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Fluorophores with donor-acceptor-donor groups with the emission spanning the second near-infrared window (NIR-II) have recently received great attention for biomedical application. Yet, the mechanism underlying the equilibrium between fluorescence (radiative decay) and photothermal effect (non-radiative decay) of these fluorophores remains elusive. Here, we demonstrate that a lipophilic NIR-II fluorophore, BPBBT, possesses both twisted intramolecular charge transfer (TICT) and aggregation-induced emission (AIE) characteristics. Human serum albumin (HSA) binds to BPBBT, which changes the planarity of the fluorophore and restricts its intramolecular rotation. The binding results in alteration to the equilibrium between AIE and TICT state of BPBBT, tailoring its fluorescence and photothermal efficiency. Under the guidance of intraoperative NIR-II fluorescence image, the prepared HSA-bound BPBBT nanoparticles delineate primary orthotopic mouse colon tumor and metastatic lesions with dimensions as small as 0.5 mm × 0.3 mm, and offer photothermal ablation therapy with optimized timing, dosing and area of the laser irradiation. There is a balance between the fluorescence and photothermal properties of fluorescent molecules. Here, the authors report on an NIR-II fluorophore which binds with human serum albumin changing the equilibrium, increasing the photothermal efficiency, and demonstrate application of this for tumour ablation.

Ischemia/reperfusion (I/R) injury significantly contributes to the morbidity and mortality associated with cardiac events. Poloxamer 188 (P188), a non-ionic triblock copolymer, has been proposed to mitigate I/R injury by stabilizing cell membranes. However, the underlying mechanisms remain incompletely understood, particularly concerning endothelial cell (EC) function and nitric oxide (NO) production. We employed human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) and ECs to elucidate the effects of P188 on cellular survival, function, and NO secretion under simulated I/R conditions. iPSC-CMs contractility and iPSC-ECs’ NO production were assessed following exposure to P188. Further, an isolated heart model using Brown Norway rats subjected to I/R injury was utilized to evaluate the ex-vivo cardioprotective effects of P188, examining cardiac function and NO production, with and without the administration of a NO inhibitor. In iPSC-derived models, P188 significantly preserved CM contractile function and enhanced cell viability after hypoxia/reoxygenation. Remarkably, P188 treatment led to a pronounced increase in NO secretion in iPSC-ECs, a novel finding demonstrating endothelial protective effects beyond membrane stabilization. In the rat isolated heart model, administration of P188 during reperfusion notably improved cardiac function and reduced I/R injury markers. This cardioprotective effect was abrogated by NO inhibition, underscoring the pivotal role of NO. Additionally, a dose-dependent increase in NO production was observed in non-ischemic rat hearts treated with P188, further establishing the critical function of NO in P188 induced cardioprotection. In conclusion, our comprehensive study unveils a novel role of NO in mediating the protective effects of P188 against I/R injury. This mechanism is evident in both cellular models and intact rat hearts, highlighting the potential of P188 as a therapeutic agent against I/R injury. Our findings pave the way for further investigation into P188’s therapeutic mechanisms and its potential application in clinical settings to mitigate I/R-related cardiac dysfunction.

Emerging evidence indicates that a vicious cycle between inflammation and microthrombosis catalyzes the pathogenesis of inflammatory bowel disease (IBD). Over‐stimulated inflammation triggers a coagulation cascade and leads to microthrombosis, which further complicates the injury through tissue hypoxia and ischemia. Herein, an injectable protein hydrogel with anti‐thrombosis and anti‐inflammation competency is developed to impede this cycle, cross‐linked by silver ion mediated metal‐ligand coordination and electronic interaction with sulfhydryl functionalized bovine serum albumin and heparin, respectively. The ex vivo experiments show that the hydrogel, HEP‐Ag‐BSA, exhibits excellent self‐healing ability, injectability, biocompatibility, and sustained drug release. HEP‐Ag‐BSA also demonstrates anti‐coagulation and anti‐inflammation abilities via coagulation analysis and lipopolysaccharide stimulation assay. The in vivo imaging confirms the longer retention time of HEP‐Ag‐BSA at inflammatory sites than in normal mucosa owing to electrostatic interactions. The in vivo study applying a mouse model with colitis also reveals that HEP‐Ag‐BSA can robustly inhibit inflammatory microthrombosis with reduced bleeding risk. This versatile protein hydrogel platform can definitively hinder the “inflammation and microthrombosis” cycle, providing a novel integrated approach against IBD. A microthrombosis and inflammation balancing protein hydrogel, HEP‐Ag‐BSA, is crosslinked by silver ion mediated metal‐ligand coordination and electronic interaction with sulfhydryl functionalized bovine serum albumin and heparin. This injectable hydrogel has prolonged retention at inflamed site, reduces the release of proinflammatory cytokines, and robustly inhibits microthrombosis, which exerts a definitive therapeutic effect on the pathogenesis of inflammatory bowel disease with guaranteed safety.

Inflammatory bowel disease (IBD) is characterized by intestinal mucosal damage that exacerbates inflammation and promotes disease recurrence. Although hydrogel‐based therapies have shown potential for mucosal repair, challenges remain due to inadequate targeting and low hydrogel density, leading to ongoing infiltration of harmful substances and delayed mucosal healing. In this study, an inflammation‐targeting‐triggered healing hydrogel (ITTH hydrogel) is developed, composed of polyvinyl alcohol‐alginate microgels (PALMs) and a cyclodextrin polymer crosslinker (CPC). This hydrogel specifically targets inflamed colonic sites and crosslinks in situ to form a dense network. The results demonstrate that the ITTH hydrogel adheres effectively to inflamed colonic tissue in both IBD mouse models and human samples. The dense crosslinked network acts like the mucosal barrier, preventing the penetration of detrimental substances such as bacteria and small molecules, thereby protecting the underlying mucosal tissue. Furthermore, the ITTH hydrogel significantly improved therapeutic outcomes in mice with dextran sulfate sodium (DSS)‐induced colitis. These findings suggest that the ITTH hydrogel is a promising candidate for in situ reconstruction of colonic mucosa and the treatment of IBD. Inflammatory bowel disease (IBD) involves mucosal damage that exacerbates inflammation and recurrence. This study introduces an inflammation‐targeting‐triggered healing (ITTH) hydrogel, which specifically targets inflamed colonic tissue and undergoes in situ re‐crosslinking to form a dense barrier. This barrier prevents harmful substance infiltration, protects mucosal tissue, and significantly improves therapeutic outcomes.

Background Reactive astrogliosis is one of the significantly pathological features in ischemic stroke accompanied with changes in gene expression, morphology, and proliferation. KCa3.1 was involved in TGF-β-induced astrogliosis in vitro and also contributed to astrogliosis-mediated neuroinflammation in neurodegeneration disease. Methods Wild type mice and KCa3.1 −/− mice were subjected to permanent middle cerebral artery occlusion (pMCAO) to evaluate the infarct areas by 2,3,5-triphenyltetrazolium hydrochloride staining and neurological deficit. KCa3.1 channels expression and cell localization in the brain of pMCAO mice model were measured by immunoblotting and immunostaining. Glia activation and neuron loss was measured by immunostaining. DiBAC4 (3) and Fluo-4AM were used to measure membrane potential and cytosolic Ca 2+ level in oxygen-glucose deprivation induced reactive astrocytes in vitro. Results Immunohistochemistry on pMCAO mice infarcts showed strong upregulation of KCa3.1 immunoreactivity in reactive astrogliosis. KCa3.1 −/− mice exhibited significantly smaller infarct areas on pMCAO and improved neurological deficit. Both activated gliosis and neuronal loss were attenuated in KCa3.1 −/− pMCAO mice. In the primary cultured astrocytes, the expressions of KCa3.1 and TRPV4 were increased associated with upregulation of astrogliosis marker GFAP induced by oxygen-glucose deprivation. The activation of KCa3.1 hyperpolarized membrane potential and, by promoting the driving force for calcium, induced calcium entry through TRPV4, a cation channel of the transient receptor potential family. Double-labeled staining showed that KCa3.1 and TRPV4 channels co-localized in astrocytes. Blockade of KCa3.1 or TRPV4 inhibited the phenotype switch of reactive astrogliosis. Conclusions Our data suggested that KCa3.1 inhibition might represent a promising therapeutic strategy for ischemia stroke.

The local, intramyocardial injection of proteins into the infarcted heart is an attractive option to initiate cardiac regeneration after myocardial infarction (MI). Liraglutide, which was developed as a treatment for type 2 diabetes, has been implicated as one of the most promising protein candidates in cardiac regeneration. A significant challenge to the therapeutic use of this protein is its short half-life in vivo. In this study, we evaluated the therapeutic effects and long-term retention of liraglutide loaded in poly(lactic- -glycolic acid)-poly(ethylene glycol) (PLGA-PEG) nanoparticles (NP-liraglutide) on experimental MI. PLGA-PEG nanoparticles (NPs) have been shown to efficiently load liraglutide and release bioactive liraglutide in a sustained manner. For in vitro test, the released liraglutide retained bioactivity, as measured by its ability to activate liraglutide signaling pathways. Next, we compared the effects of an intramyocardial injection of saline, empty NPs, free liraglutide and NP-liraglutide in a rat model of MI. NPs were detected in the myocardium for up to 4 weeks. More importantly, an intramyocardial injection of NP-liraglutide was sufficient to improve cardiac function ( <0.05), attenuate the infarct size ( <0.05), preserve wall thickness ( <0.05), promote angiogenesis ( <0.05) and prevent cardiomyocyte apoptosis ( <0.05) at 4 weeks after injection without affecting glucose levels. The local, controlled, intramyocardial delivery of NP-liraglutide represents an effective and promising strategy for the treatment of MI.

Ischemia/reperfusion (I/R) injury significantly contributes to the morbidity and mortality associated with cardiac events. Poloxamer 188 (P188), a nonionic triblock copolymer, has been proposed to mitigate I/R injury by stabilizing cell membranes. However, the underlying mechanisms remain incompletely understood, particularly concerning endothelial cell function and nitric oxide (NO) production. We employed human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) and endothelial cells (ECs) to elucidate the effects of P188 on cellular survival, function, and NO secretion under simulated I/R conditions. iPSC-CMs contractility and iPSC-ECs' NO production were assessed following exposure to P188. Further, an isolated heart model using Brown Norway rats subjected to I/R injury was utilized to evaluate the ex-vivo cardioprotective effects of P188, examining cardiac function and NO production, with and without the administration of a NO inhibitor. In iPSC-derived models, P188 significantly preserved CM contractile function and enhanced cell viability after hypoxia/reoxygenation. Remarkably, P188 treatment led to a pronounced increase in NO secretion in iPSC-ECs, a novel finding demonstrating endothelial protective effects beyond membrane stabilization. In the rat isolated heart model, administration of P188 during reperfusion notably improved cardiac function and reduced I/R injury markers. This cardioprotective effect was abrogated by NO inhibition, underscoring the pivotal role of NO. Additionally, a dose-dependent increase in NO production was observed in non-ischemic rat hearts treated with P188, further establishing the critical function of NO in P188 induced cardioprotection. In conclusion, our comprehensive study unveils a novel role of NO in mediating the protective effects of P188 against I/R injury. This mechanism is evident in both cellular models and intact rat hearts, highlighting the potential of P188 as a therapeutic agent against I/R injury. Our findings pave the way for further investigation into P188's therapeutic mechanisms and its potential application in clinical settings to mitigate I/R-related cardiac dysfunction.

Conventional supply chains face challenges in reducing overall logistics costs and optimizing the consumption of logistics resources. To address these challenges, we propose a two-phase path planning method for handling periodic logistics tasks. The novelty of our approach lies in harnessing the collective power of vehicles with periodic commuting paths to minimize logistics costs, offering a practical and convenient solution for achieving smart supply chains. In the first phase, we develop an optimization model to determine the optimal delivery paths for periodic logistics tasks, with the objective of minimizing the overall cost. Leveraging the A-star algorithm, we search for suitable sequence sets of commuting vehicles within the commuting path network for each logistics task. In the second phase, we select vehicle sequences from the available sets for each task, forming a combination that can effectively accomplish all logistics tasks. To obtain the optimal solution, we employ an adaptive genetic algorithm to refine and optimize this combination. Experimental results demonstrate that our approach effectively solves the problem of periodic logistics delivery planning in smart supply chains. It achieves cost savings of 15.6% and 13.8% in two cases compared to traditional methods, showcasing its practicality and efficiency in reducing logistics costs.

Background Clopidogrel plays an important role in the treatment of acute ischemic strokes (AIS) through antiplatelet activity. However, some patients have clopidogrel resistance (CR), which could lead to stroke recurrence and bleeding. This study aimed to explore associated factors of CR and establish a diagnostic nomogram for predicting the probability of CR in AIS patients. Methods This retrospective study involved 692 AIS patients from the Second Affiliated Hospital of Guangzhou Medical University, treated with clopidogrel (75 mg/day for 5 ± 2 days) after admission. Platelet reactivity was evaluated using thromboelastography to measure the ADP-induced platelet inhibition ratio (ADP-PIR). Patients were classified into CR (ADP-PIR < 30%) and non-clopidogrel resistance (NCR) groups. Group comparison, followed by least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic regression, was used to identify key predictors of CR. A diagnostic nomogram was developed and its performance was validated using bootstrap resampling. Results 16.76% of 692 patients experienced CR after AIS. Beta blocker use (OR: 0.47, 95% CI: 0.22–1.03, P  = 0.058) and apolipoprotein A1 (OR: 0.17, 95% CI: 0.07–0.46, P  < 0.001) were identified as protective factors, while unstable carotid plaque (OR: 10.65, 95% CI: 4.18–27.13, P  < 0.001), high apolipoprotein B levels (OR: 2.35, 95% CI: 1.23–4.51, P  = 0.01), and proton pump inhibitors use (OR: 2.09, 95% CI: 1.32–3.31, P  = 0.002) were risk factors. Our nomogram effectively validated these factors, showing strong discrimination and clinical utility in diagnosing CR probability. Conclusions We identified several significant CR predictors and further developed a diagnostic nomogram of CR to help clinicians choose antiplatelet drugs. Trial retrospectively registration Trial Retrospectively registration = ChiCTR2300073944.Data: 2023-7-25. The present study was approved by the Ethics Committee of the Second Affiliated Hospital of Guangzhou Medical University.

Objectives This study sought to investigate the severity of intracranial artery calcification (IAC) in relation to white matter hyperintensities (WMH), and whether the association was mediated by cerebral autoregulation (CA). Methods A total of 144 patients with cerebral small vessel disease were included in this study. The severity of WMH was assessed using Fazekas scores in FLAIR-MRI images. On non-contrast head computed tomography (CT) images, the severity of IAC was measured by IAC scores and further classified as intimal or medial calcification. As a proxy of CA, critical closing pressure (CrCP) was determined by analyzing blood pressure-flow velocity relationships in the middle cerebral artery. Mediation analyses were conducted to examine the proportion of mediation of CrCP on the association between IAC and WMH. Results IAC scores were found to be associated with WMH scores (β 0.364; 95% CI, 0.133-0.409; P <0.001). After multivariable adjustment, a statistically significant association was observed between IAC scores and higher CrCP values (β, 0.329; 95% confidence interval [CI], 0.129–0.528; P = 0.001). Mediation analyses revealed that CrCP partially mediated (10.3%) the association between higher IAC scores and increased WMH severity. The proportion of mediation was driven by a medial calcification pattern (13.9%). Conclusions This hospital-based study demonstrated the association between higher IAC scores and the severity of WMH in patients with cerebral small vessel disease, which can be partially mediated by cerebral autoregulation as indicated by CrCP, especially for the patients with predominantly medial calcification.