In vitro inhibitory effects of selumetinib on activity of human UDP-glucuronosyltransferases and prediction of in vivo drug-drug interactions.

Selumetinib is an oral, effective, and selective tyrosine kinase inhibitor targeting mitogen-activated protein kinase 1 and 2 (MEK1/2), which is clinically active in multiple tumor types, such as neurofibromatosis type 1 (NF1), melanoma, gliomas and non-small cell lung cancer (NSCLC). The purpose of this article was to assess the effects of selumetinib on the activities of twelve human UDP-glucosyltransferases (UGTs) including UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17, and its potential for inducing clinical drug-drug interactions (DDIs). The results demonstrated that selumetinib potently inhibited the activity of UGT2B7 through the mechanism of mixed inhibition with the inhibition constant value of 5.79 ± 0.65 µM. Furthermore, the plasma concentration of UGT2B7 substrate as the co-administered drug was predicted to be increased by at least 84 % when patients took selumetinib 75 mg twice daily, suggesting a high potential to induce clinical DDIs. Selumetinib exhibited weak inhibitory effects on other human UGTs and was unlikely to trigger off UGTs-mediated DDIs except for UGT2B7. Therefore, the combination of selumetinib with the substrate drug of UGT2B7 requires additional attention to avoid adverse events in clinical treatment.

Seismic performance of soft soil foundation with a new type of assembled wall tuned mass damper.

The design of tuned mass damper (TMD) parameters is influenced by the soil-structure-TMD coupling system; thus, it is important to consider the soil-structure interaction (SSI) for the vibration control effect of the TMD. Recently, the acquisition of TMD parameters considering soil-structure interactions has only remained at the theoretical stage, lacking relevant experimental verification. Traditional TMD face the problems of occupying a large building space, increasing construction costs, and non-replaceable components. In this study, an assembled wall-type damping TMD was designed. By comparing the dynamic response of the uncontrolled and controlled structures equipped with the newly assembled wall-type damping TMD in the shaking table test on a soft soil foundation, we analyzed whether the SSI effect was considered in the TMD design parameters on the damping effect of the newly assembled wall-type tuned mass damper. The TMD parameters optimized using the artificial intelligence algorithm were verified experimentally. The results indicated that the traditional TMD design parameters were discordant because the SSI effect was not considered. The SSI effect in the soil effectively reduces the dynamic response of the superstructure. By considering the SSI effect and improving the multi-population genetic algorithm, a wall-type damping TMD with optimized parameters can achieve a good damping effect.

Dual single atomic Ni sites constructing Janus hollow graphene for boosting electrochemical sensing of glucose.

Single atom catalysts (SACs) have attracted attention due to their excellent catalysis activity under specific reactions and conditions. However, the low density of SACs greatly limits catalytic performance. The three-dimensional graphene hollow nanospheres (GHSs) with very thin shell structure can be used as excellent carrier materials. Not only can its outer surface be used to anchor metal single atoms, but its inner surface can also provide rich sites. Here, a novel step-by-step assembly strategy is reported to anchor nickel single atoms (Ni SAs) on the inner and outer surfaces of GHSs (Ni SAs/GHSs/Ni SAs), which significantly increases the loading capacity of Ni SAs (4.8 wt%). Compared to conventional materials that only anchor Ni SAs to the outer surface of the carrier (Ni SAs/GHSs), Ni SAs/GHSs/Ni SAs exhibits significantly higher electrocatalytic activity toward glucose oxidation in alkaline media. The sensitivity of Ni SAs/GHSs/Ni SAs/GCE is nearly five times higher than that of Ni SAs/GHSs/GCE. Moreover, the sensor based on Ni SAs/GHSs/Ni SAs can detect glucose in a wide concentration range of 0.8 µM-1.1244 mM with a low detection limit of 0.19 µM (S/N = 3). This study not only provides an effective sensing material for glucose detection, but also opens a new avenue to construct high-density metal SACs.

Thermal Oxidative Aging and Service Life Prediction of Commercial Ethylene-Propylene-Diene Monomer Spacer Damping Composites for High-Voltage Transmission Lines.

The aging behavior and life prediction of rubber composites are crucial for ensuring high-voltage transmission line safety. In this study, commercially available ethylene-propylene-diene monomer (EPDM) spacer composites were chosen and investigated to elucidate the structure and performance changes under various aging conditions. The results showed an increased C=O peak intensity with increasing aging time, suggesting intensified oxidation of ethylene and propylene units. Furthermore, the surface morphology of commercial EPDM composites displayed increased roughness and aggregation after aging. Furthermore, hardness, modulus at 100% elongation, and tensile strength of commercial EPDM composites exhibited a general increase, while elongation at break decreased. Additionally, the damping performance decreased significantly after aging, with a 20.6% reduction in loss factor (20 °C) after aging at 100 °C for 672 h. With increasing aging time and temperature, the compression set gradually rose due to the irreversible movement of the rubber chains under stress. A life prediction model was developed based on a compression set to estimate the lifetime of rubber composites for spacer bars. The results showed that the product's life was 8.4 years at 20 °C. Therefore, the establishment of a life prediction model for rubber composites can provide valuable technical support for spacer product services.

Triply Interlocked [2]catenanes: Rational Synthesis, Reversible Conversion Studies and Unprecedented Application in Photothermal Responsive Elastomer.

Triply interlocked [2]catenane complexes featuring two identical, mechanically interlocked units are extraordinarily rare chemical compounds, whose properties and applications remain open to detailed studies. Herein, we introduce the rational design of a new ligand precursor, L1, suitable for the synthesis of six triply interlocked [2]catenanes by coordination-driven self-assembly. The interlocked compounds can be reversibly converted into the corresponding simple triangular prism metallacage by addition of H2O or DMF solvents to their CH3OH solutions, thereby demonstrating the importance of π···π stacking and hydrogen bonding interactions in the formation of triply interlocked [2]catenanes. Moreover, extensive studies have been conducted to assess the remarkable photothermal conversion performance. Complex 6a, exhibiting outstanding photothermal conversion performance (conversion efficiency in solution : 31.82%), is used to prepare novel photoresponsive elastomer in combination with thermally activated liquid crystal elastomer. The resultant material displays robust response to near-infrared (NIR) laser and the capability of completely reforming the shape and reversible actuation, paving the way for the application of half-sandwich organometallic units in photo-responsive smart materials.

Spleen-targeted delivery systems and strategies for spleen-related diseases.

The spleen, body's largest secondary lymphoid organ, is also a vital hematopoietic and immunological organ. It is regarded as one of the most significant organs in humans. As more researchers recognize the functions of the spleen, clinical methods for treating splenic diseases and spleen-targeted drug delivery systems to improve the efficacy of spleen-related therapies have gradually developed. Many modification strategies (size, charge, ligand, protein corona) and hitchhiking strategies (erythrocytes, neutrophils) of nanoparticles (NPs) have shown a significant increase in spleen targeting efficiency. However, most of the targeted drug therapy strategies for the spleen are to enhance or inhibit the immune function of the spleen to achieve therapeutic effects, and there are few studies on spleen-related diseases. In this review, we not only provide a detailed summary of the design rules for spleen-targeted drug delivery systems in recent years, but also introduce common spleen diseases (splenic tumors, splenic injuries, and splenomegaly) with the hopes of generating more ideas for future spleen research.

Targeting STING in dendritic cells alleviates psoriatic inflammation by suppressing IL-17A production.

Psoriasis is a common chronic inflammatory skin disease driven by the aberrant activation of dendritic cells (DCs) and T cells, ultimately leading to increased production of cytokines such as interleukin (IL)-23 and IL-17A. It is established that the cGAS-STING pathway is essential for psoriatic inflammation, however, the specific role of cGAS-STING signaling in DCs within this context remains unclear. In this study, we demonstrated the upregulation of cGAS-STING signaling in psoriatic lesions by analyzing samples from both clinical patients and imiquimod (IMQ)-treated mice. Using a conditional Sting-knockout transgenic mouse model, we elucidated the impact of cGAS-STING signaling in DCs on the activation of IL-17- and IFN-γ-producing T cells in psoriatic inflammation. Ablation of the Sting hampers DC activation leads to decreased numbers of IL-17-producing T cells and Th1 cells, and thus subsequently attenuates psoriatic inflammation in the IMQ-induced mouse model. Furthermore, we explored the therapeutic potential of the STING inhibitor C-176, which reduces psoriatic inflammation and enhances the anti-IL-17A therapeutic response. Our results underscore the critical role of cGAS-STING signaling in DCs in driving psoriatic inflammation and highlight a promising psoriasis treatment.

Study on triaxial compression performance and damage characteristics of fiber-reinforced ecological matrix cementing gangue gypsum fill material.

Polypropylene fiber was equally mixed into alkali-activated slag fly ash geopolymer in order to ensure the filling effect of mine goaf and improve the stability of cemented gangue paste filling material with ecological matrix. Triaxial compression tests were then conducted under various conditions. The mechanical properties and damage characteristics of composite paste filling materials are studied, and the damage evolution model of paste filling materials under triaxial compression is established, based on the deviatoric stress-strain curve generated by the progressive failure behavior of samples. Internal physical and chemical mechanisms of the evolution of structure and characteristics are elucidated and comprehended via the use of SEM-EDS and XRD micro-techniques. The results show that the fiber can effectively improve the ultimate strength and the corresponding effective stress strength index of the sample within the scope of the experimental study. The best strengthening effect is achieved when the amount of NaOH is 3% of the mass of the solid material, the amount of fiber is 5‰ of the mass of the solid material, and the length of the fiber is about 12 mm. The action mode of the fiber in the sample is mainly divided into single-grip anchoring and three-dimensional mesh traction. As the crack initiates and develops, connection occurs in the matrix, where the fiber has an obvious interference and retardation effect on the crack propagation, thereby transforming the brittle failure into a ductile failure and consequently improving the fracture properties of the ecological cementitious coal gangue matrix. The theoretical damage evolution model of a segmented filling body is constructed by taking the initial compaction stage end point as the critical point, and the curve of the damage evolution model of the specimen under different conditions is obtained. The theoretical model is verified by the results from the triaxial compression test. We concluded that the experimental curve is in good agreement with the theoretical curve. Therefore, the established theoretical model has a certain reference value for the analysis and evaluation of the mechanical properties of paste filling materials. The research results can improve the utilization rate of solid waste resources.

Novel 2DEG System at the HfO2/STO Interface.

Multifunctional integration in a single device has always been a hot research topic, especially for contradictory phenomena, one of which is the coexistence of ferroelectricity and metallicity. The complex oxide heterostructures, as symmetric breaking systems, provide a great possibility to incorporate different properties. Moreover, finding a series of oxide heterostructures to achieve this goal remains as a challenge. Here, taking the advantage of different physical phenomena, we use H2 plasma to pretreat the SrTiO3 (STO) substrate and then fabricate HfO2/STO heterostructures with it. The novel, well-repeatable metallic two-dimensional electron gas (2DEG) is directly obtained at the heterointerfaces without any further complex procedures, while the obvious ferroelectric-like behavior and Rashba spin-orbit coupling are also observed. The understanding of the mechanism, as well as the modified facile preparation procedure, would be meaningful for further development of ferroelectric metal in complex oxide heterostructures.

The value of whole tumor apparent diffusion coefficient histogram parameters in predicting meningiomas progesterone receptor expression.

PURPOSE: This study investigated the value of whole tumor apparent diffusion coefficient (ADC) histogram parameters and magnetic resonance imaging (MRI) semantic features in predicting meningioma progesterone receptor (PR) expression. MATERIALS AND METHODS: The imaging, pathological, and clinical data of 53 patients with PR-negative meningiomas and 52 patients with PR-positive meningiomas were retrospectively reviewed. The whole tumor was outlined using Firevoxel software, and the ADC histogram parameters were calculated. The differences in ADC histogram parameters and MRI semantic features were compared between the two groups. The predictive values of parameters for PR expression were assessed using receiver operating characteristic curves. The correlation between whole-tumor ADC histogram parameters and PR expression in meningiomas was also analyzed. RESULTS: Grading was able to predict the PR expression in meningiomas (p = 0.012), though the semantic features of MRI were not (all p > 0.05). The mean, Perc.01, Perc.05, Perc.10, Perc.25, and Perc.50 histogram parameters were able to predict meningioma PR expression (all p < 0.05). The predictive performance of the combined histogram parameters improved, and the combination of grade and histogram parameters provided the optimal predictive value, with an area under the curve of 0.849 (95%CI: 0.766-0.911) and sensitivity, specificity, ACC, PPV, and NPV of 73.08%, 81.13%, 77.14%, 79.20%, and 75.40%, respectively. The mean, Perc.01, Perc.05, Perc.10, Perc.25, and Perc.50 histogram parameters were positively correlated with PR expression (all p < 0.05). CONCLUSION: Whole tumor ADC histogram parameters have additional clinical value in predicting PR expression in meningiomas.

Avapritinib Carries the Risk of Drug Interaction via Inhibition of UDP-Glucuronosyltransferase (UGT) 1A1.

BACKGROUND: Avapritinib is the only drug for adult patients with PDGFRA exon 18 mutated unresectable or metastatic Gastrointestinal Stromal Tumor (GIST). Although avapritinib has been approved by the FDA for three years, little is known about the risk of Drug-drug Interac-tions (DDIs) via UDP-glucuronyltransferases (UGTs) inhibition. OBJECTIVE: The aim of the present study was to systematically evaluate the inhibitory effects of avapritinib against UGTs and to quantitatively estimate its potential DDIs risk in vivo. METHODS: Recombinant human UGTs were employed to catalyze the glucuronidation of sub-strates in a range of concentrations of avapritinib. The kinetics analysis was performed to evaluate the inhibition types of avapritinib against UGTs. The quantitative prediction of DDIs was done using In vitro-in vivo Extrapolation (IVIVE). RESULTS: Avapritinib had a potent competitive inhibitory effect on UGT1A1. Quantitative predic-tion results showed that avapritinib administered at clinical doses might result in a 14.85% in-crease in the Area Under the Curve (AUC) of drugs primarily cleared by UGT1A1. Moreover, the Rgut value was calculated to be 18.44. CONCLUSION: Avapritinib has the potential to cause intestinal DDIs via the inhibition of UGT1A1. Additional attention should be paid when avapritinib is coadministered with UGT1A1 substrates.

Knockdown of trem2 promotes proinflammatory microglia and inhibits glioma progression via the JAK2/STAT3 and NF-κB pathways.

BACKGROUND: In the tumor immune microenvironment (TIME), triggering receptor expressed on myeloid cells 2 (trem2) is widely considered to be a crucial molecule on tumor-associated macrophages(TAMs). Multiple studies have shown that trem2 may function as an immune checkpoint in various malignant tumors, mediating tumor immune evasion. However, its specific molecular mechanisms, especially in glioma, remain elusive. METHODS: Lentivirus was transfected to establish cells with stable knockdown of trem2. A Transwell system was used for segregated coculture of glioma cells and microglia. Western blotting, quantitative real-time polymerase chain reaction (qRT‒PCR), and immunofluorescence (IF) were used to measure the expression levels of target proteins. The proliferation, invasion, and migration of cells were detected by colony formation, cell counting kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU) and transwell assays. The cell cycle, apoptosis rate and reactive oxygen species (ROS) level of cells were assessed using flow cytometry assays. The comet assay and tube formation assay were used to detect DNA damage in glioma cells and angiogenesis activity, respectively. Gl261 cell lines and C57BL/6 mice were used to construct the glioma orthotopic transplantation tumor model. RESULTS: Trem2 was highly overexpressed in glioma TAMs. Knocking down trem2 in microglia suppressed the growth and angiogenesis activity of glioma cells in vivo and in vitro. Mechanistically, knockdown of trem2 in microglia promoted proinflammatory microglia and inhibited anti-inflammatory microglia by activating jak2/stat1 and inhibiting the NF-κB p50 signaling pathway. The proinflammatory microglia produced high concentrations of nitric oxide (NO) and high levels of the proinflammatory cytokines TNF-α, IL-6, and IL-1ß, and caused further DNA damage and promoted the apoptosis rate of tumor cells. CONCLUSIONS: Our findings revealed that trem2 in microglia plays a significant role in the TIME of gliomas. Knockdown of trem2 in microglia might help to improve the efficiency of inhibiting glioma growth and delaying tumor progression and provide new ideas for further treatment of glioma.

Effects of the fermentation quality and microbial community of waxy maize mixed with fodder soybean silage.

Waxy maize (Zea mays L. sinensis Kulesh) is highly regarded for its high nutritional content and unique taste. Although the stalks and leaves contain high carbohydrate levels after ear harvesting, inadequate crude protein (CP) limits the utilization and promotion of waxy maize silage in animal husbandry. In this study, waxy maize and fodder soybeans were mixed for sowing in different proportions [1:0 (CK), 1:1 (A1), 1:2 (A2), 1:3 (A3), and 1:4 (A4)] to investigate the effects of different mixing ratios on the growth of the waxy maize, the chemical indices, fermentation quality, and the microbial community of the mixed silage after ear harvesting. The mixed planting of waxy maize and fodder soybeans in different proportions had no effect on the yield and quality of the waxy maize ears and increased the aboveground biomass after ear harvesting. After ear harvesting, the neutral detergent fiber (NDF) and acid detergent fiber (ADF) contents significantly decreased, and the CP content and relative feeding value (RFV) gradually increased in the mixed silage. The pH of the treatments was lower than 4.2 except for A4, and the lowest ammonia nitrogen (AN) concentration was observed in A3. With increasing proportions of fodder soybeans, the abundance of beneficial bacteria increased and that of harmful bacteria decreased; Firmicutes and Lactobacillus were the dominant phylum and genus, respectively, and both increased gradually. Redundancy analysis (RDA) revealed that the fermentation indices affecting the microbial community composition in the silage were inconsistent among the different mixed sowing combinations. The Mantel test showed that the composition of the microbial communities in the treatments was significantly correlated with the ADF, water-soluble carbohydrate (WSC), and propionic acid (PA) contents. Comprehensive analysis revealed that the optimal mixed sowing ratio of waxy maize to fodder soybeans was 1:3, and waxy maize and fodder soybeans silage can increase the utilization of aboveground biomass and improve the fermentation quality and feeding quality of silage by changing the microbial community. These findings lay a certain theoretical foundation for improving the utilization of waxy maize.

The mechanism of extracellular CypB promotes glioblastoma adaptation to glutamine deprivation microenvironment.

Glioblastoma, previously known as glioblastoma multiform (GBM), is a type of glioma with a high degree of malignancy and rapid growth rate. It is highly dependent on glutamine (Gln) metabolism during proliferation and lags in neoangiogenesis, leading to extensive Gln depletion in the core region of GBM. Gln-derived glutamate is used to synthesize the antioxidant Glutathione (GSH). We demonstrated that GSH levels are also reduced in Gln deficiency, leading to increased reactive oxygen species (ROS) levels. The ROS production induces endoplasmic reticulum (ER) stress, and the proteins in the ER are secreted into the extracellular medium. We collected GBM cell supernatants cultured with or without Gln medium; the core and peripheral regions of human GBM tumor tissues. Proteomic analysis was used to screen out the target-secreted protein CypB. We demonstrated that the extracellular CypB expression is associated with Gln deprivation. Then, we verified that GBM can promote the glycolytic pathway by activating HIF-1α to upregulate the expression of GLUT1 and LDHA expressions. Meanwhile, the DRP1 was activated, increasing mitochondrial fission, thus inhibiting mitochondrial function. To explore the specific mechanism of its regulation, we constructed a si-CD147 knockout model and added human recombinant CypB protein to verify that extracellular CypB influenced the expression of downstream p-AKT through its cell membrane receptor CD147 binding. Moreover, we confirmed that p-AKT could upregulate HIF-1α and DRP1. Finally, we observed that extracellular CypB can bind to the CD147 receptor, activate p-AKT, and upregulate HIF-1α and DRP1 in order to promote glycolysis while inhibiting mitochondrial function to adapt to the Gln-deprived microenvironment.

Pilot analysis of tire tread characteristics and associated tire-wear particles in vehicles produced across distinct time periods.

Owing to stringent vehicle emission regulations and the shifting automotive landscape towards clean-energy vehicles, the emission of non-exhaust tire-wear particles and its implications for microplastic contamination have garnered substantial attention, emerging as a focal point of research interest. Unlike traditional source apportionment methods involving direct environmental sampling, this study focuses on the physical and chemical attributes of tire treads, the tread temperature changes, and the tire-wear particle emissions of three light-duty vehicles manufactured between 2011 and 2021. This study advances the understanding of the effects of tire properties on particle emissions, which provides preliminary information on low-wear tires. The results show that tire-wear particle emissions, mainly composed of ultrafine particles in terms of number, heavily depend on the elevated tread temperatures. The change in tread temperature is influenced not only by the initial tread temperature but also by tread pyrolysis characteristics. Ca, Mg, and Zn are abundantly contained in the tire tread and tire-wear particles.

Inhibition of human UDP-glucuronosyltransferase enzyme by entrectinib: Implications for drug-drug interactions.

As a new type of oral tyrosine kinase inhibitor, entrectinib can act on multiple targets and exert efficacy and has been approved for the treatment of non-small cell lung cancer (NSCLC) and solid tumors. However, whether entrectinib affects the activities of recombinant human UDP-glucuronosyltransferases (UGTs) remains unclear. Herein, we aimed to investigate the inhibitory effects of entrectinib on human UGTs and to assess the potential risk of causing drug-drug interactions (DDIs) based on the inhibition against UGTs. High-performance liquid chromatography (HPLC) was used to evaluate the inhibitory effects of entrectinib on UGTs according to the product formation rate of UGT substrate with or without entrectinib, and the inhibition kinetics experiment was conducted to assess the inhibitory type of entrectinib on UGTs. Our results showed that entrectinib exhibited extensive inhibitory effects on most human UGTs, and especially inhibited the activities of UGT1A7, UGT1A8, and UGT2B15 with Ki (Inhibition constant) of lower than 5 µM (0.95-4.38 µM). Furthermore, the results from quantitative prediction research suggested that the combination of entrectinib at 600 mg/day with substrates primarily metabolized by hepatic UGT2B15 or intestinal UGT1A7 and UGT1A8 might cause clinical DDIs. Thus, special attention should be paid to avoid adverse reactions induced by DDIs when co-administration of entrectinib and drugs metabolized by UGTs.

Synthetic biology approaches for improving the specificity and efficacy of cancer immunotherapy.

Immunotherapy has shown robust efficacy in treating a broad spectrum of hematological and solid cancers. Despite the transformative impact of immunotherapy on cancer treatment, several outstanding challenges remain. These challenges include on-target off-tumor toxicity, systemic toxicity, and the complexity of achieving potent and sustainable therapeutic efficacy. Synthetic biology has emerged as a promising approach to overcome these obstacles, offering innovative tools for engineering living cells with customized functions. This review provides an overview of the current landscape and future prospects of cancer immunotherapy, particularly emphasizing the role of synthetic biology in augmenting its specificity, controllability, and efficacy. We delineate and discuss two principal synthetic biology strategies: those targeting tumor surface antigens with engineered immune cells and those detecting intratumoral disease signatures with engineered gene circuits. This review concludes with a forward-looking perspective on the enduring challenges in cancer immunotherapy and the potential breakthroughs that synthetic biology may contribute to the field.

TDDFT Study on the ESIPT Properties of 2-(2'-Hydroxyphenyl)-Benzothiazole and Sensing Mechanism of a Derived Fluorescent Probe for Fluoride Ion.

The level of fluoride ions (F-) in the human body is closely related to various pathological and physiological states, and the rapid detection of F- is important for studying physiological processes and the early diagnosis of diseases. In this study, the detailed sensing mechanism of a novel high-efficiency probe (PBT) based on 2-(2'-hydroxyphenyl)-benzothiazole derivatives towards F- has been fully investigated based on density functional theory (DFT) and time-dependent density functional theory (TDDFT) methods. F- attacks the O-P bond of PBT to cleavage the dimethylphosphinothionyl group, and the potential products were evaluated by Gibbs free energy and spectroscopic analyses, which ultimately identified the product as HBT-Enol1 with an intramolecular hydrogen bond. Bond parameters, infrared vibrational spectroscopy and charge analysis indicate that the hydrogen bond is enhanced at the excited state (S1), favoring excited state intramolecular proton transfer (ESIPT). The mild energy barrier further evidences the occurrence of ESIPT. Combined with frontier molecular orbital (FMO) analysis, the fluorescence quenching of PBT was attributed to the photoinduced electron transfer (PET) mechanism and the fluorescence turn-on mechanism of the product was attributed to the ESIPT process of HBT-Enol1.

A Long-Acting Lyotropic Liquid Crystalline Implant Promotes the Drainage of Macromolecules by Brain-Related Lymphatic System in Treating Aged Alzheimer's Disease.

Numerous evidence has demonstrated that the brain is not an immune-privileged organ but possesses a whole set of lymphatic transport system, which facilitates the drainage of harmful waste from brains to maintain cerebral homeostasis. However, as individuals age, the shrinkage and dysfunction of meningeal and deep cervical lymphatic networks lead to reduced waste outflow and elevated neurotoxic molecules deposition, further inducing aging-associated cognitive decline, which act as one of the pathological mechanisms of Alzheimer's disease. Consequently, recovering the function of meningeal and deep cervical lymph node (dCLNs) networks (as an important part of the brain waste removal system (BWRS)) of aged brains might be a feasible strategy. Herein we showed that the drug brain-entering efficiency was highly related to administration routes (oral, subcutaneous, or dCLN delivery). Besides, by injecting a long-acting lyotropic liquid crystalline implant encapsulating cilostazol (an FDA-approved selective PDE-3 inhibitor) and donepezil hydrochloride (a commonly used symptomatic relief agent to inhibit acetylcholinesterase for Alzheimer's disease) near the deep cervical lymph nodes of aged mice (about 20 months), an increase of lymphatic vessel coverage in the nodes and meninges was observed, along with accelerated drainage of macromolecules from brains. Compared with daily oral delivery of cilostazol and donepezil hydrochloride, a single administered dual drugs-loaded long-acting implants releasing for more than one month not only elevated drug concentrations in brains, improved the clearing efficiency of brain macromolecules, reduced Aß accumulation, enhanced cognitive functions of the aged mice, but improved patient compliance as well, which provided a clinically accessible therapeutic strategy toward aged Alzheimer's diseases.