The association between FLAIR vascular hyperintensities and outcomes in patients with border zone infarcts treated with medical therapy may vary with the infarct subtype.

RATIONALE AND OBJECTIVES: Fluid-attenuated inversion recovery vessel hyperintensities (FVHs) reflect the haemodynamic state and may aid in predicting the prognosis of border zone (BZ) infarct patients. This study was to explore the relationship between FVHs and functional outcomes for different BZ infarct subtypes following medical therapy administration. MATERIALS AND METHODS: Consecutive patients with ischemic stroke were retrospectively enrolled and classified into internal BZ (IBZ) infarct, cortical BZ (CBZ) infarct and mixed-type infarct patients. FVHs were quantified using the FVH-Alberta Stroke Program Early CT Score (ASPECTS) system, and the scores were used to divide the patients into low-FVH (0-3) and high-FVH (4-7) groups. The FVH location and the cerebrovascular stenotic degree were recorded. Logistic regression was performed to identify risk factors for poor outcomes (modified Rankin scale score ≥3). RESULTS: A total of 207 BZ infarct patients (IBZ, n = 130; CBZ, n = 52; mixed-type, n = 25) were included. The FVH score was positively correlated with cerebrovascular stenosis (r = 0.332, P < 0.001) in all patients. A high FVH score was associated with poor outcomes in all (OR 2.568, 95% CI (1.147 to 5.753), P = 0.022) and in CBZ infarct patients (OR 9.258, 95% CI 1.113 to 77.035), P = 0.040). FVH-diffusion-weighted imaging (DWI) mismatch was not significantly associated with outcomes in the entire patient group or in any subgroup. CONCLUSIONS: A high FVH score is associated with poor long-term outcomes in patients with CBZ infarcts but not in those with IBZ or mixed-type infarcts.

Synthetic nanomaterials for spleen-specific mRNA delivery.

In recent years, mRNA vaccine has achieved increasing interest owing to its high potency, safety, ease of production, and low-cost manufacturing. Currently approved mRNA vaccines are administered intramuscularly to transfect local antigen-presenting cells (APCs) to initiate low to moderate immune responses. Spleen, the largest secondary lymphoid organ in the body which contains a large number of APCs close to B and T lymphocytes, could be the ideal site for effective initiation of an enhanced immune response. Here, we provide an overview of the recent advances in the development of synthetic materials for spleen-specific mRNA delivery, and lipid nanoparticle-based approaches will be highlighted. We further discuss the main challenges for spleen-specific mRNA delivery to provide a reference for the development of next-generation synthetic nanomaterials with optimal properties.

Individual and combined effects of muscle strength and visceral adiposity on incident prediabetes and type 2 diabetes in a longitudinal cohort of midlife Asian women.

AIM: To investigate the independent and combined effects of muscle strength and visceral adiposity on prediabetes and type 2 diabetes incidence among midlife women. MATERIALS AND METHODS: In this prospective study of midlife women (mean age 56.4 years), visceral adiposity, defined as visceral adipose tissue (VAT) >131 cm2 measured by dual energy X-ray absorptiometry, and poor combined muscle strength, defined as handgrip strength <18 kg and/or five-time repeated chair stand test performance ≥12 s, were determined at baseline between 2014 and 2016. After 6.6 years, the effects of VAT and muscle strength on risk of incident prediabetes (fasting blood glucose 5.6-6.9 mmol/L) and type 2 diabetes (fasting blood glucose levels ≥7 mmol/L, medication use, or physician diagnosis) were examined using modified Poisson regression analysis. RESULTS: Among the 733 initially normoglycaemic participants, 150 (20.5%) developed prediabetes or type 2 diabetes. Women with both poor combined muscle strength and high VAT had the highest risk for both prediabetes and type 2 diabetes (adjusted relative risk [aRR] 2.63, 95% confidence interval [CI] 1.81-3.82). In comparison, high VAT alone increased risk by 1.78-fold (95% CI 1.12-2.84). Stratification analyses showed that among women with low muscle strength, high VAT demonstrated increased risks of prediabetes and type 2 diabetes (aRR 2.84, 95% CI 1.95-4.14) compared to those with normal strength (aRR 1.66, 95% CI 1.04-2.65). CONCLUSIONS: Low combined muscle strength with high VAT poses a greater risk for the development of prediabetes and type 2 diabetes than high VAT alone. Muscle strengthening should be promoted alongside weight loss in diabetes prevention.

Dronedarone hydrochloride (DH) induces pancreatic cancer cell death by triggering mtDNA-mediated pyroptosis.

Pancreatic cancer is one of the leading causes of cancer-associated mortality, with a poor treatment approach. Previous study has shown that inducing pyroptosis in pancreatic ductal adenocarcinoma (PDAC) slows the growth of PDACs, implying that pyroptosis inducers are potentially effective for PDAC therapy. Here, we found that Dronedarone hydrochloride (DH), an antiarrhythmic drug, induces pyroptosis in pancreatic cancer cells and inhibits PDAC development in mice. In PANC-1 cells, DH caused cell death in a dosage- and time-dependent manner, with only pyroptosis inhibitors and GSDMD silencing rescuing the cell death, indicating that DH triggered GSDMD-dependent pyroptosis. Further work revealed that DH increased mitochondrial stresses and caused mitochondrial DNA (mtDNA) leakage, activating the cytosolic STING-cGAS and pyroptosis pathways. Finally, we assessed the anti-cancer effects of DH in a pancreatic cancer mouse model and found that DH treatment suppressed pancreatic tumor development in vivo. Collectively, our investigation demonstrates that DH triggers pyroptosis in PDAC and proposes its potential effects on anti-PDAC growth.

The effect of cumulative exposure with unhealthy lifestyles on the H-type hypertension among Chinese adults: a community-based, propensity-score-matched, and case-control study.

Objective: To assess whether cumulative exposure of unhealthy lifestyles is associated with HTH in Chinese adults and to explore the combination of unhealthy lifestyles. Methods: This study combined a community-based cross-sectional study with a 1:1 matched case-control study using propensity scores among adults in six randomly selected districts from Hunan Province, China. We recruited 5,258 people, of whom 4,012 met the criteria. Lifestyles and personal characteristics were collected by a questionnaire. Lifestyle score was calculated using cigarette smoking, heavy alcohol consumption, inactive exercise, unhealthy diet and abnormal BMI. HTH was defined as having a diagnosis of essential hypertension with Hcy ≥ 15 umol/L. Logistic regression models and multivariate analyses were used to explore the associations. We calculated odds ratios (ORs) and attributable risk proportion (ARP) for the association of HTH with lifestyle score. The dose-response relationship was evaluated using restricted cubic splines method. Results: Of the 4,012 adults, 793 had HTH, with a population prevalence of 19.8%. In the propensity-score-matched case-control study, 1,228 (614 cases and 614 controls) were included, and those with at least four unhealthy lifestyle factors had a higher risk of HTH than those with 0 unhealthy lifestyle factor (adjusted OR = 2.60, 95%CI:1.42-4.78), with an ARP of the cumulative exposure of unhealthy lifestyle was 28.23% (95% CI: 6.34-37.86%). For three unhealthy lifestyles group, the combination of heavy alcohol consumption, unhealthy diet and BMI ≥24 Kg/m2 was most associated with HTH (OR = 7.49, 95%CI: 1.12-50.08). For four unhealthy lifestyles group, the combination of smoking, heavy alcohol consumption, unhealthy diet and BMI ≥24 Kg/m2 had the greatest correlation with HTH (OR = 3.75, 95%CI: 1.24-7.38). Notably, there was a monotonically increasing curve (J-shaped) relationship between unhealthy lifestyles and the risk of HTH (p = 0.014). Conclusion: Our findings suggest that there was a significant cumulative exposure effect of unhealthy lifestyles on the risk of HTH, with the largest effect combination being heavy alcohol consumption, unhealthy diet and BMI ≥24 Kg/m2. Targeted interventions that reducing heavy alcohol consumption, quitting smoking, promoting physical activity and a healthy diet, and keep a normal BMI could substantially reduce the burden of HTH.

Diagnosing skin cancer using social spider optimization (SSO) and error correcting output codes (ECOC) with weighted hamming distance.

Skin cancer is a common disease resulting from genetic defects, and early detection is critical to improve treatment outcomes. Diagnostic programs that use computer aid especially those that use supervised learning are very useful in early diagnosis of skin cancer. This research therefore presents a new approach that integrates optimization methods with supervised learning to improve skin cancer diagnosis using machine vision approach. The presented method is initiated by data pre-processing that involves the removal of unnecessary data. Then, to segment the images, a combination of K-means clustering and social spider optimization technique is employed. The region of interest is then extracted from the segmented image and from this region a convolutional neural network extracts the significant features. To enhance the classification performance as compared with the standard classifiers, this research introduces a new concept of error correcting output codes coupled with a weighted Hamming distance in the group of gamma classifiers. The ability of the proposed approach in segmentation of skin lesions and classifying them was tested using samples from the ISIC-2017 and ISIC-2016 databases. The introduced method obtained state-of-the-art accuracy on both datasets (ISIC-2016: 97.10%, ISIC-2017: 95.17%). In particularly, the accuracy of the introduced approach for both these databases is at least 1.17% higher than the compared methods. This proves the high performance of the suggested method based on the usage of the convolutional neural networks for feature extraction and gamma classifiers with error correcting output codes for classification in skin cancer detection.

Label-Free Detection of Programmed Death-Ligand 1 for Prognosis Using a Truncated Aptamer and SYBR Green I.

The rapid and accurate detection of programmed death-ligand 1 (PD-L1) expression is of great value in the diagnosis and treatment of tumors. ELISA-based traditional method is the gold standard for protein detection, but there are still some shortcomings, especially the antigen-antibody dependence, greatly increased the detection time and cost. This work constructed a label-free fluorescent probe for rapid and sensitive detection of PD-L1 using a truncated aptamer as recognition molecules and double-stranded DNA specific dyes (SYBR Green I) as signal units. After a series of optimization conditions, this probe has good detection capability for PD-L1 in buffer solution with the detection limit as low as 0.68 ng/mL. Due to the specific recognition ability of aptamer and target, this method also has good selectivity for PD-L1 detection. The recovery of PD-L1 in human serum samples ranges from 86.20 to 96.36%. Compared with other methods, this strategy does not need to be marked, and does not need other complex design and purification process, but simple operation process and strong anti-interference ability. The whole detection process can be completed within 20 min and has good application prospect. This work will provide reference for drug dosage and prognosis evaluation of specific tumor therapy.

Evaluating the efficacy and safety of various flaps in Autologous Breast Reconstruction: a Bayesian network meta-analysis.

Aim: This analysis evaluates the efficacy and safety of different flap techniques for Autologous Breast Reconstruction by collecting all clinical trials employing these methods and applying a Bayesian network meta-analysis. Materials and methods: We systematically searched PubMed, Embase, and Web of Science for relevant literature, focusing on outcomes such as total flap loss, donor site wound dehiscence, secondary corrections at the donor site, psychosocial well-being, satisfaction with breasts, and sexual well-being. Results: Our analysis included 10 clinical studies involving 871 patients across six flap techniques. In terms of total flap loss, the TUG flap showed the highest SUCRA value (89.6%), followed by the TMG flap (64.8%). For donor site wound dehiscence, the DIEP flap ranked highest with a SUCRA value of 60.1%, followed by the PAP flap (48.6%). In secondary corrections at the donor site, the PAP flap was the leader (95.5%), followed by the DIEP flap (52.5%) and the TMG flap (41.4%). For outcomes related to psychosocial well-being, satisfaction with breasts, and sexual well-being, the Four-flap technique consistently ranked highest (81.3, 85.0, and 88.4%, respectively). Conclusion: Various flap techniques in Autologous Breast Reconstruction each present distinct benefits and risks. The Four-flap technique shows significant advantages in patient satisfaction, while the TUG flap excels in reducing total flap loss.

Co-freezing localized CRISPR-Cas12a system enables rapid and sensitive nucleic acid analysis.

Rapid and sensitive nucleic acid detection is vital in disease diagnosis and therapeutic assessment. Herein, we propose a co-freezing localized CRISPR-Cas12a (CL-Cas12a) strategy for sensitive nucleic acid detection. The CL-Cas12a was obtained through a 15-minute co-freezing process, allowing the Cas12a/crRNA complex and hairpin reporter confined on the AuNPs surface with high load efficiency, for rapid sensing of nucleic acid with superior performance to other localized Cas12a strategies. This CL-Cas12a based platform could quantitatively detect targets down to 98 aM in 30 min with excellent specificity. Furthermore, the CL-Cas12a successful applied to detect human papillomavirus infection and human lung cancer-associated single-nucleotide mutations. We also achieved powerful signal amplification for imaging Survivin mRNA in living cells. These findings highlight the potential of CL-Cas12a as an effective tool for nucleic acid diagnostics and disease monitoring.

Enhanced carbon use efficiency and warming resistance of soil microorganisms under organic amendment.

The frequency and intensity of extreme weather events, including rapid temperature fluctuations, are increasing because of climate change. Long-term fertilization practices have been observed to alter microbial physiology and community structure, thereby affecting soil carbon sequestration. However, the effects of warming on the carbon sequestration potential of soil microbes adapted to long-term fertilization remain poorly understood. In this study, we utilized 18O isotope labeling to assess microbial carbon use efficiency (CUE) and employed stable isotope probing (SIP) with 18O-H2O to identify growing taxa in response to temperature changes (5-35 °C). Organic amendment with manure or straw residue significantly increased microbial CUE by 86-181 % compared to unfertilized soils. The microorganisms inhabiting organic amended soils displayed greater resistance of microbial CUE to high temperatures (25-35 °C) compared to those inhabiting soils fertilized only with minerals. Microbial growth patterns determined by the classification of taxa into incorporators or non-incorporators based on 18O incorporation into DNA exhibited limited phylogenetic conservation in response to temperature changes. Microbial clusters were identified by grouping taxa with similar growth patterns across different temperatures. Organic amendments enriched microbial clusters associated with increased CUE, whereas clusters in unfertilized or mineral-only fertilized soils were linked to decreased CUE. Specifically, shifts in the composition of growing bacteria were correlated with enhanced microbial CUE, whereas modifications in the composition of growing fungi were associated with diminished CUE. Notably, the responses of microbial CUE to temperature fluctuations were primarily driven by changes in the bacterial composition. Overall, our findings demonstrate that organic amendments enhance soil microbial CUE and promote the enrichment of specific microbial clusters that are better equipped to cope with temperature changes. This study establishes a theoretical foundation for manipulating soil microbes to enhance carbon sequestration under global climate scenarios.

Swiprosin-1 participates in the berberine-regulated AMPK/MLCK pathway to attenuate colitis-induced tight junction damage.

BACKGROUND AND PURPOSE: Activation of AMP-activated protein kinase (AMPK) is essential in maintaining the epithelial tight junction (TJ) barrier. Berberine, a phytochemical AMPK agonist, has been widely reported to ameliorate colitis. Berberine or AMPK activation inhibits cytoskeletal contraction induced by myosin light chain kinase (MLCK), thereby ameliorating TJ barrier defects. We previously found that swiprosin-1, an actin-binding protein, affects MLCK expression. Here, we aimed to reveal the role of swiprosin-1 in the regulation of AMPK/MLCK by berberine. METHODS: Caco-2 monolayer transfected with AMPKα1 (or swiprosin-1) siRNA was treated with berberine after being stimulated with TNFα/IFNγ to assess the effect on the TJ barrier. Intestinal epithelial conditional knockout mice for AMPKα1 (or swiprosin-1) were treated with berberine after experimental colitis to evaluate the effect on the TJ barrier. TJ integrity was evaluated by immunoblotting and immunofluorescence for ZO-1 and Occludin. RESULTS: The protection of berberine against TJ barrier damage was blocked by AMPK inhibitor or knockout of AMPKα1 in epithelial cells. Swiprosin-1 was distributed in colonic epithelial cells and upregulated in colitis. Knockout of swiprosin-1 in intestinal epithelial cells ameliorated TJ barrier damage and abolished the protective effect of berberine. Impaired assembly of TJ caused by overexpression of swiprosin-1 was alleviated by MLCK inhibitor, and inhibition of the MLCK pathway by berberine also required the presence of swiprosin-1. In addition, berberine downregulated swiprosin-1 expression in an AMPK-dependent manner. CONCLUSION: Swiprosin-1 may be a key intermediate molecule in the regulation of the AMPK/MLCK pathway by berberine to attenuate colitis-induced TJ barrier damage.

Central NUCB2/nesfatin-1 signaling ameliorates liver steatosis through suppression of endoplasmic reticulum stress in the hypothalamus.

BACKGROUND & AIMS: Nucleobindin-2 (NUCB2)/nesfatin-1, a signal with recognized anorexigenic and insulin-sensitizing properties in peripheral tissues, is expressed within the hypothalamus. However, the potential involvement of central nesfatin-1 signaling in the pathophysiology of hepatic steatosis remains unknown. This study aimed to determine whether and how central NUCB2/nesfatin-1 plays a role in liver steatosis. METHODS: We generated Nucb2 knockout (Nucb2-/-) rats and administered continuous intracerebroventricular (ICV) nesfatin-1 infusion, while observing its effect on liver steatosis. The molecular mechanism of action of nesfatin-1 was elucidated via proteomics, phosphoproteomics and molecular biology methods. RESULTS: Herein, we present compelling evidence indicating diminished NUCB2 expression in the hypothalamus of obese rodents. We demonstrated that chronic ICV infusion of nesfatin-1 mitigated both diet-induced obesity and liver steatosis in high-fat diet (HFD)-fed Nucb2-/- rats by regulating hypothalamic endoplasmic reticulum (ER) stress and Akt phosphorylation. Furthermore, we revealed that the increase in hypothalamic insulin resistance (IR) and ER stress induced by tunicamycin infusion or Ero1α overexpression exacerbated hepatic steatosis and offset the favorable influence of central nesfatin-1 on hepatic steatosis. The metabolic action of central nesfatin-1 is contingent upon vagal nerve transmission to the liver. Mechanistically, nesfatin-1 impedes ER stress and interacts with Ero1α to repress its Ser106 phosphorylation. This leads to the enhancement of Akt activity in the hypothalamus, culminating in the inhibition of hepatic lipogenesis. CONCLUSIONS: These findings underscore the importance of hypothalamic NUCB2/nesfatin-1 as a key mediator in the top-down neural mechanism that combats diet-induced liver steatosis.

Transcriptome analysis of high- and low-selenium genotypes identifies genes responsible for selenium absorption, translocation, and accumulation.

Introduction: Selenium is an essential micronutrient the human body requires, which is closely linked to health. Rice, a primary staple food globally, is a major source of human selenium intake. To develop selenium-enriched rice varieties, it is imperative to understand the mechanisms behind selenium's absorption and transport within rice, alongside identifying the key genes involved in selenium uptake, transport, and transformation within the plant. Methods: This study conducted transcriptome sequencing on four types of rice materials (two with low-selenium and two with high-selenium contents) across roots, stems, leaves, and panicles to analyze the gene expression differences. Results and discussion: Differential gene expression was observed in the various tissues, identifying 5,815, 6,169, 7,609, and 10,223 distinct genes in roots, stems, leaves, and panicles, respectively. To delve into these differentially expressed genes and identify the hub genes linked to selenium contents, weighted gene co-expression network analysis (WGCNA) was performed. Ultimately, 10, 8, 7, and 6 hub genes in the roots, stems, leaves, and panicles, respectively, were identified. The identification of these hub genes substantially aids in advancing our understanding of the molecular mechanisms involved in selenium absorption and transport during the growth of rice.

A Two-Step Dry Etching Model for Non-Uniform Etching Profile in Gate-All-Around Field-Effect Transistor Manufacturing.

The Gate-All-Around Field-Effect Transistor (GAAFET) is proposed as a successor to Fin Field-Effect Transistor (FinFET) technology to increase channel length and improve the device performance. The GAAFET features a complex multilayer structure, which complicates the manufacturing process. One of the most critical steps in GAAFET fabrication is the selective lateral etching of the SiGe layers, essential for forming the inner-spacer. Industry commonly encounters a non-uniform etching profile during this step. In this paper, a continuous two-step dry etching model is proposed to investigate the mechanism behind the formation of the non-uniform profiles. The model consists of four modules: anisotropic etching simulation, Ge atom diffusion simulation, Si/SiGe etch selectivity calculation and SiGe selective etching simulation. By calibrating and verifying this model with experimental data, the edge rounding and gradient etching rates along the sidewall surface are successfully simulated. Based on further examination of the influence of chamber pressure on the profile using this model, the inner-spacer shape is improved experimentally by appropriately reducing the chamber pressure. This work aims to provide valuable insights for etching process recipes in advanced GAAFETs manufacturing.

Registered Nurses' Attitudes Towards ChatGPT and Self-Directed Learning: A Cross-Sectional Study.

BACKGROUND: Self-directed, lifelong learning is essential for nurses' competence in complex healthcare environments, which are characterised by rapid advancements in medicine and technology and nursing shortages. Previous studies have demonstrated that ChatGPT technology fosters self-directed learning by motivating users to engage with it. OBJECTIVES: To explore the relationships amongst socio-demographic data, attitudes towards ChatGPT use, and self-directed learning amongst registered nurses in Taiwan. METHODS: A cross-sectional study design with an online survey was adopted. Registered nurses from various healthcare settings were recruited through Facebook and LINE, a widely used messaging application in East Asia, reaching over 1000 nurses across five distinct online groups. An online survey was used to collect data, including socio-demographic characteristics, attitudes towards ChatGPT use, and a self-directed learning scale. Data were analysed using descriptive statistical methods, t-tests, Pearson's correlation, one-way analysis of variance, and multiple linear regression analysis. RESULTS: Amongst the 330 participants, 50.6% worked in hospitals, 51.8% had more than 15 years of work experience, and 78.2% did not hold supervisory positions. Of the participants, 46.7% had used ChatGPT. For all nurses, work experience and awareness of ChatGPT statistically significantly predicted self-directed learning, explaining 32.0% of the variance. For those familiar with ChatGPT, work experience in nursing and the technological/social influence of ChatGPT statistically significantly predicted self-directed learning, explaining 35.3% of the variance. CONCLUSIONS: Work experience in nursing provides critical opportunities for professional development and training. Therefore, ChatGPT-supported self-directed learning should be customised for degrees of experience to optimise continuous education. IMPLICATIONS FOR NURSING MANAGEMENT AND HEALTH POLICY: This study explores nurses' diverse use of and attitudes towards ChatGPT for self-directed learning. It suggests that administrators customise support and training when incorporating ChatGPT into professional development, accounting for nurses' varied experiences to enhance learning outcomes. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution. REPORTING METHOD: This study adhered to the relevant cross-sectional STROBE guidelines.

Hospital readmission after surviving sepsis: A systematic review of readmission reasons and meta-analysis of readmission rates.

PURPOSE: To review the evidence regarding hospital readmission diagnoses and analyse related readmission rates following a sepsis admission. METHODS: Five databases, grey literature, and selected article reference lists were searched in May and June 2024. Included studies investigated sepsis survivor readmissions and reported readmission diagnoses and rates. Meta-analyses of readmission rates were performed. RESULTS: After screening, 51 studies were included, with most studies (46/51; 90.2 %) investigating adult survivors. Infection or sepsis were reported as the most common readmission reason in 18 of the 21 studies investigating three or more readmission diagnoses in adults. Meta-analyses showed that 4.7 % (95 % CI: 3.1 to 6.5 %, PI: 0.3-13.4 %, n = 11 studies) of adult survivors readmitted to hospital with another sepsis diagnosis at 30 days, 8.1 % (95 % CI: 4.5 to 12.7 %, PI: <0.1-29.0 %, n = 7) at 90 days, and 16.4 % (95 % CI: 11.3 to 22.2 %, PI: <0.1-96.3 %, n = 3) at one year. At 30 days 3.5 % (95 % CI: 2.2-5.0 %, PI: 0.3-10.0 %, n = 7) of adult survivors readmitted to hospital with a cardiovascular disease diagnosis. CONCLUSIONS: Infection and sepsis are frequent readmission diagnoses for sepsis survivors, with one in 21 adult survivors readmitted for sepsis at 30-days. PROSPERO registration: CRD42023455851.

High-Density Lipoprotein Mimetic Peptide 4F Reduces Toxic Amyloid-Beta Exposure to the Blood-Brain Barrier Endothelium in Alzheimer's Disease Transgenic Mice.

Aß accumulation in the blood-brain barrier (BBB) endothelium, which lines the cerebrovascular lumen, is a significant contributor to cerebrovascular dysfunction in Alzheimer's disease (AD). Reduced high-density lipoprotein (HDL) levels are associated with increased AD risk, and the HDL mimetic peptide 4F has been developed as a promising therapeutic agent to improve cerebrovascular health in AD. In this study, we evaluated the impact of 4F on 125I-Aß42 blood-to-brain distribution using dynamic SPECT/CT imaging in both wild-type and APP/PS1 transgenic mice. Graphical analysis of the imaging data demonstrated that 4F significantly reduced the blood-to-brain influx rate in wild-type mice and the distribution of 125I-Aß42 in the BBB endothelium in APP/PS1 mice. To elucidate the molecular mechanisms underlying the effect of 4F, we evaluated its impact on the p38 pathway and its role in mediating Aß42 trafficking in human BBB endothelial cell monolayers. Treatment with 4F significantly decreased Aß42 induced p38 activation in BBB endothelial cells. Furthermore, inhibition of p38 kinase significantly reduced endothelial accumulation of fluorescence-labeled Aß42 and luminal-to-abluminal permeability across the cell monolayer. While our previous publication has hinted at the potential of 4F to reduce Aß accumulation in the brain parenchyma, the current findings demonstrated the protective effect of 4F in reducing Aß42 accumulation in the BBB endothelium of AD transgenic mice. These findings revealed the impact of a clinically tested agent, the HDL mimetic peptide 4F, on Aß exposure to the BBB endothelium and offer novel mechanistic insights into potential therapeutic strategies to treat cerebrovascular dysfunction in AD.

Phillyrin prevents sepsis-induced acute lung injury through inhibiting the NLRP3/caspase-1/GSDMD-dependent pyroptosis signaling pathway.

Acute lung injury (ALI) is a severe pulmonary disorder of sepsis with high clinical incidence and mortality. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)-cysteinyl aspartate specific proteinase 1-gasdermin D (GSDMD)-dependent pyroptosis of alveolar epithelial cells (AECs) has emerged as a crucial contributor to ALI during sepsis. Phillyrin (PHI), a natural lignan isolated from the traditional Chinese herbal medicine Forsythia suspensa, has been shown to have anti-inflammatory, antioxidant and antiviral properties. However, little is known about the protective role and potential mechanism of PHI in sepsis-induced ALI, and it is uncertain whether the protective effect of PHI in sepsis-induced ALI is connected to pyroptosis. This study aims to examine the preventive effects of PHI on sepsis-induced ALI via the inhibition of NLRP3/caspase-1/GSDMD-mediated pyroptosis in AECs. Our findings demonstrate that preadministration of PHI successfully reduces sepsis-induced pulmonary edema, systemic/pulmonary inflammation, and pulmonary histological damage in lung tissues, bronchoalveolar lavage fluid, and the serum of septic mice. Intriguingly, PHI preadministration suppresses sepsis-induced protein expressions of pyroptosis-specific markers, especially their active forms. In vitro assays show that PHI pretreatment also protects type II AECs (MLE-12) from lipopolysaccharide-induced pyroptosis by preventing the activation of the pyroptosis signaling pathway. The results from molecular docking and surface plasmon resonance reveal that PHI has a significant affinity for direct binding to the GSDMD protein, suggesting that GSDMD is a potential pharmacological target for PHI. In conclusion, PHI can prevent sepsis-triggered ALI by effectively suppressing the activation of the canonical pyroptosis signaling pathway and pyroptosis of AECs.