Biomimetic Supramolecular Assembly with IGF-1C Delivery Ameliorates Inflammatory Bowel Disease (IBD) by Restoring Intestinal Barrier Integrity.

The management of dysfunctional intestinal epithelium by promoting mucosal healing and modulating the gut microbiota represents a novel therapeutic strategy for inflammatory bowel disease (IBD). As a convenient and well-tolerated method of drug delivery, intrarectal administration may represent a viable alternative to oral administration for the treatment of IBD. Here, a biomimetic supramolecular assembly of hyaluronic acid (HA) and ß-cyclodextrin (HA-ß-CD) for the delivery of the C domain peptide of insulin-like growth factor-1 (IGF-1C), which gradually releases IGF-1C, is developed. It is identified that the supramolecular assembly of HA-ß-CD enhances the stability and prolongs the release of IGF-1C. Furthermore, this biomimetic supramolecular assembly potently inhibits the inflammatory response, thereby restoring intestinal barrier integrity. Following HA-ß-CD-IGF-1C administration, 16S rDNA sequencing reveals a significant increase in the abundance of the probiotic Akkermansia, suggesting enhanced intestinal microbiome homeostasis. In conclusion, the findings demonstrate the promise of the HA-based mimicking peptide delivery platform as a therapeutic approach for IBD. This biomimetic supramolecular assembly effectively ameliorates intestinal barrier function and intestinal microbiome homeostasis, suggesting its potential for treating IBD.

Versatile Design of NO-Generating Proteolipid Nanovesicles for Alleviating Vascular Injury.

Vascular injury is central to the pathogenesis and progression of cardiovascular diseases, however, fostering alternative strategies to alleviate vascular injury remains a persisting challenge. Given the central role of cell-derived nitric oxide (NO) in modulating the endogenous repair of vascular injury, NO-generating proteolipid nanovesicles (PLV-NO) are designed that recapitulate the cell-mimicking functions for vascular repair and replacement. Specifically, the proteolipid nanovesicles (PLV) are versatilely fabricated using membrane proteins derived from different types of cells, followed by the incorporation of NO-generating nanozymes capable of catalyzing endogenous donors to produce NO. Taking two vascular injury models, two types of PLV-NO are tailored to meet the individual requirements of targeted diseases using platelet membrane proteins and endothelial membrane proteins, respectively. The platelet-based PLV-NO (pPLV-NO) demonstrates its efficacy in targeted repair of a vascular endothelium injury model through systemic delivery. On the other hand, the endothelial cell (EC)-based PLV-NO (ePLV-NO) exhibits suppression of thrombosis when modified onto a locally transplanted small-diameter vascular graft (SDVG). The versatile design of PLV-NO may enable a promising therapeutic option for various vascular injury-evoked cardiovascular diseases.

Ligand-Controlled Regiodivergent Nickel-Catalyzed Hydroaminoalkylation of Unactivated Alkenes.

Ligand modulation of transition-metal catalysts to achieve optimal reactivity and selectivity in alkene hydrofunctionalization is a fundamental challenge in synthetic organic chemistry. Hydroaminoalkylation, an atom-economical approach for alkylating amines using alkenes, is particularly significant for amine synthesis in the pharmaceutical, agrochemical, and fine chemical industries. However, the existing methods usually require specific substrate combinations to achieve precise regio- and stereoselectivity, which limits their practical utility. Protocols allowing for regiodivergent hydroaminoalkylation from the same starting materials, controlling both regiochemical and stereochemical outcomes, are currently absent. Herein, we report a ligand-controlled, regiodivergent nickel-catalyzed hydroaminoalkylation of unactivated alkenes with N-sulfonyl amines. The reaction initiates with amine dehydrogenation and involves aza-nickelacycle intermediates. Tritert-butylphosphine promotes branched regioselectivity and syn diastereoselectivity, whereas ethyldiphenylphosphine enables linear selectivity, yielding regioisomers with inverse orientation. Systematic evaluation of diverse monodentate phosphine ligands reveals distinct regioselectivity cliffs, and % Vbur (min), a ligand steric descriptor, was established as a predictive parameter correlating ligand structure to regioselectivity. Computational investigations supported experimental findings, offering mechanistic insights into the origins of regioselectivity. Our method provides an efficient and predictable route for amine synthesis, demonstrating broad substrate scope, excellent tolerance toward various functional groups, and practical advantages. These include the use of readily available starting materials and cost-effective nickel(II) salts as precatalysts.

Calcineurin suppresses rat H9c2 cardiomyocyteprotective autophagy under chronic intermittent hypoxia by downregulating the AMPK pathway.

Calcineurin plays a key role in cardiovascular pathogenesis by exerting pro-apoptotic effects in cardiomyocytes. However, whether calcineurin can regulate cardiomyocyte autophagy under conditions of chronic intermittent hypoxia (CIH) remains unclear. Here, we showed that CIH induced calcineurin activity in H9c2 cells, which attenuated adenosine monophosphate-activated protein kinase (AMPK) signaling and inhibited autophagy. In H9c2 cells, autophagy levels, LC3 expression, and AMPK phosphorylation were significantly elevated under conditions of CIH within 3 days. However, after 5 days of CIH, these effects were reversed and calcineurin activity and apoptosis were significantly increased. The calcineurin inhibitor 17-Allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo- [22.3.1.04,9]octacos-18- ene-2,3,10,16-tetrone (FK506) restored AMPK activation and LC3 expression and attenuated CIH-induced H9c2 cell apoptosis. In contrast, calcineurin overexpression significantly attenuated the increase in LC3 expression and enhanced H9c2 cell apoptosis under conditions of CIH. Calcineurin inhibition failed to induce autophagy or alleviate apoptosis in H9c2 cells expressing a kinase-dead K45R AMPK mutant. Autophagy inhibition abrogated the protective effects of FK506-mediated calcineurin inhibition. These results indicate that calcineurin suppresses adaptive autophagy during CIH by downregulating AMPK activation. Our findings reveal the underlying mechanism of calcineurin and autophagy regulation during H9c2 cell survival under conditions of CIH and may provide a new strategy for preventing CIH-induced cardiomyocyte damage.

Intracellular delivery of nitric oxide enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction.

Cell therapy by autologous mesenchymal stem cells (MSCs) is a clinically acceptable strategy for treating various diseases. Unfortunately, the therapeutic efficacy is largely affected by the low quality of MSCs collected from patients. Here, we showed that the gene expression of MSCs from patients with diabetes was differentially regulated compared to that of MSCs from healthy controls. Then, MSCs were genetically engineered to catalyze an NO prodrug to release NO intracellularly. Compared to extracellular NO conversion, intracellular NO delivery effectively prolonged survival and enhanced the paracrine function of MSCs, as demonstrated by in vitro and in vivo assays. The enhanced therapeutic efficacy of engineered MSCs combined with intracellular NO delivery was further confirmed in mouse and rat models of myocardial infarction, and a clinically relevant cell administration paradigm through secondary thoracotomy has been attempted.

The prediction model of operative link on gastric intestinal metaplasia stage III-IV: A multicenter study.

Purpose: Intestinal metaplasia plays a crucial role in the risk stratification of gastric cancer development. The objective of the study was to develop a prediction model for Operative Link on Gastric Intestinal Metaplasia (OLGIM) Stage III-IV. Methods: We analyzed 7945 high-risk gastric cancer individuals from 115 hospitals who underwent questionnaires and gastroscope. The participants were assigned to either the development or validation cohort randomly. Demographics and clinical characteristics were obtained. The outcome measurement was OLGIM III-IV. Univariate logistic regression was used for feature selection and multivariate logistic analysis was performed to develop the nomogram. Area under the curves, calibration plots, decision curve and clinical impact analysis were used to assess the performance of the nomogram. Results: 4600 individuals and 3345 individuals were included in the development and validation cohort, of which 124 and 86 individuals were diagnosed with OLGIM III-IV, respectively. Parameters in the training validation cohort matched well and there was no significant difference between two cohorts. A nomogram model for predicting OLGIM Stage III-IV consisted of 4 significantly associated variables, including age, gender, PG I and G-17 (AUC 0.723 and 0.700 for the 2 cohorts). The nomogram demonstrated excellent performance in the calibration curve. Decision curve and clinical impact analysis suggested clinical benefit of the prediction model. Conclusions: This reliable individualized nomogram might contribute to more accurate management for patients with OLGIM III-IV. Therefore, we suggest that this study be used as an incentive to promote the application.

Genetically engineered mesenchymal stem cells as a nitric oxide reservoir for acute kidney injury therapy.

Nitric oxide (NO), as a gaseous therapeutic agent, shows great potential for the treatment of many kinds of diseases. Although various NO delivery systems have emerged, the immunogenicity and long-term toxicity of artificial carriers hinder the potential clinical translation of these gas therapeutics. Mesenchymal stem cells (MSCs), with the capacities of self-renewal, differentiation, and low immunogenicity, have been used as living carriers. However, MSCs as gaseous signaling molecule (GSM) carriers have not been reported. In this study, human MSCs were genetically modified to produce mutant ß-galactosidase (ß-GALH363A). Furthermore, a new NO prodrug, 6-methyl-galactose-benzyl-oxy NONOate (MGP), was designed. MGP can enter cells and selectively trigger NO release from genetically engineered MSCs (eMSCs) in the presence of ß-GALH363A. Moreover, our results revealed that eMSCs can release NO when MGP is systemically administered in a mouse model of acute kidney injury (AKI), which can achieve NO release in a precise spatiotemporal manner and augment the therapeutic efficiency of MSCs. This eMSC and NO prodrug system provides a unique and tunable platform for GSM delivery and holds promise for regenerative therapy by enhancing the therapeutic efficiency of stem cells.

Animals are made up of cells of different types, with each type of cell specializing on a specific role. But for the body to work properly, the different types of cells must be able to coordinate with each other to respond to internal and external stimuli. This can be achieved through signaling molecules, that is, molecules released by a cell that can elicit a specific response in other cells. There are many types of different molecules, including hormones and signaling proteins. Gases can also be potent signaling molecules, participating in various biological processes. Nitric oxide (NO) is a gas signaling molecule that can freely diffuse through the membranes of cells and has roles in blood vessel constriction and other disease processes, making it a promising therapeutic agent. Unfortunately, using artificial carriers to deliver nitric oxide to the organs and tissues where it is needed can lead to issues, including immune reactions to the carrier and long-term toxicity. One way to avoid these effects is by using cells to deliver nitric oxide to the right place. Huang, Qian, Liu et al. have used mesenchymal stem cells ­ which usually develop to form connective tissues such as bone and muscle ­ to develop a cell-based NO-delivery system. The researchers genetically modified the mesenchymal stem cells to produce a compound called ß-GAL^H363A. On its own ß-GAL^H363A does not do much, but in its presence, a non-toxic, non-reactive compound developed by Huang, Qian, Liu et al., called MGP, can drive the release of NO from cells. To confirm the usefulness of their cells as a delivery system, Huang, Qian, Liu et al. transplanted some of the genetically modified mesenchymal stem cells into the kidneys of mice, and then showed that when these mice were given MGP, the levels of NO increased in the kidneys but not in other organs. This result confirms that the cell-based delivery system provides spatial and temporal control of the production of NO. These findings demonstrate a new delivery system for therapies using gas molecules, which can be controlled spatiotemporally in mice. In the future, these types of systems could be used in the clinic for long-term treatment of conditions where artificial carriers could lead to complications.

Treatment of Candida albicans liver abscess complicated with COVID-19 after liver metastasis ablation: A case report.

BACKGROUND: Liver interventional surgery is a relatively safe and minimally invasive surgery. However, for patients who have undergone Whipple surgery, the probability of developing a liver abscess after liver interventional surgery is very high. Fungal liver abscess has a high mortality rate, especially when complicated with malignant tumors, diabetes, coronavirus disease 2019 (COVID-19) and other complications. Fungal liver abscess is rare, and there are no guidelines or expert consensus on the course of antifungal therapy. CASE SUMMARY: A 54-year-old woman with pancreatic head cancer received albumin-bound paclitaxel in combination with gemcitabine chemotherapy after laparoscopic pancreaticoduodenectomy. Liver metastasis was found 1 mo after completion of 8 cycles of chemotherapy, followed by ablation of the liver metastasis. After half a month of liver metastasis ablation, the patient experienced fever after chemotherapy and was diagnosed with liver abscess complicated with COVID-19 by contrast-enhanced abdominal computed tomography and real-time polymerase chain reaction detection. The results of pus culture showed Candida albicans, which was sensitive to fluconazole. The patient underwent percutaneous catheter drainage, antifungal therapy with fluconazole, and antiviral therapy with azvudine. During antifungal therapy, the patient showed a significant increase in liver enzyme levels and was discharged after liver protection therapy. Oral fluconazole was continued for 1 wk outside the hospital, and fluconazole was used for a total of 5 wk. The patient recovered well and received 4 cycles of fluorouracil, leucovorin, oxaliplatin, and irinotecan after 2 mo of antifungal therapy. CONCLUSION: Effective treatment of Candida albicans liver abscess requires early detection, percutaneous catheter drainage, and 5 wk of antifungal therapy. Meanwhile, complications such as COVID-19 should be actively managed and nutritional support should be provided.

Endothelium-Mimetic Surface Modification Improves Antithrombogenicity and Enhances Patency of Vascular Grafts in Rats and Pigs.

We first identified thrombomodulin (TM) and endothelial nitric oxide (NO) synthase as key factors for the antithrombogenic function of the endothelium in human atherosclerotic carotid arteries. Then, recombinant TM and an engineered galactosidase responsible for the conversion of an exogenous NO prodrug were immobilized on the surface of the vascular grafts. Surface modification by TM and NO cooperatively enhanced the antithrombogenicity and patency of vascular grafts. Importantly, we found that the combination of TM and NO also promoted endothelialization, whereas it reduced adverse intimal hyperplasia, which is critical for the maintenance of vascular homeostasis, as confirmed in rat and pig models.

Identification, characterization, and transcription of serotonin receptors in rainbow trout (Oncorhynchus mykiss) in response to bacterial infection and salinity changes.

Serotonergic system is involved in the regulation of physiological functions and behavioral traits including cognition, memory, aggression, stress coping, appetite and immunomodulation. Serotonin exerts its functions via binding distinct serotonin receptors which are classified into 7 groups. Salmonid exhibits expanded functional gene copies due to salmonid-specific whole genome duplication. However, serotonin receptor (htr) repertoire is not fully identified in rainbow trout (Oncorhynchus mykiss). In this study, we identified 39 htr genes, including 14 htr1, 4 htr2, 4 htr2 like, 3 htr3, 4 htr4, 2 htr5, 2 htr6, and 6 htr7 subtypes. We investigated physiological functions of serotonin receptors in response to bacterial pathogens exposure and salinity changes. We showed htr1, htr2, htr4 and htr7 subtypes were associated with immunomodulation in response to Vibrio anguillarum or Aeromonas salmonicida infection. Saltwater (salinity of 15) transfer significantly altered htr1, htr2, htr4, and htr7 subtypes, suggesting trout Htr was associated with osmoregulation. We further showed residues interacted with inverse agonist (methiothepin) and serotonin analogue (5-Carboxamidotryptamine) were conserved between trout and human, suggesting exogenous ligands targeting human HTRs might have a role in aquaculture. This study showed duplicated trout Htrs might be physiologically neofunctionalized and potentially exhibit pleiotropic effects in regulating immunomodulation and osmoregulation.

Structural Modification Endows Small-Molecular SN38 Derivatives with Multifaceted Functions.

As a camptothecin derivative, 7-ethyl-10-hydroxycamptothecin (SN38) combats cancer by inhibiting topoisomerase I. SN38 is one of the most active compounds among camptothecin derivatives. In addition, SN38 is also a theranostic reagent due to its intrinsic fluorescence. However, the poor water solubility, high systemic toxicity and limited action against drug resistance and metastasis of tumor cells of SN38 indicates that there is great space for the structural modification of SN38. From the perspective of chemical modification, this paper summarizes the progress of SN38 in improving solubility, increasing activity, reducing toxicity and possessing multifunction and analyzes the strategies of structure modification to provide a reference for drug development based on SN38.

Impact of Diagnosis-Related Groups on Inpatient Quality of Health Care: A Systematic Review and Meta-Analysis.

The aim of this meta-analysis was to comprehensively evaluate the effectiveness of Diagnosis-related group (DRG) based payment on inpatient quality of care. A comprehensive literature search was conducted in PubMed, EMBASE, Cochrane Central Register of Controlled Trials and Web of Science from their inception to December 30, 2022. Included studies reported associations between DRGs-based payment and length of stay (LOS), re-admission within 30 days and mortality. Two reviewers screened the studies independently, extracted data of interest and assessed the risk of bias of eligible studies. Stata 13.0 was used in the meta-analysis. A total of 29 studies with 36 214 219 enrolled patients were analyzed. Meta-analysis showed that DRG-based payment was effective in LOS decrease (pooled effect: SMD = -0.25, 95% CI = -0.37 to -0.12, Z = 3.81, P < .001), but showed no significant overall effect in re-admission within 30 days (RR = 0.79, 95% CI = 0.62-1.01, Z = 1.89, P = .058) and mortality (RR = 0.91, 95% CI = 0.72-1.15, Z = 0.82, P = .411). DRG-based payment demonstrated statistically significant superiority over cost-based payment in terms of LOS reduction. However, owing to limitations in the quantity and quality of the included studies, an adequately powered study is necessary to consolidate these findings.

How do inpatients' costs, length of stay, and quality of care vary across age groups after a new case-based payment reform in China? An interrupted time series analysis.

CONTEXT: A patient classification-based payment system called diagnosis-intervention packet (DIP) was piloted in a large city in southeast China in 2018. OBJECTIVE: This study evaluates the impact of DIP payment reform on total costs, out-of-pocket (OOP) payments, length of stay (LOS), and quality of care in hospitalised patients of different age. METHODS: An interrupted time series model was employed to examine the monthly trend changes of outcome variables before and after the DIP reform in adult patients, who were stratified into a younger (18-64 years) and an older group (≥ 65 years), further stratified into young-old (65-79 years) and oldest-old (≥ 80 years) groups. RESULTS: The adjusted monthly trend of costs per case significantly increased in the older adults (0.5%, P = 0.002) and oldest-old group (0.6%, P = 0.015). The adjusted monthly trend of average LOS decreased in the younger and young-old groups (monthly slope change: -0.058 days, P = 0.035; -0.025 days, P = 0.024, respectively), and increased in the oldest-old group (monthly slope change: 0.107 days, P = 0.030) significantly. The changes of adjusted monthly trends of in-hospital mortality rate were not significant in all age groups. CONCLUSION: Implementation of the DIP payment reform associated with increase in total costs per case in the older and oldest-old groups, and reduction in LOS in the younger and young-old groups without deteriorating quality of care.

Helicobacter pylori Infection Combined with OLGA and OLGIM Staging Systems for Risk Assessment of Gastric Cancer: A Retrospective Study in Eastern China.

Purpose: Helicobacter pylori (H. pylori) infection is a high-risk factor for gastric cancer (GC). The main aim of this study was to evaluate the effect of H. pylori on gastritis staging systems and the value of H. pylori combined with gastritis staging systems in predicting GC risk. Patients and Methods: This study enrolled 609 patients with gastric atrophy (GA) and 527 patients with gastric intestinal metaplasia (GIM), who were graded by the OLGA and OLGIM staging systems, respectively. Each individual underwent serum pepsinogen (PG) test, H. pylori detection and questionnaire investigation. We did a real-world retrospective follow-up survey for them in April 2022. Results: Compared with H. pylori-negative patients, H. pylori-positive patients had higher serum PGs/gastrin-17 (G-17) levels and lower PGR levels, regardless of OLGA/OLGIM stages I-II or III-IV. Furthermore, eight patients with atrophic gastritis who progressed to GC were previously in OLGA stages III-IV and OLGIM stages II-IV. The average duration of this process was 2.19±1.03 years. Logistic regression analysis indicated that PGI and H. pylori infection were independent risk factors of individuals with OLGA stages III-IV. Age and PGR were independent risk factors of patients with OLGIM stages III-IV. PGI and PGR had good clinical diagnostic values for OLGA stages III-IV and OLGIM stages III-IV, respectively. Conclusion: Patients with OLGA/OLGIM stages III-IV should undergo endoscopic surveillance regardless of H. pylori infection. H. pylori-positive patients with OLGIM stage II also have a high risk of GC. H. pylori combined with PGI and PGR is helpful to evaluate the severity of chronic gastritis.

Endoscopic submucosal dissection versus esophagectomy for t1 esophageal squamous cell carcinoma: a propensity score-matched analysis.

Background: Endoscopic submucosal dissection (ESD) has been a preferred treatment option for superficial esophageal squamous cell carcinoma (SESCC). Objectives: To compare the outcomes of ESD and esophagectomy in the treatment of SESCC, especially for lesions invading muscularis mucosa or submucosa (pT1a-MM/T1b). Design: We retrospectively analyzed data from patients with SESCC who underwent ESD or esophagectomy between 2015 and 2021. Methods: After propensity score matching, overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS), and treatment-related events were compared between the ESD and esophagectomy groups. Furthermore, we performed a Cox regression analysis to identify factors associated with survival. Results: OS and DSS were significantly higher in the ESD group (n = 508) than that in the esophagectomy group (n = 466). After matching, 404 patients (202 per group) were included in the study. No significant differences were found between the ESD and esophagectomy groups in OS (p = 0.566), RFS (p = 0.586), and DSS (p = 0.912). The ESD group showed less blood loss, shorter procedure duration and hospital stay, lower hospital cost, and fewer adverse events. However, a lower R0 resection rate was observed in the ESD group compared to the esophagectomy group. Subgroup analysis showed comparable survival outcomes between the two groups. In Cox regression analysis, age was the independent factor associated with OS. Conclusion: In the treatment of SESCC, ESD showed sufficient safety and advantages. Even for pT1a-MM/pT1b SESCC, ESD may be an alternative treatment to esophagectomy.

Comparison between Endoscopic Submucosal Dissection and Surgery in Patients with Early Gastric Cancer.

Background: Endoscopic submucosal dissection (ESD) has become a preferred treatment option for early gastric cancer (EGC). This study aimed to compare the clinical outcomes of ESD and surgical resection for EGC. Methods: This was a retrospective case-control study. Patients with a diagnosis of EGC who underwent ESD or surgery in our hospital from 2011 to 2020 were enrolled. We compared the clinical characteristics and treatment outcomes of these two groups according to propensity score-matching. The primary outcome comparison was overall survival (OS). Secondary outcomes were disease-specific survival (DSS), recurrence-free survival (RFS), and treatment-related events. Results: In the matched cohort, the ESD group showed comparable OS, RFS, and DSS with the surgery group. Statistical differences were shown in blood loss and adverse events. Furthermore, the ESD group showed lower hospital cost, as well as a shorter operative time and hospital duration than the surgery group. The R0 resection and recurrence rates were similar between the two groups. In Cox regression analysis, age, tumor size, poor differentiation, and lymphovascular invasion were regarded as independent factors of OS. Conclusions: With sufficient safety and advantages, ESD can be a first-line treatment of EGC. Preoperative evaluation is vital to the appropriate treatment and prognosis.

Ascyrones A-E, type B bicyclic ployprenylated acylphloroglucinol derivatives from Hypericum ascyron.

Five new polycyclic polyprenylated acylphloroglucinols (1-5), ascyrones A-E, and four known compounds (6-9) were isolated from the aerial parts of Hypericum ascyron. All of the isolates containing a bicyclo[3.3.1]nonane-2,4,9-trione core and a benzoyl group, belonged to type B bicyclic polyprenylated acylphloroglucinols (BPAPs). Their structures and absolute configurations were established based on spectroscopic analyses and calculated electronic circular dichroism (ECD) data. The anti-inflammatory, neuroprotective and cytotoxicity activities of compounds 1-4 and 6-9 were evaluated. Compound 6 exhibited obvious anti-inflammatory activity in lipopolysaccharide (LPS)-induced RAW264.7 cells. Compounds 1 and 9 exhibited slight cytotoxicity against Hep3B cells. Meanwhile, compound 1 showed mild neuroprotective activity against corticosterone (CORT)-induced PC12 cell damage at 10 µmol·L-1.

Nitric oxide improves regeneration and prevents calcification in bio-hybrid vascular grafts via regulation of vascular stem/progenitor cells.

Vascular bypass surgery continues to use autologous grafts and often suffers from a shortage of donor grafts. Decellularized xenografts derived from porcine veins provide a promising candidate because of their abundant availability and low immunogenicity. Unfortunately, transplantation outcomes are far from satisfactory because of insufficient regeneration and adverse pathologic remodeling. Herein, a nitrate-functionalized prosthesis has been incorporated into a decellularized porcine vein graft to fabricate a bio-hybrid vascular graft with local delivery of nitric oxide (NO). Exogenous NO efficiently promotes vascular regeneration and attenuates intimal hyperplasia and vascular calcification in both rabbit and mouse models. The underlying mechanism was investigated using a Sca1 2A-CreER; Rosa-RFP genetic-lineage-tracing mouse model that reveals that Sca1+ stem/progenitor cells (SPCs) are major contributors to vascular regeneration and remodeling, and NO plays a critical role in regulating SPC fate. These results support the translational potential of this off-the-shelf vascular graft.

Enzyme-responsive hybrid prodrug of nitric oxide and hydrogen sulfide for heart failure therapy.

A hybrid prodrug was synthesized to realize the combined delivery of nitric oxide and hydrogen sulfide. The NO-H2S donor can release nitric oxide and hydrogen sulfide step by step in response to the endogenous enzymes ß-galactosidase and carbonic anhydrase, providing potent therapeutic efficacy for heart failure post- myocardial infarction.

MSC-derived sEV-loaded hyaluronan hydrogel promotes scarless skin healing by immunomodulation in a large skin wound model.

Designing hydrogel-based constructs capable of adjusting immune cell functions holds promise for skin tissue regeneration. Mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have attracted increasing attention owing to their anti-inflammatory and proangiogenic effects. Herein, we constructed a biofunctional hydrogel in which MSC-derived sEVs were incorporated into the injectable hyaluronic acid hydrogel, thus endowing the hydrogel with immunomodulatory effects. When implanted onto the wound site in a mouse large skin injury model, this functional hydrogel facilitates wound healing and inhibits scar tissue formation by driving macrophages towards an anti-inflammatory and anti-fibrotic (M2c) phenotype. Further investigation showed that the M2c-like phenotype induced by MSC-derived sEVs markedly inhibited the activation of fibroblasts, which could result in scarless skin wound healing. Taken together, these results suggest that modulation of the immune response is a promising and efficient approach to prevent fibrotic scar formation.