Hyperpigmentation is a common skin disorder that affects millions of people worldwide. The growing demand for ameliorating undesirable hyperpigmentary disorders has driven the development of novel intervention strategies. Herein, we identified uralsaponin X, a licorice-derived high-mobility group box 1 (HMGB1) inhibitor, which exerts potent anti-melanogenic effects in zebrafish larval models. Cell culture experiments demonstrated that uralsaponin X did not alter melanin biosynthesis in melanocytes but specifically inhibited HMGB1-mediated melanocyte dendrite extension and melanosome transport to the plasma membrane, thereby reducing the transfer of melanosomes to keratinocytes. Furthermore, we developed a nanoscale co-delivery system to co-encapsulate uralsaponin X and glabridin, a well-known tyrosinase inhibitor, into lipid nanoparticles to enhance skin penetration and achieve a synergistic depigmenting effect. The uralsaponin X- and glabridin-loaded lipid nanoparticle (UG-LNP) effectively improved cellular internalization and skin permeability. In a UVB-triggered hyperpigmentation guinea pig model, UG-LNP demonstrated remarkable depigmenting capacity by suppressing melanin synthesis, melanosome transfer, and inflammatory cell infiltration. Compared with glabridin monotherapy, UG-LNP achieved better in vivo therapeutic outcomes, as demonstrated by the alleviation of UVB-induced epidermal thickening and melanin granule accumulation in the epidermis. Collectively, this study identified uralsaponin X as a novel HMGB1 inhibitor possessing potent anti-hyperpigmentation properties. Furthermore, lipid nanoparticle-based co-delivery of glabridin and uralsaponin X represents a promising therapeutic strategy for the management of hyperpigmentation disorders.

BACKGROUND: Regeneration of osteoporotic bone defects is a major clinical challenge due to impaired osteogenic activity and high infection risks. We developed an injectable rhBMP-2-loaded calcium phosphate cement (CPC) and chitosan (CH) composite hydrogel (rhBMP-2/CPC@CH) to evaluate its therapeutic efficacy for repairing osteoporotic bone defects. METHODS: The rhBMP-2/CPC@CH hydrogel was synthesized and characterized for its physicochemical properties and enzymatic degradation. Its osteogenic potential was assessed using BMSCs. An OVX-induced rat cranial defect model was established to evaluate in vivo bone repair via Micro-CT and histological analysis. Antibacterial activity and effects on wound healing were also investigated. RESULTS: The rhBMP-2/CPC@CH hydrogel exhibited excellent injectability, self-healing, and enzymatic degradation properties with a uniform elemental distribution. The hydrogel significantly promoted the osteogenic differentiation of BMSCs, as evidenced by increased ALP activity and mineralized nodule formation. In the OVX-induced rat model, Micro-CT and histological analysis demonstrated that the hydrogel significantly increased bone mineral density and bone volume fraction, leading to dense new bone formation. Furthermore, the hydrogel effectively inhibited the growth of S. aureus and E. coli without adverse effects on wound healing, establishing a protected regenerative microenvironment. CONCLUSIONS: The rhBMP-2/CPC@CH hydrogel accelerates the repair of osteoporotic bone defects by providing an osteoinductive microenvironment and intrinsic antibacterial defense, representing a promising minimally invasive strategy for clinical bone regeneration.

A unique multifunctional groups mixed chemosensor (viz. H3SAO) contains Salen, Acylhydrazone and Oxime groups has been meticulously designated and successfully synthesized, exhibits tremendous potential in the realm of chemical sensing. The as-prepared H3SAO chemosensor not only possesses exceptional selectivity in fluorescence detection of Zn2+ ions in aqueous environments, but also demonstrates a remarkable highsensitivity fluorescence "turn-on" response towards Zn2+ ions in aqueous solutions, which making it an ideal candidate for ultra-sensitive analytical detection. Furthermore, H3SAO's recyclability is a noteworthy feature, as it can be effectively cycled between Zn2+ ions and Na2EDTA, ensuring its sustained utility. Beyond these detection capabilities, H3SAO also exhibits low toxicity in HeLa cells, allowing for its application in biological systems. The as-prepared chemosensor has been used to monitor intracellular Zn2+ ions and Na2EDTA levels in HeLa cells, providing valuable insights into metal ion dynamics in living cells. UV-Vis titration, fluorescence titration and Job's curves have been employed to confirm the stoichiometry of the complex formation between H3SAO and Zn2+ ions, revealing 2:3 ratio. Crystallographic studies of the complex Zn6(SAO)4 further reveal its unique structure, with four five-coordinated Zn ions and two six-coordinated Zn ions interacting with four ligands to form a functionalized cage structure. This unique cage-like structure offers further opportunities for exploring the chemosensor's potential in materials science, catalysis, and other related fields.

Cembranoids represent a class of diterpenes, featuring a cyclotetradecadiene backbone substituted by an isopropyl residue and three methyl groups with diverse subtypes and a panel of bioactivities. In this study, molecular networking-based metabolomic analysis revealed the soft coral Sarcophyton glaucum containing a chemical profile of cembrane-type diterpenes. Targeted isolation of the diterpene-enriched fractions resulted in the isolation of 14 undescribed cembranoids, namely glaucumolides C-P (1–14). Their structures were determined by extensive spectroscopic data in association with the X-ray diffraction and electronic circular dichroism (ECD) data for configurational assignments. All analogs featured an unsaturated γ-lactone in the backbone. Glaucumolide M and metabolite-A exhibited significant inhibition against the proliferation of lipopolysaccharide (LPS)-induced DAKIKI cells, and upregulated the expression of mRNA of C1GalT1 and its chaperone Cosmc in DAKIKI cells dose-dependently. Those findings suggest glaucumolides to be potential to prevent imunoglobulin A (IgA) nephropathy.

Flavonoid apiosides are widely distributed in cereals, fruits, vegetables, and medicinal herbs and play critical roles in human health. Their facile and efficient synthesis has been a hot but challenging topic in the fields of both organic chemistry and biosynthesis. However, very few apiosyltransferases (ApiGTs) have been reported thus far. Here, we report the first flavonoid apiosyltransferase (CaApiGT) capable of catalyzing the 2″-O-apiosylation of flavonoid 3-O-glycosides in chickpea (Cicer arietinum). Moreover, we identify PcApiGT from parsley (Petroselinum crispum), which catalyzes the 2″-O-apiosylation of flavonoid 7-/4'-O-glycosides. To dissect the mechanisms underlying their different sugar acceptor selectivity, we obtain 10 complex crystal structures of CaApiGT and PcApiGT with resolutions ranging from 1.55 to 2.65 Å, including CaApiGT/UDP, 6 ternary structures of CaApiGT/UDP/sugar acceptors, PcApiGT/UDP, and 2 ternary structures of PcApiGT/UDP/sugar acceptors. Structural analyses, theoretical calculations, and site-directed mutagenesis indicate that flavonoid 3-O-glycosides and 7-O-glycosides exhibit a T-shape and streamline shape, respectively, and fit the active pockets of CaApiGT and PcApiGT. Moreover, the sugar acceptor selectivity of these two apiosyltransferases is determined by a key α-helix. In CaApiGT, this α-helix contains multiple polar amino acids, particularly a threonine residue at its end. Using this α-helix motif as a marker, we further characterize four apiosyltransferases from Leguminosae plants that exhibit functional similarity to CaApiGT. This work unravels detailed sugar acceptor selectivity mechanisms of plant apiosyltransferases and provides efficient biocatalysts for the synthesis of flavonoid apiosides.

The development of sensitive and selective methods for detecting zinc ions holds significant research importance in both environmental and biological contexts. Fluorescent probe methods outperform traditional detection methods in terms of sensitivity, selectivity, and real-time monitoring. In this study, we successfully synthesized a fluorescent chemosensor HL . It is derived from acylhydrazone Schiff base that features a straightforward synthesis, low toxicity and stable properties. The HL chemosensor was characterized using various spectroscopic techniques to confirm its structure and optical properties. Fluorescence spectroscopy analysis revealed that the HL chemosensor exhibits an obvious fluorescence turn-on response to zinc ions in aqueous medium., maintaining good selectivity even in the presence of various competing metal ions. The binding ratio of HL chemosensor to Zn2+ was determined to be 1:1 through UV-visible titration experiments, and this finding further supported by the crystal structure of the HL-Zn2 & thorn; complex. The results of fluorescence titration were also consistent with those from the UV-visible titration and crystallographic data. The as-prepared HL chemosensor exhibited a minimum detection limit of 8.8 x 10_8 M, lower than that of most reported zinc ion fluorescence probes. A complexation constant of 2.6 x 105 M _ 1 based the Stern-Volmer equation indicates a strong coordination binding. Importantly, the exceptionally selective and sensitive HL chemosensor demonstrates chemical reversibility and can be recycled 5 times for reuse, significantly reducing the cost of the assay. This featured experimental procedure, which employs Na2EDTA to eliminate or replace Zn2+, is an efficient, convenient, and gentle process compared to traditional methods involving heating, high temperatures, and washing. In particular, cytotoxicity tests showed that the chemosensor HL displayed low toxicity in Hela cells, confirming its suitability for detecting zinc ions in living cells. These indicate a promising application of this HL chemosensor in environmental monitoring and biological research, and future exploration can delve into its potential for practical applications.

Halogen substituents play a crucial role in the structural diversity and biological activity of natural products, and the synthesis of halogenated molecules remains an area of significant research interest. This study describes the generation of 15 new halogenated angucyclinones through the incorporation of halogen-containing phenylamines into a biosynthetic C-ring-cleaved angucyclinone under mild conditions. The newly synthesized compounds feature halogen substituents encompassing all four halogen atoms (F, Cl, Br, I), with some compounds containing multiple halogen types. Structural elucidation was accomplished through ultraviolet (UV), infrared spectroscopy (IR), mass spectrometry (MS), and nuclear magnetic resonance (NMR) spectroscopic analyses, expanding the structural diversity of angucyclinone-type polyketides. Cytotoxicity evaluations revealed that eight compounds demonstrated moderate cytotoxic activities against four human tumor cell lines, with half maximal inhibitory concentration (IC50) values ranging from 3.35 ± 0.37 to 16.02 ± 6.60 µmol·L-1. These findings highlight the significant potential of combining biosynthetic and chemical approaches in generating bioactive halogenated molecules.

Corrosion of aluminum (Al) alloys during service limits many applications. Micro-arc oxidation (MAO) coatings can enhance corrosion resistance, but porous defects in the films undermine their effectiveness. Here, by mixing a phosphate electrolyte with soluble Zn and Ce salts, zinc phosphate and cerium phosphate co-doped MAO corrosion-resistant coating is prepared on Al alloy LY12. Zinc phosphate and cerium phosphate are incorporated in situ to form an amorphous encapsulated nanocrystalline structure. During long-term corrosion, Zn2+ is released and deposited as corrosion products Zn(OH)2 to cover weak corrosion micro-regions in the coating. Simultaneously, Ce3+ released from MAO coating co-doped with zinc phosphate/cerium phosphate forms Zn(OH)2 /Ce(OH)3 due to the small solubility product Ksp to further enhance corrosion resistance. Compared to pristine Al alloy, corrosion potential increases from-1.306 to-0.819 VSCE, and corrosion current density decreases by 4 orders of magnitude from 2.6 x 10-6 to 2.5 x 10-10 Acm- 2 . Co-doped MAO coating significantly enhances corrosion resistance of Al alloy LY12 and shows great potential for a wide range of applications. (c) 2025 The Authors. Published by Elsevier B.V. on behalf of Institute of Metal Research, Chinese Academy of Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

In the present research, the NaF assisted plasma electrolytic oxidation (PEO) is designed to fabricate the high-content ZnO nanoparticles doped coating on AZ31B alloy. The microstructure, phase constituents and corrosion behavior of the PEO coatings are investigated systematically. The results reveal that the introduction of NaF promotes the formation of MgF2 nanophases in the passivation layer on Mg alloy, decreasing the breakdown voltage and discharge voltage. As a result, the continuous arcing caused by high discharge voltage is alleviated. With the increasing of NaF content, the Zn content in the PEO coating is enhanced and the pore size in the coating is decreased correspondingly. Due to the high-content ZnO doping, the PEO coating protected AZ31B alloy demonstrates the better corrosion resistance. Compared with the bare AZ31B alloy, the high-content ZnO doped PEO coated sample shows an increased corrosion potential from -1.465 V to -1.008 V, a decreased corrosion current density from 3.043×10-5 A·cm-2 to 3.960×10-8 A·cm-2 and an increased charge transfer resistance from 1.213×102 ohm·cm2 to 2.598×105 ohm·cm2. Besides, the high-content ZnO doped PEO coated sample also has the excellent corrosion resistance in salt solution, exhibiting no obvious corrosion after more than 2000 h neutral salt spraying and 28 days’ immersion testing. The improved corrosion resistance can be ascribed to the relative uniform distribution of ZnO in PEO coating which can transform to Zn(OH)2 and form a continuous protective layer along the corrosion interface.

Although it is well established that the visual complexity of a written word can influence processing, it is far less clear from a cross-script perspective, whether the overall visual complexity of the entire written lexicon also affects word recognition. This question can be answered with the data in megastudy of lexical decision in Chinese (MELD-CH), which was developed with over 800 participants responding to 12,587 simplified and traditional Chinese words. The results showed that lexical decision was slower but more accurate in simplified Chinese, which has about 22.5% less strokes, than traditional Chinese. This pattern could not be explained by a speed-accuracy trade-off. Moderate correlations were found in response times and error rates between the two scripts, indicating considerable overlap in processing despite the script difference. In addition, (generalised) linear mixed-effects modelling was used to examine whether the simplified and traditional Chinese groups differed in sensitivity towards linguistic variables. The results showed that the effects of word frequency, word length, and number of strokes were stronger in recognising simplified Chinese words, whereas the effects of number of words formed and number of meanings of the constituent characters were stronger in traditional Chinese. These results suggested that the visual-perceptual processing demands of simplified Chinese might force readers to focus more on local properties of the words, making them less sensitive to global properties that are defined over the entire lexicon. Finally, limitations and alternative explanations of the results were discussed.

Chemical investigation of Irpex sp. NBUF088, associated with an Ircinia sp. sponge located at an 84 m deep mesophotic zone, led to the discovery of two new heptaketides, named irpetones A (1) and B (2). Their structures were identified by analysis of spectroscopic data and quantum-chemical calculations. Compound 1 exhibited inhibition against the receptor activator of NF-κB ligand-induced osteoclastogenesis in bone marrow monocytes with an IC50 of 6.3 ± 0.2 μM, causing no notable cytotoxicity. It was also determined that 1 inhibited the phosphorylation of ERK1/2-JNK1/2-p38 MAPKs and the nuclear translocation of NF-κB, consequently suppressing the activation of MAPK and NF-κB signaling pathways induced by the NF-κB ligand.

A chemical fingerprinting approach utilizing LC-MS/MS coupled with 2D NMR data was established to characterize the profile of sorbicilinoid-type metabolites from a deep-sea derived fungus Penicillium rubens F54. Targeted isolation of the cultured fungus resulted in the discovery of 11 undescribed sorbicilinoids namely sorbicillinolides A-K (1–11). Their structures were identified by extensive analyses of the spectroscopic data, including the calculation of electronic circular dichroism and optical rotation for configurational assignments. The cyclopentenone core of sorbicillinolides A-D is likely derived from sorbicillin/dihydrosorbicillin through a newly oxidative rearrangement. The stereoisomers of sorbicillinolides E-G incorporate a nitrogen unit, forming a unique hydroquinoline nucleus. Sorbicillinolides A and C exhibited significant anti-neuroinflammation in LPS-stimulated BV-2 macrophages, achieved by potent inhibition of NO and PGE2 production through the interruption of RNA transcription of iNOS, COX-2 and IL6 in the NF-κB signaling pathway. Further investigation identified COX-2 as a potential target of sorbicillinolide A. These findings suggest sorbicillinolide A as a potential lead for the development of a non-steroidal anti-neuroinflammatory agent.

Background Marine diterpenes represent a promising reservoir for identifying potential anti-rheumatoid arthritis (RA) candidates. Praelolide is a gorgonian-derived briarane-type diterpenoid with antioxidative and anti-osteoclastogenetic properties. Objective This study aims to evaluate the therapeutic efficacy of praelolide against RA and investigate its underlying mechanisms both in vivo and in vitro. Method Collagen-induced arthritis (CIA) mice and human RA fibroblast-like synoviocyte MH7A cells were employed for bioassays. The VisuGait system was utilized to assess gait dysfunction resulting from joint pain. Histopathological changes in ankle and synovial tissues were evaluated using micro-computed tomography, hematoxylin and eosin staining, Safranin-O/Fast Green staining, tartrate resistant acid phosphatase staining, and immunohistochemistry. Fluorescence spectroscopy, circular dichroism, and surface plasmon resonance were employed to investigate interactions between praelolide and catalase. The production of inflammatory cytokines and expression levels of proteins were assessed using ELISA and Western blotting, respectively. Result Praelolide significantly reduced paw swelling and arthritis scores, improved gait deficits, and restored synovial histopathological alterations and bone erosion in CIA mice. In vivo and in vitro, praelolide effectively decreased the expression and production of inflammatory cytokines such as interleukin (IL)-1β and IL-6. Additionally, praelolide inhibited osteoclastogenesis on bone surface of the ankle joints and in a tumor necrosis factor-α (TNF-α)-induced MH7A/bone marrow-derived macrophages (BMMs) co-culture system, and it strongly suppressed reactive oxygen species (ROS) production. Mechanistically, praelolide modulated catalase through non-covalent interactions, inducing conformational alterations that enhanced catalase activity and stability against time- and temperature-induced degradation. Further investigation revealed that praelolide significantly upregulated the expression of Nrf2, subsequently activating downstream antioxidant enzymes. Conclusion Praelolide markedly alleviated synovial inflammation and bone destruction in CIA mice by enhancing catalase activity and activating the Nrf2 pathway to reduce disease-related ROS accumulation, highlighting praelolide as a promising candidate for multitarget treatment of RA.

Prenylated indole diketopiperazines represent a diverse array of alkaloids with complex chemical scaffolds and with a wide range of biological activities. Aiming to discover bioactive metabolites with structural novelty, genomic annotation in association with the MS/MS-based molecular networking demonstrated a deep-sea derived fungus Aspergillus puulaauensis F77 containing a profile of diketopiperazines. Targeted separation of the cultured fungus led to the isolation of 19 undescribed austamide-type diketopiperazines namely versicoines A-S. Their structures were elucidated by the 2D NMR data, in association with Snatzke'method, ECD calculations, and single-crystal X-ray diffraction data for configurational assignments. Versicoine N-S represent a unique class of austamide-type alkaloids with a spirocenter at C-3. Bioassay results demonstrated versicoine N and relevant analogs possessing inhibitory effects against NO production in LPS-stimulated BV-2 cells. Further mechanistic investigation demonstrated the significant inhibition of versicoine N against p65 expression and its nuclear translocation, along with the inhibition toward phosphorylation of IKK/IκB in NF-κB signaling pathway. In addition, versicoine N also inhibited NLRP3 inflammasome activation and its related proteins, including caspase 1, pro-caspase1, IL-1β and pro-IL-1β. This study largely extends the chemical diversity of austamide-type alkaloids, and provides promising lead compounds for anti-neuroinflammation.

One novel rearranged pimarane diterpenoid, pestanoid A (1), and two reported molecules, nodulisporenones A (2) and B (3), were discovered from Pestalotiopsis sp. NBUF145 fungus associated with a 62 m deep mesophotic ("twilight") zone Chalinidae sponge. The structures of 1-3 were identified by spectrometry, spectroscopy, quantum-chemical calculations, and X-ray crystallography. Compounds 1 and 2 inhibited bone marrow monocyte osteoclastogenesis in vitro with the IC50 values 4.2 +/- 0.2 mu M and 3.0 +/- 0.4 mu M, respectively, without observed cytotoxicity. Both 1 and 2 suppressed the receptor activator of NF-kB ligand-induced MAPK and NF-kappa B signaling by inhibiting the phosphorylation of ERK1/2-JNK1/2-p38 MAPKs and NF-kappa B nuclear translocation.

Summary We propose a linearized maximum rank correlation estimator for the single-index model. Unlike the existing maximum rank correlation and other rank-based methods, the proposed estimator has a closed-form expression, making it appealing in theory and computation. The proposed estimator is robust to outliers in the response and its construction does not need knowledge of the unknown link function or the error distribution. Under mild conditions, it is shown to be consistent and asymptotically normal when the predictors satisfy the linearity of the expectation assumption. A more general class of estimators is also studied. Inference procedures based on the plug-in rule or random weighting resampling are employed for variance estimation. The proposed method can be easily modified to accommodate censored data. It can also be extended to deal with high-dimensional data combined with a penalty function. Extensive simulation studies provide strong evidence that the proposed method works well in various practical situations. Its application is illustrated with the Beijing PM 2.5 dataset.

Plasma simulation is important in studying the plasma discharge systematically, especially the anode layer ion source which has the complex geometrical characteristics of the discharge structure. However, owing to the complex solution domain formed by the geometric profile of the anode and cathode, the traditional simulation models show extremely small computational efficiency and poor convergence. This work presents a separate simulation for the ion source structure and the plasma discharge, separately, where the cathode geometric parameters (including the size, the shape and the relative position of the inner and outer cathodes) are simplified into two magnetic mirror parameters (the magnetic mirror ratio Rm and the magnetic induction intensity in the center of the magnetic mirror B 0), and then a high-efficient particle-in-cell/Monte Carlo collision (PIC/MCC) model is established to improve the computational efficiency and stability of the plasma simulation later. As a result, the convergence time of the plasma simulation is shortened significantly from 1.00 μs to 0.45 μs, and by which the influences of the geometrical characteristics of the discharge structure on the plasma properties are systematically studied. The simulation results reveal that magnetic mirror with Rm = 2.50 and B 0 = 36 mT can best confine the plasma in the central area between the inner cathode and outer cathode. When the discharge center of the plasmacoincides with the magnetic mirror center, the anode layer ion source presents both high density output of ion beam current and significantly reduced cathode etching, suggesting that the best balance is obtained between the output and cathode etching.

In this article, we propose a robust signal recovery method for high-dimensional linear log-contrast models, when the error distribution could be heavy-tailed and asymmetric. The proposed method is built on the Huber loss with l(1) penalization. We establish the l(1) and l(2) consistency for the resulting estimator. Under conditions analogous to the irrepresentability condition and the minimum signal strength condition, we prove that the signed support of the slope parameter vector can be recovered with high probability. The finite-sample behavior of the proposed method is evaluated through simulation studies, and applications to a GDP satisfaction dataset an HIV microbiome dataset are provided.

Metastasis is the leading cause of cancer-related mortality, targeting angiogenesis emerges as a therapeutic strategy for the treatment of melanoma metastasis. Discovery of new antiangiogenic compounds with specific mechanism of action is still desired. In present study, a bioassay-guidance uncovers the EtOAc extract of a marine-derived fungus Aspergillus clavutus LZD32-24 with significant inhibitory activity against the angiogenesis in Tg (fli1a: EGFP) zebrafish model. Extensive chromatographic fractionation led to the isolation of 48 indoloquinazoline alkaloids, including 21 new analogues namely clavutoines A-U (1-21). Their structures were determined by the spectroscopic data, including the ECD, single crystal X-ray diffraction and quantum chemical calculation for the configurational assignments. Among the bioactive analogues, quinadoline B (QB) showed the most efficacy to suppress the zebrafish vascular outgrowth in zebrafish embryos. QB markedly inhibited the migration, invasion and tube formation with weak cytotoxicity in human umbilical vein endothelial cells (HUVECs). Investigation of the mode of action revealed QB suppressed the ROCK/MYPT1/MLC2/coffin and FAK /Src signaling pathways, and subsequently disrupted actin cytoskeletal organization. In addition, QB reduced the number of new vessels sprouting from the ex vivo chick chorioallantoic membrane (CAM), and inhibited the metastasis of B16F10 melanoma cells in lung of C57BL/6 mice through suppressing angiogenesis. These findings suggest that QB is a potential lead for the development of new antiangiogenic agent to inhibit melanoma metastasis.

We are pleased to read the article entitled “Early results of novel robotic surgery-assisted low anterior resection for rectal cancer and transvaginal specimen extraction by using Da Vinci XI: initial clinical experience” by Çakır et al. 1 . In this study, the authors evaluated the early outcomes of robotic surgery-assisted anterior resection for low rectal cancer and transvaginal specimen extraction (TVSE). The authors explained the importance of TVSE for women in two aspects: it can bring good cosmetic effect and effectively reduce the complications related to additional skin incision. However, there are still some problems that need our further thinking and exploration