Electrocatalytic nitrogen reduction reaction (eNRR) is a sustainable alternative to the traditional Haber–Bosch process due to its eco‐friendly nature and capability of utilizing renewable energy. ...However, its low Faradic efficiency (FE), caused by the excessive adsorption and reduction of protons, has been regarded as the main challenge, which leads to low ammonia yield as well. Herein, a carbon‐supported iron electrocatalyst is reported, which is fabricated by low‐temperature (300 °C) potassium vapor reduction of FeF3‐intercalated graphite fluoride, for efficient electrochemical nitrogen reduction. The strategy enables the unique formation of exposed Fe nanoparticles uniformly anchored on graphene and in situ doped with fluorine heteroatoms. These specific features can alter the electronic configuration of the Fe nanoparticles, leading to strong surface polarization that boosts nitrogen absorption capability for eNRR, resulting in high FE (41.6%) and ammonia yield rate (53.3 μg h‐1 mg‐1) simultaneously. First‐principle calculation attributes this enhanced eNRR capability to more empty orbitals carried by the Fe atoms through the electron transfer with F dopant and substrate. As a versatile strategy for synthesizing various ultrafine and highly dispersed metal nanoparticles on the carbon support, this work might shed light on rational designing essential electrocatalysts with effective electronic structure manipulation.
Exposed Fe nanoparticles are uniformly anchored on graphene and in situ doped with fluorine heteroatoms. These unique features can alter the electronic configuration of the Fe nanoparticles, leading to strong surface polarization that boosts nitrogen absorption capability for electrocatalytic nitrogen reduction reaction, resulting in high Faradaic efficiency (41.6%) and ammonia yield rate (53.3 μg h−1 mg−1) simultaneously.
Circular RNAs are known to regulate the biological processes of hepatocellular carcinoma (HCC), and humans with Down syndrome are at low risk of developing solid tumors due to the amplification of ...several tumor suppressor genes on human chromosome 21 (HSA21). Here, we aimed to investigate the potential role of circRNAs originating from HSA21 in the progression of HCC. CircRNA-sequencing was performed to analyze differentially expressed circRNAs in 4 HCC and peritumor tissues, and circRNAs originating from HSA21 were further analyzed. Circ_0061984 (circPTTG1IP) was chosen for further study because it showed the lowest expression in HCC tissues, and qRT-PCR was used to confirm the expression of circPTTG1IP in HCC patient tissues. The biological function of circPTTG1IP was detected in HCC cells both in vivo and in vitro. Moreover, luciferase reporter assays, circRNA immunoprecipitation, and fluorescence in situ hybridization (FISH) were used to investigate the potential mechanism of circPTTG1IP. Finally, the possible mechanisms of filgotinib in circPTTG1IP-driven HCC were assessed. CircPTTG1IP expression was decreased in HCC compared to peritumoral tissues. Moreover, low circPTTG1IP expression was revealed to be associated with a poor prognosis of HCC patients. Elevation of circPTTG1IP was revealed to inhibit HCC development both in vitro and in vivo. Mechanistically, circPTTG1IP was shown to function as a competing endogenous RNA (ceRNA) of RNF125 by binding miR-16-5p to increase the level of the E3 ubiquitin ligase RNF125, which further ubiquitinated and degraded JAK1 protein. Finally, we demonstrated that administration of filgotinib, a JAK1 inhibitor, restricted HCC progression induced by low circPTTG1IP expression. Thus, we revealed that circPTTG1IP is a novel tumor suppresser circRNA in HCC and that a low circPTTG1IP level promotes HCC development via the miR-16-5p/RNF125/JAK1 axis. Patients with low circPTTG1IP may benefit from filgotinib treatment.
•CircPTTG1IP from HSA21 crucially regulates HCC development via the miR-16-5p-RNF125-JAK1 signaling axis.•CircPTTG1IP downregulation favors the inflammatory environment by inducing macrophage recruitment and M2 polarization.•Filgotinib remodels the tumor microenvironment by inhibiting circPTTG1IP-JAK1 axis, which may benefit patient prognosis.
Expression of Oct4 maintains cancer stem cell (CSC)-like properties in lung cancer cells and is correlated with poor prognosis of lung adenocarcinoma. M2-type tumor-associated macrophages (TAMs) ...promote cancer cell migration and metastasis. Tumor microenvironments promote monocyte differentiation into M2 TAMs via a complex cytokine-based connection. We explored the role of Oct4 in cytokine secretion in lung cancer and its impact on M2 TAM polarization.
Monocytes co-cultured with the conditioned medium from Oct4-overexpressing lung cancer cells were used to investigate M2 TAM differentiation. The inflammatory factors in the conditioned medium of Oct4-overexpressing A549 cells were examined using human inflammation antibody arrays. The correlations of Oct4, macrophage colony-stimulating factor (M-CSF), and M2 TAMs were validated in lung cancer cells, syngeneic mouse lung tumor models, and clinical samples of non-small cell lung cancer (NSCLC).
Oct4-overexpressing A549 cells expressed elevated levels of M-CSF, which contributed to increased M2 macrophages and enhanced tumor migration. Overexpression of Oct4 enhanced tumor growth and reduced the survival of lung tumor-bearing mice, which was correlated with increased number of M2 macrophages in lung cancer. Notably, NSCLC patients with high expression levels of Oct4, M-CSF, and M2 TAMs had the poorest recurrence-free survival. A positive correlation between Oct4, M-CSF, and M2 TAMs was observed in the tumor tissue of NSCLC patient. Treatment with all-trans retinoic acid exerted anti-tumor effects and reduced M2 TAMs in tumor-bearing mice.
Our results indicate that Oct4 expressed by lung cancer cells promotes M2 macrophage polarization through upregulation of M-CSF secretion, leading to cancer growth and metastasis. Our findings also implicate that the Oct4/M-CSF axis in M2 macrophage polarization may be potential therapeutic targets for lung cancer.
Triple-negative breast cancer (TNBC) is a refractory type of breast cancer that does not yet have clinically effective drugs. The aim of this study is to investigate the synergistic effects and ...mechanisms of resveratrol combined with cisplatin on human breast cancer MDA-MB-231 (MDA231) cell viability, migration, and invasion in vivo and in vitro. In vitro, MTS assays showed that resveratrol combined with cisplatin inhibits cell viability as a concentration-dependent manner, and produced synergistic effects (CI < 1). Transwell assay showed that the combined treatment inhibits TGF-β1-induced cell migration and invasion. Immunofluorescence assays confirmed that resveratrol upregulated E-cadherin expression and downregulated vimentin expression. Western blot assay demonstrated that resveratrol combined with cisplatin significantly reduced the expression of fibronectin, vimentin, P-AKT, P-PI3K, P-JNK, P-ERK, Sma2, and Smad3 induced by TGF-β1 (
< 0.05), and increased the expression of E-cadherin (
< 0.05), respectively. In vivo, resveratrol enhanced tumor growth inhibition and reduced body weight loss and kidney function impairment by cisplatin in MDA231 xenografts, and significantly reduced the expressions of P-AKT, P-PI3K, Smad2, Smad3, P-JNK, P-ERK, and NF-κB in tumor tissues (
< 0.05). These results indicated that resveratrol combined with cisplatin inhibits the viability of breast cancer MDA231 cells synergistically, and inhibits MDA231 cells invasion and migration through Epithelial-mesenchymal transition (EMT) approach, and resveratrol enhanced anti-tumor effect and reduced side of cisplatin in MDA231 xenografts. The mechanism may be involved in the regulations of PI3K/AKT, JNK, ERK and NF-κB expressions.
When a black hole is enclosed in a cavity in asymptotically flat space, an effective volume can be introduced, and an effective pressure can be further defined as its conjugate variable. By this ...means, an extended phase space is constructed in a cavity, which resembles that in the anti‐de Sitter (AdS) space in many aspects. However, there are still some notable dissimilarities simultaneously. In this work, the Joule–Thomson (JT) effect of the black holes, widely discussed in the AdS space as an isenthalpic (constant‐mass) process, is shown to only have cooling region in a cavity. On the contrary, in a constant‐thermal‐energy process (the JT‐like effect), there is only heating region in a cavity. Altogether, different from the AdS case, there is no inversion temperature or inversion curve in a cavity. Our work reveals the subtle discrepancy between the two different extended phase spaces that is sensitive to the specific boundary conditions.
When a black hole is enclosed in a cavity in asymptotically flat space, an effective volume can be introduced, and an effective pressure can be further defined as its conjugate variable. By this means, an extended phase space is constructed in a cavity, which resembles that in the anti‐de Sitter (AdS) space in many aspects. However, there are still some notable dissimilarities simultaneously. In this work, the Joule–Thomson (JT) effect of the black holes, widely discussed in the AdS space as an isenthalpic (constant‐mass) process, is shown to only have cooling region in a cavity. On the contrary, in a constant‐thermal‐energy process (the JT‐like effect), there is only heating region in a cavity. Altogether, different from the AdS case, there is no inversion temperature or inversion curve in a cavity. The work presented here reveals the subtle discrepancy between the two different extended phase spaces that is sensitive to the specific boundary conditions.
Iridium (Ir)-based electrocatalysts are widely explored as benchmarks for acidic oxygen evolution reactions (OERs). However, further enhancing their catalytic activity remains challenging due to the ...difficulty in identifying active species and unfavorable architectures. In this work, we synthesized ultrathin Ir-IrO x /C nanosheets with ordered interlayer space for enhanced OER by a nanoconfined self-assembly strategy, employing block copolymer formed stable end-merged lamellar micelles. The interlayer distance of the prepared Ir-IrO x /C nanosheets was well controlled at ∼20 nm and Ir-IrO x nanoparticles (∼2 nm) were uniformly distributed within the nanosheets. Importantly, the fabricated Ir-IrO x /C electrocatalysts display one of the lowest overpotential (η) of 198 mV at 10 mA cm–2 geo during OER in an acid medium, benefiting from their features of mixed-valence states, rich electrophilic oxygen species (O(II‑δ)–), and favorable mesostructured architectures. Both experimental and computational results reveal that the mixed valence and O(II‑δ)– moieties of the 2D mesoporous Ir-IrO x /C catalysts with a shortened Ir–O(II‑δ)– bond (1.91 Å) is the key active species for the enhancement of OER by balancing the adsorption free energy of oxygen-containing intermediates. This strategy thus opens an avenue for designing high performance 2D ordered mesoporous electrocatalysts through a nanoconfined self-assembly strategy for water oxidation and beyond.
mTORC2 (mammalian target of rapamycin complex 2) plays important roles in signal transduction by regulating an array of downstream effectors, including protein kinase AKT. However, its regulation by ...upstream regulators remains poorly characterized. Although phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) is known to regulate the phosphorylation of AKT Ser473, the hydrophobic motif (HM) site, by mTORC2, it is not clear whether PtdIns(3,4,5)P3 can directly regulate mTORC2 kinase activity. Here, we used two membrane-docked AKT mutant proteins, one with and the other without the pleckstrin homology (PH) domain, as substrates for mTORC2 to dissect the roles of PtdIns(3,4,5)P3 in AKT HM phosphorylation in cultured cells and in vitro kinase assays. In HEK293T cells, insulin and constitutively active mutants of small GTPase H-Ras and PI3K could induce HM phosphorylation of both AKT mutants, which was blocked by the PI3K inhibitor LY294002. Importantly, PtdIns(3,4,5)P3 was able to stimulate the phosphorylation of both AKT mutants by immunoprecipitated mTOR2 complexes in an in vitro kinase assay. In both in vivo and in vitro assays, the AKT mutant containing the PH domain appeared to be a better substrate than the one without the PH domain. Therefore, these results suggest that PtdIns(3,4,5)P3 can regulate HM phosphorylation by mTORC2 via multiple mechanisms. One of the mechanisms is to directly stimulate the kinase activity of mTORC2.
Colorectal cancer (CRC) is among the most common malignancies with limited treatments other than surgery. The tumor microenvironment (TME) profiling enables the discovery of potential therapeutic ...targets. Here, we profile 54,103 cells from tumor and adjacent tissues to characterize cellular composition and elucidate the potential origin and regulation of tumor-enriched cell types in CRC. We demonstrate that the tumor-specific FAP
fibroblasts and SPP1
macrophages were positively correlated in 14 independent CRC cohorts containing 2550 samples and validate their close localization by immuno-fluorescent staining and spatial transcriptomics. This interaction might be regulated by chemerin, TGF-β, and interleukin-1, which would stimulate the formation of immune-excluded desmoplasic structure and limit the T cell infiltration. Furthermore, we find patients with high FAP or SPP1 expression achieved less therapeutic benefit from an anti-PD-L1 therapy cohort. Our results provide a potential therapeutic strategy by disrupting FAP
fibroblasts and SPP1
macrophages interaction to improve immunotherapy.
Viral infection is a significant risk factor for fertility issues. Here, we demonstrated that infection by neurotropic alphaherpesviruses, such as pseudorabies virus (PRV), could impair female ...fertility by disrupting the hypothalamus-pituitary-ovary axis (HPOA), reducing progesterone (P4) levels, and consequently lowering pregnancy rates. Our study revealed that PRV exploited the transient receptor potential mucolipin 1 (TRPML1) and its lipid activator, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), to facilitate viral entry through lysosomal cholesterol and Ca2+. P4 antagonized this process by inducing lysosomal storage disorders and promoting the proteasomal degradation of TRPML1 via murine double minute 2 (MDM2)-mediated polyubiquitination. Overall, the study identifies a novel mechanism by which PRV hijacks the lysosomal pathway to evade P4-mediated antiviral defense and impair female fertility. This mechanism may be common among alphaherpesviruses and could contribute significantly to their impact on female reproductive health, providing new insights for the development of antiviral therapies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)-induced neurological deficits; however, the signaling pathways are not apparent by which the upstream cellular events ...trigger innate immune and inflammatory responses that contribute to neurological impairments. Toll-like receptor 4 (TLR4) plays a role in inflammatory damage caused by brain disorders.
In this study, we investigate the role of TLR4 signaling in ICH-induced inflammation. In the ICH model, a significant upregulation of TLR4 expression in reactive microglia has been demonstrated using real-time RT-PCR. Activation of microglia was detected by immunohistochemistry, cytokines were measured by ELISA, MyD88, TRIF and NF-κB were measured by Western blot and EMSA, animal behavior was evaluated by animal behavioristics.
Compared to WT mice, TLR4(-/-) mice had restrained ICH-induced brain damage showing in reduced cerebral edema and lower neurological deficit scores. Quantification of cytokines including IL-6, TNF-α and IL-1β and assessment of macrophage infiltration in perihematoma tissues from TLR4(-/-), MyD88(-/-) and TRIF(-/-) mice showed attenuated inflammatory damage after ICH. TLR4(-/-) mice also exhibited reduced MyD88 and TRIF expression which was accompanied by decreased NF-κB activity. This suggests that after ICH both MyD88 and TRIF pathways might be involved in TLR4-mediated inflammatory injury possibly via NF-κB activation. Exogenous hemin administration significantly increased TLR4 expression and microglial activation in cultures and also exacerbated brain injury in WT mice but not in TLR4(-/-) mice. Anti-TLR4 antibody administration suppressed hemin-induced microglial activation in cultures and in the mice model of ICH.
Our findings suggest that heme potentiates microglial activation via TLR4, in turn inducing NF-κB activation via the MyD88/TRIF signaling pathway, and ultimately increasing cytokine expression and inflammatory injury in ICH. Targeting TLR4 signaling may be a promising therapeutic strategy for ICH.
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