Mitochondrial dynamics plays an important role in tumour progression. However, how these dynamics integrate tumour metabolism in hepatocellular carcinoma (HCC) metastasis is still unclear.
The ...mitochondrial fusion protein mitofusin-1 (MFN1) expression and its prognostic value are detected in HCC. The effects and underlying mechanisms of MFN1 on HCC metastasis and metabolic reprogramming are analysed both in vitro and in vivo.
Mitochondrial dynamics, represented by constant fission and fusion, are found to be associated with HCC metastasis. High metastatic HCC displays excessive mitochondrial fission. Among genes involved in mitochondrial dynamics, MFN1 is identified as a leading downregulated candidate that is closely associated with HCC metastasis and poor prognosis. While promoting mitochondrial fusion, MFN1 inhibits cell proliferation, invasion and migration capacity both in vitro and in vivo. Mechanistically, disruption of mitochondrial dynamics by depletion of MFN1 triggers the epithelial-to-mesenchymal transition (EMT) of HCC. Moreover, MFN1 modulates HCC metastasis by metabolic shift from aerobic glycolysis to oxidative phosphorylation. Treatment with glycolytic inhibitor 2-Deoxy-D-glucose (2-DG) significantly suppresses the effects induced by depletion of MFN1.
Our results reveal a critical involvement of mitochondrial dynamics in HCC metastasis via modulating glucose metabolic reprogramming. MFN1 may serve as a novel potential therapeutic target for HCC.
Tumor‐associated macrophages (TAMs) are crucial components of the tumor microenvironment. They play vital roles in hepatocellular carcinoma (HCC) progression. However, the interactions between TAMs ...and HCC cells have not been fully characterized. In this study, TAMs were induced using human monocytic cell line THP‐1 cells in vitro to investigate their functions in HCC progression. S100 calcium‐binding protein A9 (S100A9), an inflammatory microenvironment‐related secreted protein, was identified to be significantly upregulated in TAMs. S100A9 expression in tumor tissues was associated with poor survival of HCC patients. It could enhance the stem cell‐like properties of HepG2 and MHCC‐97H cells by activating nuclear factor‐kappa B signaling pathway through advanced glycosylation end product‐specific receptor in a Ca2+‐dependent manner. Furthermore, we found that, after treatment with S100A9, HepG2 and MHCC‐97H cells recruited more macrophages via chemokine (CC motif) ligand 2, which suggests a positive feedback between TAMs and HCC cells. Taken together, our findings reveal that TAMs could upregulate secreted protein S100A9 and enhance the stem cell‐like properties of HCC cells and provide a potential therapeutic target for combating HCC.
What's new?
Prognosis of hepatocellular carcinoma (HCC) is influenced by tumor‐associated macrophages (TAMs) in the tumor microenvironment. Little is known, however, about how TAMs fuel HCC progression. This comparative analysis of RNA‐sequencing and whole‐genome expression profiling between TAMs and nonactivated M0 macrophages identified three common upregulated genes with potential impact on HCC prognosis. Among them, S100 calcium binding protein A9 (S100A9) was found to enhance stem cell‐like properties in HCC cells, via Ca2+‐dependent signaling along the AGER/NF‐κB axis. Moreover, S100A9 increased TAM infiltration by facilitating CCL2 secretion. The findings warrant further investigation of S100A9 secretion and enhanced HCC cell stemness by TAMs.
Two structurally different Cu(II) and Co(II) complexes, Cu(L) (1) and Co
2
(L)
2
⋅2CH
3
OH (2), constructed from a new polyhalogen-substituted unsymmetric salamo-based ligand (H
2
L, ...4-chloro-4′-bromo-6-bromo-6′-tert-butyl-2,2′-ethylenedioxybis(nitrilomethylidyne)diphenol) were synthesized by wet-chemical methods. Complexes 1 and 2 were characterized through elemental analyses, IR and UV-vis spectroscopies and single crystal X-ray crystallography. In addition, the differences of the structures, electronic absorption characteristics and fluorescence property transitions from the ligand to complexes 1 and 2 were studied. The largest difference is that the ligand H
2
L can react with M(OAc)
2
(M = Cu(II) and Co(II)) to give two complexes with distinct structures and behaviors. There are two chemically identical but crystallographically independent structural units (molecules A and B) in 1. Moreover, each Cu(II) ion (Cu1 or Cu2) is four-coordinate and possesses a square planar geometry, but both Co(II) ions of 2 are bridged by phenoxide ions and possess five-coordinate trigonal bipyramidal configurations. At the same time, Hirshfeld surface analyses showed there are short-range interaction features from the ligand to complexes 1 and 2, the O···H/H···O interactions of the ligand are significantly stronger than those of 1 and 2.
The propensity of the activated neutrophils to form extracellular traps (NETs) is demonstrated in multiple inflammatory conditions. In this study, we investigated the roles of NETs in metastasis of ...hepatocellular carcinoma (HCC) and further explored the underlying mechanism of how NETs affect metastasis as well as the therapeutic value.
The neutrophils were isolated from the blood of human HCC patients and used to evaluate the formation of NETs. The expression of NET markers was detected in tumor specimens. A LPS-induced NET model was used to investigate the role of NETs on HCC metastasis. RNA-seq was performed to identify the key molecular event triggered by NETs, and their underlying mechanism and therapeutic significance were explored using both in vitro and in vivo assays.
NET formation was enhanced in neutrophils derived from HCC patients, especially those with metastatic HCCs. NETs trapped HCC cells and subsequently induced cell-death resistance and enhanced invasiveness to trigger their metastatic potential, which was mediated by internalization of NETs into trapped HCC cells and activation of Toll-like receptors TLR4/9-COX2 signaling. Inhibition of TLR4/9-COX2 signaling abrogated the NET-aroused metastatic potential. A combination of DNase 1 directly wrecking NETs with anti-inflammation drugs aspirin/hydroxychloroquine effectively reduced HCC metastasis in mice model.
NETs trigger tumorous inflammatory response and fuel HCC metastasis. Targeting NETs rather than neutrophils themselves can be a practice strategy against HCC metastasis.
Three-dimensional hierarchical porous carbon (3D-HPC) carriers were fabricated by pyrolyzing porous polyacrylonitrile hydrogels at high temperature, which were further applied to achieve simultaneous ...guarantee of the high energy storage density, thermal conductivity, shape stability and optical/electric-thermal energy conversion performance of PCMs.
Display omitted
•Synthesis of PAN gels is green and facile; AMPS helps polymerization and pyrolysis.•Carbonization of PAN aerogel produces high-performance 3D-HPC carriers.•3D-HPC can load PEG > 85 wt% with shape stability and thermal cycling stability.•3D-HPC/PEG CPCMs present 10 times increase in thermal conductivity than PEG.•CPCMs possess optical/electric-thermal energy conversion capability.
How to improve thermal conductivity as well as energy conversion efficiencies and to prevent melting leakage of solid–liquid phase change materials (PCMs) has been the essential challenges for the development of energy storage technology for storing a tremendous amount of waste heat and renewable and sustainable solar energy. Here, we reported the fabrication of high-performance form-stable composite PCMs (CPCMs) using the thermal conductive 3D-HPC carriers produced from the pyrolysis of porous polyacrylonitrile (PAN) copolymer hydrogels to confine the polyethylene glycol (PEG) PCMs. The porous 3D network PAN gel templates generate hierarchical cavities with micro/mesopores on the skeleton after pyrolysis which provides more space as well as the capillary adsorption and chemical interaction for the storage of PEG PCMs. The 3D-HPC/PEG CPCMs show high energy storage density (as high as 173.5 J g−1), high phase transformation efficiency and excellent thermal cycle stability. The carbon scaffold highly enhanced the thermal conductivity of CPCMs ∼ 10 times of the pure PEG and ensured its optical/electric-thermal energy conversion performance. This study demonstrates a facile, efficient and green way to fabricate hierarchical porous carbon with controllable porosity and degree of graphitization for improving the energy storage density, thermal conductivity, shape stability and energy conversion performance of PCMs.
Two solvent-induced bis(phenoxo)-acetate-bridged binuclear Ni(II) complexes, Ni
2
(L)(µ-OAc)(CH
3
OH) (1) and Ni
2
(L)(µ-OAc)(H
2
O) (2), were synthesized with a bis(salamo)-like ligand H
3
L and ...Ni(OAc)
2
·4H
2
O in two different alcohol solvents (methanol and ethanol). Complexes 1 and 2 were described by elemental analyses, single crystal X-ray diffraction, IR spectra, UV-vis spectra and fluorescence spectra. Complexes 1 and 2 have analogous crystal structures, but the non-covalent interactions are distinct. The one-dimensional chain of 1 is formed by π-π interactions, and the three-dimensional supramolecular network structure of 2 is formed by intermolecular hydrogen bonding interactions. In addition, fluorescence experiments indicated that the fluorescence of 1 and 2 undergoe a significant quenching compared to H
3
L. Intermolecular forces were investigated using Hirshfeld surface analysis. DFT calculations showed that 1 and 2 have high chemical reactivity and low kinetic stability.
Cyclic GMP‐AMP synthase (cGAS) is one of the most‐characterized cytoplasmic DNA sensors in humans and other mammals. However, knowledge about cGAS homologs in nonmammalian species remains limited. In ...this study, we report the molecular and functional identification of two cGAS homologs, namely, DrcGASa and DrcGASb, from a zebrafish (Danio rerio) model. DrcGASa and DrcGASb share the same overall conservative structural architectures and functional domains/residues to mammalian cGASs. Both homologs synthesized a 2′3′‐cGAMP isomer but not a 3′3′‐cGAMP isomer via oligomerization in response to DNA stimulation. Overexpression of DrcGASa/b in HEK293T cells and zebrafish embryos significantly activated NF‐κB and IFN‐I signaling pathways in a STING‐dependent manner. Knockdown of DrcGASa or DrSTING impaired such activations, thereby reducing the host innate immunity against bacterial and viral infections. DrcGASa, but not DrcGASb, was involved in immunoglobulin Z‐mediated mucosal immunity in gill‐associated lymphoid tissue, suggesting differential functions between the two DrcGASs. This reaction was associated with the DrcGAS‐DrSTING‐IFNφ1 signaling axis in GALT’s γδ T cells. Our findings provide experimental evidence that a modern cGAS‐STING pathway that mainly participates in IFN‐mediated immunity originated from teleost fish based on the functional constraint of cGAS and STING proteins during vertebrate evolution.
Objective
Despite the increasing number of genes associated with Charcot–Marie‐Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal ...dominant mutations in aminoacyl‐tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding seryl‐tRNA synthetase 1 (SerRS) for 3 families affected with CMT.
Methods
Whole‐exome sequencing was performed in 16 patients and 14 unaffected members of 3 unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays.
Results
Combined linkage analysis for the 3 families revealed significant linkage (Zmax LOD = 6.9) between the genomic co‐ordinates on chromosome 1: 108681600–110300504. Within the linkage region, heterozygous SerRS missense variants segregated with the clinical phenotype in the 3 families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation.
Interpretation
Our findings suggest the heterozygous SerRS variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS‐related CMT. ANN NEUROL 2023;93:244–256
A novel NIR-responsive GNR/LCE composite fiber material was prepared by a three-step sequential thiol-click chemistry approach. Taking advantage of GNRs' significant photo-thermal effect, a GNR/LCE ...composite material with a very low Au loading-level (0.09 wt%), under 808 nm NIR stimulus achieved the N-to-I transition and shrank dramatically in an ambient environment.
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, pathologically characterized by TDP-43 aggregates. Recent evidence has been indicated that phosphorylated TDP-43 ...(pTDP-43) is present not only in motor neurons but also in muscle tissues. However, it is unclear whether testing pTDP-43 aggregation in muscle tissue would assist in the diagnosis of ALS. We propose three key questions: (i) Is aggregation of pTDP-43 detectable in routine biopsied muscles? (ii) Can detection of pTDP-43 aggregation discriminate between ALS and non-ALS patients? (iii) Can pTDP-43 aggregation be observed in the early stages of ALS? We conducted a diagnostic study comprising 2 groups: an ALS group in which 18 cases underwent muscle biopsy screened from a registered ALS cohort consisting of 802 patients and a non-ALS control group, in which we randomly selected 54 muscle samples from a biospecimen bank of 684 patients. Among the 18 ALS patients, 3 patients carried pathological GGGGCC repeats in the C9ORF72 gene, 2 patients carried SOD1 mutations, and 7 patients were at an early stage with only one body region clinically affected. The pTDP-43 accumulation could be detected in routine biopsied muscles, including biceps brachii, deltoid, tibialis anterior, and quadriceps. Abnormal aggregation of pTDP-43 was present in 94.4% of ALS patients (17/18) compared to 29.6% of non-ALS controls (16/54; p < 0.001). The pTDP-43 aggregates were mainly close to the sarcolemma. Using a semi-quantified pTDP-43 aggregates score, we applied a cut-off value of 3 as a diagnostic biomarker, resulting in a sensitivity of 94.4% and a specificity of 83.3%. Moreover, we observed that accumulation of pTDP-43 occurred in muscle tissues prior to clinical symptoms and electromyographic lesions. Our study provides proof-of-concept for the detection of pTDP-43 accumulation via routine muscle biopsy which may serve as a novel biomarker for diagnosis of ALS.
PDF
