Recent advances in nanodelivery systems of resveratrol and their biomedical and food applications: a review.

Resveratrol is a non-flavonoid polyphenolic compound with numerous functional properties, such as anticancer, anti-inflammation, anti-oxidation, anti-obesity and more. However, resveratrol's poor solubility within aqueous media and low stability usually lead to compromised bioavailability, ultimately limiting its uptake and applications. Nanodelivery technologies have been studied intensively due to their potential in effectively improving resveratrol properties, thereby providing promising solutions for enhancing the bioavailability of resveratrol. Thus, this article aimed to review the recent advances of resveratrol nanodelivery systems, specifically on the types of nanodelivery systems, the corresponding preparation principles, advantages, as well as potential limitations associated. Meanwhile, studies have also found that coupled with nanodelivery systems, the functional properties of resveratrol could trigger apoptosis in cancer cells and inflammatory cells through various signaling pathways. Therefore, this article will also lead into discussions on the application aspects of resveratrol nanodelivery systems, emphasizing toward the fields of biomedical and food sciences. Potential pitfalls of resveratrol nanodelivery systems, such as issues with toxicity and target release, as well as outlooks regarding resveratrol nanodelivery systems are included in the Conclusion section, in the hope to provide insights for relevant future research.

Does an environmental stringent policy really matter to achieve environmental sustainability in BRICS-T region? Evidence from novel method of moments quantile regression approach.

Amidst pressing global environmental challenges, exacerbated by climate change and the imminent threat of global warming, there is a critical need to assess the efficacy of environmental policies. This study centers its attention on the pivotal role of these policies in addressing environmental concerns. Specifically, our research aims to scrutinize the impact of stringent environmental policies on environmental quality under the theoretical underpinnings of environmental Kuznets curve. To achieve this objective, the study collected data from BRICS-T economies over the period of 1990-2020. This study employed the method of moments quantile regression technique for empirical analysis. Our study validates the presence of the Environmental Kuznets curve (EKC hypothesis). Empirical findings reveal the sustained significance of environmental stringency across all quantiles, demonstrating a positive correlation in lower quantiles and a negative correlation in higher quantiles. At lower quantiles, the impact is insignificant initially, but pronounced due to efficiency improvements induced by stringent policies. The effects became negative at middle quantiles, indicating stringent policies might encounter diminishing returns where policy measures start stabilizing ecological impacts. At higher quantiles, the influence of ESI remains significant, reflecting ongoing adaptations in larger economies with higher ecological footprints. This suggests the potential effectiveness of stringent regulatory measures in mitigating environmental impacts and reducing ecological footprints. The identified inverted U-shaped curve signifies that while stringent policies may not inherently enhance environmental health, beyond a certain threshold, they can indeed contribute to its improvement. Our policy recommendation advocates for the widespread adoption and promotion of such stringent measures to safeguard environmental health.

Clinical and genetic characteristics of patients with TRG 0 and TRG III in esophageal squamous cell carcinoma after neoadjuvant therapy.

Neoadjuvant therapy (NAT) is an important treatment for patients with resectable locally advanced esophageal squamous cell carcinoma (ESCC), but neoadjuvant resistance affects the overall treatment outcome. Therefore, it is particularly important to accurately screen the population for NAT and explore the mechanism of resistance. Usually, different chemotherapy regimens cause different drug resistance mechanisms. Prior to combining immunotherapy with chemotherapy, extensive research has been conducted on previous drug resistance mechanisms. Currently, the mainstream NAT for ESCC involves chemotherapy combined with immunotherapy. We have witnessed the remarkable effect of this combination therapy; however, there are still a considerable number of patients whose tumor tissues show no change or even progress after NAT, and their drug resistance mechanisms remain unclear. Hence, we aim to identify relevant evidence that can distinguish and predict the effectiveness of NAT from a clinical perspective in order to provide a clinical basis for future screening of suitable populations for NAT and discovery of drug resistance mechanisms. This study is based in China's high incidence area of esophageal cancer, where enrolled patients all receive the current mainstream NAT regimen resulting in more reliable outcomes.

A53T α-synuclein mutation increases susceptibility to postoperative delayed neurocognitive recovery via hippocampal Ang-(1-7)/MasR axis.

Delayed neurocognitive recovery (dNCR) is a common complication in geriatric surgical patients. The impact of anesthesia and surgery on patients with neurodegenerative diseases, such as Parkinson's disease (PD) or prion disease, has not yet been reported. In this study, we aimed to determine the association between a pre-existing A53T genetic background, which involves a PD-related point mutation, and the development of postoperative dNCR. We observed that partial hepatectomy induced hippocampus-dependent cognitive deficits in 5-month-old A53T transgenic mice, a model of early-stage PD without cognitive deficits, unlike in age-matched wild-type (WT) mice. We respectively examined molecular changes at 6 h, 1 day, and 2 days after partial hepatectomy and observed that cognitive changes were accompanied by weakened angiotensin-(1-7)/Mas receptor [Ang-(1-7)/MasR] axis, increased alpha-synuclein (α-syn) expression and phosphorylation, decreased methylated protein phosphatase-2A (Me-PP2A), and prompted microglia M1 polarization and neuronal apoptosis in the hippocampus at 1 day after surgery. Nevertheless, no changes in blood-brain barrier (BBB) integrity or plasma α-syn levels in either A53T or WT mice. Furthermore, intranasal administration of selective MasR agonist AVE 0991, reversed the mentioned cognitive deficits in A53T mice, enhanced MasR expression, reduced α-syn accumulation and phosphorylation, and attenuated microglia activation and apoptotic response. Our findings suggest that individuals with the A53T genetic background may be more susceptible to developing postoperative dNCR. This susceptibility could be linked to central α-syn accumulation mediated by the weakened Ang-(1-7)/MasR/methyl-PP2A signaling pathway in the hippocampus following surgery, independent of plasma α-syn level and BBB.

Silencing HEATR1 Rescues Cisplatin Resistance of Non-Small Cell Lung Cancer by Inducing Ferroptosis via the p53/SAT1/ALOX15 Axis.

BACKGROUND: Cisplatin (DDP) is a commonly used chemotherapy agent. However, its resistance to the drug is a major challenge in its clinical application. Earlier research has suggested a connection between HEATR1 and chemoresistance in cancer. However, additional investigation is needed to better understand its involvement in resistance to DDP. In this study, we aimed to determine the regulatory effect of HEATR1 on the resistance of cisplatin in NSCLC. METHODS: We collected specimens of both DDP-resistant and non-resistant NSCLC to examine the expression of HEATR1. Additionally, we established cisplatin-resistant cells of NSCLC using the A549 cell line. Cell ability was examined by CCK-8 assay. Cell apoptosis and lipid ROS were examined by flow cytometry. The expressions of HEATR1, p53, SAT1, and ALOX15 were determined by qRT-PCR and Western blot. The tumor xenograft experiment was conducted to assess the impact of silencing HEATR1 on cisplatin resistance in vivo in NSCLC. RESULTS: The expression levels of HEATR1 were found to be significantly elevated in DDP-resistant tissues and cells of NSCLC as compared to non-resistant counterparts. Conversely, the expression levels of p53, SAT1, and ALOX15 were observed to be reduced in DDP-resistant cells. Through the inhibition of HEATR1, the proliferation of DDP-resistant cells was significantly suppressed, while the generation of lipid ROS was enhanced. This effect was achieved by activating ferroptosis and the p53/SAT1/ALOX15 pathway, as demonstrated both in vitro and in vivo. Conversely, the overexpression of HEATR1 exhibited opposite effects. Furthermore, the silencing of p53 and ALOX15 reversed the oncogenic effects of HEATR1 and inhibited ferroptosis in DDP-resistant NSCLC cells, suggesting the involvement of p53 and ALOX15 in HEATR1-mediated DDP resistance. CONCLUSION: Finally, the findings revealed that HEATR1 silencing reduced DDP resistance in NSCLC by inducing ferroptosis via the p53/SAT1/ALOX15 axis. HEATR1 might become a potential target for overcoming DDP resistance in NSCLC treatment.

A multi-channel electrochemical biosensor based on polyadenine tetrahedra for the detection of multiple drug resistance genes.

Antimicrobial resistance poses a serious threat to human health due to the high morbidity and mortality caused by drug-resistant microbial infections. Therefore, the development of rapid, sensitive and selective identification methods is key to improving the survival rate of patients. In this paper, a sandwich-type electrochemical DNA biosensor based on a polyadenine-DNA tetrahedron probe was constructed. The key experimental conditions were optimized, including the length of polyadenine, the concentration of the polyadenine DNA tetrahedron, the concentration of the signal probe and the hybridization time. At the same time, poly-avidin-HRP80 was used to enhance the electrochemical detection signal. Finally, excellent biosensor performance was achieved, and the detection limit for the synthetic DNA target was as low as 1 fM. In addition, we verified the practicability of the system by analyzing E. coli with the MCR-1 plasmid and realized multi-channel detection of the drug resistance genes MCR-1, blaNDM, blaKPC and blaOXA. With the ideal electrochemical interface, the polyA-based biosensor exhibits excellent stability, which provides powerful technical support for the rapid detection of antibiotic-resistant strains in the field.

Zebrafish mylipb attenuates antiviral innate immunity through two synergistic mechanisms targeting transcription factor irf3.

IFN regulatory factor 3 (IRF3) is the transcription factor crucial for the production of type I IFN in viral defence and inflammatory responses. The activity of IRF3 is strictly modulated by post-translational modifications (PTMs) to effectively protect the host from infection while avoiding excessive immunopathology. Here, we report that zebrafish myosin-regulated light chain interacting protein b (mylipb) inhibits virus-induced type I IFN production via two synergistic mechanisms: induction of autophagic degradation of irf3 and reduction of irf3 phosphorylation. In vivo, mylipb-null zebrafish exhibit reduced lethality and viral mRNA levels compared to controls. At the cellular level, overexpression of mylipb significantly reduces cellular antiviral capacity, and promotes viral proliferation. Mechanistically, mylipb associates with irf3 and targets Lys 352 to increase K6-linked polyubiquitination, dependent on its E3 ubiquitin ligase activity, leading to autophagic degradation of irf3. Meanwhile, mylipb acts as a decoy substrate for the phosphokinase tbk1 to attenuate irf3 phosphorylation and cellular antiviral responses independent of its enzymatic activity. These findings support a critical role for zebrafish mylipb in the limitation of antiviral innate immunity through two synergistic mechanisms targeting irf3.

[Retracted] MicroRNA­584 prohibits hepatocellular carcinoma cell proliferation and invasion by directly targeting BDNF.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the Transwell invasion assay data shown in Fig. 2C and D on p. 1997 were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes that had either already been published, or were submitted for publication at around the same time (and in some cases, have subsequently been retracted).  Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a  reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports  20: 1994-2001, 2019; DOI: 10.3892/mmr.2019.10424].

Systematic characterization of CsbZIP transcription factors in Camelina sativa and functional analysis of CsbZIP-A12 mediating regulation of unsaturated fatty acid-enriched oil biosynthesis.

The basic leucine zipper (bZIP) transcription factors (TFs) function importantly in numerous life processes in plants. However, bZIP members and their biological roles remain unknown in Camelina sativa, a worldwide promising oil crop. Here, 220 CsbZIP proteins were identified in camelina and classified into thirteen groups. Two and 347 pairs of tandem and segmental duplication genes were detected to be underwent purification selection, with segmental duplication as the main driven-force of CsbZIP gene family expansion. Most CsbZIP genes displayed a tissue-specific expression pattern. Particularly, CsbZIP-A12 significantly positively correlated with many FA/oil biosynthesis-related genes, indicating CsbZIP-A12 may regulate lipid biosynthesis. Notably, yeast one-hybrid (Y1H), ß-Glucuronidase (GUS), dual-luciferase (LUC) and EMSA assays evidenced that CsbZIP-A12 located in nucleus interacted with the promoters of CsSAD2-3 and CsFAD3-3 genes responsible for unsaturated fatty acid (UFA) synthesis, thus activating their transcriptions. Overexpression of CsbZIP-A12 led to an increase of total lipid by 3.275 % compared to the control, followed with oleic and α-linolenic acid levels enhanced by 3.4 % and 5.195 %, and up-regulated the expressions of CsSAD2-3, CsFAD3-3 and CsPDAT2-3 in camelina seeds. Furthermore, heterogeneous expression of CsbZIP-A12 significantly up-regulated the expressions of NtSAD2, NtFAD3 and NtPDAT genes in tobacco plants, thereby improving the levels of total lipids and UFAs in both leaves and seeds without negative effects on other agronomic traits. Together, our findings suggest that CsbZIP-A12 upregulates FA/oil biosynthesis by activating CsSAD2-3 and CsFAD3-3 as well as possible other related genes. These data lay a foundation for further functional analyses of CsbZIPs, providing new insights into the TF-based lipid metabolic engineering to increase vegetable oil yield and health-beneficial quality in oilseeds.

Penalized weighted smoothed quantile regression for high-dimensional longitudinal data.

Quantile regression, known as a robust alternative to linear regression, has been widely used in statistical modeling and inference. In this paper, we propose a penalized weighted convolution-type smoothed method for variable selection and robust parameter estimation of the quantile regression with high dimensional longitudinal data. The proposed method utilizes a twice-differentiable and smoothed loss function instead of the check function in quantile regression without penalty, and can select the important covariates consistently using the efficient gradient-based iterative algorithms when the dimension of covariates is larger than the sample size. Moreover, the proposed method can circumvent the influence of outliers in the response variable and/or the covariates. To incorporate the correlation within each subject and enhance the accuracy of the parameter estimation, a two-step weighted estimation method is also established. Furthermore, we prove the oracle properties of the proposed method under some regularity conditions. Finally, the performance of the proposed method is demonstrated by simulation studies and two real examples.

Establishment and preliminary evaluation of CT-based classification for distal radius fracture.

Establish a new classification system of distal radius fracture based on computed tomographic (CT), and evaluate its reliability and reproducibility preliminarily, and provide a new theoretical reference for clinicians to use the clinical classification system. The imaging data and clinical data of 204 inpatients with distal radius fracture during 6 years from January 1, 2014 to January 1, 2019 in orthopaedic department were analyzed retrospectively and classified based on CT. Three observers evaluated the image data of 48 randomly selected cases based on CT at different time nodes of T1 and T2. Cohen's kappa was used to calculate the consistency. At the last follow-up, patients' Disabilities of the Arm, Shoulder and Hand (DASH), Patient Rated Wrist Evaluation (PRWE), and VAS scores were collected. Among 204 cases, there were 12 cases of type 1, including 6 cases of type 1-D, 4 cases of type 1-V and 2 cases of type 1-R. There were 6 cases of type 2, including 2 cases of type 2-DV, 2 cases of type 2-DR and 2 cases of type 2-VR. There were 186 cases of type 3, including 32 cases of type 3-0, 127 cases of type 3-1 and 27 cases of type 3-2. There was no significant difference in DASH, PRWE and VAS scores among all types (P > 0.05). The results of interobserver reproducibility were kappa = 0.985, ICC = 0.984 in the first evaluation, kappa = 0.986, ICC = 0.986 in the second evaluation. The results of intraobserver reproducibility were O1 = 0.991, O2 = 0.991, O3 = 0.989 respectively. The new classification system of distal radius fracture based on CT has theoretical and practical significance for incision selection, fracture reduction and internal fixation. 123 classification system is clear, comprehensive, easy to understand and remember. Moreover, it has higher interobserver reliability and intraobserver reproducibility than other systems reported at present.

Triblock PolyA-Mediated Protein Biosensor Based on a Size-Matching Proximity Hybridization Analysis.

The antibodies in the natural biological world utilize bivalency/multivalency to achieve a higher affinity for antigen capture. However, mimicking this mechanism on the electrochemical sensing interface and enhancing biological affinity through precise spatial arrangement of bivalent aptamer probes still pose a challenge. In this study, we have developed a novel self-assembly layer (SAM) incorporating triblock polyA DNA to enable accurate organization of the aptamer probes on the interface, constructing a "lock-and-key-like" proximity hybridization assay (PHA) biosensor. The polyA fragment acts as an anchoring block with a strong affinity for the gold surface. Importantly, it connects the two DNA probes, facilitating one-to-one spatial proximity and enabling a controllable surface arrangement. By precisely adjusting the length of the polyA fragment, we can tailor the distance between the probes to match the molecular dimensions of the target protein. This design effectively enhances the affinity of the aptamers. Notably, our biosensor demonstrates exceptional specificity and sensitivity in detecting PDGF-BB, as confirmed through successful validation using human serum samples. Overall, our biosensor presents a novel and versatile interface for proximity assays, offering a significantly improved surface arrangement and detection performance.

Biomimetic Nano-Degrader Based CD47-SIRPα Immune Checkpoint Inhibition Promotes Macrophage Efferocytosis for Cardiac Repair.

CD47-SIRPα axis is an immunotherapeutic target in tumor therapy. However, current monoclonal antibody targeting CD47-SIRPα axis is associated with on-target off-tumor and antigen sink effects, which significantly limit its potential clinical application. Herein, a biomimetic nano-degrader is developed to inhibit CD47-SIRPα axis in a site-specific manner through SIRPα degradation, and its efficacy in acute myocardial infarction (AMI) is evaluated. The nano-degrader is constructed by hybridizing liposome with red blood cell (RBC) membrane (RLP), which mimics the CD47 density of senescent RBCs and possesses a natural high-affinity binding capability to SIRPα on macrophages without signaling capacity. RLP would bind with SIRPα and induce its lysosomal degradation through receptor-mediated endocytosis. To enhance its tissue specificity, Ly6G antibody conjugation (aRLP) is applied, enabling its attachment to neutrophils and accumulation within inflammatory sites. In the myocardial infarction model, aRLP accumulated in the infarcted myocardium blocks CD47-SIRPα axis and subsequently promoted the efferocytosis of apoptotic cardiomyocytes by macrophage, improved heart repair. This nano-degrader efficiently degraded SIRPα in lysosomes, providing a new strategy for immunotherapy with great clinical transformation potential.

Cyfluthrin exposure during pregnancy causes neurotoxicity in offspring-Ca2+ overload via IP3R-GRP75-VDAC1 pathway.

Cyfluthrin (Cy) is a widely used pyrethroid insecticide. There is growing evidence that Cy can cause damage to the nervous, reproductive, and immune systems, but there is limited evidence on the potential effects of maternal Cy exposure on offspring. A model of maternal Cy exposure was used to assess its neurobehavioral effects on young-adult offspring. We found that gestational Cy exposure affected pregnancy outcomes and fetal development, and that offspring showed impairments in anxiety as well as learning and memory, accompanied by impairments in hippocampal synaptic ultrastructure and synaptic plasticity. In addition, the IP3R-GRP75-VDAC1 apoptogenic pathway was also upregulated, and in vitro models showed that inhibition of this pathway alleviated neuronal apoptosis as well as synaptic plasticity damage. In conclusion, maternal Cy exposure during pregnancy can cause neurobehavioral abnormalities and synaptic damage in offspring, which may be related to neuronal apoptosis induced by activation of the IP3R-GRP75-VDAC1 pathway in the hippocampus of offspring. Our findings provide clues to understand the neurotoxicity mechanism of maternal Cy exposure to offspring during pregnancy.

Deep learning model to predict lupus nephritis renal flare based on dynamic multivariable time-series data.

OBJECTIVES: To develop an interpretable deep learning model of lupus nephritis (LN) relapse prediction based on dynamic multivariable time-series data. DESIGN: A single-centre, retrospective cohort study in China. SETTING: A Chinese central tertiary hospital. PARTICIPANTS: The cohort study consisted of 1694 LN patients who had been registered in the Nanjing Glomerulonephritis Registry at the National Clinical Research Center of Kidney Diseases, Jinling Hospital from January 1985 to December 2010. METHODS: We developed a deep learning algorithm to predict LN relapse that consists of 59 features, including demographic, clinical, immunological, pathological and therapeutic characteristics that were collected for baseline analysis. A total of 32 227 data points were collected by the sliding window method and randomly divided into training (80%), validation (10%) and testing sets (10%). We developed a deep learning algorithm-based interpretable multivariable long short-term memory model for LN relapse risk prediction considering censored time-series data based on a cohort of 1694 LN patients. A mixture attention mechanism was deployed to capture variable interactions at different time points for estimating the temporal importance of the variables. Model performance was assessed according to C-index (concordance index). RESULTS: The median follow-up time since remission was 4.1 (IQR, 1.7-6.7) years. The interpretable deep learning model based on dynamic multivariable time-series data achieved the best performance, with a C-index of 0.897, among models using only variables at the point of remission or time-variant variables. The importance of urinary protein, serum albumin and serum C3 showed time dependency in the model, that is, their contributions to the risk prediction increased over time. CONCLUSIONS: Deep learning algorithms can effectively learn through time-series data to develop a predictive model for LN relapse. The model provides accurate predictions of LN relapse for different renal disease stages, which could be used in clinical practice to guide physicians on the management of LN patients.

Genetically Engineered Macrophages Co-Loaded with CD47 Inhibitors Synergistically Reconstruct Efferocytosis and Improve Cardiac Remodeling Post Myocardial Ischemia Reperfusion Injury.

Efferocytosis, mediated by the macrophage receptor MerTK (myeloid-epithelial-reproductive tyrosine kinase), is a significant contributor to cardiac repair after myocardial ischemia-reperfusion (MI/R) injury. However, the death of resident cardiac macrophages (main effector cells), inactivation of MerTK （main effector receptor), and overexpression of "do not eat me" signals (brake signals, such as CD47), collectively lead to the impediment of efferocytosis in the post-MI/R heart. To date, therapeutic strategies targeting individual above obstacles are relatively lacking, let alone their effectiveness being limited due to constraints from the other concurrent two. Herein, inspired by the application research of chimeric antigen receptor macrophages (CAR-Ms) in solid tumors, a genetically modified macrophage-based synergistic drug delivery strategy that effectively challenging the three major barriers in an integrated manner is developed. This strategy involves the overexpression of exogenous macrophages with CCR2 (C-C chemokine receptor type 2) and cleavage-resistant MerTK, as well as surface clicking with liposomal PEP-20 (a CD47 antagonist). In MI/R mice model, this synergistic strategy can effectively restore cardiac efferocytosis after intravenous injection, thereby alleviating the inflammatory response, ultimately preserving cardiac function. This therapy focuses on inhibiting the initiation and promoting active resolution of inflammation, providing new insights for immune-regulatory therapy.

Preoperative prognostic nutritional index value as a predictive factor for postoperative delirium in older adult patients with hip fractures: a secondary analysis.

BACKGROUND: Malnutrition is a common geriatric syndrome and can be targeted preoperatively to decrease the risk of postoperative delirium (POD) in older adult patients. To analyze the value of the prognostic nutritional index (PNI) to predict the incidence of POD in older adult patients with hip fractures. METHODS: This was a prospective, observational, cohort study of older adult patients with hip fractures. Preoperative PNI was calculated as 10 × serum albumin (g/dL) + 0.005 × total lymphocyte count (/µL) using preoperative laboratory results. Patients were divided into POD and non-POD groups using the Confusion Assessment Method (CAM). The risk factors associated with POD as well as the relationship between PNI values and the incidence of POD were analyzed using univariate and multivariate logistic regression analyses. The predictive value of PNI for POD was assessed using receiver operating characteristic curve analysis. RESULTS: In this cohort of 369 patients who underwent hip fracture surgery, 67 patients (18.2%) were diagnosed with POD by the CAM results. Low PNI increased the risk of POD (odds ratio (OR) = 0.928, 95% confidence interval (CI): 0.864-0.997). General anesthesia (OR = 2.307, 95% CI: 1.279-4.162) and Mini-Mental State Examination (MMSE) score (OR = 0.956, 95% CI: 0.920-0.994) were also identified as risk factors for POD. Receiver operating characteristic curve analysis suggested that PNI combined with the anesthetic method and MMSE score may be used as a potential predictive indicator of POD after hip fracture surgery. CONCLUSION: Preoperative PNI value is related to POD in older adult patients with hip fractures. TRIAL REGISTRATION: This secondary analysis study was approved by the Peking University Third Hospital Medical Science Research Ethics Committee (approval No. M2022578) and registered in the Chinese Clinical Trial Registry (ChiCTR2300070569).

Melatonin regulates the circadian rhythm to ameliorate postoperative sleep disorder and neurobehavioral abnormalities in aged mice.

BACKGROUND: Postoperative sleep disorder (PSD) and delirium, which may be associated with surgery and inhalational anesthetics, induce adverse effects in old adults. Emerging evidence indicates that circadian rhythm contributes to various neuropathological diseases, including Alzheimer's disease. Thus, we analyzed the potential role of circadian rhythm in PSD and delirium-like behavior in aged mice and determined whether exogenous melatonin could facilitate entrainment of the circadian rhythm after laparotomy under sevoflurane anesthesia. METHODS: We selected old C57BL/6J mice which receiving laparotomy/sevoflurane anesthesia as model animals. We employed buried food, open field, and Y maze test to assess delirium-like behavior, and electroencephalography/electromyography (EEG/EMG) were used to investigate sleep changes. We analyzed the transcription rhythm of clock genes in superchiasmatic nucleus (SCN) to explore the effects of surgery and melatonin pretreatment on the circadian rhythm. Then, we measured melatonin receptor levels in SCN and ERK/CREB pathway-related proteins in hippocampus and prefrontal cortex to assess their role in PSDs and delirium-like behavior. RESULTS: Laparotomy under sevoflurane anesthesia had a greater influence than sevoflurane alone, leading to sleep disorder, a shift in sleep-wake rhythm, and delirium-like behavior. Bmal1, Clock, and Cry1 mRNA expression showed a peak shift, MT1 melatonin receptor expression level was increased in the SCN, and p-ERK/ERK and p-CREB/CREB were decreased in hippocampus and prefrontal cortex of aged mice 1 day after laparotomy. Melatonin showed significant efficacy in ameliorating PSD and delirium-like behavior and restoring the circadian rhythm, reversing melatonin receptor and ERK/CREB pathway expression abnormalities. In addition, most of the beneficial effect of melatonin was antagonized by luzindole, a melatonin receptor antagonist. CONCLUSIONS: Melatonin receptors in SCN, circadian rhythm, and ERK/CREB signaling pathway participate in the pathophysiological processes of PSD and delirium-like behavior. Melatonin intervention could be a potential preventative approach for PSD and delirium.

Hippo pathway-manipulating neutrophil-mimic hybrid nanoparticles for cardiac ischemic injury via modulation of local immunity and cardiac regeneration.

The promise of regeneration therapy for restoration of damaged myocardium after cardiac ischemic injury relies on targeted delivery of proliferative molecules into cardiomyocytes whose healing benefits are still limited owing to severe immune microenvironment due to local high concentration of proinflammatory cytokines. Optimal therapeutic strategies are therefore in urgent need to both modulate local immunity and deliver proliferative molecules. Here, we addressed this unmet need by developing neutrophil-mimic nanoparticles NM@miR, fabricated by coating hybrid neutrophil membranes with artificial lipids onto mesoporous silica nanoparticles (MSNs) loaded with microRNA-10b. The hybrid membrane could endow nanoparticles with strong capacity to migrate into inflammatory sites and neutralize proinflammatory cytokines and increase the delivery efficiency of microRNA-10b into adult mammalian cardiomyocytes (CMs) by fusing with cell membranes and leading to the release of MSNs-miR into cytosol. Upon NM@miR administration, this nanoparticle could home to the injured myocardium, restore the local immunity, and efficiently deliver microRNA-10b to cardiomyocytes, which could reduce the activation of Hippo-YAP pathway mediated by excessive cytokines and exert the best proliferative effect of miR-10b. This combination therapy could finally improve cardiac function and mitigate ventricular remodeling. Consequently, this work offers a combination strategy of immunity modulation and proliferative molecule delivery to boost cardiac regeneration after injury.