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Abstract Esophageal cancer is common worldwide, with ESCC being the most frequent tumor in East Asia. Tumor-associated macrophages are an important component of the ESCC microenvironment. SUMOylation is a post-translational modification of proteins, and SUMO-specific proteases (SENPs) play an important role in de-SUMOylation. In human patients, we discovered that the levels of SENP3 were upregulated in the tumor-associated macrophages. Furthermore, the loss of SENP3 enhanced the alternative activation of macrophages in the 4-NQO-induced ESCC mice model. This is the first study to identify SENP3-mediated macrophage polarization via the de-SUMOylation of interferon regulatory factor 4 (IRF4) at the K349 site. Alternative activation of macrophages increases the migration and invasion potential of ESCC cells and promotes their progression in vivo. Moreover, patients with relatively low SENP3 expression in macrophages exhibit higher primary PET SUVmax value and lymph node metastasis rates. In summary, this study revealed that SENP3-mediated IRF4 de-SUMOylation is crucial for the alternative activation of macrophages and influences the progression of ESCC. Graphical Abstract

Abstract Rechargeable neutral aqueous zinc−air batteries (ZABs) are a promising type of energy storage device with longer operating life and less corrosiveness compared with conventional alkaline ZABs. However, the neutral ZABs normally possess poor oxygen evolution reactions (OERs) and oxygen reduction reactions performance, resulting in a large charge–discharge voltage gap and low round‐trip efficiency. Herein, we demonstrate a sunlight‐assisted strategy for achieving an ultralow voltage gap of 0.05 V in neutral ZABs by using the FeOOH‐decorated BiVO4 (Fe‐BiVO4) as an oxygen catalyst. Under sunlight, the electrons move from the valence band (VB) of Fe‐BiVO4 to the conduction band producing holes in VB to promote the OER process and hence reduce the overpotential. Meanwhile, the photopotential generated by the Fe‐BiVO4 compensates a part of the charging potential of neutral ZABs. Accordingly, the energy loss of the battery could be compensated via solar energy, leading to a record‐low gap of 0.05 V between the charge and discharge voltage with a high round‐trip efficiency of 94%. This work offers a simple but efficient pathway for solar‐energy utilization in storage devices, further guiding the design of high energy efficiency of neutral aqueous ZABs.

Esophageal squamous cell carcinoma (ESCC) has a poor prognosis, and its metabolic reprogramming mechanism remains unclear. Small ubiquitin-like modifier(SUMO) -specific protease(SENP2) is highly related to fatty acids metabolism in some normal tissue. Thus, this study investigates the correlation between SENP2 and ESCC, and the possible mechanism. SENP2 expression was up-regulated in ESCC tissues compared to normal tissues, with high levels associated with poor overall survival rates. Knockdown of SENP2 inhibited ESCC proliferation, fatty acid uptake, and oxidation in vitro. RNA-seq indicated that SENP2 upregulated PPARγ, CPT1A, ACSL1, and CD36, through the deSUMOylation of SETDB1. SENP2 promotes ESCC proliferation and enhances fatty acid uptake and oxidation. High expression of SENP2 may be a poor prognostic biomarker for ESCC patients.

Background: Infection is the leading cause of acute lung injury (ALI). Macrophages, which are pivotal innate immune cells, play a critical role in mediating inflammatory processes. Intracellular lipopolysaccharide (LPS) from invasive Gram-negative bacteria can activate the caspase-11 inflammasome, leading to the induction of pyroptosis in macrophages. This process subsequently triggers the release of inflammatory cytokines and damage-associated molecular patterns from pyroptotic macrophages, thereby exacerbating inflammatory progression in ALI. However, the precise regulatory mechanisms governing caspase-11 activation is still unclear. Sentrin-specific proteases (SENPs) have been identified as notable targets for their anti-inflammatory properties. Nevertheless, the specific role of SENPs in macrophage pyroptosis during the pathogenesis of ALI remains unknown. Methods: We used LPS as an endotoxin to induce ALI. We analyzed the expression and location of sentrin-specific protease 1 (SENP1), pulmonary impairment, macrophage infiltration, caspase-11 inflammasome expression and activation, caspase-11 SUMOylation, and inflammatory cytokine secretion. Results: Upregulated expression of SENP1 in lung tissue and macrophages was observed following LPS stimulation. SENP1 mediates de-SUMOylation and activation of caspase-11 inflammasome in macrophages. Moreover, pharmacological inhibition or genetic deficiency of SENP1 in macrophages significantly improved ALI-related histological damage by reducing the secretion of inflammatory cytokines and suppressing caspase-11-dependent pyroptosis. Conclusions: Collectively, our findings highlight the involvement of SENP1 in caspase-11 activation and inflammatory progression in macrophages, thereby establishing a scientific foundation for the exploration of novel therapeutic strategies aimed at treating ALI.

Traditional needles for haemodialysis access can cause complications and discomfort. Indwelling needles may have advantages, but their efficacy needs to be investigated. Our study sought to compare the safety and efficacy of indwelling needles to traditional needles for haemodialysis access. A single-center retrospective study at the Pingyang County Hospital of Traditional Chinese Medicine included 70 haemodialysis patients. The intervention group used indwelling needles, whereas the control group used traditional needles. The rate of complications, limb mobility, blood chemistry, puncture success rates, operation times, haemostasis times, pain and comfort scores, and internal fistula failure rates were all compared. Overall, complication rates were slightly higher in the control group, but not statistically significant. Both groups improved their limb mobility and blood chemistry, but there were no significant differences. The intervention group had significantly higher puncture success rates (88.4% vs. 80.0%), shorter operation times (65.4 vs. 72.3 seconds), and faster haemostasis times (23.7 vs. 28.2 seconds) than the control group. Patients in the intervention group experienced less pain (3.7 vs. 4.2) and more comfort (8.1 vs. 7.5). The intervention group had slightly lower internal fistula failure rates (2.9% vs. 5.7%), but the difference was not statistically significant. Indwelling needles appear to improve puncture efficiency and patient comfort during hemodialysis.

Manganese oxide materials for high-performance supercapacitors are as popular electrode materials of energy storage devices based on their high theoretical capacitance. However, its development is limited by its poor electrical conductivity and insufficient contact surface area, which causes the supercapacitor to fail to achieve its theoretical specific capacitance. In this paper, unique sea urchin-like MnO2/biomass carbon (BC) composite materials were prepared for supercapacitors, showing the lower resistance compared with pure MnO2, which possesses superior electrochemical performance due to the advances in outstanding electrical conductivity. The single electrode test results show that the composite material achieves a specific capacitance of 205.5 F·g−1 at the current density of 0.5 A·g−1; with the current density increasing by a factor of 20, the supercapacitor loaded with this composite still retained 63.2% of its initial capacitance, showing its high rate performance. Meanwhile, the constructed asymmetric supercapacitor can change the color of electrochromic devices and drive the light of electrochemiluminescent devices, indicating its promising application. This work provided a promising route for the rational construction of multiple dimensioned high-performance electrode materials for use in new energy storage devices.

Abstract Colorless‐to‐black switching has attracted widespread attention for smart windows and multifunctional displays because they are more useful to control solar energy. However, it still remains a challenge owing to the tremendous difficulties in the design of completely reverse absorptions in transmissive and colored states. Herein, we report on an electrochemical device that can switch between colorless and black by using the electrochemical process of hybrid organic–inorganic perovskite MAPbBr3, which shows a high integrated contrast ratio of up to 73% from 400 to 800 nm. The perovskite solution can be used as the active layer to assemble the device, showing superior transmittance over the entire visible region in neutral states. By applying an appropriate voltage, the device undergoes reversible switching between colorless and black, which is attributed to the formation of lead and Br2 in the redox reaction induced by the electron transfer process in MAPbBr3. In addition, the contrast ratio can be modulated over the entire visible region by changing the concentration and the applied voltage. These results contribute toward gaining an insightful understanding of the electrochemical process of perovskites and greatly promoting the development of switchable devices.

Macrophages preferentially polarize to the anti-inflammatory M2 subtype in response to alterations in the wound microenvironment. SUMO-specific protease 3 (SENP3), a SUMO-specific protease, has been proven to regulate inflammation in macrophages by deSUMOylating substrate proteins, but its contribution to wound healing is poorly defined. Here, we report that SENP3 deletion promotes M2 macrophage polarization and accelerates wound healing in macrophage-specific SENP3 knockout mice. Notably, it affects wound healing through the suppression of inflammation and promotion of angiogenesis and collagen remodeling. Mechanistically, we identified that SENP3 knockout facilitates M2 polarization through the Smad6/IκB/p65 signaling pathway. SENP3 knockout elevated the expression of Smad6 and IκB. Moreover, Smad6 silencing enhanced the expression of p-p65 and proinflammatory cytokines while inhibiting the level of IκB. Our study revealed the essential role of SENP3 in M2 polarization and wound healing, which offers a theoretical basis for further research and a therapeutic strategy for wound healing.

Glytrexate, developed by our team, as a novel multitarget folate antagonist, has inhibitory effects on a variety of cancer cell types, especially KB tumor cells (IC50 0.078 nM), and thus has antitumor drug development prospects. However, its pharmacokinetics and plasma protein binding properties remain unknown. In this study a selective and sensitive liquid chromatography-tandem mass spectrometry (LC‒MS/MS) method was developed and verified to facilitate biological analysis. The bioanalysis method was applied to evaluate the stability, plasma protein binding, and pharmacokinetics of glytrexate. Glytrexate is more stable in human plasma than in rat plasma and in human liver microsomes. The binding of glytrexate to human plasma proteins was higher than that to rat plasma proteins, both of which were less than 30%, suggesting that glytrexate may be at a higher concentration at the pharmacologic target receptor(s) in tissues. Pharmacokinetic characteristics were determined by noncompartmental analysis after administration of single oral (12.5, 25 and 50 mg/kg) and intravenous (2 mg/kg) doses in rats. According to the rat oral pharmacokinetic characteristics, glytrexate had linear dynamics in a dose range of 12.5–50 mg/kg and a poor oral bioavailability of 0.57–1.15%. The investigation revealed that the intravenous half-life, AUC, and Cmax of glytrexate were higher than those of pemetrexed. Pemetrexed is generally produced as an injection preparation. This provides ideas for the development of glytrexate formulations. Therefore, glytrexate injection has clinical application prospects compared to oral administration. This study provides a basis for further investigations into the pharmacological effects and clinical uses of glytrexate.

Memory T cells are particularly reliant on fatty acid oxidation as a source of energy. Here the authors show this reliance is controlled by AMPK sensing of glucose deprivation that triggers SENP1-Sirt3 signalling, driving fatty acid oxidation and memory differentiation in T cells via deacetylation of YME1L1 to induce mitochondrial fusion.

Abstract Background Myocardial ischaemia reperfusion injury (MIRI) is a difficult problem in clinical practice, and it may involve various microRNAs. This study investigated the role that endogenous microRNA-146a plays in myocardial ischaemia reperfusion and explored the possible target genes. Methods MIRI models were established in microRNA-146a deficient (KO) and wild type (WT) mice. MicroRNA-146a expression was evaluated in the myocardium of WT mice after reperfusion. The heart function, area of myocardium infarction and in situ apoptosis were compared between the KO and WT mice. Microarray was used to explore possible target genes of microRNA-146a, while qRT-PCR and dual luciferase reporter assays were used for verification. Western blotting was performed to detect the expression levels of the target gene and related signalling molecules. A rescue study was used for further testing. Results MicroRNA-146a was upregulated 1 h after reperfusion. MicroRNA-146a deficiency decreased heart function and increased myocardial infarction and apoptosis. Microarray detected 19 apoptosis genes upregulated in the KO mice compared with the WT mice. qRT-PCR and dual luciferase verified that Med1 was one target gene of microRNA-146a. TRAP220, encoded by Med1 in the KO mice, was upregulated, accompanied by an amplified ratio of Bax/Bcl2 and increased cleaved caspase-3. Inhibition of microRNA-146a in H9C2 cells caused increased TRAP220 expression and more apoptosis under the stimulus of hypoxia and re-oxygenation, while knockdown of the increased TRAP220 expression led to decreased cell apoptosis. Conclusions MicroRNA-146a exerts a protective effect against MIRI, which might be partially mediated by the target gene Med1 and related to the apoptosis signalling pathway.

Ischemia reperfusion (IR) can lead to acute kidney injury and can be complicated by acute lung injury, which is one of the leading causes of acute kidney injury-related death. Peptidyl arginine deiminase-4 (PAD4) is a member of the PAD enzyme family and plays a critical role in inflammatory reactions and neutrophil extracellular trap formation in a variety of pathological conditions. It has been reported that PAD4 inhibition can protect certain organs from ischemic injury. In this study, we aimed to understand the mode of action of PAD4 in renal ischemia-reperfusion-mediated acute lung injury. Bilateral renal pedicle occlusion was induced for 30 min followed by reperfusion for 24 h. A specific inhibitor of PAD4, GSK484, was delivered via intraperitoneal injection to alter the PAD4 activity. The pulmonary PAD4 expression, pulmonary impairment, neutrophil infiltration, Cit-H3 expression, neutrophil extracellular trap formation, inflammatory cytokine secretion, and pulmonary apoptosis were analyzed. We found that renal ischemia reperfusion was associated with pulmonary pathological changes and increases in neutrophil infiltration, neutrophil extracellular trap formation, and inflammatory cytokine secretion in the lungs of the recipient animals. Suppression of PAD4 by GSK484 reduced remote lung injury by mitigating neutrophil infiltration, neutrophil extracellular trap formation, apoptosis, and inflammatory factor secretion. Our findings demonstrate that specific PAD4 inhibition by GSK484 may be an effective strategy to attenuate distant lung injury complicating renal ischemia-reperfusion injury.

Abstract Background Myocardial ischemia-reperfusion injury (IRI) has become one of the most serious complications after reperfusion therapy in patients with acute myocardial infarction. Small ubiquitin-like modification (SUMOylation) is a reversible process, including SUMO E1-, E2-, and E3-mediated SUMOylation and SUMO-specific protease-mediated deSUMOylation, with the latter having been shown to play a vital role in myocardial IRI previously. However, little is known about the function and regulation of SUMO E3 ligases in myocardial IRI. Results In this study, we found dramatically decreased expression of PIAS1 after ischemia/reperfusion (I/R) in mouse myocardium and H9C2 cells. PIAS1 deficiency aggravated apoptosis and inflammation of cardiomyocytes via activating the NF-κB pathway after I/R. Mechanistically, we identified PIAS1 as a specific E3 ligase for PPARγ SUMOylation. Moreover, H9C2 cells treated with hypoxia/reoxygenation (H/R) displayed reduced PPARγ SUMOylation as a result of down-regulated PIAS1, and act an anti-apoptotic and anti-inflammatory function through repressing NF-κB activity. Finally, overexpression of PIAS1 in H9C2 cells could remarkably ameliorate I/R injury. Conclusions Collectively, our findings demonstrate the crucial role of PIAS1-mediated PPARγ SUMOylation in protecting against myocardial IRI.

Abstract: MAPKs play important roles in platelet activation. However, the molecular mechanisms by which MAPKs are regulated in platelets remain largely unknown. Real-time polymerase chain reaction and western blot data showed that MEKK3, a key MAP3K family member, was expressed in human and mouse platelets. Then, megakaryocyte/platelet-specific MEKK3-deletion (MEKK3−/−) mice were developed to elucidate the platelet-related function(s) of MEKK3. We found that agonist-induced aggregation and degranulation were reduced in MEKK3−/− platelets in vitro. MEKK3 deficiency significantly impaired integrin αIIbβ3–mediated inside-out signaling but did not affect the outside-in signaling. At the molecular level, MEKK3 deficiency led to severely impaired activation of extracellular signal–regulated kinases 1/2 (ERK1/2) and c-Jun NH2-terminal kinase 2 but not p38 or ERK5. In vivo, MEKK3−/− mice showed delayed thrombus formation following FeCl3-induced carotid artery injury. Interestingly, the tail bleeding time was normal in MEKK3−/− mice. Moreover, MEKK3−/− mice had fewer microthrombi, reduced myocardial infarction (MI) size, and improved post-MI heart function in a mouse model of MI. These results suggest that MEKK3 plays important roles in platelet MAPK activation and may be used as a new effective target for antithrombosis and prevention of MI expansion.

Insufficient therapeutic strategies for acute kidney injury (AKI) necessitate precision therapy targeting its pathogenesis. This study reveals the new mechanism of the marine-derived anti-AKI agent, piericidin glycoside S14, targeting peroxiredoxin 1 (PRDX1). By binding to Cys83 of PRDX1 and augmenting its peroxidase activity, S14 alleviates kidney injury efficiently in Prdx1-overexpression (Prdx1-OE) mice. Besides, S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production. Due to the limited druggability of S14 with low bioavailability (2.6%) and poor renal distribution, a pH-sensitive kidney-targeting dodecanamine-chitosan nanoparticle system is constructed to load S14 for precise treatment of AKI. l-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1 (Kim-1)-overexpressed cells. The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly. By encapsulation with micelles, the AUC0‒t, half-life time, and renal distribution of S14 increase 2.5-, 1.8-, and 3.1-fold, respectively. The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDP-glycosyltransferase (UGT)-mediated biotransformation. In summary, this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology, thereby driving advancements in marine drug development for AKI.

PurposeBased on the efficacy data from the previous study of B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell injection, we further examined the delayed toxicity for 8 weeks after a single dose of BCMA CAR T-cell injection to observe possible toxic reactions.MethodsB-NDG mice transplanted with multiple myeloma (MM) cells were given a single dose of BCMA CAR T-cell injection at two dosages or human normal T cells and then subjected to examinations including clinical signs, weight and food intake measurements, haematology, blood biochemical analysis, cytokine assay, T-lymphocyte subpopulation quantification and histopathology on days 28 and 56 after dosing. In addition, quantitative polymerase chain reaction (qPCR) was used to quantify DNA fragments in different tissues to assess the tissue distribution of CAR and provide a basis for its preclinical safety evaluation and clinical dosing.ResultsIn the delayed toxicity study, no mortality or significant toxic effects such as reductions in food intake, body weight, relevant biochemical parameters and target organ weights were observed in the BCMA CAR T-cell-treated groups. Compared to the model group, restorative changes in clinical signs and clinicopathology indicating therapeutic effects were seen in the BCMA CAR T-cell-treated groups. Human-derived cytokines interleukin-2 (IL-2), IL-4, IL-6, IL-12, IL-10, tumor necrosis factor α (TNF-α), and interferon-γ (IFN-γ) could be detected in all cancer cell–bearing mice by cytokine level measurement. IFN-γ levels showed a geometric increase due to the graft versus host disease (GVHD) response induced in the mice, while the levels of the other cytokines did not show significant changes. Histopathological examination indicated that the BCMA CAR T-cell treatment groups showed mixed cellular infiltration of human-derived T cells, cancer cells, and inflammatory cells in several target organs including the liver, spleen, lung, and kidney, and some of them showed mild tissue damage, but the number of the animals and the severity of damage were significantly less than those of the T-cell control group as well as the model group. The results of the tissue distribution study showed that BCMA CAR T cells were mainly concentrated in the kidney, lung, bone marrow and the related immune organs/tissues, and the distribution of BCMA CAR T cells was highly consistent with that of MM cells, suggesting that BCMA CAR T cells could follow the cancer cells during metastatic targeting of the tissues.ConclusionsThe present study demonstrated a low toxicity of BCMA CAR T-cell injection, with manageable side effects and good anticancer activity and without observable adverse effects. This study provides data to support future clinical studies of BCMA CAR T-cell injection for MM.