Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation.

Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl oxindoles for targeted protein degradation, we designed and synthesized a series of heterobifunctional compounds by conjugating different alkenyl oxindoles with bromodomain-containing protein 4 (BRD4) inhibitor JQ1. Through structure-activity relationship study, we successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, we found that these molecules degrade BRD4 through the ubiquitin-proteasome system, rather than the autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, we revealed that JQ1-alkenyl oxindole conjugates recruit the E3 ubiquitin ligase complex CRL4DCAF11 for substrate degradation. Furthermore, we validated the most potent heterobifunctional molecule HL435 as a promising drug-like lead compound to exert antitumor activity both in vitro and in a mouse xenograft tumor model. Our research provides new employable proteolysis targeting chimera (PROTAC) moieties for targeted protein degradation, providing new possibilities for drug discovery.

Combined Effects of Cadmium and Lead on Growth Performance and Kidney Function in Broiler Chicken.

Cadmium (Cd) and lead (Pb) are heavy metals prevalent in the environment and feed, and they reduce production performance of domestic animals, as well as they result in residue in animal tissues. The kidney is the target tissue for Cd and Pb. And the kidney is crucial for the reabsorption of calcium (Ca), which consequently influences bone strength. However, there are relatively few studies related to the effects of Cd and Pb exposure on performance, bone strength and kidney damage in livestock. The purpose of this experiment was to explore the combined effect of Cd and Pb on growth performance and renal impairment and the possible underlying mechanism. For this, 168 1-day-old Ross 308 broilers were randomly divided into four groups of six birds each, with seven replicates in each group: control group, 50 mg Cd/kg body weight group, 200 mg Pb/kg body weight group and 50 mg Cd/kg body weight + 200 mg Pb/kg body weight group. Feed intake was recorded daily and body weight was recorded weekly. The results show that at the end of the 3rd and 6th week, one broiler from each replicate was randomly selected for sampling. Boilers co-exposed to Cd and Pb for 3 weeks and 6 weeks had significantly decreased average daily feed intake (ADFI) and average daily body weight gain (ADG) than the control group, and the ratio of feed-to-weight gain (F/G) significantly increased after 6 weeks of co-exposure to Cd and Pb. Microscopic picture and ultrastructure analyses of the kidneys showed that Cd and Pb caused kidney damage to broiler chickens, and the damage was more serious in the Cd + Pb group, which was manifested by increased renal tubular epithelial degeneration and increased interstitial stasis points. Dietary exposure to Cd and Pb impaired production performance and induced renal oxidative damage in broilers. The combined effects of Cd and Pb on the kidneys are greater than their effects alone. The PERK-ATF4 pathway mediated endoplasmic reticulum stress participates the renal oxidative damage during chronic Cd and Pb exposure.

Associations between carotid plaque shape, biomechanical parameters, and ischemic stroke in mild carotid stenosis with a single plaque.

PURPOSE: This cross-sectional cohort-comparison observational study investigated the value of high-frame-rate vector flow (V Flow) imaging for evaluating differences in carotid plaque shape and biomechanical parameters in patients with mild stenosis according to a recent history of ipsilateral ischemic stroke. METHODS: The present study included 352 patients from February 2023 to October 2023, who were categorized as symptomatic or asymptomatic based on a history of recent ischemic stroke and ipsilateral ischemic lesions detected on head computed tomography or magnetic resonance imaging. A Mindray Resona R9 system was used for B-mode ultrasonography and V Flow imaging. The upstream and downstream surfaces of the plaques were examined at the carotid bifurcation for wall shear stress (WSS), oscillatory shear index (OSI), and turbulence index, which performed peri-plaque biomechanical condition. Multivariable logistic regression models were used to determine associations between plaque shape, V Flow parameters, and ischemic stroke. RESULTS: Symptomatic patients exhibited higher WSS values for the upstream and downstream surfaces of carotid plaque, as well as higher OSI and turbulence index values for the downstream surface. Type Ⅲ plaques and higher WSS and OSI values for the downstream surface of the plaque were significantly associated with ischemic stroke. Type Ⅲ plaques were more prevalent in symptomatic patients and demonstrated much higher WSS and OSI values for the downstream plaque surface in both groups. CONCLUSION: High-frame-rate V Flow imaging could assess peri-plaque biomechanical forces and may provide effective imaging biomarkers for early prediction of ischemic stroke in patients with mild stenosis.

Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol.

Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.

Metagenomics and metabolomics reveal that gut microbiome adapts to the diet transition in Hyla rabbits.

There is still a lack of longitudinal dynamic studies on the taxonomic features, functional reserves, and metabolites of the rabbit gut microbiome. An experiment was conducted to characterize the bacterial community of rabbits. By combining metagenomics and metabolomics, we have comprehensively analyzed the longitudinal dynamics of the rabbit gut microbiota and its effect on host adaptability. Our data reveal an overall increasing trend in microbial community and functional gene diversity and richness during the pre-harvest lifespan of rabbits. The introduction of solid feed is an important driving factor affecting rabbit gut microbiological compositions. Clostridium and Ruminococcus had significantly higher relative abundances in the solid feed stage. Further, the starch and fiber in solid feed promote the secretion of carbohydrate-degrading enzymes, which helps the host adapt to dietary changes. The rabbit gut microbiota can synthesize lysine, and the synthase is gradually enriched during the diet transformation. The gut microbiota of newborn rabbits has a higher abundance of lipid metabolism, which helps the host obtain more energy from breast milk lipids. The rabbit gut microbiota can also synthesize a variety of secondary bile acids after the introduction of solid feed. These findings provide a novel understanding of how the gut microbiota mediates adaptability to environment and diet in rabbits and provide multiple potential strategies for regulating intestinal health and promoting higher feed efficiency.

Curcumin alleviates cecal oxidative injury in diquat-induced broilers by regulating the Nrf2/ARE pathway and microflora.

This study evaluated the alleviative effect of curcumin (CUR) on the diquat (DQ)-induced cecal injury in broilers. A total of 320 one-day-old Cobb broilers were selected and randomly divided into 4 treatments, namely control, DQ, CUR 100, and CUR150 groups. The control and DQ groups were fed a basal diet, while the CUR 100 and CUR150 groups were fed the basal diet supplemented with 100 and 150 mg/kg CUR, respectively. Each group had 8 replicates, with 10 broilers per replicate. On day 21 of the experiment, 1 broiler was selected from each replicate and intraperitoneally injected 20 mg/kg body weight of DQ for DQ, CUR 100, and CUR 150 groups. Broilers in control group received equivalent volume of saline. Broilers were euthanized 48h postinjection for tissue sampling. The results showed that DQ injection could cause oxidative stress and inflammatory reactions in the cecum, affecting the fatty acid production and flora structure, thus leading to cecum damage. Compared with the DQ group, the activity of superoxide dismutase, the level of interleukin 10, acetic acid, and total volatile fatty, and the abundance of nuclear factor E2-related factor 2, copper and zinc superoxide dismutase and catalase mRNA in the cecal mucosa of broilers in the CUR group increased significantly (P < 0.05). However, the levels of malondialdehyd, reactive oxygen species, tumor necrosis factor-alpha, and the expression of cysteine-aspartic acid protease-3 and tumor necrosis factor-alpha decreased significantly (P < 0.05) in the CUR group. In addition, CUR treatment alleviated the damage to the cecum and restored the flora structure, and Lactobacillus and Lactobacillaceae promoted the alleviative effect of CUR on DQ. In summary, CUR could alleviate the cecal injury caused by DQ-induced oxidative damage and inflammatory reactions by regulating the Nrf2-ARE signaling pathway and intestinal flora, thus protecting the cecum.

Tumour cell-expressed PD-L1 reprograms lipid metabolism via EGFR/ITGB4/SREBP1c signalling in liver cancer.

Background & Aims: The programmed death-ligand 1 (PD-L1) is a major co-inhibitory checkpoint factor that controls T-cell activities in tumours. PD-L1 is expressed on immune cells and tumour cells. Whether tumour cell-expressed PD-L1 affects tumour cells in an immune cell-independent fashion remains largely elusive. In this study, we investigated the significance of tumour cell-expressed PD-L1 with a focus on downstream signals and changes in lipid metabolism. Methods: Immune-independent functions of PD-L1 in tumour growth were investigated in vitro and in immuno-deficient mice in vivo. The global influence of PD-L1 in targeted/untargeted lipidomic metabolites was studied by comprehensive mass spectrometry-based metabolomic analysis in liver cancer. Effects on lipid metabolism were confirmed by triglyceride and cholesterol assays as well as by Oil Red O staining in liver, pancreatic, breast, and oesophageal squamous cancer. Underlying mechanisms were investigated by real-time quantitative PCR, Western blot analysis, co-immunoprecipitation, pull-down assays, immunofluorescence staining, and RNA sequencing. Results: PD-L1 enhanced the accumulation of triglycerides, cholesterol, and lipid droplets in tumours. PD-L1 influenced targeted/untargeted lipidomic metabolites in hepatoma, including lipid metabolism, glucose metabolism, amino acid metabolism, nucleotide metabolism, and energy metabolism, suggesting that PD-L1 globally modulates the metabolic reprogramming of tumours. Mechanistically, PD-L1 activated epidermal growth factor receptor (EGFR) and/or integrin ß4 (ITGB4) by forming a complex of PD-L1/EGFR/ITGB4 in the cell membrane, prior to activating PI3K/mTOR/SREBP1c signalling, leading to reprogramming of lipid metabolism in tumours. Functionally, PD-L1-mediated lipid metabolism reprogramming supported the tumour growth in vitro and in vivo through EGFR and/or ITGB4 in an immune cell-independent manner. Conclusions: Our findings on lipogenesis and EGFR activation by tumour cell-expressed PD-L1 suggest that, in addition to its immunostimulatory effects, anti-PD-L1 may restrict lipid metabolism and EGFR/ITGB4 signalling in liver cancer therapy. Impact and implications: In this study, we present evidence that PD-L1 drives the reprogramming of lipid metabolism in tumours. PD-L1 forms a complex with epidermal growth factor receptor (EGFR) and ITGB4, activating the PI3K/Akt/mTOR/SREBP1c signalling pathway and thereby contributing to lipid metabolism in cancer progression. Our findings offer novel insights into the mechanisms by which PD-L1 initiates the reprogramming of lipid metabolism in tumours. From a clinical perspective, the anti-PD-L1 antibody may alleviate resistance to the anti-EGFR antibody cetuximab and inhibit the reprogramming of lipid metabolism in tumours.

Development of a Dual Fluorescence Signal-Enhancement Immunosensor Based on Substrate Modification for Simultaneous Detection of Interleukin-6 and Procalcitonin.

High-sensitivity detection of biomarkers is of great significance to improve the accuracy of disease diagnosis and the rate of occult disease diagnosis. Using a substrate modification and two-color quantum dot (QD) nanobeads (QBs), we have developed a dual fluorescence signal-enhancement immunosensor for sensitive, simultaneous detection of interleukin 6 (IL-6) and procalcitonin (PCT) at low volumes (∼20 µL). First, the QBs compatible with QDs with different surface ligands were prepared by optimizing surfactants based on the microemulsion method. Through the use of a fluorescence-linked immunosorbent assay (FLISA), the feasibility of a dual signal-enhancement immunosensor was verified, and a 5-fold enhancement of fluorescence intensity was achieved after the directional coating of the antibodies on sulfhydryl functionalization (-SH) substrates and the preparation of QBs by using a polymer and silica double-protection method. Next, a simple polydimethylsiloxane (HS-PDMS) immunosensor with a low volume consumption was prepared. Under optimal conditions, we achieved the simultaneous detection of IL-6 and PCT with a linear range of 0.05-50 ng/mL, and the limit of detection (LOD) was 24 and 32 pg/mL, respectively. The result is comparable to two-color QBs-FLISA with a sulfhydryl microplate, even though only 20% of its volume was used. Thus, the dual fluorescence signal-enhancement HS-PDMS immunosensor offers the capability of early microvolume diagnosis of diseases, while the detection of inflammatory factors is clinically important for assisting disease diagnosis and determining disease progression.

High-Temperature Phase Transition with Switchable Dielectric Behavior and Significant Photoluminescence Changes in a Zero-Dimensional Hybrid SbBr6 Perovskite.

In the past decade, metal halide materials have been favored by many researchers because of their excellent physical and chemical properties under thermal, electrical, and light stimuli, such as ferroelectricity, dielectric, nonlinearity, fluorescence, and semiconductors, greatly promoting their application in optoelectronic devices. In this study, we successfully constructed an unleaded organic-inorganic hybrid perovskite crystal: [Cl-C6H4-(CH2)2NH3]3SbBr6 (1), which underwent a high-temperature reversible phase transition near Tp = 368 K. The phase transition behavior of 1 was characterized by differential scanning calorimetry, accompanied by a thermal hysteresis of 6 K. In addition, variable-temperature Raman spectroscopy analysis and PXRD further verified the sensitivity of 1 to temperature and the phase transition from low symmetry to high symmetry. Temperature-dependent dielectric testing shows that 1 can be a sensitive switching dielectric constant switching material. Remarkably, 1 exhibits strong photoluminescence emission with a wavelength of 478 nm and a narrow band gap of 2.7 eV in semiconductors. As the temperature increases and decreases, fluorescence undergoes significant changes, especially near Tc, which further confirms the reversible phase transition of 1. All of these findings provide new avenues for designing and assembling new phase change materials with high Tp and photoluminescence properties.

Large-scale interplant exchange of macromolecules between soybean and dodder under nutrient stresses.

Parasitic plants and their hosts communicate through haustorial connections. Nutrient deficiency is a common stress for plants, yet little is known about whether and how host plants and parasites communicate during adaptation to such nutrient stresses. In this study, we used transcriptomics and proteomics to analyze how soybean (Glycine max) and its parasitizing dodder (Cuscuta australis) respond to nitrate and phosphate deficiency (-N and -P). After -N and -P treatment, the soybean and dodder plants exhibited substantial changes of transcriptome and proteome, although soybean plants showed very few transcriptional responses to -P and dodder did not show any transcriptional changes to either -N or -P. Importantly, large-scale interplant transport of mRNAs and proteins was detected. Although the mobile mRNAs only comprised at most 0.2% of the transcriptomes, the foreign mobile proteins could reach 6.8% of the total proteins, suggesting that proteins may be the major forms of interplant communications. Furthermore, the interplant mobility of macromolecules was specifically affected by the nutrient regimes and the transport of these macromolecules was very likely independently regulated. This study provides new insight into the communication between host plants and parasites under stress conditions.

Facile electrolysis-solvothermal synthesis of NiOx/graphene for enhanced ethanol oxidation to acetate.

In this work, low-crystalized and defective NiOx/graphene was synthesized by a facile electrolysis-solvothermal method. In the electrolytic process, Ni ions originate from the Ni anode, and graphene is produced from the graphite cathode. Then, Ni ions are reduced into oxides and deposited on graphene in the subsequent solvothermal process. The NiOx/graphene displays excellent electrocatalytic activity and selectivity for ethanol oxidation reaction to acetate. The peak current density was 296.5 mA cm-2 on a glassy carbon electrode. The FE of acetate was more than 93% at the potential range between 1.4 and 1.7 V. We propose that the mechanism is a cooperation between the chemical deprotonating process of ethanol by Ni3+ species and the electrochemical oxidation of the CH3CH2O* intermediate to acetate at the interface between NiOx and graphene.

The HIF-1α/PKM2 Feedback Loop in Relation to EGFR Mutational Status in Lung Adenocarcinoma.

OBJECTIVE: Gene mutations in tumor cells can lead to several unique metabolic phenotypes, which are crucial for the proliferation of cancer cells. EGFR mutation (EGFR-mt) is the main oncogenic driving mutation in lung adenocarcinoma (LUAD). HIF-1 α and PKM2 are two key metabolic regulatory proteins that can form a feedback loop and promote cancer growth by promoting glycolysis. Here, the linkage between EGFR mutational status and HIF-1α/PKM2 feedback loop in LUAD were evaluated. METHODS: Retrospective study were performed on LUAD patients (n = 89) undergoing first-time therapeutic surgical resection. EGFR mutation was analyzed by real-time PCR. Immunohistochemistry was used to measure the expressions of HIF-1α and PKM2. RESULTS: We found that the protein expressions of HIF-1α and PKM2 were significantly higher in LUAD than normal lung tissues. In adenocarcinomas, the two protein expressions were both correlated with worse pTNM stage. Moreover, the correlation between the proteins of HIF-1α/PKM2 feedback loop and the EGFR mutational status were also analyzed. We found that EGFR-mt tumors showed higher HIF-1α and PKM2 proteins compared to tumors with EGFR wild-type. Meanwhile, HIF-1α expression was significantly correlated with higher pTNM stage, and PKM2 showed a similar trend, only in EGFR-mutated tumors. The expression of HIF-1α was positively correlated with PKM2 in LUAD, furthermore, this correlation was mainly in patients with EGFR-mt. CONCLUSION: Different expression and clinical features of HIF-1α/PKM2 feedback loop was existed between LUAD and normal lung tissues, especially in EGFR mutational tumors, supporting the relationship between EGFR mutation and the key related proteins of aerobic glycolysis (HIF-1α and PKM2) in lung adenocarcinomas.

Combination of alkaline biodiesel-derived crude glycerol pretreated corn stover with dilute acid pretreated water hyacinth for highly-efficient single cell oil production by oleaginous yeast Cutaneotrichosporon oleaginosum.

Single cell oil (SCO) prepared from biodiesel-derived crude glycerol (BCG) and lignocellulosic biomass (LCB) via oleaginous yeasts is an intriguing alternative precursor of biodiesel. Here, a novel strategy combining alkaline BCG pretreated corn stover and dilute acid pretreated water hyacinth for SCO overproduction was developed. The mixed pretreatment liquors (MPLs) were naturally neutralized and adjusted to a proper carbon-to-nitrogen ratio beneficial for SCO overproduction by Cutaneotrichosporon oleaginosum. The toxicity of inhibitors was relieved by dilution detoxification. The enzymatic hydrolysate of solid fractions was suitable for SCO production either separately or simultaneously with MPLs. Fed-batch fermentation of the MPLs resulted in high cell mass, SCO content, and SCO titer of 80.7 g/L, 75.7 %, and 61.1 g/L, respectively. The fatty acid profiles of SCOs implied high-quality biodiesel characteristics. This study offers a novel BCG&LCB-to-SCO route integrating BCG-based pretreatment and BCG/LCB hydrolysates co-utilization, which provides a cost-effective technical route for micro-biodiesel production.

Il1r2 and Tnfrsf12a in transcranial magnetic stimulation effect of ischemic stroke via bioinformatics analysis.

Ischemic stroke refers to ischemic necrosis or softening of localized brain tissue. Transcranial magnetic stimulation (TMS) is a painless, noninvasive and green treatment method, which acts on the central nervous system through a pulsed magnetic field to assist in the treatment of central nervous system injury diseases. However, the role of Il1r2 and Tnfrsf12a in this is unknown. The ischemic stroke datasets GSE81302 and TMS datasets GSE230148 were downloaded from Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened and weighted gene co-expression network analysis (WGCNA) was performed. The construction and analysis of protein-protein interaction (PPI) network and functional enrichment analysis were performed. Draw heat map gene expression. Through the Comparative Toxicogenomics Database (CTD) to find the most relevant and core gene diseases. TargetScan was used to screen miRNAs regulating DEGs. A total of 39 DEGs were identified. According to gene ontology (GO) analysis results, in biological process (BP) analysis, they were mainly enriched in the positive regulation of apoptosis process, inflammatory response, positive regulation of p38MAPK cascade, and regulation of cell cycle. In cellular component (CC) analysis, they were mainly enriched in the cell surface, cytoplasm, and extracellular space. In Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, they were mainly enriched in nf-κB signaling pathway, fluid shear stress and atherosclerosis, P53 signaling pathway, TNF signaling pathway, and apoptosis. Among the enrichment items of metascape, negative regulation of T cell activation, hematopoietic cell lineage, positive regulation of apoptotic process, fluid shear stress and atherosclerosis were observed in GO enrichment items. Five core genes (Socs3, Irf1, Il1r2, Ccr1, and Tnfrsf12a) were obtained, which were highly expressed in ischemic stroke samples. Il1r2 and Tnfrsf12a were lowly expressed in TMS samples. CTD analysis found that the core gene (Socs3, Irf1 and Il1r2, Ccr1, Tnfrsf12a) and ischemic stroke, atherosclerosis, hypertension, hyperlipidemia, thrombosis, stroke, myocardial ischemia, myocardial infarction, and inflammation. Il1r2 and Tnfrsf12a are highly expressed in ischemic stroke, but lowly expressed in TMS samples.

Design and synthesis of dual BRD4/Src inhibitors for treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an extremely aggressive tumor with limited treatment options and effectiveness. Dual-target inhibitors capable of simultaneously suppressing invasion may represent a promising therapeutic approach for TNBC. In this work, we developed a series of dual BRD4/Src inhibitors by connecting JQ1 and dasatinib using various linkers and evaluated their efficacy against TNBC both in vitro and in vivo. Among these compounds, HL403 demonstrated IC50 values of 133 nM for BRD4 inhibition and 4.5 nM for Src inhibition. Most importantly, HL403 not only exhibited potent anti-proliferative capabilities, but also effectively suppressed the invasion of MDA-MB-231 cells in vitro. Finally, the anti-tumor efficacy of HL403 was validated in a mouse MDA-MB-231 xenograft tumor model, achieving a tumor growth inhibition rate (TGI) of 70.7 %, which was superior to the combination of JQ1 and dasatinib (TGI = 54.0 %). Our research provides a promising and feasible new strategy for improving the treatment of TNBC.

M335, a novel small-molecule STING agonist activates the immune response and exerts antitumor effects.

In the context of antitumor immune responses, the activation of the stimulator of interferon genes (STING) assumes a critical role and imparts enhanced immunogenicity. An effective strategy for exogenously activating the immune system involves the utilization of STING agonists, and prior investigations primarily concentrated on modifying endogenous cyclic dinucleotides (CDNs) to achieve this. Nevertheless, the practical utility of CDNs was restricted due to limitations associated with their physicochemical attributes and administration protocols. In this article, we present the discovery of a novel small-molecule agonist denoted as M335, identified through high-throughput screening using surface plasmon resonance (SPR). M335 demonstrates the ability to activate the TBK1-IRF3-IFN axis in a STING-dependent manner in vitro. Through experimentation on mouse models bearing tumors, we observed that the administration of M335 resulted in the activation of immune cells. Notably, significant antitumor effects were achieved with both intratumoral and intraperitoneal administration of M335. These findings suggest the potential of M335 as a promising agent for cancer immunotherapy, which will promote the development of STING agonists in anti-tumor applications.

Fe-induced crystalline-amorphous interface engineering of a NiMo-based heterostructure for enhanced water oxidation.

Engineering heterostructures with a unique surface/interface structure is one of the effective strategies to develop highly active noble-metal-free catalysts for the oxygen evolution reaction (OER), because the surface/interface of catalysts is the main site for the OER. Herein, we design a coralloid NiMo(Fe)-20 catalyst with a crystalline-amorphous interface through combining a hydrothermal method and an Fe-induced surface reconfiguration strategy. That is, after Fe3+ impregnation treatment, the Ni(OH)2-NiMoO4 pre-catalyst with a complete crystalline surface is restructured into a trimetallic heterostructure with a crystalline-amorphous interface, which facilitates mass diffusion and charge transfer during the OER. As expected, self-supported NiMo(Fe)-20 exhibits excellent electrocatalytic water oxidation performance (overpotential: η-10 = 220 mV, η-100 = 239 mV) in the alkaline electrolyte, and its electrocatalytic performance hardly changes after maintaining the current density of 50 mA cm-2 for 10 hours. Furthermore, nickel foam (NF) supported commercial Pt/C and self-supported NiMo(Fe)-20 served as the cathode and anode of the Pt/C‖NiMo(Fe)-20 electrolyzer, respectively, which exhibits a lower cell voltage (E-100 = 1.53 V) than that of the Pt/C‖RuO2 electrolyzer (E-100 = 1.58 V) assembled with noble metal-based catalysts. The enhanced electrocatalytic performance of the NiMo(Fe)-20 catalyst is mainly attributed to the synergistic effect between the crystalline-amorphous interface and the coralloid trimetallic heterostructure.

Precise Tuning of Hollow and Pore Size of Bimetallic MOFs Derivate to Construct High-Performance Nanoscale Materials for Supercapacitors and Sodium-Ion Batteries.

Precise control of pore volume and size of carbon nanoscale materials is crucial for achieving high capacity and rate performances of charge/discharge. In this paper, starting from the unique mechanism of the role of In, Zn combination, and carboxyl functional groups in the formation of the lumen and pore size, the composition of InZn-MIL-68 is regulated to precisely tune the diameter and wall pore size of the hollow carbon tubes. The hollow carbon nanotubes (CNT) with high-capacity storage and fast exchange of Na+ ions and charges are prepared. The CNT possess ultra-high specific capacitance and ultra-long cycle life and also offer several times higher Na+ ion storage capacity and rate performance than the existing CNTs. Density functional theory calculations and tests reveal that these superior characteristics are attributed to the spacious hollow structure, which provides sufficient space for Na+ storage and the tube wall's distinctive porosity of tube wall as well as open ends for facilitating Na+ rapid desorption. It is believed that precise control of sub-nanopore volume and pore size by tuning the composition of the carbon materials derived from bimetallic metal-organic frameworks (MOFs) will establish the basis for the future development of high-energy density and high-power density supercapacitors and batteries.

Interfacial carbon dots introduced distribution-structure modulation of Pt loading on graphene towards enhanced electrocatalytic hydrogen evolution reaction.

To easily load Pt on smoothy graphene synthesized by cathodic exfoliation method and achieve adjacent plane distribution of Pt, carbon dots (CDs) are used to construct anchoring points to load highly dispersed Pt species due to strong interaction between CDs and Pt species. The composite of Pt-CDs/graphene is synthesized via a continuous process of cathodic exfoliation-hydrothermal-impregnation-reduction. Characterization results indicate the distribution configuration of Pt varies from coated structure of CDs@Pt to dispersed configuration of CDs&Pt or Pt&CDs, then to wrapping configuration of Pt@CDs with increased amount of CDs. It's found that suitable introduction of CDs promotes the adjacent plane distribution of Pt species. The obtained best Pt-4CDs/G shows the low overpotential of 36 mV (10 mA⋅cm-2) and high mass activity of 3747.8 mA mg-1 at -40 mV towards electrocatalytic hydrogen evolution reaction (HER), 9.2 times more active than that of Pt/C (406.2 mA mg-1). The superior HER performance of Pt-4CDs/G is attributed to its relatively adjacent plane distribution of Pt, which supports high electrochemically active surface area and more adjacent Pt sites for H* adsorption. Benefitting from that, the HER process for Pt-4CDs/G favorably follows the Tafel pathway, resulting in low hydrogen adsorption free energy and excellent HER activity.

Ochratoxin A-enhanced glycolysis induces inflammatory responses in human gastric epithelium cells through mTOR/HIF-1α signaling pathway.

Ochratoxin A (OTA) is a mycotoxin commonly found in several food commodities worldwide with potential nephrotoxic, hepatotoxic and carcinogenic effects. We previously showed for the first time that OTA treatment enhanced glycolysis in human gastric epithelium (GES-1) cells in vitro. Here, we found that OTA exposure activated inflammatory responses, evidenced by increasing of NF-κB signaling pathway-related protein (p-p65 and p-IκBα) expressions and elevating of inflammatory cytokine (IL-1ß and IL-6) mRNA expressions in GES-1 cells. To elucidate the role of glycolysis in inflammatory effects triggered by OTA, we pretreated GES-1 cells with glycolysis inhibitor (2-deoxy-D-glucose, 2-DG) before OTA exposure. The result showed that 2-DG reduced the protein expressions of p-p65 and p-IκBα and alleviated the mRNA expressions of inflammatory cytokines in OTA-treated GES-1 cells. Furthermore, OTA activated the mTOR/HIF-1α pathway by increasing the protein expressions of p-mTOR, p-eIF4E and HIF-1α, and inhibition of mTOR with rapamycin or silencing HIF-1α with siRNA significantly attenuated OTA-enhanced glycolysis by reducing glycolysis related genes and thereby decreasing inflammatory effects of GES-1 cells. These results demonstrate that OTA activates inflammatory responses in GES-1 cells and this is controlled by mTOR/HIF-1α pathway-mediated glycolysis enhancement. Our findings provide a novel mechanistic view into OTA-induced gastric cytotoxicity.