Ferroptosis holds great promise for cancer immunotherapy, yet elevated cholesterol levels in tumor cells impose substantial structural and functional barriers to ferroptosis. Here, a cascade-catalytic nanocomposite microneedle platform (CSMZC MNs) is developed to convert this tumor-intrinsic cholesterol shield into an oxidative spear for ferroptosis-amplified cancer immunotherapy. By integrating superoxide dismutase (SOD) and cholesterol oxidase (COD) within Mn-doped zeolitic imidazolate framework nanoparticles and embedding them into dissolvable poly(γ-glutamic acid) microneedles, the platform enables localized intratumoral delivery and coordinated catalytic activation. After tumor cell internalization, the SOD-COD-Mn2+ cascade rewires redox metabolism and membrane lipid homeostasis by depleting cholesterol and 7-dehydrocholesterol, thereby dismantling tumor resistance to ferroptosis while amplifying reactive oxygen species generation and lipid peroxidation. This self-reinforcing oxidative amplification induces ferroptosis-associated immunogenic cell death and promotes cytosolic accumulation of nuclear and mitochondrial DNA, resulting in endogenous cGAS-STING activation. Meanwhile, Mn2+ enhances cGAS sensitivity to cytosolic DNA and amplifies type I interferon-mediated innate immune signaling. Through catalytic amplification and immune remodeling, CSMZC MNs reshape the immunosuppressive tumor microenvironment and elicit systemic T cell-mediated antitumor immunity against both primary and distant tumors. This work establishes an agonist-free immunometabolic strategy for converting tumor-protective cholesterol metabolism into a therapeutic vulnerability for tumor immunotherapy.

Chronic diabetic wounds represent a severe complication of diabetes mellitus and a prototypical form of chronic nonhealing wounds, characterized by biofilm-associated infection, persistent inflammation, and impaired angiogenesis. Herein, a multifunctional microneedle platform incorporating cationic chitosan-coated ruthenium dioxide nanozymes (RuO2@QCS NPs), termed RuO2@QCS-MN, is developed to accelerate diabetic wound healing through microenvironment reprogramming. This integrated system combines photothermal antibacterial activity, reactive oxygen species (ROS) scavenging, and in situ oxygen generation to coordinately regulate the pathological milieu of infected wounds. The microneedles effectively penetrate bacterial biofilms and deliver nanozymes to bacteria-enriched regions, enabling efficient yet mild photothermal antibacterial therapy. Meanwhile, RuO2@QCS NPs exhibit catalase-like activity, catalyzing endogenous hydrogen peroxide into oxygen, thereby enhancing nanozyme diffusion, alleviating oxidative stress, modulating inflammatory responses, and promoting macrophage polarization. Simultaneous oxygen generation may alleviate hypoxia and promote angiogenic responses. Both in vitro and diabetic in vivo models demonstrate efficient bacterial elimination, inflammation suppression, and enhanced re-epithelialization and neovascularization, ultimately accelerating wound repair. This work establishes a highly integrated nanozyme-enabled therapeutic paradigm for the localized treatment of infected diabetic wounds.

Objective To investigate the occurrence and mechanism of acute Karoshi and explore its forensic identification.Methods SD rats were divided into the control group(n=15)and experimental groups(n=45,acute Karoshi group and overwork survival group).A severe fatigue model was estab-lished by combining forced swimming under load to exhaustion and sleep deprivation.Their daily ac-tivities,diets,weight,respiratory functions,electrocardiogram and echocardiography were recorded.After the rats were sacrificed,samples were collected at autopsies.HE staining was used to observe the pathological morphology,and GC-MS was used to detect the changes of substance metabolism in se-rum,myocardium and liver.Results The mortality rate of the experimental group was 33.3%.There were decreases of aminobutyric acid and arachidonic acid in myocardium tissues,decreases of urea and increases of methionine and phenylalanine in serum.In liver tissues,the content of amino acids sush as histidine increased.The blood biochemical testing showed increases of alanine aminotransferase,as-partate aminotransferase,creatine kinase and creatine kinase isoenzymes and decreases of glucose and uric acid.There were interferences of energy metabolism pathways in serum,heart,and liver tissues.After three days,the experimental group developed cardiac conduction block and ventricular arrhyth-mia.Ventricular fibrillation and ventricular flutter appeared in acute Karoshi group.Echocardiogram showed ejection fraction and left ventricular short axis shortening rate decreased.The histological exami-nation showed granular swelling and sarcoplasmic condensation in myocardium and increased dark neu-rons in the brain stem.The combination of differential metabolites of serum urea,methionine and phe-nylalanine was highly correlated with Karoshi with a diagnostic rate of 90.6%.Conclusion Acute Karoshi can trigger a cascade reaction of metabolic,functional and morphological changes.The mecha-nism of death,especially central failure and sudden cardiac death,may be associated with multi-organ failure.

Multifunctional wound dressings are promising medical materials for various applications. Among them, dressings with antimicrobial activity, high biosafety, and real-time monitoring have attracted considerable research interest. Herein, a biodegradable hemostatic sponge comprising a chitosan skeleton and polyelectrolyte-surfactant complex (CS-PEC) was developed as a versatile wound dressing for wound pH monitoring and inhibition of bacterial infection. CS-PEC sponge with high porosity exhibited satisfactory fluid absorption capacity and biocompatibility, along with antibacterial properties against E. coli and S. aureus. In vivo experiments in rat liver trauma model revealed that wounds treated with the CS-PEC sponge recorded less blood loss (97.1 mg) and shorter hemostasis time (27.2 s) than those treated with commercial gelatin sponge (309.1 mg and 163.5 s, respectively). Furthermore, PECs based on unconventional luminescent molecules (L-C16-Hyp) were used as pH fluorescent indicators, which endowed the sponge with fluorescence-responsive behavior to wound pH changes in the range of 5.0-8.5. Visual images can be captured using a smartphone and converted to RGB color mode values for on-site assessment of wound status. This study sheds light on the design and application of unconventional luminescent materials in wound dressing and provides a smart and effective solution for wound management.

A hierarchically micro-/nanostructured Si@Au-based artificial enzyme with high-density accessible active sites shows high peroxidase-mimicking catalytic activity, excellent stability and good reusability.

Herein, a novel bioinspired radial porous zinc-based metal-organic framework (Zn-MOF) doped sodium alginate/chitosan derivatives/pullulan-based SA/PSCS/Pul/Zn-MOF (SPCP/Zn) composites sponge with excellent antioxidant and antibacterial properties was fabricated by the ice-templating method. Boric acid (BA) and Ca2+, which were respectively used as hydrogen- and ionic- bonding cross-linkers, provided strong mechanical properties for sponge matrix composed of SA, PSCS, and Pul. The obtained SPCP/Zn sponge exhibited uniform porous morphology, proper hydrophilicity, and admirable biocompatibility. In addition, the SPCP/Zn sponge achieved a sustained release of Zn2+ and gallic acid, which displayed powerful antibacterial and antioxidant activities. Importantly, the SPCP/Zn sponge exhibited shorter rapid hemostasis (20.4 ± 2.9 s) and lower blood loss (19.8 ± 4.3 mg). The SPCP/Zn sponge also showed faster wound closure ratio for the rat full-thickness skin defect model. It was revealed that SPCP/Zn sponge could significantly accelerate and enhance wound healing through downregulating inflammatory cytokines (TNF-α, IL-6) and increasing the expression of growth factors (VEGF). Due to its excellent properties, the SPCP/Zn sponge may have promising potential in wound healing applications.

Irregular hemorrhagic traumas always threaten the health of patients due to uncontrollable bleeding and wound infections. The traditional hemostatic materials show dissatisfactory hemostatic efficiency and antibacterial activity in solving these potential bleeding dangers. Herein, we proposed a kind of composites based on flexible wood membrane (FWM) loaded with chitosan/alginate derivative for accelerating rapid hemostasis and preventing infection. FWM was removed part of hemicellulose and lignin by using NaOH/Na2SO3 mixture to obtain excellent flexibility while retaining the original porous structure, followed by loading silver nanoparticles on the FWM surface to prepare AgNPs-FWM as an antibacterial bio-carrier. Then, AgNPs-FWM was coated with polyoxyethylene stearate-modified chitosan and multi-aldehyde sodium alginate to fabricate the composites of chitosan/alginate/AgNPs-FWM (CSA/AgNPs-FWM) using in-situ Schiff base reaction. Furthermore, in vitro and in vivo experiments showed that the CSA/AgNPs-FWM composites exhibited lower BCI value (2.6 ± 1.3 %), more rapid hemostasis (26 s) and lower blood loss (67.8 mg) than that of the traditional materials. The possible mechanism for the hemostasis process was not only the high blood absorption capacity, but also the synergistic interaction between hydrophobic alkane chains, amino groups, aldehydes, hydroxyl groups and blood cells. Moreover, CSA/AgNPs-FWM showed exceptional superiorities in mechanical properties and antibacterial activity, which endowed composites high potential in hemostasis application for irregular external wound.

Abstract Escaping from primary tumors and entering into blood flow, circulating tumor cells (CTCs) contain significant information for both the original tumors and metastasis mechanisms. CTCs detection has become an effective liquid biopsy of tumors and shows great promise in early cancer detection, disease monitoring, prognosis and personalized medicine. Despite the urgent need from clinics, CTCs isolation from blood is still a huge challenge due to their extreme rareness in blood. Well‐defined micro/nanostructures and nature‐inspired hierarchical architectures offer unique avenues to address this challenge by matching well with the special physical properties of CTCs to sort cells or forming local topographic interactions to strengthen cell adhesion, thereby improving the CTC‐isolation performance. In this review, we first summarize researches on CTCs isolation with diverse micro/nanostructured substrates, which mainly include nanomaterials, microfluidics, DNA nanostructures, micromotors and in vivo detection devices. In sequence, various CTC‐isolation biomimetic architectures, which are inspired by different natural creatures (e.g., viruses, cells, extracellular matrix [ECM], plants, and animals), have been highlighted. At last, remaining challenges and future perspectives in designing CTC‐isolation platforms for clinical applications are also discussed.

Uncontrolled bleeding is thought to be the most deadly cause of pre-hospital, traffic, and military accidents death. However, the popular commercial hemostats can only realize the hemostasis of mild bleeding. Therefore, we developed polydopamine (PDA) composite materials (PMs), which applied hydroxyapatite as the parent body. The PMs were produced via lyophilization and functionalized with amino, phenol hydroxyls groups, which endowed hydrophobicity to materials. This ensured a high aggregation ability of blood cells to the PMs and they were tested to be as high as 300% compared with the negative control group. The clotting time was shortened to 79.7% compared with the usually used commercial hemostat (Celox) in the test of in vitro hemostasis. Through the results of PT and APTT tests, blood coagulation index test, and the analysis of intracellular Ca2+ activation, we further understood the mechanism of the hemostasis of the materials, which explained the low blood loss and quick coagulation time of the PM hemostats in detail. Besides, the low hemolysis and cytotoxicity of the PMs suggested the good biocompatibility of the hemostats, which was further proved by the regular morphology maintained by erythrocytes in the hemolysis tests. The study of nanoscale composites led the research for the methods of hemostasis.

Montmorillonite (MMT) powder, as the most effective hemostats in natural silicates, is restricted for commercial application due to its embolic effect. Until now, it's still a challenge to control the leakage of MMT and avoid its side-effects. Herein, poly aldehyde dextran (PDA)/MMT composite sponge (PM) with commendable tissue adhesion, antibacterial, and wound healing performances is developed for massive hemorrhage control. Based on the high degree of perfect synergism of PDA and MMT, the PM sponge can rapidly seal the wound, and promote cells aggregation and adhesion, whole coagulation system activation, resulting in shortened clotting time from 480 s to <10 s in vitro. Therefore, PM sponge with low exothermic effects achieves hemostasis in limited time, decreasing nearly 95% blood loss in the femoral artery and vein incision in rat models. Furthermore, with the intensive tissue adhesion (~47 kPa), PM sponge not only exhibits antibacterial activity to Escherichia coli, but also succeeds in accelerating wound healing. Importantly, the low cytotoxic sponge verifies to be a little hemolytic and skin irritant hemostat. Thus, the biocompatible PM sponge may provide a new strategy for reintroduction of MMT in hemostatic fields, and a safe-effective avenue for clays to control bleeding.

Cell behaviors are influenced by the surrounding dynamic microenvironment where the extracellular matrix (ECM) composed of different micro/nano-structures plays a key role. Many micro/nano-structures have been developed to mimic the structure of ECM, but these structures are almost static, and fail to emulate the dynamicity and function of the ECM in vivo. Notably, certain micro/nano-structures based on shape-memory polymers (SMPs), including patterns, fibers, porous scaffolds and microspheres, have attracted increasing attention due to the unique spatiotemporal variations. The dynamical shifting of these biomimetic micro/nano-structures arising from the shape-memory effect endows the materials with unique functions, e.g., regulating cell behaviors and prompting tissue growth. Therefore, the dynamically tunable biomimetic micro/nano-structures based on SMPs can be an ideal platform to mimic dynamic changes in the ECM structure both in vitro and in vivo. This review summarizes the latest advances in the development of the methodologies for fabricating various SMP biomimetic micro/nano structures, spatiotemporal control of cell behaviors, and broad applications in biomedical engineering. Several crucial points for future research are presented. (C) 2020 Elsevier Ltd. All rights reserved.

Wound dressing is of significant importance to promote cutaneous wound healing process. To develop an effective wound dressing, a PVA/DA hydrogel was prepared using a Poly (vinyl alcohol)/Dextran-aldehyde solution blend, followed by crosslinking via freeze-thaw method and freeze-drying. We characterized the hydrogel by infrared spectroscopy, mechanical property tests, swelling behavior test and biocompatibility test. Results showed that the PVA/DA hydrogels had a 3-dimensional, highly porous structure with uniformly distributed pores of 5-10 mu m, strong tensile strength of 5.6 MPa, efficient ability to absorb fluid of 6 time its weight and suitable water vapor transmission rate of 2100 g m(-2) day(-1) to keep a moist environment and good biocompatibility shown by very low hemolysis and no cytotoxicity. In wound healing tests using a full-thickness skin wound model, macroscopic observations showed that the wound covered by the PVA/DA hydrogel almost reached complete healing faster by 10 days, while histological analysis indicated a faster regeneration of skin. Thus, the PVA/DA hydrogel was suitable for application as a wound dressing and may have potential for use in various biomedical applications. (C) 2019 Elsevier B.V. All rights reserved.

Uncontrolled hemorrhage is closely related to the high risk of death. However, local hemostats still have various defects and side effects. Herein, an aldehyde dextran (PDA) sponge with proper absorption and adhesion properties is developed for hemorrhage control. PDA sponge with pore size of similar to 30-50 mu m fabricated by lyophilization not only absorbs blood quickly (47.7 g/g), but also possesses strong tissue adhesion (similar to 100 kPa). PDA sponge with low cytotoxicity and hemolysis achieves effective hemostasis and remarkable blood loss reduction in the ear vein, femoral artery and liver injuries of rabbit models. Furthermore, the exploration of hemostatic mechanisms related to tissue, blood, plasma, cells and coagulation system indicates that PDA sponge can significantly accelerate coagulation by rapid wound block, fast cells aggregation and initiation, and high coagulation factors concentration, instead of by the coagulation cascade activation. Importantly, this hemostat exhibits excellent biodegradability and nearly no skin irritation. Overall, the biodegradable and tissue adhesive PDA sponge will be a promising quick-hemostatic dressing for uncontrollable hemorrhage.

Severe global metabolic deterioration is a key feature of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). To investigate the global metabolic changes of HBV-ACLF patients and explore the prognostic potential, extracted metabolic profiling information will shed new light on the pathophysiological process and prognosis of this disease. An NMR-based metabolomics study and its coupled survival prediction ability analysis were applied to the serum samples of healthy controls (HC, n=23), chronic hepatitis B patients (CHB, n=27), surviving HBV-ACLF patients (ACLF-S, n=24) and non-surviving HBV-ACLF patients (ACLF-NS, n=30). The score plots from the metabolomics analysis reveal clear metabolic separations of the HBV-ACLF patients from the CHB individuals and of the surviving HBV-ACLF individuals from the non-surviving ones. Ultimately, 14 discriminative metabolites, including lipids, LDL and twelve amino acids, presented consecutive changes with the progression of HBV-ACLF. These metabolites potentially play important roles in the progression of HBV-ACLF. The averaged sensitivity and specificity values of the survival prediction models based on metabolomics data are 76.7% and 83.3%, respectively. The combined use of metabolomics data and clinical parameters raises the sensitivity and specificity values of the predicted score plot up to 91.7% and 90%, respectively. The phenotypic metabolomics analyses of HC, CHB, ACLF, ACLF-S and ACLF-NS individuals provides an encouraging basis for deeper studies of the HBV-ACLF pathophysiological process and demonstrates a proof of concept that global metabolic profiling data is a reliable source to improve the accuracy of predicting the survival outcome of HBV-ACLF patients.

Enzymatic glucosylation of unnatural products by natural glycosyltransferases (GTs) has great potential in creating novel and bioactive glucosides. A new GT (AaGT3) from Aloe arborescens exhibited catalytic promiscuity and high efficiency to diverse unnatural naphthols. By combing the substrate flexibility and catalytic reversibility of AaGT3, a cost-effective enzymatic approach to novel and bioactive unnatural glucosides was established. These studies indicate the significant potential of promiscuous natural GTs in synthesis of unnatural bioactive glucosides in drug discovery. (C) 2017 Elsevier Ltd. All rights reserved.

Two new cytochalasans, periconiasin I (1) with 9/6/5 tricyclic ring, and periconiasin J (2) with 5/6/6/5 tetracyclic ring, were isolated from the endophytic fungus Periconia sp. F-31. Their structures including absolute configurations were elucidated through extensive spectroscopic analyses, calculated ECD, and the circular dichroism data of the [Rh-2(OCOCF3)(4)] complex. Compound I showed in vitro cytotoxicity against human MCF-7 tumor cell line with an IC50 value of 4.8 mu M, compound 2 exhibited weak anti HIV activity with an IC50 value of 25.0 mu M. (C) 2016 Elsevier Ltd. All rights reserved.

Background: To get a broader view of global ischemia-induced cerebral disorders at the metabolic level, a nuclear magnetic resonance-based metabolomic study was performed to evaluate the metabolic profile changes on regional brain tissues of female and male mice upon bilateral common carotid arteries occlusion (BCCAO) operation.Results: Significant metabolic disorders were observed in both cerebral cortex and hippocampus tissues of the experimental mice upon global cerebral ischemic attack. Multiple amino acids were identified as the dominantly perturbed metabolites. It was also shown that although the metabolic profile change patterns in the brain tissues were quite similar in male and female BCCAO mice, metabolic disorders in the cortex tissues were more severe in the female mice than in the male mice.Conclusions: In the present study, significant changes in amino acid metabolic pathways were confirmed in the early stage of global ischemia. Meanwhile, cerebral metabolic dysfunctions were more severe in the female BCCAO mice than in the male mice, suggesting that gender may play a role in different metabolic responses to the ischemic attack, which may provide an important hypothesis for a better understanding of the clinically observed gender-dependent pathological outcome of cerebral ischemia.

Hyperuralones C-H (1-6), six new 1,9-seco-bicyclic polyprenylated acylphloroglucinols (1,9-seco-BPAPs) derived from the normal polyprenylated acylphloroglucinols with a bicyclo[3.3.1]nonane-2,4,9-trione core, together with six known analogues, were isolated from the aerial parts of Hypericum uralum. The structures of 1-6 were elucidated on the basis of the interpretation of NMR. and MS spectroscopic data. The structure of attenuatumione B, a known compound isolated from H. attenuatum, was revised to that of a 1,9-seco-BPAP by NMR spectroscopic analysis and previous biomimetic synthesis methods. The inhibitory activities of these isolates on acetylcholinesterase were tested, and compounds 1 and 2 exhibited moderate activities with IC50 values of 9.6 and 7.1 mu M, respectively.

Correction for ‘Novel dextran/graphene oxide composite material as a sorbent for solid-phase microextraction of polar aromatic compounds’ by Xiudan Hou et al., RSC Adv., 2015, 5, 21720–21727.