevents pulverization of the solid electrolyte interface film, increases the local concentration of intermediate phases, makes the electrochemical catalytic conversion reaction occur easily, and ensures fast transfer of electrons and increased transport of lithium ions.
Impaired macroautophagy/autophagy is involved in the pathogenesis of hepatic fibrosis. However, how aberrant autophagy promotes fibrosis is far from understood. Here, we aimed to define a previously ...unrevealed pro-fibrotic mechanism for the stress protein TRIB3 (tribbles pseudokinase 3)-mediated autophagy dysfunction. Human fibrotic liver tissues were obtained from patients with cirrhosis who underwent an open surgical repair process. The functional implications of TRIB3 were evaluated in mouse models of hepatic fibrosis induced by bile duct ligation (BDL) or thioacetamide (TAA) injection. Human fibrotic liver tissues expressed higher levels of TRIB3 and selective autophagic receptor SQSTM1/p62 (sequestosome 1) than nonfibrotic tissues and the elevated expression of TRIB3 and SQSTM1 was positively correlated in the fibrotic tissues. Silencing Trib3 protected against experimentally induced hepatic fibrosis, accompanied by restored autophagy activity in fibrotic liver tissues. Furthermore, TRIB3 interacted with SQSTM1 and hindered its binding to MAP1LC3/LC3, which caused the accumulation of SQSTM1 aggregates and obstructed autophagic flux. The TRIB3-mediated autophagy impairment not only suppressed autophagic degradation of late endosomes but also promoted hepatocellular secretion of INHBA/Activin A-enriched exosomes which caused migration, proliferation and activation of hepatic stellate cells (HSCs), the effector cells of liver fibrosis. Disrupting the TRIB3-SQSTM1 interaction with a specific helical peptide exerted potent protective effects against hepatic fibrosis by restoring autophagic flux in hepatocytes and HSCs. Together, stress-elevated TRIB3 expression promotes hepatic fibrosis by interacting with SQSTM1 and interfering with its functions in liver-parenchymal cells and activating HSCs. Targeting this interaction is a promising strategy for treating fibroproliferative liver diseases.
Abbreviations: 3-MA: 3-methyladenine; AAV: adeno-associated virus; ACTA2/α-SMA: actin, alpha 2, smooth muscle, aorta; BDL: bile duct ligation; BECN1/Beclin 1: beclin 1, autophagy related; CHX: cycloheximide; CQ: chloroquine; Edu: 5-ethynyl-2-deoxyuridine; ESCRT: endosomal sorting complexes required for transport; HSC: hepatic stellate cell; ILV: intralumenal vesicle; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MVB: multivesicular body; PIK3C3: phosphatidylinositol 3-kinase, catalytic subunit type 3; PPI: protein-protein interaction; SQSTM1/p62: sequestosome 1; TAA: thioacetamide; TEM: transmission electron microscopy; TGFB1/TGFβ1: transforming growth factor, beta 1; TLR2: toll-like receptor 2; TRIB3: tribbles pseudokinase 3
Intermittent food deprivation (fasting, IF) improves mood and cognition and protects neurons against excitotoxic degeneration in animal models of epilepsy and Alzheimer's disease (AD). The mechanisms ...by which neuronal networks adapt to IF and how such adaptations impact neuropathological processes are unknown. We show that hippocampal neuronal networks adapt to IF by enhancing GABAergic tone, which is associated with reduced anxiety-like behaviors and improved hippocampus-dependent memory. These neuronal network and behavioral adaptations require the mitochondrial protein deacetylase SIRT3 as they are abolished in SIRT3-deficient mice and wild type mice in which SIRT3 is selectively depleted from hippocampal neurons. In the App
mouse model of AD, IF reduces neuronal network hyperexcitability and ameliorates deficits in hippocampal synaptic plasticity in a SIRT3-dependent manner. These findings demonstrate a role for a mitochondrial protein deacetylase in hippocampal neurons in behavioral and GABAergic synaptic adaptations to IF.
In contrast with the well-developed C-C and C-N axial chirality, research focusing on the catalytically asymmetric synthesis of N-N axially chiral compounds is still limited. As a privileged subunit ...of many antibiotics, the synthesis of N-N axially chiral 3,3′-bisquinazolinones has not been updated with atroposelective construction. Herein, we firstly report a chiral phosphoric acid-catalyzed dual-ring formation strategy leading to the aforementioned compounds with good chemical yields and enantioselectivities. Notably, metal-free reaction conditions are another advantage of this procedure.
An efficient, CPA-catalyzed, dual-ring formation strategy to construct a class of N-N axially chiral 3,3′-bisquinazolinones is reported for the first time. Notably, metal-free reaction conditions were also involved in this procedure.
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