Positive GLI1/INHBA feedback loop drives tumor progression in gastric cancer.

GLI1, a key transcription factor of the Hedgehog (Hh) signaling pathway, plays an important role in the development of cancer. However, the function and mechanisms by which GLI1 regulates gene transcription are not fully understood in gastric cancer (GC). Here, we found that GLI1 induced the proliferation and metastasis of GC cells, accompanied by transcriptional upregulation of INHBA. This increased INHBA expression exerted a promoting activity on Smads signaling and then transcriptionally activated GLI1 expression. Notably, our results demonstrate that disrupting the interaction between GLI1 and INHBA could inhibit GC tumorigenesis in vivo. More intriguingly, we confirmed the N6-methyladenosine (m6A) activation mechanism of the Helicobacter pylori/FTO/YTHDF2/GLI1 pathway in GC cells. In conclusion, our study confirmed that the GLI1/INHBA positive feedback loop influences GC progression and revealed the mechanism by which H. pylori upregulates GLI1 expression through m6A modification. This positive GLI1/INHBA feedback loop suggests a novel noncanonical mechanism of GLI1 activity in GC and provides potential therapeutic targets for GC treatment.

PKP2 induced by YAP/TEAD4 promotes malignant progression of gastric cancer.

Gastric cancer (GC) exhibits significant heterogeneity and its prognosis remains dismal. Therefore, it is essential to investigate new approaches for diagnosing and treating GC. Desmosome proteins are crucial for the advancement and growth of cancer. Plakophilin-2 (PKP2), a member of the desmosome protein family, frequently exhibits aberrant expression and is strongly associated with many tumor types' progression. In this study, we found upregulation of PKP2 in GC. Further correlation analysis showed a notable association between increased PKP2 expression and both tumor stage and poor prognosis in individuals diagnosed with gastric adenocarcinoma. In addition, our research revealed that the Yes-associated protein1 (YAP1)/TEAD4 complex could stimulate the transcriptional expression of PKP2 in GC. Elevated PKP2 levels facilitate activation of the AKT/mammalian target of rapamycin signaling pathway, thereby promoting the malignant progression of GC. By constructing a mouse model, we ultimately validated the molecular mechanism and function of PKP2 in GC. Taken together, these discoveries suggest that PKP2, as a direct gene target of YAP/TEAD4 regulation, has the potential to be used as an indication of GC progression and prognosis. PKP2 is expected to be a promising therapeutic target for GC.

Crystal-Plane-Engineered TiO2-Anchored Vanadium Single Atoms and Clusters for Boosting Ultradeep Aerobic Oxidative Desulfurization of Diesel.

The crystal plane effect has gained extensive attention in heterogeneous catalysis reactions; however, it is far from being systematically probed in titanium dioxide (TiO2)-supported vanadium catalysts. Herein, a series of vanadium (V) single atoms and clusters anchored on TiO2 with different crystal planes was fabricated by an improved "top-down" protocol. The dispersion state, electronic structure, and redox properties of the V single-atom and VOx cluster-supported catalysts were systematically analyzed by a series of characterization methods, including X-ray absorption near edge structure (XANES) and density functional theory (DFT) calculations, and their catalytic performances were examined for aerobic oxidative desulfurization (AODS) of 4,6-dimethyl-dibenzothiophen (4,6-DMDBT) with O2 as the oxidant. The results unveiled that the synergistic effect between the V single atom and the VOx cluster perceptibly promoted the catalytic performances of VOx/TiO2 samples. Therein, VOx/TiO2-(001) shows the lowest apparent activation energy (Ea) value of 46.3 kJ/mol and the optimal AODS performance with complete 4,6-DMDBT conversion to 4,6-dimethyldibenzothiophene sulfone (4,6-DMDBTO2) within 60 min at 120 °C as compared with VOx/TiO2-(101) (81.9 kJ/mol and 180 min) and VOx/TiO2-(100) (68.0 kJ/mol and 240 min), which should be attributed to its higher V5+/V4+ ratio, the optimal redox behavior of the V species, the moderate adsorption energy between 4,6-DMDBT and VOx active centers, and the synthetic effect of V single atoms and VOx clusters. Moreover, VOx/TiO2-(001) exhibits robust durability in seven cycles of reuse, showcasing the potential for practical applications in the future.

Targeted ferritinophagy in gastrointestinal cancer: from molecular mechanisms to implications.

Gastrointestinal cancer is a significant global health burden, necessitating the development of novel therapeutic strategies. Emerging evidence has highlighted the potential of targeting ferritinophagy as a promising approach for the treatment of gastrointestinal cancer. Ferritinophagy is a form of selective autophagy that is mediated by the nuclear receptor coactivator 4 (NCOA4). This process plays a crucial role in regulating cellular iron homeostasis and has been implicated in various pathological conditions, including cancer. This review discusses the molecular mechanisms underlying ferritinophagy and its relevance to gastrointestinal cancer. Furthermore, we highlight the potential therapeutic implications of targeting ferritinophagy in gastrointestinal cancer. Several approaches have been proposed to modulate ferritinophagy, including small molecule inhibitors and immunotherapeutic strategies. We discuss the advantages and challenges associated with these therapeutic interventions and provide insights into their potential clinical applications.

Helicobacter pylori-induced aberrant demethylation and expression of GNB4 promotes gastric carcinogenesis via the Hippo-YAP1 pathway.

BACKGROUND: Helicobacter pylori (H. pylori) infection causes aberrant DNA methylation and contributes to the risk of gastric cancer (GC). Guanine nucleotide-binding protein subunit beta-4 (GNB4) is involved in various tumorigenic processes. We found an aberrant methylation level of GNB4 in H. pylori-induced GC in our previous bioinformatic analysis; however, its expression and underlying molecular mechanisms are poorly understood. METHODS: The expression, underlying signaling pathways, and clinical significance of GNB4 were analyzed in a local cohort of 107 patients with GC and several public databases. H. pylori infection was induced in in vitro and in vivo models. Methylation-specific PCR, pyrosequencing, and mass spectrometry analysis were used to detect changes in methylation levels. GNB4, TET1, and YAP1 were overexpressed or knocked down in GC cell lines. We performed gain- and loss-of-function experiments, including CCK-8, EdU, colony formation, transwell migration, and invasion assays. Nude mice were injected with genetically manipulated GC cells, and the growth of xenograft tumors and metastases was measured. Real-time quantitative PCR, western blotting, immunofluorescence, immunohistochemistry, chromatin immunoprecipitation, and co-immunoprecipitation experiments were performed to elucidate the underlying molecular mechanisms. RESULTS: GNB4 expression was significantly upregulated in GC and correlated with aggressive clinical characteristics and poor prognosis. Increased levels of GNB4 were associated with shorter survival times. Infection with H. pylori strains 26695 and SS1 induced GNB4 mRNA and protein expression in GC cell lines and mice. Additionally, silencing of GNB4 blocked the pro-proliferative, metastatic, and invasive ability of H. pylori in GC cells. H. pylori infection remarkably decreased the methylation level of the GNB4 promoter region, particularly at the CpG#5 site (chr3:179451746-179451745). H. pylori infection upregulated TET1 expression via activation of the NF-κB. TET binds to the GNB4 promoter region which undergoes demethylation modification. Functionally, we identified that GNB4 induced oncogenic behaviors of tumors via the Hippo-YAP1 pathway in both in vitro and in vivo models. CONCLUSIONS: Our findings demonstrate that H. pylori infection activates the NF-κB-TET1-GNB4 demethylation-YAP1 axis, which may be a potential therapeutic target for GC.

PHKG2 regulates RSL3-induced ferroptosis in Helicobacter pylori related gastric cancer.

Ferroptosis is a newly discovered form of regulatory cell death induced by iron-dependent lipid peroxidation. Infection with Helicobacter pylori (H. pylori) is regarded as a high-risk factor for the development of gastric cancer (GC) and is associated with an increase in the levels of reactive oxygen species with activation of oncogenic signaling pathways. However, whether GC arising in the context of infection with H. pylori is correlated with ferroptosis is still unknown. In this study, we demonstrate that H. pylori infection increased the sensitivity of GC cells to RSL3 (RAS-selective lethal3)-induced ferroptosis. The molecular subtypes mediated by ferroptosis-related genes are associated with tumor microenvironment (TME) cell infiltration and patient survival. Importantly, we identified that the expression of phosphorylase kinase G2 (PHKG2) was remarkably correlated with H. pylori infection, metabolic biological processes, patient survival and therapy response. We further found the mechanism of H. pylori-induced cell sensitivity to ferroptosis, which involves PHKG2 regulation of the lipoxygenase enzyme Arachidonate 5-Lipoxygenase (ALOX5). In conclusion, PHKG2 facilitates RSL3-induced ferroptosis in H. pylori-positive GC cells by promoting ALOX5 expression. These findings may contribute to a better understanding of the unique pathogenesis of H. pylori-induced GC and allow for maximum efficacy of genetic, cellular, and immune therapies for controlling ferroptosis in diverse contexts.

Single Mo Atoms Stabilized on High-Entropy Perovskite Oxide: A Frontier for Aerobic Oxidative Desulfurization.

The design and preparation of catalysts with both excellent stability and maximum exposure of catalytic active sites is highly desirable; however, it remains challenging in heterogeneous catalysis. Herein, a entropy-stabilized single-site Mo catalyst via a high-entropy perovskite oxide LaMn0.2Fe0.2Co0.2Ni0.2Cu0.2O3 (HEPO) with abundant mesoporous structures was initiated by a sacrificial-template strategy. The presence of electrostatic interaction between graphene oxide and metal precursors effectively inhibits the agglomeration of precursor nanoparticles in a high-temperature calcination process, thereby endowing the atomically dispersed Mo6+ coordinated with four O atoms on the defective sites of HEPO. The unique structure of single-site Mo atoms' random distribution with an atomic scale greatly enriches the oxygen vacancy and increases surface exposure of the catalytic active sites on the Mo/HEPO-SAC catalyst. As a result, the obtained Mo/HEPO-SAC exhibits robust recycling stability and ultra-high oxidation activity (turnover frequency = 3.28 × 10-2) for the catalytic removal of dibenzothiophene (DBT) with air as the oxidant, which represents the top level and is strikingly higher than the state-of-the-art oxidation desulfurization catalysts reported previously under the same or similar reaction conditions. Therefore, the finding here for the first time expands the application of single-atom Mo-supported HEPO materials into the field of ultra-deep oxidative desulfurization.

Boosting Catalytic Oxidative Desulfurization Performance over Yolk-Shell Nickel Molybdate Fabricated by Defect Engineering.

Developing catalysts with optimized surface properties is significant for advanced catalysis. Herein, a rational architectural design is proposed to successfully synthesize yolk-shell nickel molybdate with abundant oxygen vacancies (YS-VO-NMO) via an acid-assisted defect engineering strategy. Notably, YS-VO-NMO with the yolk-shell structure shows complex nanoconfined interior space, which is beneficial to the mass transfer and active sites exposure. Moreover, the defect engineering strategy is of great importance to modulate the surface electronic structure and atomic composition, which contributes to the enrichment of oxygen vacancies. Benefiting from these features, the higher hydrogen peroxide activation is achieved by YS-VO-NMO to produce more hydroxyl radicals compared with untreated nickel molybdate. Consequently, the defect-engineered YS-VO-NMO not only features superior catalytic activity (99.5%) but also retains high desulfurization efficiency after recycling eight times. This manuscript provides new inspiration for designing more promising defective materials via defect engineering and architecture for different applications besides oxidative desulfurization.

3D Printing Technique Fortifies the Ultradeep Hydrodesulfurization Process of Diesel: A Journey of NiMo/Al2O3-MMT.

In this contribution, we rationally designed and controllably fabricated a NiMo/Al2O3-montmorillonite (3D-NiMo/Al2O3-MMT) monolithic catalyst via a 3D printing strategy with economical montmorillonite (MMT) as a binder. The catalytic performance of the resulting NiMo/Al2O3-MMT for 4,6-dimethyldibenzothiophene (4,6-DMDBT) hydrodesulfurization (HDS) was evaluated. The experimental results unveil that the 3D-NiMo/Al2O3-MMT monolithic catalyst exhibits robust stability and exceptional HDS activity with 99.2% 4,6-DMDBT conversion (residual 4 ppm of S), which is remarkably superior to that of conventional NiMo/Al2O3 (61.5%), NiMo/MMT (63.2%), and even NiMo/Al2O3-MMT (76.5%) prepared by the mechanical-mixing method. This should be ascribed to the synthetic effect between the MMT binder and the Al2O3 substrate, which effectively weakens the interaction between the Mo species and the Lewis acids on the original Al2O3 surface, thereby significantly increasing the content of reducible Mo species and considerably facilitating the formation of more highly active NiMoS phase (Type II) with optimal average stacking layers and thereafter remarkably enhancing the ultradeep HDS activity of the 3D-NiMo/Al2O3-MMT monolithic catalyst.

Design and Synthesis of Amphiphilic Catalyst [C16mim]5VW12O40Br and Its Application in Deep Desulfurization with Superior Cyclability at Room Temperature.

Achieving long-term stable deep desulfurization at room temperature and recovering high value-added sulfone products is a challenge at present. Herein, a series of catalysts [Cnmim]5VW12O40Br (CnVW12, 1-alkyl-3-methylimidazolium bromide tungstovanadate, n = 4, 8, 16) were presented for the room temperature catalytic oxidation of dibenzothiophene (DBT) and its derivatives. Factors affecting the reaction process, such as the amount of catalyst, oxidant, and temperature, were systematically discussed. C16VW12 showed higher catalytic performance, and 100% conversion and selectivity could be achieved in 50 min with only 10 mg. The mechanism study showed that the hydroxyl radical was the active radical in the reaction. Benefiting from the "polarity strategy", the sulfone product accumulated after 23 cycles in a C16VW12 system, and the yield and purity were about 84% and 100%, respectively.

Edge-Site-Rich Ordered Macroporous BiOCl Triggers CO Activation for Efficient CO2 Photoreduction.

Endowing a semiconductor with tunable edge active sites will effectively enhance catalytic performance. Herein, an edge-site-rich ordered macroporous BiOCl (BiOCl-P) with abundant dangling bonds is constructed via the colloidal crystal template method. The edge-site-rich ordered macroporous structure provides abundant adsorption sites for CO2 molecules, as well as forms numerous localized electron enrichment areas, accelerating charge transfer. DFT calculations reveal that the dangling bonds-rich configuration can effectively reduce the CO2 activation energy barrier, boost the CO double bond dissociation, and facilitate the proton electron coupling reaction. As a result, the BiOCl-P achieves a higher CO and CH4 generation rate of 78.07 and 3.03 µmol g-1 under 4 h Xe lamp irradiation in a solid-gas system. Finally, the CO2 molecules' conversion process is further investigated by in situ Fourier-transform infrared spectroscopy. This work realizes a new avenue toward the design of vibrant semiconductors on the nanoscale to boost inert CO2 photoreduction.

Modulating Electronic Characteristics of Nickel Molybdate via an Effective Manganese-Doping Strategy to Enhance Oxidative Desulfurization Performance.

Modulating the electronic characteristics of catalysts plays a significant role in optimizing their catalytic activity. Herein, Mn-doped nickel molybdate (MNMO) nanorods are synthesized via replacing the partial Ni sites by the Mn element, engineering a bimetallic synergistic effect to enhance the activation of oxygen (O2). Compared with the extremely low catalytic activity of pristine nickel molybdate (NiMoO4), complete desulfurization can be achieved by MNMO under the same reaction conditions. Characterization results show that the electronic structure and surface atomic composition of pure NiMoO4 will be modulated owing to the introduction of Mn atoms, leading to the enhancement of the oxygen vacancy content and stronger O2 activation capacity. Besides, the optimized catalyst MNMO-20 also displays satisfactory cycle performance, and the sulfur removal of dibenzothiophene still maintains 96.1% after six times of recycling. The distinctive engineering strategy and simple synthesis method provide a new insight in designing and developing oxidative desulfurization catalysts with high stability and effectivity.

Heteroatom Bridging Strategy in Carbon-Based Catalysts for Enhanced Oxidative Desulfurization Performance.

Carbon-based catalysts are found to be promising metal-free species for aerobic oxidative desulfurization of fuel oil. Thus, a proper approach to promote their catalytic performances is very much in demand. In this contribution, a heteroatom bridging strategy is proposed to enhance the catalytic activities of carbon-based catalysts. As proof of the strategy, a series of boron (B)-doped graphite catalysts were synthesized. Detailed characterizations showed that the hetero-B atoms were uniformly dispersed in graphite. More importantly, it was found that the doped B atoms functioned as a bridge for electron transfer. With the existence of the heteroatom bridge, the activation of oxygen by graphite during the catalytic oxidation process was enhanced remarkably, leading to an ultradeep oxidative desulfurization performance. Moreover, the catalyst can be readily recycled five times without a significant decrease in desulfurization performance.

Defect Engineering on Boron Nitride for O2 Activation and Subsequent Oxidative Desulfurization.

The rational design of highly active hexagonal boron nitride (h-BN) catalysts at the atomic level is urgent for aerobic reactions. Herein, a doping impurity atom strategy is adopted to increase its catalytic activities. A series of doping systems involving O, C impurities and B, N antisites are constructed and their catalytic activities for molecular O2 have been studied by density functional theory (DFT) calculations. It is demonstrated that O2 is highly activated on ON and BN defects, and moderately activated on CB and CN defects, however, it is not stable on NB and OB defects. The subsequent application in oxidative desulfurization (ODS) reactions proves the ON and C-doped (CB , CN ) systems to be good choice for sulfocompounds oxidization, especially for dibenzothiophene (DBT). While the BN antisite is not suitable for such aerobic reaction due to the extremely stable B-O* -B species formed during the oxidation process.

Rational design of the carbon doping of hexagonal boron nitride for oxygen activation and oxidative desulfurization.

The doping of hexagonal boron nitride (h-BN) materials has a great influence on their catalytic oxidation performance, but the mechanism of doping has still not been studied in depth to date. Herein, carbon-doped h-BN materials were systematically investigated. Three different doping modes were established, and their performance for O2 activation and oxidative desulfurization (ODS) were explored. DFT calculation showed that not all carbon-doped forms of the h-BN surface could activate O2. Specifically, two of the dispersed doping forms could activate O2, whereas the π-doping form could not activate O2, and thus the ODS reaction could not be carried out. For the two dispersed doping forms, the O2 adsorption on the CB-doped h-BN surface (C-doped in B position) was too strong, which hampered its ODS performance; whereas the O2 adsorption on the CN-doped h-BN surface (C-doped in the N position) was moderate, resulting in good catalytic activity for ODS. Therefore, to design effective BN-based catalysts by C doping, it is suggested that the C dopant should be dispersed to substitute the N atom of h-BN, and CN-doped h-BN will play an important role in ODS with moderate O2 activation. This study can be used as a reference for the catalytic oxidation of boron nitride.

Few-Layer Boron Nitride with Engineered Nitrogen Vacancies for Promoting Conversion of Polysulfide as a Cathode Matrix for Lithium-Sulfur Batteries.

Lithium-sulfur (Li-S) batteries have become one of the most promising candidates as next-generation batteries, owing to their high specific capacity, low cost, and environmental benignity. Although many strategies have been proposed to restrain the shuttle of lithium polysulfides (LiPSs) through physical trapping and chemical binding, the sluggish kinetics of PS conversion still degrade the capacity, rate, and cycling performance of Li-S batteries. Herein, a novel kind of few-layer BN with engineered nitrogen vacancies (v-BN) has been developed as a cathode matrix for Li-S batteries. The positive vacancies in the BN nanosheets not only promote the immobilization and conversion of LiPSs, but also accelerate the lithium ion diffusion in cathode electrodes. Compared with pristine BN, the v-BN cathodes exhibit higher initial capacities from 775 mA h g-1 to 1262 mA h g-1 at 0.1 C and a high average coulombic efficiency of over 98 % during 150 cycles. Upon increasing the current density to 1 C, the cell still preserves a capacity of 406 mA h g-1 after 500 cycles, exhibiting a capacity decay of only 0.084 % per cycle. The new vacancy-engineered material provides a promising method for achieving excellent performance in Li-S batteries.

The mechanism of thiophene oxidation on metal-free two-dimensional hexagonal boron nitride.

Hexagonal boron nitride (h-BN) as an outstanding catalyst has been applied in oxidative desulfurization (ODS). In order to increase its catalytic performance, deep insight into the catalytic mechanism is urgent. In this work, DFT calculations were carried out to explore thiophene oxidation on the h-BN surface sites, involving the perfect and zigzag B, zigzag N, and armchair edge sites, and B- or N-monovacancy site. The calculated results show that O2 is easily activated on defect sites such as the edge sites and N-vacancy sites. For the thiophene oxidation mechanism, our results show that the zigzag N edge site is the most favorable active site, followed by the armchair and zigzag B edge sites. For the vacancy sites, although they are active for O2 dissociation, the dissociated O is trapped in the vacancy site, and they are not active for eventual sulfone formation.

Analysis of the affinity of influenza A virus protein epitopes for swine MHC I by a modified in vitro refolding method indicated cross-reactivity between swine and human MHC I specificities.

In vitro refolding assays can be used to investigate the affinity and stability of the binding of epitope peptides to major histocompatibility complex (MHC) class I molecules, which are key factors in the presentation of peptides to cytotoxic T lymphocytes (CTLs). The recognition of peptide epitopes by CTLs is crucial for protection against influenza A virus (IAV) infection. The peptide-binding motif of the swine SLA-3*hs0202 molecule has been previously reported and partly overlaps with the binding motif of the most abundant human MHC allele, HLA-A*0201. In this study, we screened all the protein sequences of the swine-origin epidemic IAV strain A/Beijing/01/2009 (H1N1), and a total of 73 9-mer epitope peptides were predicted to fit the consensus motif of the swine SLA-3*hs0202 or HLA-A*0201 molecule. Then, 14 peptides were selected, and their affinities to SLA-3*hs0202 were tested by a modified in vitro refolding assay. Our results show that ten epitopes could tolerate gel filtration, indicating that these epitopes formed stable or partly stable complexes with SLA-3*hs0202. Eight out of the ten epitopes have been previously reported as HLA-A2-restricted epitopes, which implied cross-reactivity between swine and human MHC I specificities. Furthermore, the modified mini-system refolding method could be applied for the screening of peptides because the refolding efficiency remained almost unchanged with the positive peptide (HA-KMN9) subjected to size-exclusion chromatography and Resource Q anion-exchange chromatography. The results presented here provide new insight into the development of epitope-based vaccines to control IAV and increase our understanding of swine molecular immunology.

Gas-exfoliated porous monolayer boron nitride for enhanced aerobic oxidative desulfurization performance.

Hexagonal boron nitride has been regarded to be an efficient catalyst in aerobic oxidation fields, but limited by the less-exposed active sites. In this contribution, we proposed a simple green liquid nitrogen gas exfoliation strategy for preparation of porous monolayer nanosheets (BN-1). Owing to the reduced layer numbers, decreased lateral sizes and artificially-constructed pores, increased exposure of active sites was expected, further contributed to an enhanced aerobic oxidative desulfurization (ODS) performance up to ∼98% of sulfur removal, achieving ultra-deep desulfurization. This work not only introduced an excellent catalyst for aerobic ODS, but also provided a strategy for construction of some other highly-efficient monolayer two-dimensional materials for enhanced catalytic performance.

Tailoring N-Terminated Defective Edges of Porous Boron Nitride for Enhanced Aerobic Catalysis.

Tailoring terminated edge of hexagonal boron nitride (h-BN) for enhancing catalysis has turned to be an imperative for the rational design of a highly active aerobic catalyst. Herein, a tailoring N-terminated porous BN (P-BN) strategy is reported with a zinc (Zn) salt as a dual-functional template. The Zn salt acts as both an in situ template and an N-terminated defective edges directing agent. The zinc salt template turns to Zn nanoparticles (Zn NPs) and functions as physical spacers, which are subsequently removed at a higher temperature, for producing P-BN, whose high surface area is high to 1579 m2 g-1 . Moreover, because of the lower electronegativity of Zn, boron (B) atoms are partly replaced by Zn atoms and ultimately preferred to N-terminated edges with the volatilization of Zn NPs. Owing to the moderate dissociative energy of oxygen atoms on N-terminated edges, the N-terminated edges are proved to be the origin of an enhanced aerobic catalytic activity by density functional theory (DFT) calculations. Moreover, the DFT calculation result is experimentally verified.