Ruthenium-Based Binary Alloy with Oxide Nanosheath for Highly Efficient and Stable Oxygen Evolution Reaction in Acidic Media.

Traditional noble metal oxide, such as RuO2, is considered a benchmark catalyst for acidic oxygen evolution reaction (OER). However, its practical application is limited due to sluggish activity and severe electrochemical corrosion. In this study, Ru-Fe nanoparticles loading on carbon felt (RuFe@CF) is synthesized via an ultrafast Joule heating method as an active and durable OER catalyst in acidic conditions. Remarkably low overpotentials of 188 and 269 mV are achieved at 10 and 100 mA cm-2, respectively, with a robust stability up to 620 h at 10 mA cm-2. When used as an anode in a proton exchange membrane water electrolyzer, the catalyst shows more than 250 h of stability at a water-splitting current of 200 mA cm-2. Experimental characterizations reveal the presence of a Ru-based oxide nanosheath on the surface of the catalyst during OER tests, suggesting a surface reconstruction process that enhances the intrinsic activity and inhibits continuous metal dissolution. Moreover, density functional theory calculations demonstrate that the introduction of Fe into the RuFe@CF catalyst reduces the energy barrier and boosts its activities. This work offers an effective and universal strategy for the development of highly efficient and stable catalysts for acidic water splitting.

PIEZO1 regulates leader cell formation and cellular coordination during collective keratinocyte migration.

The collective migration of keratinocytes during wound healing requires both the generation and transmission of mechanical forces for individual cellular locomotion and the coordination of movement across cells. Leader cells along the wound edge transmit mechanical and biochemical cues to ensuing follower cells, ensuring their coordinated direction of migration across multiple cells. Despite the observed importance of mechanical cues in leader cell formation and in controlling coordinated directionality of cell migration, the underlying biophysical mechanisms remain elusive. The mechanically-activated ion channel PIEZO1 was recently identified to play an inhibitory role during the reepithelialization of wounds. Here, through an integrative experimental and mathematical modeling approach, we elucidate PIEZO1's contributions to collective migration. Time-lapse microscopy reveals that PIEZO1 activity inhibits leader cell formation at the wound edge. To probe the relationship between PIEZO1 activity, leader cell formation and inhibition of reepithelialization, we developed an integrative 2D continuum model of wound closure that links observations at the single cell and collective cell migration scales. Through numerical simulations and subsequent experimental validation, we found that coordinated directionality plays a key role during wound closure and is inhibited by upregulated PIEZO1 activity. We propose that PIEZO1-mediated retraction suppresses leader cell formation which inhibits coordinated directionality between cells during collective migration.

Structured Reporting of Computed Tomography Enterography in Crohn's Disease.

BACKGROUND: To compare the integrity, clarity, conciseness, etc., of the structured report (SR) versus free-text report (FTR) for computed tomography enterography of Crohn's disease (CD). METHODS: FTRs and SRs were generated for 30 patients with CD. The integrity, clarity, conciseness etc., of SRs versus FTRs, were compared. In this study, an evidence-based medicine practice model was utilized on 92 CD patients based on SR in order to evaluate its clinical value. Then, the life quality of the patients in two groups was evaluated before and after three months of intervention using an Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: SRs received higher ratings for satisfaction with integrity (median rating 4.27 vs. 3.75, P=0.008), clarity (median rating 4.20 vs. 3.43, P=0.003), conciseness (median rating 4.23 vs. 3.20, P=0.003), the possibility of contacting a radiologist to interpret (median rating 4.17 vs. 3.20, P<0.001), and overall clinical impact (median rating 4.23 vs. 3.27, P<0.001) than FTRs. Besides, research group had higher score of IBDQ intestinal symptom dimension (median score 61.13 vs. 58.02, P=0.003), IBDQ systemic symptom dimension (median score 24.48 vs. 20.67, P<0.001), IBDQ emotional capacity dimension (median score 65.65 vs. 61.74, P<0.001), IBDQ social ability dimension (median score 26.80 vs. 22.37, P<0.001), and total IBDQ score (median score 178.07 vs. 162.80, P<0.001) than control group. CONCLUSION: The SR of CTE in CD patients was conducive to improving the quality and readability of the report, and CD patients' life quality could significantly improve after the intervention of an evidence-based medicine model based on SR.

Non-Noble Metal High-Entropy Alloy-Based Catalytic Electrode for Long-Life Hydrogen Gas Batteries.

The development of efficient, stable, and low-cost bifunctional catalysts for the hydrogen evolution/oxidation reaction (HER/HOR) is critical to promote the application of hydrogen gas batteries in large scale energy storage systems. Here we demonstrate a non-noble metal high-entropy alloy grown on Cu foam (NNM-HEA@CF) as a self-supported catalytic electrode for nickel-hydrogen gas (Ni-H2) batteries. Experimental and theoretical calculation results reveal that the NNM-HEA catalyst greatly facilitates the HER/HOR catalytic process through the optimized electronic structures of the active sites. The assembled Ni-H2 battery with NNM-HEA@CF as the anode shows excellent rate capability and exceptional cycling performance of over 1800 h without capacity decay at an areal capacity of 15 mAh cm-2. Furthermore, a scaled-up Ni-H2 battery fabricated with an extended capacity of 0.45 Ah exhibits a high cell-level energy density of ∼109.3 Wh kg-1. Moreover, its estimated cost reaches as low as ∼107.8 $ kWh-1 based on all key components of electrodes, separator and electrolyte, which is reduced by more than 6 times compared to that of the commercial Pt/C-based Ni-H2 battery. This work provides an approach to develop high-efficiency non-noble metal-based bifunctional catalysts for hydrogen batteries in large-scale energy storage applications.

Highly Bioactive MXene-M2-Exosome Nanocomposites Promote Angiogenic Diabetic Wound Repair through Reconstructing High Glucose-Derived Immune Inhibition.

The repair of diabetic wounds remains challenging, primarily due to the high-glucose-derived immune inhibition which often leads to the excessive inflammatory response, impaired angiogenesis, and heightened susceptibility to infection. However, the means to reduce the immunosuppression and regulate the conversion of M2 phenotype macrophages under a high-glucose microenvironment using advanced biomaterials for diabetic wounds are not yet fully understood. Herein, we report two-dimensional carbide (MXene)-M2 macrophage exosome (Exo) nanohybrids (FM-Exo) for promoting diabetic wound repair by overcoming the high-glucose-derived immune inhibition. FM-Exo showed the sustained release of M2 macrophage-derived exosomes (M2-Exo) up to 7 days and exhibited broad-spectrum antibacterial activity. In the high-glucose microenvironment, relative to the single Exo, FM-Exo could significantly induce the optimized M2a/M2c polarization ratio of macrophages by activating the PI3K/Akt signaling pathway, promoting the proliferation, migration of fibroblasts, and angiogenic ability of endothelial cells. In the diabetic full-thickness wound model, FM-Exo effectively regulated the polarization status of macrophages and promoted their transition to the M2 phenotype, thereby inhibiting inflammation, promoting angiogenesis through VEGF secretion, and improving proper collagen deposition. As a result, the healing process was accelerated, leading to a better healing outcome with reduced scarring. Therefore, this study introduced a promising approach to address diabetic wounds by developing bioactive nanomaterials to regulate immune inhibition in a high-glucose environment.

Exogenous brassinolide treatment regulates phenolic accumulation in mung bean sprouts through the modulation of sugar and energy metabolism.

BACKGROUND: The effects of exogenous brassinolide (BR) treatment (3.0 µmol L-1 ) on phenolic biosynthesis in mung bean sprouts were investigated. This investigation included the analysis of sugar content, substrates within the phenylpropane pathway, energy substances, enzymatic activity within the phenylpropane pathway, sugar metabolism and energy metabolism. RESULTS: Results showed that BR treatment significantly increased the levels of total phenolics, p-hydroxybenzoic acid, p-coumaric acid, gallic acid, fumalic acid and caffeic acid. This enhancement was accomplished through the elevation of l-phenylalanine levels and the activation of enzymes associated with the phenylpropane pathway in mung bean sprouts, including phenylalanine ammonia-lyase, cinnamate 4-hydroxylase and 4-coumarate CoA ligase. Furthermore, BR treatment induced alterations in sugar metabolism in mung bean sprouts as evidenced by the increased levels of glucose, fructose, sucrose and phosphoenolpyruvate. Moreover, increased activity was observed for enzymes linked to sucrose metabolism and glycolysis in the BR-treated group. Concurrently, BR treatment bolstered the levels of adenosine triphosphate and energy charge in mung bean sprouts, which was attributed to the activation of H+ -adenosine triphosphatase, Ca2+ -adenosine triphosphatase and succinic dehydrogenase. CONCLUSION: These results suggest that BR treatment can accelerate the accumulation of phenolic compounds in mung bean sprouts. This effect is achieved not only through the activation of the phenylpropane pathway, but also through the modulation of sugar and energy metabolism. The modulation provides ample energy and a substrate for the biosynthesis of phenolics. © 2023 Society of Chemical Industry.

Aqueous Organic Hydrogen Gas Proton Batteries with Ultrahigh-Rate and Ultralow-Temperature Performance.

Aqueous proton batteries (APBs) have emerged as one of the most promising batteries for large-scale energy storage technology. However, they usually show an undesirable electrochemical performance. Herein, we demonstrate a novel aqueous catalytic hydrogen gas powered organic proton (HOP) battery, which is driven by hydrogen evolution/oxidation redox reactions via commercial nanocatalysts on the anode and coordination/decoordination reactions of C═O with H+ on the cathode. The HOP battery shows an excellent rate capacity of 190.1 mAh g-1 at 1 A g-1 and 71.4 mAh g-1 at 100 A g-1. It also delivers a capacity of 96.6 mAh g-1 after 100000 cycles and operates at temperatures down to -70 °C. Moreover, the HOP battery is fabricated in a large-scale pouch cell with an extended capacity, exhibiting its potential for practical energy storage applications. This work provides new insights into the building of sustainable APBs, which will broaden the horizons of high-performance aqueous batteries.

Breaking Local Charge Symmetry of Iron Single Atoms for Efficient Electrocatalytic Nitrate Reduction to Ammonia.

The electrochemical conversion of nitrate pollutants into value-added ammonia is a feasible way to achieve artificial nitrogen cycle. However, the development of electrocatalytic nitrate-to-ammonia reduction reaction (NO3 - RR) has been hampered by high overpotential and low Faradaic efficiency. Here we develop an iron single-atom catalyst coordinated with nitrogen and phosphorus on hollow carbon polyhedron (denoted as Fe-N/P-C) as a NO3 - RR electrocatalyst. Owing to the tuning effect of phosphorus atoms on breaking local charge symmetry of the single-Fe-atom catalyst, it facilitates the adsorption of nitrate ions and enrichment of some key reaction intermediates during the NO3 - RR process. The Fe-N/P-C catalyst exhibits 90.3 % ammonia Faradaic efficiency with a yield rate of 17980 µg h-1 mgcat -1 , greatly outperforming the reported Fe-based catalysts. Furthermore, operando SR-FTIR spectroscopy measurements reveal the reaction pathway based on key intermediates observed under different applied potentials and reaction durations. Density functional theory calculations demonstrate that the optimized free energy of NO3 - RR intermediates is ascribed to the asymmetric atomic interface configuration, which achieves the optimal electron density distribution. This work demonstrates the critical role of atomic-level precision modulation by heteroatom doping for the NO3 - RR, providing an effective strategy for improving the catalytic performance of single atom catalysts in different electrochemical reactions.

Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice.

Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE), but the mechanism remains unclear. GABAergic neurons in substantia nigra pars reticulata (SNr) contribute to the motor deficit of HE. The present study aims to investigate the effects of oxidative stress on HE in male mice. The results validate the existence of oxidative stress in both liver and SNr across two murine models of HE induced by thioacetamide (TAA) and bile duct ligation (BDL). Systemic mitochondria-targeted antioxidative drug mitoquinone (Mito-Q) rescues mitochondrial dysfunction and oxidative injury in SNr, so as to restore the locomotor impairment in TAA and BDL mice. Furthermore, the GAD2-expressing SNr population (SNrGAD2) is activated by HE. Both overexpression of mitochondrial uncoupling protein 2 (UCP2) targeted to SNrGAD2 and SNrGAD2-targeted chemogenetic inhibition targeted to SNrGAD2 rescue mitochondrial dysfunction in TAA-induced HE. These results define the key role of oxidative stress in the pathogenesis of HE.

Selective Inhibition of Kinase Activity in Mammalian Cells by Bioorthogonal Ligand Tethering.

Enzymes are critical for cellular functions, and malfunction of enzymes is closely related to many human diseases. Inhibition studies can help in deciphering the physiological roles of enzymes and guide conventional drug development programs. In particular, chemogenetic approaches enabling rapid and selective inhibition of enzymes in mammalian cells have unique advantages. Here, we describe the procedure for rapid and selective inhibition of a kinase in mammalian cells by bioorthogonal ligand tethering (iBOLT). Briefly, a non-canonical amino acid bearing a bioorthogonal group is genetically incorporated into the target kinase by genetic code expansion. The sensitized kinase can react with a conjugate containing a complementary biorthogonal group linked with a known inhibitory ligand. As a result, tethering of the conjugate to the target kinase allows selective inhibition of protein function. Here, we demonstrate this method by using cAMP-dependent protein kinase catalytic subunit alpha (PKA-Cα) as the model enzyme. The method should be applicable to other kinases, enabling their rapid and selective inhibition.

Nuciferine improves random skin flap survival via TFEB-mediated activation of autophagy-lysosomal pathway.

Due to their simplicity and reliability, random-pattern skin flaps are commonly utilized in surgical reconstruction to repair cutaneous wounds. However, the post-operative necrosis frequently happens because of the ischemia and high-level of oxidative stress of random skin flaps, which can severely affect the healing outcomes. Earlier evidence has shown promising effect of Nuciferine (NF) on preventing hydrogen peroxide (H2O2)-induced fibroblast senescence and ischemic injury, however, whether it can function on promoting ischemic flap survival remains unknown. In this work, using network pharmacology analysis, it was possible to anticipate the prospective targets of NF in the context of ischemia. The results revealed that NF treatment minimized H2O2-induced cellular dysfunction of human umbilical vein endothelial cells (HUVECs), and also improved flap survival through strengthening angiogenesis and alleviating oxidative stress, inflammation and apoptosis in vivo. These outcomes should be attributed to TFEB-mediated enhancement of autophagy-lysosomal degradation via the AMPK-mTOR signaling pathway, whilst the restriction of autophagy stimulation with 3MA effectively diminished the above advantages of NF treatment. The increased nuclear translocation of TFEB not only restored lysosome function, but also promoted autophagosome-lysosome fusion, eventually restoring the inhibited autophagic flux and filling the high energy levels. The outcomes of our research can provide potent proof for the application of NF in the therapy of vascular insufficiency associated disorders, including random flaps.

Ultrafast Electrical Pulse Synthesis of Highly Active Electrocatalysts for Beyond-Industrial-Level Hydrogen Gas Batteries.

The high reliability and proven ultra-longevity make aqueous hydrogen gas (H2 ) batteries ideal for large-scale energy storage. However, the low alkaline hydrogen evolution and oxidation reaction (HER/HOR) activities of expensive platinum catalysts severely hamper their widespread applications in H2 batteries. Here, cost-effective, highly active electrocatalysts, with a model of ruthenium-nickel alloy nanoparticles in ≈3 nm anchored on carbon black (RuNi/C) as an example, are developed by an ultrafast electrical pulse approach for nickel-hydrogen gas (NiH2 ) batteries. Having a competitive low cost of about one fifth of Pt/C benckmark, this ultrafine RuNi/C catalyst displays an ultrahigh HOR mass activity of 2.34 A mg-1 at 50 mV (vs RHE) and an ultralow HER overpotential of 19.5 mV at a current density of 10 mA cm-2 . As a result, the advanced NiH2 battery can efficiently operate under all-climate conditions (from -25 to +50 °C) with excellent durability. Notably, the NiH2 cell stack achieves an energy density up to 183 Wh kg-1 and an estimated cost of ≈49 $ kWh-1 under an ultrahigh cathode Ni(OH)2 loading of 280 mg cm-2 and a low anode Ru loading of ≈62.5 µg cm-2 . The advanced beyond-industrial-level hydrogen gas batteries provide great opportunities for practical grid-scale energy storage applications.

Effects of exercise therapy on patients with poststroke cognitive impairment: A systematic review and meta-analysis.

Objective: To evaluate the effects of exercise therapy on patients with poststroke cognitive impairment and compare the differences in the effect of this method when compared with conventional measures, providing evidence for a more standardized and effective clinical application of exercise therapy. Methods: A search was conducted using 7 electronic databases, including PubMed, CINAHL, Web of Science, CENTRAL, CNKI, Wanfang, SinoMed, and clinical trials registry platforms for randomized controlled trials concerning exercise therapy on patients with poststroke cognitive impairment. Two researchers independently screened the literature, evaluated the quality, and extracted information. Meta-analysis was carried out using Review Manager 5.4 software. Results: There were 11 studies with 1,382 patients. Meta-analysis showed that exercise therapy could improve cognitive function [SMD = 0.67, 95% CI (0.31, 1.04), P = 0.0003], motor function [SMD = 1.81, 95% CI (0.41, 3.20), P = 0.01], and the activities of daily living [MD = 8.11, 95% CI (3.07, 13.16), P = 0.002] in patients with poststroke cognitive impairment. Conclusion: Exercise therapy can not only improve cognitive function in patients with poststroke cognitive impairment but also improve motor function and the activities of daily living. Medical staff should prioritize the management of patients with poststroke cognitive impairment and carry out exercise therapy actively to improve the cognitive function of patients with stroke. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42023397553.

Nerve-on-a-Chip Derived Biomimicking Microfibers for Peripheral Nerve Regeneration.

Fibrous scaffolds have shown their advantages in tissue engineering, such as peripheral nerve regeneration, while most of the existing fiber-shaped scaffolds are with simple structures, and the in vitro performance for nerve regeneration lacks systematic analysis. Here, novel nerve-on-a-chip derived biomimicking microfibers for peripheral nerve regeneration are presented. The microfibers with controllable core-shell structures and functionalities are generated through capillary microfluidic devices. By integrating these microfibers into a multitrack-architectured chip, and coculturing them with nerve cells as well as gradient bioactive elements, the nerve-on-a-chip with the capabilities of systematically assessing the performances of nerve fiber formation in the hollow microfibers at in vitro level is constructed. Based on a rat sciatic nerve injury model, the rapid promotion ability is demonstrated of optimized microfibers in nerve regeneration and function recovery in vivo, which implies the credibility of the nerve-on-a-chip on biomimicking microfibers evaluation for peripheral nerve regeneration. Thus, it is convinced that the organ-on-a-chip will undoubtedly open up a new chapter in evaluating biological scaffolds for in vivo tissue engineering.

Exploring the Functioning of Online Self-Organizations during Public Health Emergencies: Patterns and Mechanism.

With the increasing use of social media, online self-organized relief has become a crucial aspect of crisis management during public health emergencies, leading to the emergence of online self-organizations. This study employed the BERT model to classify the replies of Weibo users and used K-means clustering to summarize the patterns of self-organized groups and communities. We then combined the findings from pattern discovery and documents from online relief networks to analyze the core components and mechanisms of online self-organizations. Our findings indicate the following: (1) The composition of online self-organized groups follows Pareto's law. (2) Online self-organized communities are mainly composed of sparse and small groups with loose connections, and bot accounts can automatically identify those in need and provide them with helpful information and resources. (3) The core components of the mechanism of online self-organized rescue groups include the initial gathering of groups, the formation of key groups, the generation of collective action, and the establishment of organizational norms. This study suggests that social media can establish an authentication mechanism for online self-organizations, and that authorities should encourage online interactive live streams about public health issues. However, it is important to note that self-organizations are not a panacea for all issues during public health emergencies.

Combining a Density Gradient of Biomacromolecular Nanoparticles with Biological Effectors in an Electrospun Fiber-Based Nerve Guidance Conduit to Promote Peripheral Nerve Repair.

Peripheral nerve injury is a serious medical problem with limited surgical and clinical treatment options. It is of great significance to integrate multiple guidance cues in one platform of nerve guidance conduits (NGCs) to promote axonal elongation and functional recovery. Here, a multi-functional NGC is constructed to promote nerve regeneration by combining ordered topological structure, density gradient of biomacromolecular nanoparticles, and controlled delivery of biological effectors to provide the topographical, haptotactic, and biological cues, respectively. On the surface of aligned polycaprolactone nanofibers, a density gradient of bioactive nanoparticles capable of delivering recombinant human acidic fibroblast growth factor is deposited. On the graded scaffold, the proliferation of Schwann cells is promoted, and the directional extension of neurites from both PC12 cells and dorsal root ganglions is improved in the direction of increasing particle density. After being implanted in vivo for 6 and 12 weeks to repair a 10-mm rat sciatic nerve defect, the NGC promotes axonal elongation and remyelination, achieving the regeneration of the nerve not only in anatomical structure but also in functional recovery. Taken together, the NGC provides a favorable microenvironment for peripheral nerve regeneration and holds great promise for realizing nerve repair with an efficacy close to autograft.

A clinical study of inferior mesenteric artery typing in laparoscopic radical resections with left colonic artery preservation of rectal cancer.

OBJECTIVES: An investigation of the effects of different types of the inferior mesenteric artery (IMA) on laparoscopic left colic artery (LCA) radical resection of rectal cancer was conducted. METHODS: Clinical data were collected from 92 patients who underwent laparoscopic radical resection of rectal cancer with preservation of the LCA at Nantong University's Second Affiliated Hospital. All patients underwent full-abdominal dual-energy CT enhancement examination before surgery and 3D post-processing reconstruction of the IMA. Two radiologists with >3 years of experience in abdominal radiology jointly conducted the examination. A total of three types of IMA were identified among the patients: IMA type I (the LCA arising independently from the IMA), type II (LCA and sigmoid colon artery [SA] branching from a common trunk from IMA), and type III (LCA, SA, and superior rectal artery [SRA] branching from the IMA at the same point). The baseline data, pathological results, and intra-operative and post-operative indicators of the groups were analyzed. RESULTS: The proportions of type I, type II, and type III IMA were 58.70% (54/92), 18.48% (17/92), and 22.82% (21/92), respectively. IMA typing was consistent with the preoperative CT evaluation results. The intra-operative blood loss of type III IMA patients [median (interquartile spacing), M (P25, P75): 52.00 (39.50, 68.50) ml] was higher than that of type I and II IMA patients [35.00 (24.00, 42.00) and 32.00 (25.50, 39.50) ml, respectively] (P<0.05). The incidence of anastomotic fistula in type III IMA patients (4 cases, 19.05%) was higher than that in non-type III IMA patients (1 case, 1.41%) (X2=6.679, P=0.010). The incidence of postoperative complications among the three types of IMA was not significantly different (P>0.05). CONCLUSIONS: Among rectal cancer patients undergoing laparoscopic LCA preservation, type III IMA patients had more intraoperative bleeding and a higher incidence of postoperative anastomotic fistula. However, this did not increase the risk of overall postoperative complications.

Design of Multi-Functional Superhydrophobic Coating via Bacterium-Induced Hierarchically Structured Minerals on Steel Surface.

The fabrication of an eco-friendly, multi-functional, and mechanically robust superhydrophobic coating using a simple method has many practical applications. Here, inspired by shell nacre, the micro- or nano-scale surface roughness that is necessary for superhydrophobic coatings was formed via Bacillus subtilis-induced mineralization. The biomineralized film coated with hexadecyltrimethoxysilane (HDTMS) exhibited superhydrophobicity with water contact angles of 156°. The biomimetic HDTMS/calcite-coating showed excellent self-cleaning, anti-icing, and anti-corrosion performances. Furthermore, mechanically robust superhydrophobicity could be realized by hierarchically structured biomineralized surfaces at two different length scales, with a nano-structure roughness to provide water repellency and a micro-structure roughness to provide durability. Our design strategy may guide the development of "green" superhydrophobic coatings that need to retain effective multi-functional abilities in harsh marine environments.

MDL-800, the SIRT6 Activator, Suppresses Inflammation via the NF-κB Pathway and Promotes Angiogenesis to Accelerate Cutaneous Wound Healing in Mice.

Sirtuin 6 (SIRT6) is an NAD+-dependent deacetylase belonging to the sirtuin family. It has been shown to participate in wound healing and some inflammation-related disorders. However, the effect of MDL-800, a highly efficient and selective SIRT6 activator, on wound healing and inflammation has not been reported. Therefore, this study investigated whether MDL-800 confers anti-inflammatory effects and promotes wound healing and uncovered the molecular mechanisms involved. This was achieved using mouse models of full-thickness wounds. Results showed that MDL-800 significantly downregulated inflammation by attenuating the release of inflammatory mediators and improved collagen deposition and neovascularization of wounds, thereby accelerating cutaneous wound healing. Furthermore, MDL-800 significantly downregulated expression levels of TNF-α and IL-6 in the dorsal skin tissue of mice via the NF-κB pathway. These results demonstrated that MDL-800 exerted anti-inflammatory and prohealing effects, indicating that the SIRT6/NF-κB/IκB signaling pathway may play an important role in wound healing.

Selective Inhibition of Cysteine-Dependent Enzymes by Bioorthogonal Tethering.

A general approach for the rapid and selective inhibition of enzymes in cells using a common tool compound would be of great value for research and therapeutic development. We previously reported a chemogenetic strategy that addresses this challenge for kinases, relying on bioorthogonal tethering of a pan inhibitor to a target kinase through a genetically encoded non-canonical amino acid. However, pan inhibitors are not available for many enzyme classes. Here, we expand the scope of the chemogenetic strategy to cysteine-dependent enzymes by bioorthogonal tethering of electrophilic warheads. For proof of concept, selective inhibition of two E2 ubiquitin-conjugating enzymes, UBE2L3 and UBE2D1, was demonstrated in biochemical assays. Further development and optimization of this approach should enable its use in cells as well as with other cysteine-dependent enzymes, facilitating the investigation of their cellular function and validation as therapeutic targets.