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.
Rechargeable lithium–oxygen batteries (LOBs) are considered to be one of the most promising energy storage systems. However, the use of reactive lithium (Li) metal and the formation of Li dendrites ...during battery operation would lead to serious safety concerns, especially when flammable liquid electrolytes are utilized. Herein, superior metal–organic framework (MOF) glass‐based solid‐state electrolytes (SSEs) is developed for stable all‐solid‐state LOBs (SSLOBs). These non‐flammable and boundary‐free MOF glass SSEs are capable of suppressing the dendrite growth and exhibiting long‐term Li stripping/plating stability, contributing to superior Li+ conductivity (5 × 10−4 S cm−1 at 20 °C), high Li+ transference number (0.86), and good electrochemical stability. It is discovered that discharge product deposition behavior in the solid‐solid interface can be well regulated by the ion/electron mixed conducted cathode fabricated with MOF glass SSEs and electronic conductive polymers. As a result, the SSLOBs can be stably recharged for 400 cycles with a low polarization gap and deliver a high capacity of 13552 mAh g−1. The development of this proposed MOF glass displays great application potential in energy storage systems with good safety and high energy density.
High‐performance metal–organic framework (MOF) glass‐based solid‐state electrolytes (SSEs) are developed for safe and stable all‐solid‐state lithium–oxygen batteries (SSLOBs). Taking advantage of the highly mechanical stability and boundary‐free properties, the MOF glass‐based SSEs display superior lithium stripping/plating stability and endow the SSLOBs with high capacity and long‐term cycling stability.
Li‐N2 batteries have received widespread attention for their potential to integrate N2 fixation, energy storage, and conversion. However, because of the low activity and poor stability of cathode ...catalysts, the electrochemical performance of Li‐N2 batteries is suboptimal, and their electrochemical reversibility has rarely been proven. In this study, a novel bifunctional photo‐assisted Li‐N2 battery system was established by employing a plasmonic Au nanoparticles (NPs)‐modified defective carbon nitride (Au‐Nv‐C3N4) photocathode. The Au‐Nv‐C3N4 exhibits strong light‐harvesting, N2 adsorption, and N2 activation abilities, and the photogenerated electrons and hot electrons are remarkably beneficial for accelerating the discharge and charge reaction kinetics. These advantages enable the photo‐assisted Li‐N2 battery to achieve a low overpotential of 1.32 V, which is the lowest overpotential reported to date, as well as superior rate capability and prolonged cycle stability (≈500 h). Remarkably, a combination of theoretical and experimental results demonstrates the high reversibility of the photo‐assisted Li‐N2 battery. The proposed novel strategy for developing efficient cathode catalysts and fabricating photo‐assisted battery systems breaks through the overpotential bottleneck of Li‐N2 batteries, providing important insights into the mechanism underlying N2 fixation and storage.
A novel bifunctional photo‐assisted Li‐N2 battery system is established by employing a plasmonic Au nanoparticles (NPs)‐modified defective carbon nitride (Au‐Nv‐C3N4) photocathode. Benefiting from the strong light‐harvesting, N2 adsorption, and N2 activation abilities of the Au‐Nv‐C3N4 cathode, the photo‐assisted Li‐N2 battery displays the highest round‐trip efficiency (56.2 %) to date, superior rate capability, and stable cycle life of over 500 h.
Solid‐state lithium (Li) batteries promise both high energy density and safety while existing solid‐state electrolytes (SSEs) fail to satisfy the rigorous requirements of battery operations. Herein, ...novel polyoxometalate SSEs, Li3PW12O40 and Li3PMo12O40, are synthesized, which exhibit excellent interfacial compatibility with electrodes and chemical stability, overcoming the limitations of conventional SSEs. A high ionic conductivity of 0.89 mS cm−1 and a low activation energy of 0.23 eV are obtained due to the optimized three‐dimensional Li+ migration network of Li3PW12O40. Li3PW12O40 exhibits a wide window of electrochemical stability that can both accommodate the Li anode and high‐voltage cathodes. As a result, all‐solid‐state Li metal batteries fabricated with Li/Li3PW12O40/LiNi0.5Co0.2Mn0.3O2 display a stable cycling up to 100 cycles with a cutoff voltage of 4.35 V and an areal capacity of more than 4 mAh cm−2, as well as a cost‐competitive SSEs price of $5.68 kg−1. Moreover, Li3PMo12O40 homologous to Li3PW12O40 was obtained via isomorphous substitution, which formed a low‐resistance interface with Li3PW12O40. Applications of Li3PW12O40 and Li3PMo12O40 in Li‐air batteries further demonstrate that long cycle life (650 cycles) can be achieved. This strategy provides a facile, low‐cost strategy to construct efficient and scalable solid polyoxometalate electrolytes for high‐energy solid‐state Li metal batteries.
Polyoxometalates are proposed as a groundbreaking platform for high‐energy all‐solid‐state lithium‐metal batteries. Benefiting from rational structure design, Li3PW12O4o electrolytes exhibit remarkable cost‐effectiveness ($5.68 kg−1), electrochemical stability, and high ionic conductivity (0.89 mS cm−1). The lithium‐metal batteries utilizing sustainable electrolyte achieve more than 200 cycles and the lithium‐air batteries operate over 600 cycles.
Background
NASH is one of the fastest growing liver diseases that leads to severe steatosis, inflammation and ultimately liver injury. However, the pathophysiological mechanisms of NASH remain ...unclear and pharmacological treatment against the disease is unavailable currently. Ferroptosis is a non‐apoptotic form of cell death induced by iron‐dependent lipid peroxidation. Since NASH progression is accompanied by massive lipid accumulation, which generates lipotoxic species, we investigated the role of ferroptosis in NASH progression.
Method
Mice were fed on MCD‐diet to mimic NASH progression and gene expression in liver was analysed by RNA‐seq. The occurrence of hepatic ferroptosis was measured by lipid ROS level, electron microscopy and in vivo PI staining. The beneficial effects of ferroptosis inhibitors on NASH was evaluated by liver pathology analysis. The mechanism of lipid ROS induced lipid droplets accumulation was investigated by in vitro cell culture.
Results
RNA‐seq analysis suggested that elevated arachidonic acid metabolism promotes ferroptosis in MCD‐diet fed mouse livers, which was further demonstrated by lipid ROS accumulation, morphological change of mitochondria and increased cell death. Iron accumulation was detected in the liver and the serum of MCD‐fed mice. Scavenging of ferroptosis‐linked lipid peroxides reduced lipid accumulation both in vivo and in vitro. Importantly, ferroptosis inhibitors alleviated MCD‐diet induced inflammation, fibrogenesis and liver injury. Finally, lipid ROS promotes liver steatosis by boosting lipid droplets formation.
Conclusion
Our results demonstrate an important role of ferroptosis in the progression of MCD‐diet induced NASH and suggest that ferroptosis may serve as a therapeutic target for NASH treatment.
An asymmetric intermolecular, three-component radical-initiated dicarbofunctionalization of 1,1-diarylalkenes with diverse carbon-centered radical precursors and electron-rich heteroaromatics by a ...copper(I) and chiral phosphoric acid cooperative catalysis strategy has been developed, providing straightforward access to chiral triarylmethanes bearing quaternary all-carbon stereocenters with high efficiency as well as excellent chemo- and enantioselectivity. The key to success is not only the introduction of a sterically demanding chiral phosphoric acid to favor radical difunctionalization over the otherwise remarkable side reactions but also the in situ generation of carbocation intermediates from benzylic radical to realize asymmetric induction with the aid of a removable hydroxy directing group via cooperative interactions with chiral phosphate. Density functional theory calculations elucidated the critical chiral environment created by the hydrogen-bonding and ion-pair interactions between the chiral phosphoric acid catalyst and substrates, which leads to the enantioselective C–C bond formation.
The ability of cells to respond to changes in nutrient availability is essential for the maintenance of metabolic ho- meostasis and viability. One of the key cellular responses to nutrient withdrawal ...is the upregulation of autophagy. Recently, there has been a rapid expansion in our knowledge of the molecular mechanisms involved in the regula- tion of mammalian autophagy induction in response to depletion of key nutrients. Intracellular amino acids, ATP, and oxygen levels are intimately tied to the cellular balance of anabolic and catabolic processes. Signaling from key nutrient-sensitive kinases mTORC1 and AMP-activated protein kinase （AMPK） is essential for the nutrient sensing of the autophagy pathway. Recent advances have shown that the nutrient status of the cell is largely passed on to the autophagic machinery through the coordinated regulation of the ULK and VPS34 kinase complexes. Identification of extensive crosstalk and feedback loops converging on the regulation of ULK and VPS34 can be attributed to the im- portance of these kinases in autophagy induction and maintaining cellular homeostasis.
The success of cancer immunotherapy in solid tumors depends on a sufficient distribution of effector T cells into malignant lesions. However, immune-cold tumors utilize many T-cell exclusion ...mechanisms to resist immunotherapy. T cells have to go through three steps to fight against tumors: trafficking to the tumor core, surviving and expanding, and maintaining the memory phenotype for long-lasting responses. Cytokines and chemokines play critical roles in modulating the recruitment of T cells and the overall cellular compositions of the tumor microenvironment. Manipulating the cytokine or chemokine environment has brought success in preclinical models and early-stage clinical trials. However, depending on the immune context, the same cytokine or chemokine signals may exhibit either antitumor or protumor activities and induce unwanted side effects. Therefore, a comprehensive understanding of the cytokine and chemokine signals is the premise of overcoming T-cell exclusion for effective and innovative anti-cancer therapies.
Hepatocellular carcinoma (HCC) is one of the most common human malignancies worldwide with very poor prognosis. Resistance to targeted therapeutic drugs such as sorafenib remains one of the major ...challenges in clinical treatment. In the present study, PARP1 was found to be highly expressed in human embryonic stem cells, but progressively decreased upon specified hepatic differentiation. Reactivation of PARP1 expression was also detected in HCC residual tumors after sorafenib treatment in xenograft mouse model, indicating the potential important roles of PARP1 in stem cell pluripotency and HCC sorafenib treatment resistance. Overexpression of PARP1 was frequently observed in HCC patients, and closely associated with poor clinical outcome. Treatment of Sorafenib induced activation of DNA damage repair signaling, which is highly active and essential for maintenance of stem cell pluripotency in HCC residual tumors. PARP inhibitor Olaparib extensively suppressed the DNA damage repair signaling, and significantly inhibited the global pluripotent transcriptional network. The repression of key pluripotent transcriptional factors and DNA damage repair signaling by Olaparib was mainly through CHD1L-mediated condensation of the chromatin structure at their promotor regions. The global reshaping of the pluripotent transcriptome by Olaparib might reinforce Sorafenib in eliminating HCC residual tumors and enhance therapeutic efficiency.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Growing evidences suggest that cancer stem cells exhibit many molecular characteristics and phenotypes similar to their ancestral progenitor cells. In the present study, human embryonic stem cells ...are induced to differentiate into hepatocytes along hepatic lineages to mimic liver development in vitro. A liver progenitor specific gene, RALY RNA binding protein like (RALYL), is identified. RALYL expression is associated with poor prognosis, poor differentiation, and metastasis in clinical HCC patients. Functional studies reveal that RALYL could promote HCC tumorigenicity, self-renewal, chemoresistance, and metastasis. Moreover, molecular mechanism studies show that RALYL could upregulate TGF-β2 mRNA stability by decreasing N6-methyladenosine (m
A) modification. TGF-β signaling and the subsequent PI3K/AKT and STAT3 pathways, upregulated by RALYL, contribute to the enhancement of HCC stemness. Collectively, RALYL is a liver progenitor specific gene and regulates HCC stemness by sustaining TGF-β2 mRNA stability. These findings may inspire precise therapeutic strategies for HCC.
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