Efficacy and safety of robotic versus laparoscopic liver resection for hepatocellular carcinoma: a propensity score-matched retrospective cohort study.

BACKGROUND: Evidence concerning long-term outcome of robotic liver resection (RLR) and laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) patients is scarce. METHODS: This study enrolled all patients who underwent RLR and LLR for resectable HCC between July 2016 and July 2021. Propensity score matching (PSM) was employed to create a 1:3 match between the RLR and LLR groups. A comprehensive collection and analysis of patient data regarding efficacy and safety have been conducted, along with the evaluation of the learning curve for RLR. RESULTS: Following PSM, a total of 341 patients were included, with 97 in the RLR group and 244 in the LLR group. RLR group demonstrated a significantly longer operative time (median [IQR], 210 [152.0-298.0] min vs. 183.5 [132.3-263.5] min; p = 0.04), with no significant differences in other perioperative and short-term postoperative outcomes. Overall survival (OS) was similar between the two groups (p = 0.43), but RLR group exhibited improved recurrence-free survival (RFS) (median of 65 months vs. 56 months, p = 0.006). The estimated 5-year OS for RLR and LLR were 74.8% (95% CI: 65.4-85.6%) and 80.7% (95% CI: 74.0-88.1%), respectively. The estimated 5-year RFS for RLR and LLR were 58.6% (95% CI: 48.6-70.6%) and 38.3% (95% CI: 26.4-55.9%), respectively. In the multivariate Cox regression analysis, RLR (HR: 0.586, 95% CI (0.393-0.874), p = 0.008) emerged as an independent predictor of reducing recurrence rates and enhanced RFS. The operative learning curve indicates that approximately after the 11th case, the learning curve of RLR stabilized and entered a proficient phase. CONCLUSIONS: OS was comparable between RLR and LLR, and while RFS was improved in the RLR group. RLR demonstrates oncological effectiveness and safety for resectable HCC.

Potential mitigation of titanium dioxide nanoparticles against 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis through inhibiting the canonical NF-κB pathway.

Titanium dioxide nanoparticles (TiO2 NPs) have been widely employed in various industry fields, which makes consumers concerned about their health impact. Our previous work displayed that TiO2 NPs participate in the mitigation of TNBS-induced colitis, but the mechanism is still unknown. This work aimed to explore the role of oxidative stress and NF-κB pathway in the effect of TiO2 NPs on TNBS-induced colitis. The results showed that TiO2 NPs administration reduced the DAI score of colitis mice after TNBS enema. TiO2 NPs did not alter oxidative stress states (GSH/GSSG), but repaired the gut dysbacteriosis and inhibited the canonical NF-κB pathway activation in TNBS-induced colitis mice, manifested as a decrease in pathogenic bacteria and an increase in beneficial bacteria, as well as down-regulation of Toll-like receptors (TLRs), IKKα, IKKß, p65 and pro-inflammatory cytokines (IL-1ß, IL-6, TNF-α and IFN-γ) in mRNA level, and the increased transcription of anti-inflammatory cytokines (IL-10, TGF-ß, and IL-12), along with the declined protein level of TNF-α in TiO2 NPs treated colitis mice. The present study suggested that oral TiO2 NPs administration inhibited the canonical NF-κB pathway activation by repairing gut dysbacteriosis, which made a predominant role in alleviating colitis. These findings provided a new perspective for exploring the safety of TiO2 NPs.

Autonomous ultrasound scanning robotic system based on human posture recognition and image servo control: an application for cardiac imaging.

In traditional cardiac ultrasound diagnostics, the process of planning scanning paths and adjusting the ultrasound window relies solely on the experience and intuition of the physician, a method that not only affects the efficiency and quality of cardiac imaging but also increases the workload for physicians. To overcome these challenges, this study introduces a robotic system designed for autonomous cardiac ultrasound scanning, with the goal of advancing both the degree of automation and the quality of imaging in cardiac ultrasound examinations. The system achieves autonomous functionality through two key stages: initially, in the autonomous path planning stage, it utilizes a camera posture adjustment method based on the human body's central region and its planar normal vectors to achieve automatic adjustment of the camera's positioning angle; precise segmentation of the human body point cloud is accomplished through efficient point cloud processing techniques, and precise localization of the region of interest (ROI) based on keypoints of the human body. Furthermore, by applying isometric path slicing and B-spline curve fitting techniques, it independently plans the scanning path and the initial position of the probe. Subsequently, in the autonomous scanning stage, an innovative servo control strategy based on cardiac image edge correction is introduced to optimize the quality of the cardiac ultrasound window, integrating position compensation through admittance control to enhance the stability of autonomous cardiac ultrasound imaging, thereby obtaining a detailed view of the heart's structure and function. A series of experimental validations on human and cardiac models have assessed the system's effectiveness and precision in the correction of camera pose, planning of scanning paths, and control of cardiac ultrasound imaging quality, demonstrating its significant potential for clinical ultrasound scanning applications.

Superconductivity above 105 K in Nonclathrate Ternary Lanthanum Borohydride below Megabar Pressure.

Hydrides are promising candidates for achieving room-temperature superconductivity, but a formidable challenge remains in reducing the stabilization pressure below a megabar. In this study, we successfully synthesized a ternary lanthanum borohydride by introducing the nonmetallic element B into the La-H system, forming robust B-H covalent bonds that lower the pressure required to stabilize the superconducting phase. Electrical transport measurements confirm the presence of superconductivity with a critical temperature (Tc) of up to 106 K at 90 GPa, as evidenced by zero resistance and Tc shift under an external magnetic field. X-ray diffraction and transport measurements identify the superconducting compound as LaB2H8, a nonclathrate hydride, whose crystal structure remains stable at pressures as low as ∼ half megabar (59 GPa). Stabilizing superconductive stoichiometric LaB2H8 in a submegabar pressure regime marks a substantial advancement in the quest for high-Tc superconductivity in polynary hydrides, bringing us closer to the ambient pressure conditions.

Novel pyxinol amide derivatives bearing an aliphatic heterocycle as P-glycoprotein modulators for overcoming multidrug resistance.

P-glycoprotein (Pgp) modulators are promising agents for overcoming multidrug resistance (MDR) in cancer chemotherapy. In this study, via structural optimization of our lead compound S54 (nonsubstrate allosteric inhibitor of Pgp), 29 novel pyxinol amide derivatives bearing an aliphatic heterocycle were designed, synthesized, and screened for MDR reversal activity in KBV cells. Unlike S54, these active derivatives were shown to transport substrates of Pgp. The most potent derivative 4c exhibited promising MDR reversal activity (IC50 of paclitaxel = 8.80 ± 0.56 nM, reversal fold = 211.8), which was slightly better than that of third-generation Pgp modulator tariquidar (IC50 of paclitaxel = 9.02 ± 0.35 nM, reversal fold = 206.6). Moreover, the cytotoxicity of this derivative was 8-fold lower than that of tariquidar in human normal HK-2 cells. Furthermore, 4c blocked the efflux function of Pgp and displayed high selectivity for Pgp but had no effect on its expression and distribution. Molecular docking revealed that 4c bound preferentially to the drug-binding domain of Pgp. Overall, 4c is a promising lead compound for developing Pgp modulators.

Cholesterol neutralized vemurafenib treatment by promoting melanoma stem-like cells via its metabolite 27-hydroxycholesterol.

Vemurafenib has been used as first-line therapy for unresectable or metastatic melanoma with BRAFV600E mutation. However, overall survival is still limited due to treatment resistance after about one year. Therefore, identifying new therapeutic targets for melanoma is crucial for improving clinical outcomes. In the present study, we found that lowering intracellular cholesterol by knocking down DHCR24, the limiting synthetase, impaired tumor cell proliferation and migration and abrogated the ability to xenotransplant tumors. More importantly, administration of DHCR24 or cholesterol mediated resistance to vemurafenib and promoted the growth of melanoma spheroids. Mechanistically, we identified that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol synthesized by the enzyme cytochrome P450 27A1 (CYP27A1), reproduces the phenotypes induced by DHCR24 or cholesterol administration and activates Rap1-PI3K/AKT signaling. Accordingly, CYP27A1 is highly expressed in melanoma patients and upregulated by DHCR24 induction. Dafadine-A, a CYP27A1 inhibitor, attenuates cholesterol-induced growth of melanoma spheroids and abrogates the resistance property of vemurafenib-resistant melanoma cells. Finally, we confirmed that the effects of cholesterol on melanoma resistance require its metabolite 27HC through CYP27A1 catalysis, and that 27HC further upregulates Rap1A/Rap1B expression and increases AKT phosphorylation. Thus, our results suggest that targeting 27HC may be a useful strategy to overcome treatment resistance in metastatic melanoma.

Pre-programmable pneumatic actuator: leveraging mechanical anisotropy of nonwoven fabrics with an integrated tensile sensor.

The emergence of flexible fabric-based pneumatic actuators (FPAs) with pre-programmable motion capabilities, enhanced security and versatile interaction features significantly advances the construction of sophisticated soft robotic systems, owing to their enhanced security and versatile interaction features. Despite these promising attributes, the commercial viability of FPA products faces a considerable amount of challenges, primarily stemming from the scarcity of highly deformable fabric structures and the availability of industrial fabrication approaches. Taking inspiration from the anisotropic nature of lobster antennae, we propose a scalable and economical strategy to fabricate functional FPAs using nonwoven fabric material with superior mechanical anisotropy. This innovative method involves the adoption of tunable inelastic constrained wires sewn onto extensible nonwoven fabrics with regular wrinkles. This nonwoven fabric-based pneumatic actuator (NFPA) demonstrates specific motion profiles with curvature of over 0.6 cm-1 and output forces of over 140 cN under adjustable pressure conditions. Guided by the constrained wire combinations, NFPA enables diverse programmable motions like spiraling, assistance, and grasping. Furthermore, NFPA incorporated with specific sensors exhibits significant potential in wearable devices with real-time environmental detection for rehabilitation applications. Our work contributes a distinctive insight into the design of programmable NFPAs and enlightens an arena toward versatile soft robotic applications.

High-Sensitivity Flexible Capacitive Pressure Sensors Based on Biomimetic Hibiscus Flower Microstructures.

The integration of low-dimensional nanomaterials with microscale architectures in flexible pressure sensors has garnered significant interest due to their outstanding performance in healthcare monitoring. However, achieving high sensitivity across different magnitudes of external pressure remains a critical challenge. Herein, we present a high-performance flexible pressure sensor crafted from biomimetic hibiscus flower microstructures coated with silver nanowires. When compared with a flat electrode, these microstructures as electrodes display significantly enhanced sensitivity and an extended stimulus-response range. Furthermore, we utilized an ionic gel film as the dielectric layer, resulting in an enhancement of the overall performance of the flexible pressure sensor through an increase in interfacial capacitance. Consequently, the capacitive pressure sensor exhibits an extraordinary ultrahigh sensitivity of 48.57 [Kpa]-1 within the pressure range of 0-1 Kpa, 15.24 [Kpa]-1 within the pressure range of 1-30 Kpa, and 3.74 [Kpa]-1 within the pressure range of 30-120 Kpa, accompanied by a rapid response time (<58 ms). The exceptional performance of our flexible pressure sensor serves as a foundation for its numerous applications in healthcare monitoring. Notably, the flexible pressure sensor excels not only in detecting subtle physiological signals such as finger and wrist pulse signals, vocal cord vibrations, and breathing intensity but also demonstrates excellent performance in monitoring higher pressures, such as plantar pressure. We foresee that this flexible pressure sensor possesses significant potential in the field of wearable electronics.

PCC0208057 as a small molecule inhibitor of TRPC6 in the treatment of prostate cancer.

Prostate cancer (PCa) is a common malignant tumor, whose morbidity and mortality keep the top three in the male-related tumors in developed countries. Abnormal ion channels, such as transient receptor potential canonical 6 (TRPC6), are reported to be involved in the carcinogenesis and progress of prostate cancer and have become potential drug targets against prostate cancer. Here, we report a novel small molecule inhibitor of TRPC6, designated as PCC0208057, which can suppress the proliferation and migration of prostate cancer cells in vitro, and inhibit the formation of Human umbilical vein endothelial cells cell lumen. PCC0208057 can effectively inhibit the growth of xenograft tumor in vivo. Molecular mechanism studies revealed that PCC0208057 could directly bind and inhibit the activity of TRPC6, which then induces the prostate cancer cells arrested in G2/M phase via enhancing the phosphorylation of Nuclear Factor of Activated T Cells (NFAT) and Cdc2. Taken together, our study describes for the first time that PCC0208057, a novel TRPC6 inhibitor, might be a promising lead compound for treatment of prostate cancer.

Surface shape alters perceived material softness.

When a human strokes the surface of an object with his/her finger, the surface shape influences the perceived softness of the object. This study introduced a curved surface softness illusion, which alters the perception of material softness. When a surface with curvature is felt by sliding a finger over it, it feels softer than a flat surface made of the same material. In contrast, a rugged surface is perceived as harder. This illusion indicates that, in addition to mechanical hardness, humans judge an object's softness based on its surface shape.

Characterization and validation of fatty acid metabolism-related genes predicting prognosis, immune infiltration, and drug sensitivity in endometrial cancer.

Endometrial cancer is considered to be the second most common tumor of the female reproductive system, and patients diagnosed with advanced endometrial cancer have a poor prognosis. The influence of fatty acid metabolism in the prognosis of patients with endometrial cancer remains unclear. We constructed a prognostic risk model using transcriptome sequencing data of endometrial cancer and clinical information of patients from The Cancer Genome Atlas (TCGA) database via least absolute shrinkage and selection operator regression analysis. The tumor immune microenvironment was analyzed using the CIBERSORT algorithm, followed by functional analysis and immunotherapy efficacy prediction by gene set variation analysis. The role of model genes in regulating endometrial cancer in vitro was verified by CCK-8, colony formation, wound healing, and transabdominal invasion assays, and verified in vivo by subcutaneous tumor transplantation in nude mice. A prognostic model containing 14 genes was constructed and validated in 3 cohorts and clinical samples. The results showed differences in the infiltration of immune cells between the high-risk and low-risk groups, and that the high-risk group may respond better to immunotherapy. Experiments in vitro confirmed that knockdown of epoxide hydrolase 2 (EPHX2) and acyl-CoA oxidase like (ACOXL) had an inhibitory effect on EC cells, as did overexpression of hematopoietic prostaglandin D synthase (HPGDS). The same results were obtained in experiments in vivo. Prognostic models related to fatty acid metabolism can be used for the risk assessment of endometrial cancer patients. Experiments in vitro and in vivo confirmed that the key genes HPGDS, EPHX2, and ACOXL in the prognostic model may affect the development of endometrial cancer.

Sulfatase-Induced In Situ Formulation of Antineoplastic Supra-PROTACs.

Proteolysis targeting chimera (PROTAC) technology is an innovative strategy for cancer therapy, which, however, suffers from poor targeting delivery and limited capability for protein of interest (POI) degradation. Here, we report a strategy for the in situ formulation of antineoplastic Supra-PROTACs via intracellular sulfatase-responsive assembly of peptides. Coassembling a sulfated peptide with two ligands binding to ubiquitin VHL and Bcl-xL leads to the formation of a pro-Supra-PROTAC, in which the ratio of the two ligands is rationally optimized based on their protein binding affinity. The resulting pro-Supra-PROTAC precisely undergoes enzyme-responsive assembly into nanofibrous Supra-PROTACs in cancer cells overexpressing sulfatase. Mechanistic studies reveal that the pro-Supra-PROTACs selectively cause apparent cytotoxicity to cancer cells through the degradation of Bcl-xL and the activation of caspase-dependent apoptosis, during which the rationally optimized ligand ratio improves the bioactivity for POI degradation and cell death. In vivo studies show that in situ formulation enhanced the tumor accumulation and retention of the pro-Supra-PROTACs, as well as the capability for inhibiting tumor growth with excellent biosafety when coadministrating with chemodrugs. Our findings provide a new approach for enzyme-regulated assembly of peptides in living cells and the development of PROTACs with high targeting delivering and POI degradation efficiency.

A comprehensive review for artificial intelligence on neuroimaging in rehabilitation of ischemic stroke.

Stroke is the second leading cause of death worldwide, with ischemic stroke accounting for a significant proportion of morbidity and mortality among stroke patients. Ischemic stroke often causes disability and cognitive impairment in patients, which seriously affects the quality of life of patients. Therefore, how to predict the recovery of patients can provide support for clinical intervention in advance and improve the enthusiasm of patients for rehabilitation treatment. With the popularization of imaging technology, the diagnosis and treatment of ischemic stroke patients are often accompanied by a large number of imaging data. Through machine learning and Deep Learning, information from imaging data can be used more effectively. In this review, we discuss recent advances in neuroimaging, machine learning, and Deep Learning in the rehabilitation of ischemic stroke.

A Multistage Hemiplegic Lower-Limb Rehabilitation Robot: Design and Gait Trajectory Planning.

Most lower limb rehabilitation robots are limited to specific training postures to adapt to stroke patients in multiple stages of recovery. In addition, there is a lack of attention to the switching functions of the training side, including left, right, and bilateral, which enables patients with hemiplegia to rehabilitate with a single device. This article presents an exoskeleton robot named the multistage hemiplegic lower-limb rehabilitation robot, which has been designed to do rehabilitation in multiple training postures and training sides. The mechanism consisting of the thigh, calf, and foot is introduced. Additionally, the design of the multi-mode limit of the hip, knee, and ankle joints supports delivering therapy in any posture and training sides to aid patients with hemiplegia in all stages of recovery. The gait trajectory is planned by extracting the gait motion trajectory model collected by the motion capture device. In addition, a control system for the training module based on adaptive iterative learning has been simulated, and its high-precision tracking performance has been verified. The gait trajectory experiment is carried out, and the results verify that the trajectory tracking performance of the robot has good performance.

Electrocatalytic hydrogenation of acetonitrile to ethylamine in acid.

Electrochemical hydrogenation of acetonitrile based on well-developed proton exchange membrane electrolyzers holds great promise for practical production of ethylamine. However, the local acidic condition of proton exchange membrane results in severe competitive proton reduction reaction and poor selection toward acetonitrile hydrogenation. Herein, we conduct a systematic study to screen various metallic catalysts and discover Pd/C exhibits a 43.8% ethylamine Faradaic efficiency at the current density of 200 mA cm-2 with a specific production rate of 2912.5 mmol g-1 h-1, which is about an order of magnitude higher than the other screened metal catalysts. Operando characterizations indicate the in-situ formed PdHx is the active centers for catalytic reaction and the adsorption strength of the *MeCH2NH2 intermediate dictates the catalytic selectivity. More importantly, the theoretical analysis reveals a classic d-band mediated volcano curve to describe the relation between the electronic structures of catalysts and activity, which could provide valuable insights for designing more effective catalysts for electrochemical hydrogenation reactions and beyond.

Long term survival outcomes of surgery combined with hyperthermic intraperitoneal chemotherapy for perforated low-grade appendiceal mucinous neoplasms: A multicenter retrospective study.

BACKGROUND: Low-grade appendiceal mucinous neoplasms (LAMN) are very rare, accounting for approximately 0.2%-0.5% of gastrointestinal tumors. We conducted a multicenter retrospective study to explore the impact of different surgical procedures combined with HIPEC on the short-term outcomes and long-term survival of patients. METHODS: We retrospectively analyzed the clinicopathological data of 91 LAMN perforation patients from 9 teaching hospitals over a 10-year period, and divided them into HIPEC group and non-HIPEC group based on whether or not underwent HIPEC. RESULTS: Of the 91 patients with LAMN, 52 were in the HIPEC group and 39 in the non-HIPEC group. The Kaplan-Meier method predicted that 52 patients in the HIPEC group had 5- and 10-year overall survival rates of 82.7% and 76.9%, respectively, compared with predicted survival rates of 51.3% and 46.2% for the 39 patients in the non-HIPEC group, with a statistically significant difference between the two groups (χ2 = 10.622, p = 0.001; χ2 = 10.995, p = 0.001). Compared to the 5-year and 10-year relapse-free survival rates of 75.0% and 65.4% in the HIPEC group, respectively, the 5-year and 10-year relapse-free survival rates of 48.7% and 46.2% in the non-HIPEC group were significant different between the two outcomes (χ2 = 8.063, p = 0.005; χ2 = 6.775, p = 0.009). The incidence of postoperative electrolyte disturbances and hypoalbuminemia was significantly higher in the HIPEC group than in the non-HIPEC group (p = 0.023; p = 0.044). CONCLUSIONS: This study shows that surgery combined with HIPEC can significantly improve 5-year and 10-year overall survival rates and relapse-free survival rates of LAMN perforation patients, without affecting their short-term clinical outcomes.

Novel selective agents for the degradation of AR/AR-V7 to treat advanced prostate cancer.

The androgen receptor AR antagonists, such as enzalutamide and apalutamide, are efficient therapeutics for the treatment of prostate cancer (PCa). Even though they are effective at first, resistance to both drugs occurs frequently. Resistance is mainly driven by aberrations of the AR signaling pathway including AR gene amplification and the expression of AR splice variants (e.g. AR-V7). This highlights the urgent need for alternative therapeutic strategies. Here, a total of 24 compounds were synthesized and biologically evaluated to disclose compound 20i, exhibiting potent AR antagonistic activities (IC50 = 172.85 ± 21.33 nM), promising AR/AR-V7 protein degradation potency, and dual targeting site of probably AR (ligand-binding domain, LBD and N-terminal domain, NTD). It potently inhibits cell growth with IC50 values of 4.87 ± 0.52 and 2.07 ± 0.34 µM in the LNCaP and 22RV1 cell lines, respectively, and exhibited effective tumor growth inhibition (TGI = 50.9 %) in the 22RV1 xenograft study. These data suggest that 20i has the potential for development as an AR/AR-V7 inhibitor with degradation ability to treat advanced prostate cancer.

Research on the impact of equity incentive model on enterprise performance: A mediating effect analysis based on executive entrepreneurship.

In implementing the equity incentive system, this paper delves into the listed enterprises' selection of equity incentive models. While previous research has extensively covered the effects, models, and influencing factors of equity incentives, there needs to be more in-depth literature focusing on the diverse incentive models and their impact on corporate performance. Notably, there needs to be more literature on considering entrepreneurial spirit as a mechanism. It aims to explore the relationship between executives' choices under different incentive models, the entrepreneurial spirit fostered by these models, and their combined impact on corporate performance. The findings reveal that adopting the restricted stock incentive model by listed enterprises implementing the equity incentive system significantly positively affects enterprise performance. Mechanistic tests show that when a company implements the restricted stock incentive model, executives prioritize maximizing their interests, leading them to embrace more risk in their investment decisions. This behavior, in turn, stimulates the adventurous spirit of executives, positively impacting enterprise performance, particularly pronounced in companies with more concentrated executive power. Moreover, executives may be more inclined to invest in high-risk, high-reward innovative projects, a behavior indicative of innovation and more prevalent in firms with higher research and development (R&D) investment. However, the limitation of this paper is that the study evaluates the operation of the equity incentive system in China by taking listed companies in China as an example, which is not necessarily suitable for foreign developed capitalist countries. This study contributes to the study of principal-agent problems by exploring the relationship between executives, entrepreneurship and firm performance.

Identification of a prognosis-related gene signature and ceRNA regulatory networks in lung adenocarcinoma.

The ceRNA network, consisting of both noncoding RNA and protein-coding RNA, governs the occurrence, progression, metastasis, and infiltration of lung adenocarcinoma. Signatures comprising multiple genes can effectively determine survival stratification and prognosis of patients with lung adenocarcinoma. To explore the mechanisms of lung adenocarcinoma progression and identify potential biological targets, we carried out systematic bioinformatics analyses of the genetic profiles of lung adenocarcinoma, such as weighted gene co-expression network analysis (WGCNA), differential expression (DE) assessment, univariate and multivariate Cox proportional hazard regression models, ceRNA modulatory networks generated using the ENCORI and miRcode databases, nomogram models, ROC curve assessment, and Kaplan-Meier survival curve analysis. The ceRNA network encompassed 37 nodes, comprising 12 mRNAs, 22 lncRNAs, and three miRNAs. Simultaneously, we performed integration analysis using the 12 genes from the ceRNA network. Our findings revealed that the signature established by these 12 genes serves as an adverse element in lung adenocarcinoma, contributing to unfavorable patient prognosis. To ensure the credibility of our results, we used in vitro experiments for further verification. In conclusion, our study delved into the potential mechanisms underlying lung adenocarcinoma via the ceRNA regulatory network, specifically focusing on the PIF1 and has-miR-125a-5p axis. Additionally, a signature comprising 12 genes was identified as a biomarker related to the prognosis of lung adenocarcinoma.

Engineering of VCAM-1-targeted nanostructured lipid carriers for delivery of melatonin against acute lung injury through SIRT1/NLRP3 mediated pyroptosis signaling pathway.

Acute lung injury (ALI) is a prevalent and critical condition in clinical practice. Although certain pharmacological interventions have demonstrated benefits in preclinical studies, none have been proven entirely effective thus far. Therefore, the development of more efficient treatment strategies for ALI is imperative. In this study, we prepared nanostructured lipid carriers (NLCs) conjugated with anti-VCAM-1 antibodies to encapsulate melatonin (MLT), resulting in VCAM/MLT NLCs. This approach aimed to enhance the distribution of melatonin in lung vascular endothelial cells. The VCAM/MLT NLCs had an average diameter of 364 nm, high drug loading content, and a sustained drug release profile. Notably, the NLCs conjugated with anti-VCAM-1 antibodies demonstrated more specific cellular delivery mediated by the VCAM-1 receptors, increased cellular internalization, and enhanced accumulation in lung tissues. Treatment with VCAM/MLT NLCs effectively alleviated pulmonary inflammation by activating NLRP3 inflammasome-dependent pyroptosis through up-regulation of Sirtuin 1. Our findings suggest that VCAM/MLT NLCs demonstrate remarkable therapeutic effects on ALI in both in vitro and in vivo settings, making them a promising and efficient treatment strategy for ALI.