Advanced Science最新文献

Colorectal cancer (CRC) usually creates an immunosuppressive microenvironment, thereby hindering immunotherapy response. Effective treatment options remain elusive. Using scRNA-seq analysis in a tumor-bearing murine model, it is found that lobeline, an alkaloid from the herbal medicine lobelia, promotes polarization of tumor-associated macrophages (TAMs) toward M1-like TAMs while inhibiting their polarization toward M2-like TAMs. Additionally, lobeline upregulates mRNA expression of secreted Ly-6/UPAR-related protein 1 (Slurp1) in cancer cells. The inhibitory effects of lobeline on tumor load and TAM polarization are almost completely eliminated when Slurp1-deficient MC38 cells are subcutaneously injected into mice, suggesting that lobeline exerts an antitumor effect in a Slurp1-dependent manner. Furthermore, using target-responsive accessibility profiling, MAPK14 is identified as the direct target protein of lobeline. Mechanistically, upon binding to MAPK14 in colon cancer cells, lobeline prevents nuclear translocation of MAPK14, resulting in decreased levels of phosphorylated p53. Consequently, negative transcriptional regulation of SLURP1 by p53 is suppressed, leading to enhanced transcription and secretion of SLURP1. Finally, combination therapy using lobeline and anti-PD1 exhibits stronger antitumor effects. Taken together, these findings suggest that remodeling the immunosuppressive microenvironment using small-molecule lobeline may represent a promising therapeutic strategy for CRC.

The mechanism of multiple enzymes mediated drug metabolism in gut microbiota is still unclear. This study explores multiple enzyme interaction process of typhactyloside (TYP) with gut microbiota and its lipid-lowering pharmacological activity. TYP, with bioavailability of only 2.78%, is an active component of Typha angustifolia L. and Pushen capsules which is clinically treated for hyperlipidemia. The metabolic process of TYP is identified, and key enzymes involved in TYP metabolism are validated through gene knockout and overexpression techniques. Through overexpressing α-rhamnosidase (Rha) in Escherichia coli, TYP is verified to metabolize into isorhamnetin-3-O-neohesperidin (M1) and isorhamnetin-3-O-glucoside (M2) after removing rhamnose through Rha. Besides, knockout of β-glucosidase (Glu) confirms that TYP generates M3 through Glu after removing glucose. Combined with molecular docking, M3 is transformed to generate 3,4-dihydroxyphenylacetic acid (M4), protocatechuic acid (M5), and 3-hydroxyphenylacetic acid (M6) through flavonoid reductase (Flr) and chalcone isomerase (Chi). In conclusion, multiple enzymes involved in TYP metabolism (Rha/Glu→Flr→Chi) are identified. Through in vivo experiments, combined use of M3 and M5 also shows excellent anti-hyperlipidemia efficacy. This is the first study on complex metabolism mechanism and pharmacological activity of natural flavonoids mediated by multiple enzymes, which provide insight to investigate analogous natural products.

Metal halide perovskites (MHPs) are commonly used in polarization-sensitive photodetectors (PDs) for applications such as polarization imaging, remote sensing, and optical communication. Although various methods exist to adjust the polarization-sensitive photocurrent, a universal and effective approach for continuous control of MHPs' optoelectronic and polarized properties is lacking. A universal strategy to electrically modulate the polarization ratio (PR) of self-powered polarized PDs using the ferro-pyro-phototronic effect (FPPE) in 2D perovskites is presented. By varying the amplitude and direction of ferroelectric polarization voltage, the built-in electric field in the heterojunction can be modulated, allowing for controllable PR regulation and adjustable polarization characteristics. Moreover, the polarized pyroelectric photoresponses are realized, significantly enhancing the responsivity, response speed of the polarized PDs. Both the pyroelectric currents and photocurrents exhibit obvious polarization characteristics. This method's versatility is demonstrated by creating three additional quasi-2D MHP ferroelectric-based polarized-sensitive PDs. A proof-of-concept for encrypted optical communication is achieved using the UV-sensitive PDs as light-sensing units. These findings highlight FPPE's potential to enhance ferroelectric device polarization control, enabling high-performance and self-powered polarization photodetection.

Establishing the protein-protein interaction network sheds light on functional genomics studies by providing insights from known counterparts. However, the rice interactome has barely been studied due to the lack of massive, reliable, and cost-effective methodologies. Here, the development of a barcode-indexed PCR coupled with HiFi long-read sequencing pipeline (BIP-seq) is reported for high throughput Protein Protein Interaction (PPI)identification. BIP-seq is essentially built on the integration of library versus library Y2H mating strategy to facilitate the efficient acquisition of random PPI colonies, semi-mechanized dual barcode-indexed yeast colony PCR for the large-scale indexed amplification of bait and prey cDNAs, and massive pac-bio sequencing of PCR amplicon pools. It is demonstrated that BIP-seq could map over 15 000 high-confidence (≈62.5% could be verified by Bimolecular fluorescence Complementation (BiFC)) rice PPIs within 2 months, outperforming the other reported methods. In addition, the obtained 23 032 rice PPIs, including 22,665 newly identified PPIs, greatly expanded the current rice PPI dataset, provided a comprehensive overview of the rice PPIs networks, and could be a valuable asset in facilitating functional genomics research in rice.

Osteoarthritis (OA) is increasingly recognized as a whole-organ disease predominantly affecting the elderly, characterized by typical alterations in subchondral bone and cartilage, along with recurrent synovial inflammation. Despite the availability of various therapeutics and medications, a complete resolution of OA remains elusive. In this study, novel functional hydrogels are developed by integrating natural bioactive molecules for OA treatment. Specifically, baicalin (Bai) is combined with 2-hydroxyethyl acrylate (HEA) to form a polymerizable monomer (HEA-Bai) through esterification, which is subjected to reversible addition-fragmentation chain transfer (RAFT) polymerization to produce Bai-based polymer (P_m). These macromolecules are incorporated into Schiff-base hydrogels, which demonstrate excellent mechanical properties and self-healing performance. Notably, the Bai-based formulations are taken up by fibroblast-like synoviocytes (FLSs), where they regulate glycolysis. Mechanistically, inhibition of yes-associated protein 1 (YAP1) by the formulations suppressed the FLSs glycolysis and reduced the secretion of inflammatory factors, including interleukin 1β (IL-1β), IL-6, and IL-8. Furthermore, the functional hydrogel (AG-P_m)-OC, severing as a lubricant and nutrient, prolonged joint retention of Bai, thereby reducing cartilage degradation and synovial inflammation. Meanwhile, (AG-P_m)-OC alleviated joint pain by targeting the YAP1 signaling and inhibiting macrophage recruitment and polarization. Taken together, this flavonoid-based injectable hydrogel exhibits enhanced biocompatibility and efficacy against OA.

The serum nanoparticle-protein corona (NPC) provides specific disease information, thus opening a new avenue for high-throughput in-depth proteomics to facilitate biomarker discovery. Yet, little is known about the interactions between NPs and proteins, and its role in enhanced depth of serum proteomics. Herein, a series of protein spike-in experiments are conducted to systematically investigate protein depletion and enrichment during NPC formation. Proteomic depth is serum concentration-dependent, and NPC exhibits powerful tolerance to ultra-high abundant proteins. In addition, protein-protein interactions (PPI), especially those involving albumin, play a pivotal role in promoting proteomic depth. Furthermore, a triple-protein assay is established to interrogate the relationship between protein binding affinity and concentration. NPC formation is a product of balancing binding affinity, concentration, and PPI. Overall, this study elucidates how NPs achieve protein depletion and enrichment for enhanced serum proteomic depth to gain a better understanding of NPC as an essential tool of proteome profiling.

Fractures, with a yearly incidence of 1.2%, can lead to healing complications in up to 10% of cases. The angiogenic stimulant deferoxamine (DFO) is recognized for enhancing bone healing when administered into the fracture gap. This systematic review with meta-analysis investigates the effect of local DFO application on bone healing in rat and mouse models. EMBASE, MEDLINE (PubMed), and Web of Science are systematically searched in January 2024. The study is prospectively registered in PROSPERO (CRD42024492533), and the SYRCLE tool is used to assess study quality and risk of bias. Outcome values contain the primary endpoint bone volume fraction (BV/TV) as well as the secondary endpoints bone volume, tissue volume, bone mineral density, trabecular separation, trabecular thickness, vessel formation and the mechanical properties, assessed by µCT, angiography and mechanical strength tests. Out of 21 included studies, 18 qualify for meta-analysis, involving 539 animals. DFO-treated groups exhibit significantly higher BV/TV values (p < 0.0001) compared to controls, with similarly significant improvements in secondary outcomes. These findings highlight the substantial benefit of DFO in promoting bone healing, especially after radiotherapy. Rapid clinical implementation is recommended to help patients at high risk of fracture healing complications.

Innovative anode materials are essential for achieving high-energy-density lithium-ion batteries (LIBs) with longer lifetimes. Thus far, only a few studies have explored the use of layered perovskite structures as LIB anode materials. In this study, the study demonstrates the performance and charge/discharge mechanism of the previously undefined Ruddlesden-Popper Li₂La₂Ti₃O₁₀ (RPLLTO) as an anode material for LIBs. RPLLTO exhibits two unique voltage plateaus ≈0.6 and 0.4 V(vs Li/Li⁺), due to the insertion of lithium ions into different sites within its layered structure. The electrical state of Ti is analyzed using X-ray photoelectron spectroscopy and X-ray absorption near edge spectra, revealing a reduction from Ti⁴⁺ to Ti²⁺, corresponding to a capacity of 170 mAh·g⁻¹. In situ X-ray diffraction patterns and extended X-ray absorption fine structure spectra demonstrate the crystal structure changes during lithiation. Complementary expansion along the a/b axes and contraction along the c axis result in a volume change of only 4%. This structural stability is evidenced by an 88% capacity retention after 1000 cycles. This study successfully showcases the lithium-ion storage capability of RPLLTO and contributes to the development of perovskite anode materials with diverse compositions and structures.

In triple-negative breast cancer (TNBC), pro-tumoral macrophages promote metastasis and suppress the immune response. To target these cells, a previously identified CD206 (mannose receptor)-binding peptide, mUNO was engineered to enhance its affinity and proteolytic stability. The new rationally designed peptide, MACTIDE, includes a trypsin inhibitor loop, from the Sunflower Trypsin Inhibitor-I. Binding studies to recombinant CD206 revealed a 15-fold lower K_D for MACTIDE compared to parental mUNO. Mass spectrometry further demonstrated a 5-fold increase in MACTIDE's half-life in tumor lysates compared to mUNO. Homing studies in TNBC-bearing mice shows that fluorescein (FAM)-MACTIDE precisely targeted CD206⁺ tumor-associated macrophages (TAM) upon intravenous, intraperitoneal, and even oral administration, with minimal liver accumulation. MACTIDE was conjugated to Verteporfin, an FDA-approved photosensitizer and YAP/TAZ pathway inhibitor to create the conjugate MACTIDE-V. In the orthotopic 4T1 TNBC mouse model, non-irradiated MACTIDE-V-treated mice exhibited anti-tumoral effects comparable to those treated with irradiated MACTIDE-V, with fewer signs of toxicity, prompting further investigation into the laser-independent activity of the conjugate. In vitro studies using bone marrow-derived mouse macrophages showed that MACTIDE-V excluded YAP from the nucleus, increased phagocytic activity, and upregulated several genes associated with cytotoxic anti-tumoral macrophages. In mouse models of TNBC, MACTIDE-V slowed primary tumor growth, suppressed lung metastases, and increased markers of phagocytosis and antigen presentation in TAM and monocytes, increasing the tumor infiltration of several lymphocyte subsets. MACTIDE-V is proposed as a promising peptide-drug conjugate for modulating macrophage function in breast cancer immunotherapy.

High-performance flexible pressure sensors are crucial for applications such as wearable electronics, interactive systems, and healthcare technologies. Among these, iontronic pressure sensors have garnered particular attention due to their superior sensitivity, enabled by the giant capacitance variation of the electric double layer (EDL) at the ionic-electronic interface under deformation. Key advancements, such as incorporating microstructures into ionic layers and employing diverse materials, have significantly improved sensor properties like sensitivity, accuracy, stability, and response time. This review highlights advancements in flexible EDL pressure sensors, focusing on structural designs and material engineering. These strategies are tailored to optimize key metrics such as sensitivity, detection limit, linearity, stability, response speed, hysteresis, transparency, wearability, selectivity, and multifunctionality. Key fabrication techniques, including micropatterning and externally assisted methods, are reviewed, along with strategies for sensor comparison and guidelines for selecting appropriate sensors. Emerging applications in healthcare, environmental and aerodynamic sensing, human-machine interaction, robotics, and machine learning-assisted intelligent sensing are explored. Finally, this review discusses the challenges and future directions for advancing EDL-based pressure sensors.