Improvement of sleep duration and quality through GABAA receptor by whey protein hydrolysate containing DIQK as the active main compound.

This study characterized the sleep activity, sleep mechanism, and active peptides of whey protein hydrolysates selected through behavioral analysis of fruit-flies (Drosophila melanogaster). Sleep-inducing whey protein (WP) hydrolysate was selected through fruit fly behavior analysis, and sleep activity was measured using a pentobarbital model and electroencephalographic analysis. The mechanism of action was confirmed using a γ-aminobutyric acid (GABA) receptor antagonist, and the active peptide was identified using liquid chromatography-mass spectroscopy. Whey protein hydrolysate, prepared using Alcalase and Prozyme (WP-AP), increased sleep time in a dose-dependent manner. WP-AP significantly increased not only sleep time but also slow-wave sleep and showed an insomnia-alleviating effect in a caffeine-induced insomnia mouse model. In addition, the gene and protein expression levels of GABA sub-type A (GABAA) receptors increased in the brains of mice orally administered with WP-AP. Through peptide analysis, the mixture of DIQK, VPPF peptide, and GABA contained in WP-AP was estimated to exhibit sleep activity, and due to its high content, DIQK was speculated to be the main sleep -inducing ingredient. These results indicate that WP-AP has the potential to be used as a new ingredient to improve sleep quality.

A machine-learning-enabled smart neckband for monitoring dietary intake.

The increasing need for precise dietary monitoring across various health scenarios has led to innovations in wearable sensing technologies. However, continuously tracking food and fluid intake during daily activities can be complex. In this study, we present a machine-learning-powered smart neckband that features wireless connectivity and a comfortable, foldable design. Initially considered beneficial for managing conditions such as diabetes and obesity by facilitating dietary control, the device's utility extends beyond these applications. It has proved to be valuable for sports enthusiasts, individuals focused on diet control, and general health monitoring. Its wireless connectivity, ergonomic design, and advanced classification capabilities offer a promising solution for overcoming the limitations of traditional dietary tracking methods, highlighting its potential in personalized healthcare and wellness strategies.

Baicalin and baicalein from Scutellaria baicalensis Georgi alleviate aberrant neuronal suppression mediated by GABA from reactive astrocytes.

AIMS: γ-aminobutyric acid (GABA) from reactive astrocytes is critical for the dysregulation of neuronal activity in various neuroinflammatory conditions. While Scutellaria baicalensis Georgi (S. baicalensis) is known for its efficacy in addressing neurological symptoms, its potential to reduce GABA synthesis in reactive astrocytes and the associated neuronal suppression remains unclear. This study focuses on the inhibitory action of monoamine oxidase B (MAO-B), the key enzyme for astrocytic GABA synthesis. METHODS: Using a lipopolysaccharide (LPS)-induced neuroinflammation mouse model, we conducted immunohistochemistry to assess the effect of S. baicalensis on astrocyte reactivity and its GABA synthesis. High-performance liquid chromatography was performed to reveal the major compounds of S. baicalensis, the effects of which on MAO-B inhibition, astrocyte reactivity, and tonic inhibition in hippocampal neurons were validated by MAO-B activity assay, qRT-PCR, and whole-cell patch-clamp. RESULTS: The ethanolic extract of S. baicalensis ameliorated astrocyte reactivity and reduced excessive astrocytic GABA content in the CA1 hippocampus. Baicalin and baicalein exhibited significant MAO-B inhibition potential. These two compounds downregulate the mRNA levels of genes associated with reactive astrogliosis or astrocytic GABA synthesis. Additionally, LPS-induced aberrant tonic inhibition was reversed by both S. baicalensis extract and its key compounds. CONCLUSIONS: In summary, baicalin and baicalein isolated from S. baicalensis reduce astrocyte reactivity and alleviate aberrant tonic inhibition of hippocampal neurons during neuroinflammation.

Spongy Ag Foam for Soft and Stretchable Strain Gauges.

Strain gauges, particularly for wearable sensing applications, require a high degree of stretchability, softness, sensitivity, selectivity, and linearity. They must also steer clear of challenges such as mechanical and electrical hysteresis, overshoot behavior, and slow response/recovery times. However, current strain gauges face challenges in satisfying all of these requirements at once due to the inevitable trade-offs between these properties. Here, we present an innovative method for creating strain gauges from spongy Ag foam through a steam-etching process. This method simplifies the traditional, more complex, and costly manufacturing techniques, presenting an eco-friendly alternative. Uniquely, the strain gauges crafted from this method achieve an unparalleled gauge factor greater than 8 × 103 at strains exceeding 100%, successfully meeting all required attributes without notable trade-offs. Our work includes systematic investigations that reveal the intricate structure-property-performance relationship of the spongy Ag foam with practical demonstrations in areas such as human motion monitoring and human-robot interaction. These breakthroughs pave the way for highly sensitive and selective strain gauges, showing immediate applicability across a wide range of wearable sensing applications.

Rapid Self-Healing Hydrogel with Ultralow Electrical Hysteresis for Wearable Sensing.

Self-healing hydrogels are in high demand for wearable sensing applications due to their remarkable deformability, high ionic and electrical conductivity, self-adhesiveness to human skin, as well as resilience to both mechanical and electrical damage. However, these hydrogels face challenges such as delayed healing times and unavoidable electrical hysteresis, which limit their practical effectiveness. Here, we introduce a self-healing hydrogel that exhibits exceptionally rapid healing with a recovery time of less than 0.12 s and an ultralow electrical hysteresis of less than 0.64% under cyclic strains of up to 500%. This hydrogel strikes an ideal balance, without notable trade-offs, between properties such as softness, deformability, ionic and electrical conductivity, self-adhesiveness, response and recovery times, durability, overshoot behavior, and resistance to nonaxial deformations such as twisting, bending, and pressing. Owing to this unique combination of features, the hydrogel is highly suitable for long-term, durable use in wearable sensing applications, including monitoring body movements and electrophysiological activities on the skin.

A flexible, thin-film microchannel electrode array device for selective subdiaphragmatic vagus nerve recording.

The vagus nerve (VN) plays an important role in regulating physiological conditions in the gastrointestinal (GI) tract by communicating via the parasympathetic pathway to the enteric nervous system (ENS). However, the lack of knowledge in the neurophysiology of the VN and GI tract limits the development of advanced treatments for autonomic dysfunctions related to the VN. To better understand the complicated underlying mechanisms of the VN-GI tract neurophysiology, it is necessary to use an advanced device enabled by microfabrication technologies. Among several candidates including intraneural probe array and extraneural cuff electrodes, microchannel electrode array devices can be used to interface with smaller numbers of nerve fibers by securing them in the separate channel structures. Previous microchannel electrode array devices to interface teased nerve structures are relatively bulky with thickness around 200 µm. The thick design can potentially harm the delicate tissue structures, including the nerve itself. In this paper, we present a flexible thin film based microchannel electrode array device (thickness: 11.5 µm) that can interface with one of the subdiaphragmatic nerve branches of the VN in a rat. We demonstrated recording evoked compound action potentials (ECAP) from a transected nerve ending that has multiple nerve fibers. Moreover, our analysis confirmed that the signals are from C-fibers that are critical in regulating autonomic neurophysiology in the GI tract.

A Wearable Device Towards Automatic Detection and Treatment of Opioid Overdose.

Opioid-induced overdose is one of the leading causes of death among the US population under the age of 50. In 2021 alone, the death toll among opioid users rose to a devastating number of over 80,000. The overdose process can be reversed by the administration of naloxone, an opioid antagonist that rapidly counteracts the effects of opioid-induced respiratory depression. The idea of a closed-loop opioid overdose detection and naloxone delivery has emerged as a potential engineered solution to mitigate the deadly effects of the opioid epidemic. In this work, we introduce a wrist-worn wearable device that overcomes the portability issues of our previous work to create a closed-loop drug-delivery system, which includes (1) a Near-Infrared Spectroscopy (NIRS) sensor to detect a hypoxia-driven opioid overdose event, (2) a MOSFET switch, and (3) a Zero-Voltage Switching (ZVS) electromagnetic heater. Using brachial artery occlusion (BAO) with human subjects (n = 8), we demonstrated consistent low oxygenation events. Furthermore, we proved our device's capability to release the drug within 10 s after detecting a hypoxic event. We found that the changes in the oxyhemoglobin, deoxyhemoglobin and oxygenation saturation levels ( SpO2) were different before and after the low-oxygenation events ( 0.001). Although additional human experiments are needed, our results to date point towards a potential tool in the battle to mitigate the effects of the opioid epidemic.

Wearable Sensor Patch with Hydrogel Microneedles for In Situ Analysis of Interstitial Fluid.

Continuous real-time monitoring of biomarkers in interstitial fluid is essential for tracking metabolic changes and facilitating the early detection and management of chronic diseases such as diabetes. However, developing minimally invasive sensors for the in situ analysis of interstitial fluid and addressing signal delays remain a challenge. Here, we introduce a wearable sensor patch incorporating hydrogel microneedles for rapid, minimally invasive collection of interstitial fluid from the skin while simultaneously measuring biomarker levels in situ. The sensor patch is stretchable to accommodate the swelling of the hydrogel microneedles upon extracting interstitial fluid and adapts to skin deformation during measurements, ensuring consistent sensing performance in detecting model biomarker concentrations, such as glucose and lactate, in a mouse model. The sensor patch exhibits in vitro sensitivities of 0.024 ± 0.002 µA mM-1 for glucose and 0.0030 ± 0.0004 µA mM-1 for lactate, with corresponding linear ranges of 0.1-3 and 0.1-12 mM, respectively. For in vivo glucose sensing, the sensor patch demonstrates a sensitivity of 0.020 ± 0.001 µA mM-1 and a detection range of 1-8 mM. By integrating a predictive model, the sensor patch can analyze and compensate for signal delays, improving calibration reliability and providing guidance for potential optimization in sensing performance. The sensor patch is expected to serve as a minimally invasive platform for the in situ analysis of multiple biomarkers in interstitial fluid, offering a promising solution for continuous health monitoring and disease management.

Bionanotechnology and bioMEMS (BNM): state-of-the-art applications, opportunities, and challenges.

The development of micro- and nanotechnology for biomedical applications has defined the cutting edge of medical technology for over three decades, as advancements in fabrication technology developed originally in the semiconductor industry have been applied to solving ever-more complex problems in medicine and biology. These technologies are ideally suited to interfacing with life sciences, since they are on the scale lengths as cells (microns) and biomacromolecules (nanometers). In this paper, we review the state of the art in bionanotechnology and bioMEMS (collectively BNM), including developments and challenges in the areas of BNM, such as microfluidic organ-on-chip devices, oral drug delivery, emerging technologies for managing infectious diseases, 3D printed microfluidic devices, AC electrokinetics, flexible MEMS devices, implantable microdevices, paper-based microfluidic platforms for cellular analysis, and wearable sensors for point-of-care testing.

Analysis of the Status and Future Direction for Digital Therapeutics in Children and Adolescent Psychiatry.

Digital therapeutics based on software, such as artificial intelligence, virtual reality, games, and smartphone applications, are in the spotlight as new therapeutic alternatives in child and adolescent psychiatry. It draws attention to overcoming conventional therapeutics' limitations, such as toxicity, cost, and accessibility, and encourages patients to participate in the treatment attractively. The growth potential of the digital therapeutics market for psychiatric disorders in children and adolescents in Korea and abroad has been highlighted. Clinical studies and Food and Drug Administration approvals for digital therapeutics have increased, and cases approved by the Ministry of Food and Drug Safety have emerged in Korea. As seen above, digital transformation in child and adolescent psychiatry will change treatment paradigms significantly. Therefore, as this new field has just begun to emerge, it is necessary to verify the effectiveness and scope of the application of digital therapeutics and consider preparing a compensation system and institutional arrangements. Accordingly, this study analyzed the development trends and application status of digital therapeutics in children and adolescents and presented limitations and development directions from the perspective of application in healthcare. Further, the study is expected to identify the utility and limitations of digital therapeutics for children and adolescents and establish effective application measures.

Association between body composition and chronic low back pain in Korean adults aged over 50 years: The Korea National Health and Nutrition Examination Survey (KNHANES) 2010-2011.

Background The relationship between overweight or obesity and low back pain (LBP) has previously been investigated. Several recent studies have focused on the relationship between other indicators of obesity, particularly indicators of fat and the risk of LBP. However, the results of body composition and LBP have been inconsistent. Methods All data for the present retrospective, cross-sectional study was extracted from the Korea National Health and Nutrition Examination Survey (KNHANES) versions V-1 and 2 conducted in 2010 and 2011 by the Korean Centers for Disease Control and Prevention. In KNHANES V-1 (2010) and V-2 (2011), those over 50 years of age completed the surveys on LBP, body weight, and body composition assessed using dual-energy X-ray absorptiometry (DXA) were included. The multivariable logistic regression analysis was used to examine the relationship between the presence of chronic LBP and body composition adjusting for confounders. Results We analyzed 3,579 persons who completed the question. In the multivariable analyses adjusting for age and sex, none of the variables, including fat mass and fat-free mass, remained positively or negatively associated with LBP. Additionally, when depression, smoking, alcohol intake, physical activity, diabetes mellitus, and fat or lean tissue mass were included in the multivariable logistic model, no significant associations were found between all measures of fat mass, fat-free mass, and LBP Conclusion This study is contrary to previous studies that concluded that there is a correlation between obesity and fat mass and LBP. LBP is not associated with increased levels of obesity and fat mass.

Automatically detecting activities of daily living from in-home sensors as indicators of routine behaviour in an older population.

Objective: The NEX project has developed an integrated Internet of Things (IoT) system coupled with data analytics to offer unobtrusive health and wellness monitoring supporting older adults living independently at home. Monitoring involves visualising a set of automatically detected activities of daily living (ADLs) for each participant. ADL detection allows the incorporation of additional participants whose ADLs are detected without system re-training. Methods: Following a user needs and requirements study involving 426 participants, a pilot trial and a friendly trial of the deployment, an action research cycle (ARC) trial was completed. This involved 23 participants over a 10-week period each with ∼20 IoT sensors in their homes. During the ARC trial, participants took part in two data-informed briefings which presented visualisations of their own in-home activities. The briefings also gathered training data on the accuracy of detected activities. Association rule mining was used on the combination of data from sensors and participant feedback to improve the automatic ADL detection. Results: Association rule mining was used to detect a range of ADLs for each participant independently of others and then used to detect ADLs across participants using a single set of rules for each ADL. This allows additional participants to be added without the necessity of them providing training data. Conclusions: Additional participants can be added to the NEX system without the necessity to re-train the system for automatic detection of their ADLs.

Development of electrochemical Zn2+ sensors for rapid voltammetric detection of glucose-stimulated insulin release from pancreatic ß-cells.

Diabetes is a chronic disease characterized by elevated blood glucose levels resulting from absent or ineffective insulin release from pancreatic ß-cells. ß-cell function is routinely assessed in vitro using static or dynamic glucose-stimulated insulin secretion (GSIS) assays followed by insulin quantification via time-consuming, costly enzyme-linked immunosorbent assays (ELISA). In this study, we developed a highly sensitive electrochemical sensor for zinc (Zn2+), an ion co-released with insulin, as a rapid and low-cost method for measuring dynamic insulin release. Different modifications to glassy carbon electrodes (GCE) were evaluated to develop a sensor that detects physiological Zn2+ concentrations while operating within a biological Krebs Ringer Buffer (KRB) medium (pH 7.2). Electrodeposition of bismuth and indium improved Zn2+ sensitivity and limit of detection (LOD), and a Nafion coating improved selectivity. Using anodic stripping voltammetry (ASV) with a pre-concentration time of 6 min, we achieved a LOD of 2.3 µg/L over the wide linear range of 2.5-500 µg/L Zn2+. Sensor performance improved with 10-min pre-concentration, resulting in increased sensitivity, lower LOD (0.18 µg/L), and a bilinear response over the range of 0.25-10 µg/L Zn2+. We further characterized the physicochemical properties of the Zn2+ sensor using scanning electron microscopy (SEM), cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS). Finally, we demonstrated the sensor's capability to measure Zn2+ release from glucose-stimulated INS-1 ß-cells and primary mouse islets. Our results exhibited a high correlation with secreted insulin and validated the sensor's potential as a rapid alternative to conventional two-step GSIS plus ELISA methods.

Visualizing reactive astrocyte-neuron interaction in Alzheimer's disease using 11C-acetate and 18F-FDG.

Reactive astrogliosis is a hallmark of Alzheimer's disease (AD). However, a clinically validated neuroimaging probe to visualize the reactive astrogliosis is yet to be discovered. Here, we show that PET imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. To investigate the alterations of acetate and glucose metabolism in the diseased brains and their impact on the AD pathology, we adopted multifaceted approaches including microPET imaging, autoradiography, immunohistochemistry, metabolomics, and electrophysiology. Two AD rodent models, APP/PS1 and 5xFAD transgenic mice, one adenovirus-induced rat model of reactive astrogliosis, and post-mortem human brain tissues were used in this study. We further curated a proof-of-concept human study that included 11C-acetate and 18F-FDG PET imaging analyses along with neuropsychological assessments from 11 AD patients and 10 healthy control subjects. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD. The elevated acetate uptake is associated with reactive astrogliosis and boosts the aberrant astrocytic GABA synthesis when amyloid-ß is present. The excessive astrocytic GABA subsequently suppresses neuronal activity, which could lead to glucose uptake through decreased glucose transporter-3 in the diseased brains. We further demonstrate that 11C-acetate uptake was significantly increased in the entorhinal cortex, hippocampus and temporo-parietal neocortex of the AD patients compared to the healthy controls, while 18F-FDG uptake was significantly reduced in the same regions. Additionally, we discover a strong correlation between the patients' cognitive function and the PET signals of both 11C-acetate and 18F-FDG. We demonstrate the potential value of PET imaging with 11C-acetate and 18F-FDG by visualizing reactive astrogliosis and the associated neuronal glucose hypometablosim for AD patients. Our findings further suggest that the acetate-boosted reactive astrocyte-neuron interaction could contribute to the cognitive decline in AD.

Fractal Microelectrodes for More Energy-Efficient Cervical Vagus Nerve Stimulation.

Vagus nerve stimulation (VNS) has the potential to treat various peripheral dysfunctions, but the traditional cuff electrodes for VNS are susceptible to off-target effects. Microelectrodes may enable highly selective VNS that can mitigate off-target effects, but they suffer from the increased impedance. Recent studies on microelectrodes with non-Euclidean geometries have reported higher energy efficiency in neural stimulation applications. These previous studies use electrodes with mm/cm-scale dimensions, mostly targeted for myelinated fibers. This study evaluates fractal microelectrodes for VNS in a rodent model (N = 3). A thin-film device with fractal and circle microelectrodes is fabricated to compare their neural stimulation performance on the same radial coordinate of the nerve. The results show that fractal microelectrodes can activate C-fibers with up to 52% less energy (p = 0.012) compared to circle microelectrodes. To the best of the knowledge, this work is the first to demonstrate a geometric advantage of fractal microelectrodes for VNS in vivo.

Smart soft contact lenses for continuous 24-hour monitoring of intraocular pressure in glaucoma care.

Continuous monitoring of intraocular pressure, particularly during sleep, remains a grand challenge in glaucoma care. Here we introduce a class of smart soft contact lenses, enabling the continuous 24-hour monitoring of intraocular pressure, even during sleep. Uniquely, the smart soft contact lenses are built upon various commercial brands of soft contact lenses without altering their intrinsic properties such as lens power, biocompatibility, softness, transparency, wettability, oxygen transmissibility, and overnight wearability. We show that the smart soft contact lenses can seamlessly fit across different corneal curvatures and thicknesses in human eyes and therefore accurately measure absolute intraocular pressure under ambulatory conditions. We perform a comprehensive set of in vivo evaluations in rabbit, dog, and human eyes from normal to hypertension to confirm the superior measurement accuracy, within-subject repeatability, and user comfort of the smart soft contact lenses beyond current wearable ocular tonometers. We envision that the smart soft contact lenses will be effective in glaucoma care.

Shape Memory Polymer-Based Endovascular Devices: Design Criteria and Future Perspective.

Devices for the endovascular embolization of intracranial aneurysms (ICAs) face limitations related to suboptimal rates of lasting complete occlusion. Incomplete occlusion frequently leads to residual flow within the aneurysm sac, which subsequently causes aneurysm recurrence needing surgical re-operation. An emerging method for improving the rates of complete occlusion both immediately after implant and in the longer run can be the fabrication of patient-specific materials for ICA embolization. Shape memory polymers (SMPs) are materials with great potential for this application, owing to their versatile and tunable shape memory properties that can be tailored to a patient's aneurysm geometry and flow condition. In this review, we first present the state-of-the-art endovascular devices and their limitations in providing long-term complete occlusion. Then, we present methods for the fabrication of SMPs, the most prominent actuation methods for their shape recovery, and the potential of SMPs as endovascular devices for ICA embolization. Although SMPs are a promising alternative for the patient-specific treatment of ICAs, there are still limitations that need to be addressed for their application as an effective coil-free endovascular therapy.

Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma.

BACKGROUND: The PD-L1 antibody is an immune checkpoint inhibitor (ICI) attracting attention. The third-generation anticancer drug has been proven to be very effective due to fewer side effects and higher tumor-specific reactions than conventional anticancer drugs. However, as tumors produce additional resistance in the host immune system, the effectiveness of ICI is gradually weakening. Therefore, it is very important to develop a combination therapy that increases the anticancer effect of ICI by removing anticancer resistance factors present around the tumor. METHODS: The syngeneic model was used (n = 6) to investigate the enhanced anti-tumor effect of PD-L1 antibody with the addition of PLAG. MB49 murine urothelial cancer cells were implanted into the C57BL/6 mice subcutaneously. PLAG at different dosages (50/100 mpk) was daily administered orally for another 4 weeks with or without 5 mpk PD-L1 antibody (10F.9G2). PD-L1 antibody was delivered via IP injection once a week. RESULTS: The aPD-L1 monotherapy group inhibited tumor growth of 56% compared to the positive group, while the PLAG and aPD-L1 co-treatment inhibited by 89%. PLAG treatment effectively reduced neutrophils infiltrating localized in tumor and converted to a tumor microenvironment with anti-tumor effective T-cells. PLAG increased tumor infiltration of CD8 positive cytotoxic T-cell populations while effectively inhibiting the infiltration of neoplastic T-cells such as CD4/FoxP3. Eventually, neutrophil-induced tumor ICI resistance was resolved by restoring the neutrophil-to-lymphocyte ratio to the normal range. In addition, regulation of cytokine and chemokine factors that inhibit neutrophil infiltration and increase the killing activity of cytotoxic T cells was observed in the tumors of mice treated with PLAG + aPD-L1. CONCLUSIONS: PLAG effectively turned the tumor-promoting microenvironment into a tumor-suppressing microenvironment. As a molecule that increases the anti-tumor effectiveness of aPD-L1, PLAG has the potential to be an essential and effective ICI co-therapeutic agent.

PLAG co-treatment increases the anticancer effect of Adriamycin and cyclophosphamide in a triple-negative breast cancer xenograft mouse model.

Chemotherapy induces tumor cell death and inhibits tumor progression, but the accompanying immune responses in the surrounding dying tissue cause significant inflammation. These responses, such as excessive neutrophil infiltration into tumor tissue, are the main causes of resistance to anticancer treatment. The development of drugs that reduce neutrophil infiltration into tumors is necessary to increase the anticancer effect of chemotherapy. Here, we show that the antitumor effect of the chemotherapy AC regimen (Adriamycin and cyclophosphamide) was increased by 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) cotreatment in the MDA-MB-231 triple-negative breast cancer xenograft mouse model. Tumor growth was inhibited up to 56% in mice treated with AC and inhibited up to 94% in mice cotreated with AC and PLAG. Side effects of chemotherapy, such as a reduction in body weight, were alleviated in mice cotreated with AC and PLAG. Excessive neutrophil infiltration caused by the AC regimen was successfully cleared in mice cotreated with AC and PLAG. We conclude that PLAG inhibits excessive neutrophil infiltration that aids tumor growth. Reduced neutrophils and increased lymphocytes in PLAG-treated mice can maximize the antitumor effect of the AC regimen and inhibit tumor growth.

Suppression of tumor progression by thioredoxin-interacting protein-dependent adenosine 2B receptor degradation in a PLAG-treated Lewis lung carcinoma-1 model of non-small cell lung cancer.

Extracellular adenosine in the tumor microenvironment plays a vital role in cancer development. Specifically, activation of adenosine receptors affects tumor cell growth and adenosine release. We examined the anti-tumor efficacy of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) in animal models, revealing the role of PLAG in inhibiting tumor progression by promoting the degradation of adenosine 2B receptors (A2BRs) in tumors. PLAG induced the expression of thioredoxin-interacting protein (TXNIP), a type of α-arrestin that accelerates A2BR internalization by interacting with A2BR complexes containing ß-arrestin. Engulfed receptors bound to TXNIP were rapidly degraded after E3 ligase recruitment and ubiquitination, resulting in early termination of intracellular signals that promote tumor overgrowth. However, in control cancer cells, A2BRs bound to protein phosphatase 2A and were returned to the cell membrane instead of being degraded, resulting in continuous receptor-mediated signaling by pathways including the Raf-Erk axis, which promotes tumor proliferation. A TXNIP-silenced cell-implanted mouse model and TXNIP knockout (KO) mice were used to verify that PLAG-mediated suppression of tumor progression is dependent on TXNIP expression. Increased tumor growth was observed in TXNIP-silenced cell-implanted mice, and the anti-tumor effects of PLAG, including delayed tumor overgrowth, were greatly reduced. However, the anti-tumor effects of PLAG were observed in cancer cell-implanted TXNIP-KO mice, which indicates that PLAG produces anti-tumor effects by enhancing TXNIP expression in tumor cells. These essential functions of PLAG, including delaying tumor growth via A2BR degradation, suggest innovative directions for anticancer drug development.