Pharmacodynamic insights into maresin 1: Enhancing flap viability via the keap1/Nrf2 axis to control ROS-driven apoptosis and ferroptosis.

Random flaps are widely used in tissue reconstruction, but the high incidence of flap necrosis after operation remains a significant challenge. Maresin 1 (MaR1), a mediator derived from docosahexaenoic acid, has been shown to have significant effects in resolving inflammation and promoting tissue regeneration. This study investigated the role of MaR1 in the survival of random flaps. Histological analysis, laser Doppler blood flow imaging, Masson trichrome staining, and survival area analysis were used to assess the viability of the flaps. Apoptosis, ferroptosis, oxidative stress, angiogenesis, and the underlying mechanisms were explored by examining the expression of specific molecules using immunofluorescence, western blotting, and other immunological and molecular biology techniques. The findings demonstrated that MaR1 could improve flap lifespan by significantly reducing oxidative stress, apoptosis, and ferroptosis, as well as by enhancing angiogenesis. The Keap1-Nrf2 pathway was upregulated by MaR1, which inhibited ROS-mediated apoptosis and ferroptosis. The protective effect of MaR1 on flap survival was abolished by ML385. Our findings indicate that MaR1 could be a novel therapeutic agent for enhancing flap treatment outcomes.

PKM2-Driven Lactate Overproduction Triggers Endothelial-To-Mesenchymal Transition in Ischemic Flap via Mediating TWIST1 Lactylation.

The accumulation of lactate is a rising risk factor for patients after flap transplantation. Endothelial-to-mesenchymal transition (EndoMT) plays a critical role in skin fibrosis. Nevertheless, whether lactate overproduction directly contributes to flap necrosis and its mechanism remain unknown. The current study reveals that skin flap mice exhibit enhanced PKM2 and fibrotic response. Endothelial-specific deletion of PKM2 attenuates flap necrosis and ameliorates flap fibrosis in mice. Administration of lactate or overexpressing PKM2 promotes dysfunction of endothelial cells and stimulates mesenchymal-like phenotype following hypoxia. Mechanistically, glycolytic-lactate induces a correlation between Twist1 and p300/CBP, leading to lactylation of Twist1 lysine 150 (K150la). The increase in K150la promotes Twist1 phosphorylation and nuclear translocation and further regulates the transcription of TGFB1, hence inducing fibrosis phenotype. Genetically deletion of endothelial-specific PKM2 in mice diminishes lactate accumulation and Twist1 lactylation, then attenuates EndoMT-associated fibrosis following flap ischemia. The serum lactate levels of flap transplantation patients are elevated and exhibit predictive value for prognosis. This findings suggested a novel role of PKM2-derived lactate in mediating Twist1 lactylation and exacerbates flap fibrosis and ischemia. Inhibition of glycolytic-lactate and Twist1 lactylation reduces flap necrosis and fibrotic response might become a potential therapeutic strategy for flap ischemia.

Enhancing the Electrocatalytic Oxidation of 5-Hydroxymethylfurfural Through Cascade Structure Tuning for Highly Stable Biomass Upgrading.

Electrocatalytic 5-hydroxymethylfurfural oxidation reaction (HMFOR) provides a promising strategy to convert biomass derivative to high-value-added chemicals. Herein, a cascade strategy is proposed to construct Pd-NiCo2O4 electrocatalyst by Pd loading on Ni-doped Co3O4 and for highly active and stable synergistic HMF oxidation. An elevated current density of 800 mA cm-2 can be achieved at 1.5 V, and both Faradaic efficiency and yield of 2,5-furandicarboxylic acid remained close to 100% over 10 consecutive electrolysis. Experimental and theoretical results unveil that the introduction of Pd atoms can modulate the local electronic structure of Ni/Co, which not only balances the competitive adsorption of HMF and OH- species, but also promote the active Ni3+ species formation, inducing high indirect oxidation activity. We have also discovered that Ni incorporation facilitates the Co2+ pre-oxidation and electrophilic OH* generation to contribute direct oxidation process. This work provides a new approach to design advanced electrocatalyst for biomass upgrading.

Puerarin enhances TFEB-mediated autophagy and attenuates ROS-induced pyroptosis after ischemic injury of random-pattern skin flaps.

BACKGROUND AND AIM: Necrosis of random-pattern flaps restricts their application in clinical practice. Puerarin has come into focus due to its promising therapeutic effects in ischemic diseases. Here, we employed Puerarin and investigated its role and potential mechanisms in flap survival. EXPERIMENTAL PROCEDURE: The effect of Puerarin on the viability of human umbilical vein endothelial cells (HUVECs) was assessed by CCK-8, EdU staining, migration, and scratch assays. Survival area measurement and laser Doppler blood flow (LDBF) were utilized to assess the viability of ischemic injury flaps. Levels of molecules related to oxidative stress, pyroptosis, autophagy, transcription factor EB (TFEB), and the AMPK-TRPML1-Calcineurin signaling pathway were detected using western blotting, immunofluorescence, dihydroethidium (DHE) staining, RT-qPCR and Elisa. KEY RESULTS: The findings demonstrated that Puerarin enhanced the survivability of ischemic flaps. Autophagy, oxidative stress, and pyroptosis were implicated in the ability of Puerarin in improving flap survival. Increased autophagic flux and augmented tolerance to oxidative stress contribute to Puerarin's suppression of pyroptosis. Additionally, Puerarin modulated the activity of TFEB through the AMPK-TRPML1-Calcineurin signaling pathway, thereby enhancing autophagic flux. CONCLUSIONS AND IMPLICATIONS: Puerarin promoted flap survival from ischemic injury through upregulation of TFEB-mediated autophagy and inhibition of oxidative stress. Our findings offered valuable support for the clinical application of Puerarin in the treatment of ischemic diseases, including random-pattern flaps.

Local CO Generator Enabled by a CO-Producing Core for Kinetically Enhancing Electrochemical CO2 Reduction to Multicarbon Products.

CO plays a crucial role as an intermediate in electrochemical CO2 conversion to generate multicarbon (C2+) products. However, optimizing the coverage of the CO intermediate (*CO) to improve the selectivity of C2+ products remains a great challenge. Here, we designed a hierarchically structured double hollow spherical nanoreactor featuring atomically dispersed nickel (Ni) atoms as the core and copper (Cu) nanoparticles as the shell, which can greatly improve the catalytic activity and selectivity for C2+ compounds. Within this configuration, CO generated at the active Ni sites on the inner layer accumulates in the cavity before spilling over neighboring Cu sites on the outer layer, thus enhancing CO dimerization within the cavity. Notably, this setup achieves a sustained faradaic efficiency of 74.4% for C2+ production, with partial current densities reaching 337.4 mA cm-2. In situ Raman spectroscopy and finite-element method (FEM) simulations demonstrate that the designed local CO generator can effectively increase the local CO concentration and restrict CO evolution, ultimately boosting C-C coupling. The hierarchically ordered architectural design represents a promising solution for achieving highly selective C2+ compound production in the electroreduction of CO2.

Dihydrocapsaicin suppresses the STING-mediated accumulation of ROS and NLRP3 inflammasome and alleviates apoptosis after ischemia-reperfusion injury of perforator skin flap.

Avascular necrosis frequently occurs as a complication following surgery involving the distal perforator flap. Dihydrocapsaicin (DHC) can protect tissue from ischemia-reperfusion (I/R) injury, but its specific role in multizone perforator flaps remains unclear. In this study, the prospective target of DHC in the context of I/R injury was predicted using network pharmacology analysis. Flap viability was determined through survival area analysis, laser Doppler blood flow, angiograms, and histological examination. The expressions of angiogenesis, apoptosis, NLR family pyrin domain containing 3 (NLRP3) inflammasome, oxidative stress, and molecules related to cyclic guanosine monophosphate (GMP)-adenosine monophosphate synthase (cGAS)-interferon gene stimulant (STING) pathway were assessed using western blotting, immunofluorescence, TUNEL staining, and dihydroethidium (DHE) staining. Our finding revealed that DHC promoted the perforator flap survival, which involves the cGAS-STING pathway, oxidative stress, NLRP3 inflammasome, apoptosis, and angiogenesis. DHC induced oxidative stress resistance and suppressed the NLRP3 inflammasome, preventing apoptosis in vascular endothelial cells. Through regulation of STING pathway, DHC controlled oxidative stress in endothelial cells and NLRP3 levels in ischemic flaps. However, activation of the cGAS-STING pathway led to the accumulation of reactive oxygen species (ROS) and NLRP3 inflammasome, thereby diminishing the protective role of DHC. DHC enhanced the survival of multidomain perforator flaps by suppressing the cGAS-STING pathway, oxidative stress, and the formation of NLRP3 inflammasome. These findings unveil a potentially novel mechanism with clinical significance for promoting the survival of multidomain perforator flaps.

Alleviating OH Blockage on the Catalyst Surface by the Puncture Effect of Single-Atom Sites to Boost Alkaline Water Electrolysis.

Nonprecious transition metal catalysts have emerged as the preferred choice for industrial alkaline water electrolysis due to their cost-effectiveness. However, their overstrong binding energy to adsorbed OH often results in the blockage of active sites, particularly in the cathodic hydrogen evolution reaction. Herein, we found that single-atom sites exhibit a puncture effect to effectively alleviate OH blockades, thereby significantly enhancing the alkaline hydrogen evolution reaction (HER) performance. Typically, after anchoring single Ru atoms onto tungsten carbides, the overpotential at 10 mA·cm-2 is reduced by more than 130 mV (159 vs 21 mV). Also, the mass activity is increased 16-fold over commercial Pt/C (MA100 = 17.3 A·mgRu-1 vs 1.1 A·mgPt-1, Pt/C). More importantly, such electrocatalyst-based alkaline anion-exchange membrane water electrolyzers can exhibit an ultralow potential (1.79 Vcell) and high stability at an industrial current density of 1.0 A·cm-2. Density functional theory (DFT) calculations reveal that the isolated Ru sites could weaken the surrounding local OH binding energy, thus puncturing OH blockage and constructing bifunctional interfaces between Ru atoms and the support to accelerate water dissociation. Our findings exhibit generality to other transition metal catalysts (such as Mo) and contribute to the advancement of industrial-scale alkaline water electrolysis.

Axial Dual Atomic Sites Confined by Layer Stacking for Electroreduction of CO2 to Tunable Syngas.

Arranging atoms in an orderly manner at the atomic scale to create stable polyatomic structures is a very challenging task. In this study, we have developed three-dimensional confinement areas on the two-dimensional surface by creating regional defects. These areas are composed of vertically stacked graphene layers, where Ni and Fe atoms are anchored concentrically to form axial dual atomic sites in high yield. These sites can be used to produce tunable syngas through the electroreduction of CO2. Theoretical calculations indicate that the Ni sites vertically regulate the charge distribution of the adjacent Fe sites in the layer below, resulting in a lower d-band center. This, in turn, weakens the adsorption of the *CO intermediate and inhibits the production of H2 at the Fe site. Our research presents a novel approach for concentrated creation of dual atomic sites by building a confinement-selective surface.

Establishment and Validation of a Pathologic Upgrade Prediction Nomogram Model for Gastric Low-Grade Intraepithelial Neoplasia Patients After the Eradication of Helicobacter pylori.

BACKGROUND: As yet, there is no unified method of treatment for the evaluation and management of gastric low-grade intraepithelial neoplasia (LGIN) worldwide. METHODS: Patients with gastric LGIN who had been treated with Helicobacter pylori eradication were gathered retrospectively. Based on several relevant characteristics described and analyzed by LASSO regression analysis and multivariable logistic regression, a prediction nomogram model was established. C-index, the area under the receiver operating characteristic curve (AUC), calibration plot, and decision curve analysis (DCA) were adopted to evaluate the accuracy and reliability of the model. RESULTS: A total of 309 patients with LGIN were randomly divided into the training groups and the validation groups. LASSO regression analysis and multivariable logistic regression identified that 6 variables including gender, size, location, borderline, number, and erosion were independent risk factors. The nomogram model displayed good discrimination with a C-index of .765 (95% confidence interval: .702-.828). The accuracy and reliability of the model were also verified by an AUC of .764 in the training group and .757 in the validation group. Meanwhile, the calibration curve and the DCA suggested that the predictive nomogram had promising accuracy and clinical utility. CONCLUSIONS: A predictive nomogram model was constructed and proved to be clinically applicable to identify high-risk groups with possible pathologic upgrade in patients with gastric LGIN. Since it is regarded that strengthening follow-up or endoscopic treatment of high-risk patients may contribute to improving the detection rate or reducing the incidence of gastric cancer, the predictive nomogram model provides a reliable basis for the treatment of LGIN.

Precise Regulation of Iron Spin States in Single FeN4 Sites for Efficient Peroxidase-Mimicking Catalysis.

The catalytic activity and selectivity of single-atom sites catalysts is strongly dependent on the supports structure and central metal coordination environment. However, the further optimization of electronic configuration to improve the catalytic performance is usually hampered by the strong coordination effect between the support and metal atoms. Herein, it is discovered that enzyme-mimicking catalytic performance can be enhanced at the fixed coordination single-atom Fe sites by regulating the Fe spin states. The X-ray absorption fine structure, 57 Fe Mössbauer spectrum, and temperature-dependent magnetization measurements reveal that the spin states of Fe in single FeN4  sites can be well manipulated via changing the pyrolysis temperature. The intermediate-spin Fe sites catalyst (t2g 4 eg 1) demonstrates a much higher peroxidase-mimicking activity in comparison with high-spin structure (t2g 3 eg 2). More importantly, the based enzymes system realizes sensitive detection of H2 O2  and glucose by colorimetric sensors with high catalytic activity and selectivity. Furthermore, theoretical calculations unveil that the intermediate-spin FeN4  promotes the OH* desorption process, thus greatly reducing the reaction energy barrier. These findings provide a route to design highly active enzyme-mimicking catalysts and an engineering approach for regulating spin states of metal sites to enhance their catalytic performance.