mRNA-responsive two-in-one nanodrug for enhanced anti-tumor chemo-gene therapy.

The combination of chemotherapy and gene therapy holds great promise for the treatment and eradication of tumors. However, due to significant differences in physicochemical properties between chemotherapeutic agents and functional nucleic acid drugs, direct integration into a single nano-agent is hindered, impeding the design and construction of an effective co-delivery nano-platform for synergistic anti-tumor treatments. In this study, we have developed an mRNA-responsive two-in-one nano-drug for effective anti-tumor therapy by the direct self-assembly of 2'-fluoro-substituted antisense DNA against P-glycoprotein (2'F-DNA) and chemo drug paclitaxel (PTX). The 2'-fluoro modification of DNA could significantly increase the interaction between the therapeutic nucleic acid and the chemotherapeutic drug, promoting the successful formation of 2'F-DNA/PTX nanospheres (2'F-DNA/PTX NSs). Due to the one-step self-assembly process without additional carrier materials, the prepared 2'F-DNA/PTX NSs exhibited considerable loading efficiency and bioavailability of PTX. In the presence of endogenous P-glycoprotein mRNA, the 2'F-DNA/PTX NSs were disassembled. The released 2'F-DNA could down-regulate the expression of P-glycoprotein, which decreased the multidrug resistance of tumor cells and enhanced the chemotherapy effect caused by PTX. In this way, the 2'F-DNA/PTX NSs could synergistically induce the apoptosis of tumor cells and realize the combined anti-tumor therapy. This strategy might provide a new tool to explore functional intracellular co-delivery nano-systems with high bioavailability and exhibit potential promising in the applications of accurate diagnosis and treatment of tumors.

Pirin Promotes the Progression of Non-Small-Cell Lung Cancer by Increasing ODC1 to Suppress Autophagy.

Non-small-cell lung cancer (NSCLC), a common malignant tumor, requires deeper pathogenesis investigation. Autophagy is an evolutionarily conserved lysosomal degradation process that is frequently blocked during cancer progression. It is an urgent need to determine the novel autophagy-associated regulators in NSCLC. Here, we found that pirin was upregulated in NSCLC, and its expression was positively correlated with poor prognosis. Overexpression of pirin inhibited autophagy and promoted NSCLC proliferation. We then performed data-independent acquisition-based quantitative proteomics to identify the differentially expressed proteins (DEPs) in pirin-overexpression (OE) or pirin-knockdown (KD) cells. Among the pirin-regulated DEPs, ornithine decarboxylase 1 (ODC1) was downregulated in pirin-KD cells while upregulated along with pirin overexpression. ODC1 depletion reversed the pirin-induced autophagy inhibition and pro-proliferation effect in A549 and H460 cells. Immunohistochemistry showed that ODC1 was highly expressed in NSCLC cancer tissues and positively related with pirin. Notably, NSCLC patients with pirinhigh/ODC1high had a higher risk in terms of overall survival. In summary, we identified pirin and ODC1 as a novel cluster of prognostic biomarkers for NSCLC and highlighted the potential oncogenic role of the pirin/ODC1/autophagy axis in this cancer type. Targeting this pathway represents a possible therapeutic approach to treat NSCLC.

Self-assembled metal-phenolic nanocomplexes comprised of green tea catechin for tumor-specific ferroptosis.

Ferroptosis, a newly discovered form of regulated cell death, has garnered significant attention in the field of tumor therapy. However, the presence of overexpressed glutathione (GSH) and insufficient levels of H2O2 in the tumor microenvironment (TME) hinders the occurrence of ferroptosis. In response to these challenges, here we have constructed the self-assembled nanocomplexes (FeE NPs) utilizing epigallocatechin-3-gallate (EGCG) from green tea polyphenols and metal ions (Fe3+) as components. After grafting PEG, the nanocomplexes (FeE@PEG NPs) exhibit good biocompatibility and synergistically enhanced tumor-inhibitory properties. FeE@PEG NPs can be disassembled by H2O2 in the TME, leading to the rapid release of Fe3+ and EGCG. The released Fe3+ produces large amounts of toxic •OH by the Fenton reactions while having minimal impact on normal cells. The generated •OH effectively induces lipid peroxidation, which leads to ferroptosis in tumor cells. Meanwhile, the released EGCG can autoxidize to produce H2O2, which further promotes the production of •OH radicals and increases lipid peroxide levels. Moreover, EGCG also depletes the high levels of intracellular GSH, leading to an intracellular redox imbalance and triggering ferroptosis. This study provides new insights into advancing anticancer ferroptosis through rational material design, offering promising avenues for future research.

Efficient liquid phase photothermal catalysis realized by Ag2O/Bi4O5I2via heat-localization in a microreactor.

By constructing a Ag2O/Bi4O5I2 p-n heterojunction and applying a heat-localization microreactor, efficient photocatalysis enhanced by both photoinduced carrier separation and the photothermal effect was realized. This work focuses on the utilization of near-infrared light to broaden the absorption spectrum and accelerate the transportation of carriers. Through the production and localization of heat, it provides a novel thought for full-spectrum photocatalysis.

Synthesis of urolithin derivatives and their anti-inflammatory activity.

Two series of urolithin derivatives, totally 38 compounds, were synthesized. Their anti-inflammatory activity was investigated by detecting the inhibitory effects on the expression of TNF-α in bone marrow-derived macrophages (BMDMs), showing that 24 of 38 ones reduced the expression of TNF-α. Compound B2, the ring C opened derivative of urolithin B with a butoxycarbonyl substitution in ring A, showed the strongest inhibitory activity compared with that of indomethacin. Furthermore, B2 treatment decreased the expression of pro-inflammatory factors IL-1ß, IL-6, iNOS and COX-2. Mechanically, the anti-inflammatory effect of B2 was related to the inhibition of NF-κB signaling pathway. These results clearly illustrated that B2 hold potential for application as an anti-inflammatory agent. The present study provided a viable approach to modify the gut metabolites for anti-inflammatory drug development.

Proansamycin B derivatives from the post-PKS modification gene deletion mutant of Amycolatopsis mediterranei S699.

Ten new proansamycin B congeners (1-10) together with one known (11) were isolated and characterized on the basis of 1D and 2D NMR spectroscopic and HRESIMS data from the Amycolatopsis mediterranei S699 ΔPM::rifR+rif-orf19 mutant. Compounds 8 and 9 featured with six-membered ring and five-membered ring hemiketal, respectively. Compounds 1, 2, and 9 displayed antibacterial activity against MRSA (methicillin-resistant Staphylococcus aureus), with the MIC (minimal inhibitory concentration) values of 64, 8, and 128 µg/mL, respectively. Compound 1 showed significant cytotoxicity against MDA-MB-231, HepG2 and Panc-1 cell lines with IC50 (half maximal inhibitory concentration) values of 2.3 ± 0.2, 2.5 ± 0.3 and 3.8 ± 0.5 µM, respectively.

Phytotoxic phenols from the needles of Cedrus deodara.

During the course of screening for anti-seed germination phytochemicals, the methanol fraction of the Cedrus deodara fresh needles showed potent activity. Bioactivity-guided fractionation led to the isolation of thirty-eight phenolic compounds. Four ones were identified as previously undescribed including (7S,8S)-3-methoxy-9'-acetoxy-3',7-epoxy-8,4'-oxyneoligna-4,9-diol (7), (7S,8R)-dihydro-3'-hydroxy-8-acetoxymethyl-7-(4-hydroxy-3-methoxy-phenyl)-1'-benzofuranpropanol (10), (8S)-4,9,9'-trihydroxy-3,3'-dimethoxy-8,4'-oxyneolignan (11) and (7S,8S)-4,7,9'-trihydroxy-3,3'-dimethoxy-9-acetoxy-8,4'-oxyneolignan (16), respectively. The potential phytotoxic effects of these compounds on the seed germination and root elongation of Arabidopsis thaliana were evaluated by the filter paper assay developed in our laboratory. Bioassay results indicated that caffeic acid (36) displayed most significant inhibitory activities against the seed germination and root elongation of A. thaliana, stronger than those of the commercial herbicides acetochlor and glyphosate at the same concentration of 200 µg/mL. Ditetrahydrofuran lignan (1), dihydrochalcone (25), and eight simple phenols (28, 29, 31, 33-35, 37 and 38) completely inhibited the seed germination of A. thaliana at the concentration of 400 µg/mL, which were as active as acetochlor. Dihydroflavone (21) and the simple phenols 32-34 displayed stronger inhibitory effects on the root elongation of A. thaliana than that of glyphosate. The inhibitory effects of these active compounds on the seed germination and root elongation of Amaranthus tricolor and Lactuca sativa were evaluated as well. The phytotoxic activity of 11, 16, 22, 25, 31, 34, 37 and 38 were detected for the first time. In addition, the structure-activity relationships of the same class of these phytochemicals were discussed.

Elevating the Photocatalytic Performance of BiOCl by Promoting Light Utilization: From Co doping to the Microreactor.

Owing to its unique layered structure, BiOCl demonstrates high photocatalytic activity. However, its wide bandgap hinders the absorption of visible light. Doping modification is an effective method to expand the light absorption edge of photocatalysts by creating a doping energy level within the bandgap. Herein, Co as a variable valence element was used to dope the BiOCl nanosheets through a simple hydrothermal approach. As a result, the absorption edge of Co-BiOCl extends to the visible light region, and the photocatalytic performance was enhanced by 3.02 times. To overcome the shortcoming of photons being consumed easily in the bulk reactor, a planar microreactor was introduced to reduce the attenuation of light and accelerate the mass transfer. By comparison to the bulk reactor, a maximum of 15.3-fold additional activity promotion emerged. This work combines doping modification and reactor improvement to realize highly efficient photocatalysis in practical application.

New bioactive secondary metabolites from the soil-derived Streptomyces sp. S045 and their anti-bacterial and anti-type III secretion system activities.

A total of seven compounds were isolated from the ISP3 agar cultures of a soil-derived Streptomyces sp. S045 strain. Their structures were determined based on 1D, 2D NMR spectroscopic data, HR ESI mass spectroscopy, X-ray diffraction analysis and comparison with the reported data. The new compounds were identified to be (S)-4-(1-hydroxyethyl)quinoline-2-carboxamide (1) and methyl 4-(hydroxymethyl)-2-(4-methylpentyl)-4,5-dihydrofuran-3-carboxylate (3), respectively. Their anti-bacterial and anti-type III secretion system (T3SS) activities were evaluated.

Resveratrol-derived inhibitors of the E3 ubiquitin ligase PELI1 inhibit the metastasis of triple-negative breast cancer.

Triple-negative breast cancer (TNBC), as the most challenging subtype of breast cancer, exerts highly invasive ability and metastatic nature to the lymph nodes, which is correlated with poor survival rates among patients. Pellino-1 (PELI1) is an E3 ubiquitin ligase involved in tumor invasion and metastasis, and has the potential to be developed as a novel therapeutic target for TNBC. In this study, we identified a potent inhibitor of PELI1, namely compound 3d, on the basis of natural stilbene framework through medicinal chemistry approaches. This novel PELI1 inhibitor 3d showed potent binding affinity to PELI1 (Kd 8.2 µM) in fluorescence quenching assay, and markedly interrupted the interaction of PELI1 and SNAIL/SLUG confirmed by co-immunoprecipitation. Moreover, 3d exhibited potent antitumor activity in inhibiting tumor cell migration in scratch wound healing assay without affecting cell proliferation in vitro, and down-regulated the downstream EMT-effectors of PELI1 as assessed by western blotting. In the experimental lung metastasis model, 3d showed anti-TNBC metastasis efficacy without observable toxicity in vivo.

PELI2 regulates early B-cell progenitor differentiation and related leukemia via the IL-7R expression.

Little is known about the transition mechanisms that govern early lymphoid lineage progenitors from common lymphoid progenitors (CLPs). Pellino2 (PELI2) is a newly discovered E3 ubiquitin ligase, which plays important roles in inflammation and immune system. However, the physiological and molecular roles of PELI2 in the differentiation of immune cells are largely unknown. Here, by using a conditional knockout mouse model, we demonstrated that PELI2 is required for the early B-cell development and stressed hematopoiesis. PELI2 interacted with and stabilized PU.1 via K63- polyubiquitination to regulate IL-7R expression. The defects of B cell development induced by PELI2 deletion were restored by overexpression of PU.1. Similarly, PELI2 promoted TCF3 protein stability via K63- polyubiquitination to regulate IL-7R expression, which is required for the proliferation of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells. These results underscore the significance of PELI2 in both normal B lymphopoiesis and malignant B-cell acute lymphoblastic leukemia via the regulation of IL-7R expression, providing a potential therapeutic approach for BCP-ALL.

DNA Origami-Based Letterpress Printing of Gold Nanostructures with Predesigned Morphologies.

Creating customizable metallic nanostructures in a simple and controllable manner has been a long-standing goal in nanoscience. In this study, we use DNA origami as a letterpress printing plate and gold nanoparticles as ink to produce predesigned gold nanostructures. The letterpress plate is reusable, enabling the repetitive production of predesigned gold nanostructures. Furthermore, by modifying the DNA origami letterpress plate on magnetic beads, we can simplify the printing processes. We have successfully printed gold nanoparticle dimers, trimers, straight and quadrilateral tetramers, and other nanostructures. Our approach improves the flexibility and stability of metallic nanostructures, simplifying both their design and their operation. It promises universal applicability in the fabrication of metamaterials, biosensors, and surface plasma nanooptics.

Loss of the vitamin D receptor triggers senescence in chronic myeloid leukemia via DDIT4-mediated DNA damage.

Chronic myeloid leukemia (CML) is a hematopoietic malignancy driven by the fusion gene BCR: ABL1. Drug resistance to tyrosine kinase inhibitors (TKIs) due to BCR: ABL1 mutation and residual leukemia stem cells (LSCs) remain major challenges for CML treatment. Here, we revealed the requirement of VDR in the progression of CML, in which VDR was upregulated by BCR: ABL1, accounting for its high expression. Interestingly, VDR knockdown inhibited the CML cell proliferation driven by BCR: ABL1 regardless of its mutations with resistance to TKIs. Mechanistically, VDR transcriptionally regulated DDIT4 expression, and the inhibition of DDIT4 triggered DNA damage-induced senescence via p53 signaling activation in CML cells. Furthermore, VDR deficiency was sufficient to not only ameliorate the disease burden and progression in primary CML mice but also reduce the self-renewal of CML-LSCs. Together, our study demonstrated that targeting VDR is a promising strategy to overcome TKI resistance and eradicate leukemia stem cells in CML.

Carbon network-hosted porphyrin as a highly biocompatible nanophotosensitizer for enhanced photodynamic therapy.

Photodynamic therapy (PDT) has the characteristics of being simple and non-invasive, and with on-demand light control. However, most photosensitizers exhibit strong hydrophobicity, low quantum yields in water and low tumor selectivity. In this study, carbon network-hosted porphyrins (CPs) with high biocompatibility and efficient singlet oxygen (1O2) generation were developed to reduce the biotoxicity of photosensitizers and avoid quenching caused by hydrophobic aggregation for enhanced PDT. The CPs were prepared by a simple solid-phase synthesis method using porphyrin, green non-toxic citric acid and urea as the raw materials. The CPs exhibited excellent water solubility and high biocompatibility. Even when the concentration reached 1.5 mg mL-1, cells still had good biological activity. By separately fixing the porphyrins in the carbon network, the CPs avoided aggregation-induced inactivation and had high generation efficiency of 1O2. Furthermore, in order to improve the PDT effect, the CPs were modified with the upper nuclear targeting peptide TAT (T-CPs), which was used to target the nucleus and generate 1O2in situ to directly destroy genetic material. The proposed strategy provides a simple and green path to prepare nanophotosensitizers with high biocompatibility and efficient 1O2 generation for PDT.

Asymmetric Plasmonic Moth-Eye Nanoarrays with Side Opening for Broadband Incident-Angle-Insensitive Antireflection and Absorption.

Plasmonic absorbers with broadband angle-insensitive antireflection have attracted intense interests because of its wide applications in optical devices. Hybrid surfaces with multiple different sub-wavelength array units can provide broadened antireflection, while many of these antireflective surfaces only work for specific angles and require high complexity of nanofabrication. Here, a plasmonic asymmetric nanostructure composed of the moth-eye dielectric nanoarray partially modified with the top Ag nanoshell providing a side opening for broadband incident-angle-insensitive antireflection and absorption, is rationally designed by nanoimprinting lithography and oblique angle deposition. This study illustrates that the plasmonic asymmetric nanostructure not only excites strong plasmonic resonance, but also induces more light entry into the dielectric nanocavity and then enhances the internal scattering, leading to optimized light localization. Hence, the asymmetric nanostructure can effectively enhance light confinement at different incident angles and exhibit better antireflection and the corresponding absorption performance than that of symmetric nanostructure over the visible wavelengths, especially suppressing at least 16.4% lower reflectance in the range of 645-800 nm at normal incidence.Moreover, the reflectance variance of asymmetric nanostructure with the incident angle changing from 5° to 60° is much smaller than that of symmetric nanostructure, making our approach relevant for various applications in photocatalysis, photothermal conversion, and so on.

Double Bond Geometric Isomers of Pentaketide Ansamycins from Streptomyces sp. S008.

Six new pentaketide ansamycins, namely, shengliangmycins A-F (1-6, respectively), were obtained from the fermentation products of Streptomyces sp. S008OEslmR2 that was derived by constitutive expression of LAL regulator gene slmR2. The structures of 1-6 were determined through comprehensive spectroscopic analysis and single-crystal X-ray diffraction. Compound 1 has a cis-C6═C7 bond, which is different from that of compounds 2-5. Compounds 3-6 feature a morpholinone structural moiety, whereas 5 is characterized by a pyrazoline ring, which is rare in natural products.

Lapachol inhibits the growth of lung cancer by reversing M2-like macrophage polarization via activating NF-κB signaling pathway.

Resetting tumor-associated macrophages (TAMs) is a promising strategy to ameliorate the immunosuppressive tumor microenvironment (TME) and improve innate and adaptive antitumor immunity. Lapachol, a naturally occurring 1,4-naphthoquinone, exhibits various pharmacological activities including antitumor, anti-leishmanial, antimalarial and antiseptic. In this study, we investigated the relevance of macrophage polarization and the antitumor effect of lapachol in Lewis lung cancer (LLC) both in vitro and in vivo. This study demonstrated that lapachol significantly reversed the polarization of M2-like macrophages thus that were endowed with the ability to kill LLC cells by activating NF-κB signaling pathway. Furthermore, lapachol effectively suppressed tumor growth in C57BL/6 mice bearing lung tumors by reducing the proportion of M2-like macrophages. Overall, our findings clearly illustrated that lapachol could reverse the polarization of M2-like macrophages to improve the immunosuppressive tumor microenvironment, and had the potential to be developed as an immunomodulatory antitumor agent.

Microansamycins J and K from Micromonospora sp. HK160111mas13OE.

Microansamycins were novel pentaketide ansamycins isolated from Micromonospora sp. HK160111mas13OE with AHBA-C2-C2-C3-C3 skeleton and diverse post-PKS modifications. In this paper, two new congeners, namely microansamycins J (1) and K (2), were identified based on their NMR, HRESIMS data and compared with those of microansamycins F and E. Neither showed antibacterial activity against Staphy-lococcus aureus ATCC25923 and Escherichia coli at 40 µg/mL.

Carrier-Free Nanovaccine: An Innovative Strategy for Ultrahigh Melanoma Neoantigen Loading.

In personalized cancer immunotherapy, developing an effective neoantigen nanovaccine with high immunogenicity is a significant challenge. Traditional nanovaccine delivery systems often require nanocarriers, which can hinder the delivery of the neoantigen and cause significant toxicity. In this study, we present an innovative strategy of carrier-free nanovaccine achieved through direct self-assembly of 2'-fluorinated CpG (2'F-CpG) with melanoma neoantigen peptide (Obsl1). Molecular dynamics simulations demonstrated that the introduction of a fluorine atom into CpG increases the noncovalent interaction between 2'F-CpG and Obsl1, which enhanced the loading of Obsl1 on 2'F-CpG, resulting in the spontaneous formation of a hybrid 2'F-CpG/Obsl1 nanovaccine. This nanovaccine without extra nanocarriers showed ultrahigh Obsl1 loading up to 83.19 wt %, increasing the neoantigen peptide uptake by antigen-presenting cells (APCs). In C57BL/6 mice models, we demonstrated the long-term preventive and therapeutic effects of the prepared 2'F-CpG/Obsl1 nanovaccine against B16F10 melanoma. Immunocellular analysis revealed that the nanovaccine activated innate and adaptive immune responses to cancer cells. Hence, this study established a simple, safe, and effective preparation strategy for a carrier-free neoantigen nanovaccine, which could be adapted for the future design of personalized cancer vaccines in clinical settings.

Influence of Nano-SiO2 Content on Cement Paste and the Interfacial Transition Zone.

Nano-SiO2 (NS) is widely used in cement-based materials due to its excellent physical properties. To study the influence of NS content on a cement paste and the interfacial transition zone (ITZ), cement paste samples containing nano content ranging from 0 to 2% (by weight of cement) were prepared, and digital image correlation (DIC) technology was applied to test the mechanical properties. Finally, the optimal NS content was obtained with statistical analysis. The mini-slump cone test showed that, with the help of superplasticizer and ultrasonic treatment, the flowability decreased continuously, as the NS content increased. The DIC experimental results showed that NS could effectively improve the mechanical properties of the cement paste and the ITZ. Specifically, at the content level of 1%, the elastic modulus of cement paste and ITZ was 20.95 GPa and 3.20 GPa, respectively. When compared to that without nanomaterials, the increased amplitude was 73.50% and 90.50%, respectively. However, with the further increase in NS content, the mechanical properties decreased, which was mainly caused by the agglomeration of nanomaterials. Additionally, the NS content did not exhibit a significant effect on the thickness of the ITZ, and its value was maintained at 76.91-91.38 µm. SEM confirmed that NS would enhance the microstructure of both cement paste and ITZ.