Hepatocellular carcinoma (HCC) is an aggressive disease with a poor clinical outcome. The cancer stem cell (CSC) model states that tumour growth is powered by a subset of tumour stem cells within ...cancers. This model explains several clinical observations in HCC (as well as in other cancers), including the almost inevitable recurrence of tumours after initial successful chemotherapy and/or radiotherapy, as well as the phenomena of tumour dormancy and treatment resistance. The past two decades have seen a marked increase in research on the identification and characterization of liver CSCs, which has encouraged the design of novel diagnostic and treatment strategies for HCC. These studies revealed novel aspects of liver CSCs, including their heterogeneity and unique immunobiology, which are suggestive of opportunities for new research directions and potential therapies. In this Review, we summarize the present knowledge of liver CSC markers and the regulators of stemness in HCC. We also comprehensively describe developments in the liver CSC field with emphasis on experiments utilizing single-cell transcriptomics to understand liver CSC heterogeneity, lineage-tracing and cell-ablation studies of liver CSCs, and the influence of the CSC niche and tumour microenvironment on liver cancer stemness, including interactions between CSCs and the immune system. We also discuss the potential application of liver CSC-based therapies for treatment of HCC.
Gluconic metabolic reprogramming, immune response, and inflammation are intimately linked. Glycolysis involves in the pathologic progress in acute and chronic inflammatory diseases. However, the ...involvement of glycolysis in the acute lung injury (ALI) is still unclear. This study investigated the role of glycolysis in an animal model of ALI. First, we found that lactate content in serum was remarkably increased in ALI patients and a murine model induced by intratracheal administration of lipopolysaccharide (LPS). The key proteins involving in glycolysis were robustly elevated, including HK2,
PKM2, and
HIF‐1α. Intriguingly, inhibition of glycolysis by 2‐deoxyglucose (2‐DG) pronouncedly attenuated the lung tissue pathological injury, accumulation of neutrophil, oxidative stress, expression of proinflammatory factors in the lung of ALI mice induced by LPS. The 2‐DG treatment also strongly suppressed the activation of the NOD‐like receptor (NLR) family and pyrin domain‐containing protein 3 (NLRP3) inflammasome. Furthermore, we investigated the role of glycolysis in the inflammatory response of primary murine macrophages activated by LPS in vitro. We found that the 2‐DG treatment remarkably reduced the expression of proinflammatory factors induced by LPS, including tumor necrosis factor‐α messenger RNA (mRNA), pro‐interleukin (IL)‐1β mRNA, pro‐IL‐18 mRNA, NLRP3 mRNA, caspase‐1 mRNA, and IL‐1β protein. Altogether, these data provide a novel link between gluconic metabolism reprogramming and uncontrolled inflammatory response in ALI. This study suggests glycolytic inhibition as an effective anti‐inflammatory strategy in treating ALI.
This article provides a novel link between gluconic metabolism reprogramming and uncontrolled inflammatory response in acute lung injury (ALI). This study suggests glycolytic inhibition as an effective anti‐inflammatory strategy in treating ALI.
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•Loofah sponge-derived 3D porous activated carbon is facilely prepared.•Hierarchical pores are constructed in the resulting SAC-x architecture.•SAC-4 exhibits excellent capacity ...performance in the three- and two-electrode systems.•The resulting materials have tremendous potentials for the energy storage applications.
Biomass carbon source is generally cheap, environmentally friendly and readily available in high quality and quantity. In this work, a series of loofah sponge-derived activated carbon (SAC-x) with hierarchical porous structures are prepared by KOH chemical activation and used as electrode materials for supercapacitors. The pore size can be easily controllable by changing the dosage of KOH. The optimized material (SAC-4) exhibits a high specific capacitance of 309.6Fg−1 at 1Ag−1 in the three-electrode system using 6M KOH electrolyte. More importantly, the as-assembled symmetric supercapacitor based on SAC-4 exhibits a high energy density of 16.1Whkg−1 at a power density of 160.0Wkg−1 using 1M Na2SO4 electrolyte. These remarkable results demonstrate the exciting commercial potential of SAC-x for high-performance supercapacitor applications due to their high specific surface area, appropriately porous structure, and the trace heteroatom (O and N) functionalities.
Pulmonary fibrosis (PF) is a senescence‐associated disease with poor prognosis. Currently, there is no effective therapeutic strategy for preventing and treating the disease process. Mounting ...evidence suggests that arachidonic acid (ARA) metabolites are involved in the pathogenesis of various fibrosis. However, the relationship between the metabolism of ARA and PF is still elusive. In this study, we observed a disorder in the cyclooxygenase‐2/cytochrome P450 (COX‐2/CYP) metabolism of ARA in the lungs of PF mice induced by bleomycin (BLM). Therefore, we aimed to explore the role of COX‐2/CYP‐derived ARA metabolic disorders in PF. PTUPB, a dual COX‐2 and soluble epoxide hydrolase (sEH) inhibitor, was used to restore the balance of COX‐2/CYP metabolism. sEH is an enzyme hydrolyzing epoxyeicosatrienoic acids derived from ARA by CYP. We found that PTUPB alleviated the pathological changes in lung tissue and collagen deposition, as well as reduced senescence marker molecules (p16Ink4a and p53‐p21Waf1/Cip1) in the lungs of mice treated by BLM. In vitro, we found that PTUPB pretreatment remarkably reduced the expression of senescence‐related molecules in the alveolar epithelial cells (AECs) induced by BLM. In conclusion, our study supports the notion that the COX‐2/CYP‐derived ARA metabolic disorders may be a potential therapeutic target for PF via inhibiting the cellular senescence in AECs.
Here, we observed a disorder in the cyclooxygenase‐2/cytochrome P450 (COX‐2/CYP) metabolism of arachidonic acid in the lungs of mice with pulmonary fibrosis (PF) induced by bleomycin. PTUPB, a dual COX‐2 and soluble epoxide hydrolase inhibitor, was used to restore the balance of COX‐2/CYP metabolism. Our findings showed that PTUPB alleviated bleomycin‐induced PF via inhibiting the cellular senescence in alveolar epithelial cells, indicating a potential therapeutic target for PF.
Abstract
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca
2+
-mobilizing second messenger which uniquely mobilizes Ca
2+
from acidic endolysosomal organelles. However, the ...molecular identity of the NAADP receptor remains unknown. Given the necessity of the endolysosomal two-pore channel (TPC1 or TPC2) in NAADP signaling, we performed affinity purification and quantitative proteomic analysis of the interacting proteins of NAADP and TPCs. We identified a Sm-like protein Lsm12 complexed with NAADP, TPC1, and TPC2. Lsm12 directly binds to NAADP via its Lsm domain, colocalizes with TPC2, and mediates the apparent association of NAADP to isolated TPC2 or TPC2-containing membranes. Lsm12 is essential and immediately participates in NAADP-evoked TPC activation and Ca
2+
mobilization from acidic stores. These findings reveal a putative RNA-binding protein to function as an NAADP receptor and a TPC regulatory protein and provides a molecular basis for understanding the mechanisms of NAADP signaling.
Epoxyeicosatrienoic acids (EETs) derived from arachidonic acid exert anti‐inflammation effects. We have reported that blocking the degradation of EETs with a soluble epoxide hydrolase (sEH) inhibitor ...protects mice from lipopolysaccharide (LPS)‐induced acute lung injury (ALI). The underlying mechanisms remain essential questions. In this study, we investigated the effects of EETs on the activation of nucleotide‐binding domain leucine‐rich repeat‐containing receptor, pyrin domain‐containing‐3 (NLRP3) inflammasome in murine macrophages. In an LPS‐induced ALI murine model, we found that sEH inhibitor 1‐trifluoromethoxyphenyl‐3‐(1‐propionylpiperidin‐4‐yl), TPPU, profoundly attenuated the pathological injury and inhibited the activation of the NLRP3 inflammasome, characterized by the reduction of the protein expression of NLRP3, ASC, pro‐caspase‐1, interleukin precursor (pro‐IL‐1β), and IL‐1β p17 in the lungs of LPS‐treated mice. In vitro, primary peritoneal macrophages from C57BL/6 were primed with LPS and activated with exogenous adenosine triphosphate (ATP). TPPU treatment remarkably reduced the expression of NLRP3 inflammasome‐related molecules and blocked the activation of NLRP3 inflammasome. Importantly, four EETs (5,6‐EET, 8,9‐EET, 11,12‐EET, and 14,15‐EET) inhibited the activation of NLRP3 inflammasome induced by LPS + ATP or LPS + nigericin in macrophages in various degree. While the inhibitory effect of 5,6‐EET was the weakest. Mechanismly, EETs profoundly decreased the content of reactive oxygen species (ROS) and restored the calcium overload in macrophages receiving LPS + ATP stimulation. In conclusion, this study suggests that EETs inhibit the activation of the NLRP3 inflammasome by suppressing calcium overload and ROS production in macrophages, contributing to the therapeutic potency to ALI.
We have reported that blocking the degradation of epoxyeicosatrienoic acids (EETs) derived from arachidonic acid could attenuate the lipopolysaccharide‐induced acute lung injury (ALI) in mice. The underlying mechanisms remain important questions. Herein, we found that EETs inhibit the activation of nucleotide‐binding domain leucine‐rich repeat‐containing receptor, pyrin domain‐containing‐3 inflammasome by suppressing calcium overload and reactive oxygen species production in macrophages, contributing to the therapeutic potency to ALI.
Three-level converters typically feature low switching loss and small filter size. In order to realize a high-power-density design for three-level converters, SiC MOSFETs may be selected instead of ...using Si insulated-gate bipolar transistors. However, all-SiC-MOSFET-based converters suffer from extremely high total cost. In this paper, a SiC MOSFET and Si device hybrid active neutral-point-clamped (ANPC) converter is proposed. It consists of four Si active switches and only two SiC MOSFETs. Thus, it has lower total cost compared to the all-SiC-MOSFET-based ANPC converter. Furthermore, a dedicated modulation scheme is proposed to completely move all the switching events from Si devices to SiC MOSFETs by using redundant switching states. As a result, the switching losses are significantly reduced and extremely high efficiency is achieved. The proposed converter has fully utilized the low-switching-loss advantage of SiC MOSFETs and the low-cost advantage of Si devices, which shows significant superiority in high-end grid-connected inverter and rectifier applications.
: Dysregulation of arachidonic acid (ARA) metabolism results in inflammation; however, its role in acute lung injury (ALI) remains elusive. In this study, we addressed the role of dysregulated ARA ...metabolism in cytochromes P450 (CYPs) /cyclooxygenase-2 (COX-2) pathways in the pathogenesis of lipopolysaccharide (LPS)-induced ALI in mice.
: The metabolism of CYPs/COX-2-derived ARA in the lungs of LPS-induced ALI was investigated in C57BL/6 mice. The COX-2/sEH dual inhibitor PTUPB was used to establish the function of CYPs/COX-2 dysregulation in ALI. Primary murine macrophages were used to evaluate the underlying mechanism of PTUPB involved in the activation of NLRP3 inflammasome
.
: Dysregulation of CYPs/COX-2 metabolism of ARA occurred in the lungs and in primary macrophages under the LPS challenge. Decrease mRNA expression of
and
was observed, which metabolize ARA into epoxyeicosatrienoic acids (EETs). The expressions of COX-2 and soluble epoxide hydrolase (sEH), on the other hand, was significantly upregulated. Pre-treatment with the dual COX-2 and sEH inhibitor, PTUPB, attenuated the pathological injury of lung tissues and reduced the infiltration of inflammatory cells. Furthermore, PTUPB decreased the pro-inflammatory factors, oxidative stress, and activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in LPS-induced ALI mice. PTUPB pre-treatment remarkably reduced the activation of macrophages and NLRP3 inflammasome
. Significantly, both preventive and therapeutic treatment with PTUPB improved the survival rate of mice receiving a lethal dose of LPS.
: The dysregulation of CYPs/COX-2 metabolized ARA contributes to the uncontrolled inflammatory response in ALI. The dual COX-2 and sEH inhibitor PTUPB exerts anti-inflammatory effects in treating ALI by inhibiting the NLRP3 inflammasome activation.
Adsorption and photocatalytic degradation are effective strategies to purify the wastewater caused by organic dyes. In this study, graphitic carbon nitride (g-C3N4) powders are prepared from melamine ...with a thermal decomposition method, which are applied to synthesize the direct Z-scheme g-C3N4-ZnO@graphene aerogel (g-C3N4-ZnO@GA) heterojunctions with a hydrothermal self-assembly combined with freeze-drying. As adsorbents and photocatalysts, the heterojunctions exhibit superior adsorption capacity and catalytic activity for the elimination of organic pollutants irradiated by UV and visible light. Among all the materials, g-C3N4-ZnO@GA(30%) displays the best purification efficiencies of rhodamine B (RhB) under both UV and visible light illumination, reaching 81.0% and 82.7%, respectively, because of its hierarchical porous structure and the synergistic effect among the components. More importantly, g-C3N4-ZnO@GA(30%) possesses good reusability, which can keep 87.1% of the initial activity after four cycles. What's more, the heterojunctions also demonstrate high removal efficiency for other organic dyes, such as methyl orange (MO), demonstrating their promising application in environmental remediation. Finally, based on the experimental investigations, a reasonable photocatalytic mechanism is proposed and analyzed. The present work provides a promising way to construct the direct Z-scheme porous heterojunctions for elimination of environmental pollutants.
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•The direct Z-scheme g-C3N4-ZnO@GA heterojunctions are facilely constructed.•They possess superior removal performance for various organic pollutants.•A reasonable photocatalytic mechanism is proposed and analyzed.
Necroptosis, a recently described form of programmed cell death, is the main way of alveolar epithelial cells (AECs) death in acute lung injury (ALI). While the mechanism of how to trigger ...necroptosis in AECs during ALI has been rarely evaluated. Long optic atrophy protein 1 (L‐OPA1) is a crucial mitochondrial inner membrane fusion protein, and its deficiency impairs mitochondrial function. This study aimed to investigate the role of L‐OPA1 deficiency‐mediated mitochondrial dysfunction in AECs necroptosis. We comprehensively investigated the detailed contribution and molecular mechanism of L‐OPA1 deficiency in AECs necroptosis by inhibiting or activating L‐OPA1. First, our data showed that L‐OPA1 expression was downregulated in the lungs and AECs under the lipopolysaccharide (LPS) challenge. Furthermore, inhibition of L‐OPA1 aggravated the pathological injury, inflammatory response, and necroptosis in the lungs of LPS‐induced ALI mice. In vitro, inhibition of L‐OPA1 induced necroptosis of AECs, while activation of L‐OPA1 alleviated necroptosis of AECs under the LPS challenge. Mechanistically, inhibition of L‐OPA1 aggravated necroptosis of AECs by inducing mitochondrial fragmentation and reducing mitochondrial membrane potential. While activation of L‐OPA1 had the opposite effects. In summary, these findings indicate for the first time that L‐OPA1 deficiency mediates mitochondrial fragmentation, induces necroptosis of AECs, and exacerbates ALI in mice.
L‐OPA1 deficiency mediates mitochondrial fragmentation, induces necroptosis of alveolar epithelial cells, and exacerbates acute lung injury in mice.
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