Comprehensive transcriptome and scRNA-seq analyses uncover the expression and underlying mechanism of SYNJ2 in papillary thyroid carcinoma.

Synaptojanin 2 (SYNJ2) has crucial role in various tumors, but its role in papillary thyroid carcinoma (PTC) remains unexplored. This study first detected SYNJ2 protein expression in PTC using immunohistochemistry method and further assessed SYNJ2 mRNA expression through mRNA chip and RNA sequencing data and its association with clinical characteristics. Additionally, KEGG, GSVA, and GSEA analyses were conducted to investigate potential biological functions, while single-cell RNA sequencing data were used to explore SYNJ2's underlying mechanisms in PTC. Meanwhile, immune infiltration status in different SYNJ2 expression groups were analyzed. Besides, we investigated the immune checkpoint gene expression and implemented drug sensitivity analysis. Results indicated that SYNJ2 is highly expressed in PTC (SMD = 0.66 [95% CI: 0.17-1.15]) and could distinguish between PTC and non-PTC tissues (AUC = 0.74 [0.70-0.78]). Furthermore, the study identified 134 intersecting genes of DEGs and CEGs, mainly enriched in the angiogenesis and epithelial-mesenchymal transition (EMT) pathways. Subsequent analysis showed the above pathways were activated in PTC epithelial cells. PTC patients with high SYNJ2 expression showed higher sensitivity to the six common drugs. Summarily, SYNJ2 may promote PTC progression through angiogenesis and EMT pathways. High SYNJ2 expression is associated with better response to immunotherapy and chemotherapy.

Affinity-based 3D-printed microfluidic chip for clinical sepsis detection with CD69, CD64, and CD25.

Sepsis is a life-threatening immune response to infection in the body, eventually resulting in fatal organ failure. Current methods utilize blood cultures and quick-Sequential-Organ-Failure-Assessment (qSOFA), but there is a need for more accurate and time-sensitive diagnostic methods to improve survival rates. We present a 3D-printed microfluidic chip that bioconjugates antibodies CD69, CD64, and CD25 to channel surfaces to capture sepsis cells in blood samples and validate it with clinical samples (n = 125 septic, n = 10 healthy). Other variables were taken such as healthy volunteer blood samples and patient demographics to validate and confirm our device's diagnostic ability. Statistical differences were found between healthy volunteer and sepsis patient antigen cell counts (CD69 p-value < 0.001, CD64 p-value < 0.004, CD25 p-value < 0.0009), and were confirmed using principal component analysis. Demographics such as length of stay, age, culture results, and need for surgery also factored into sepsis detection on a smaller scale than the antigen cell counts. The receiver operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.989, 0.988, and 0.992 for CD69, CD64, and CD25, respectively, and a combined biomarker panel of 0.997. Overall, the device performed within a shorter time frame of 4 h compared to standard blood culture tests and was validated for use in detecting sepsis in patients.

Multifunctional EGCG@ZIF-8 Nanoplatform with Photodynamic Therapy/Chemodynamic Therapy Antibacterial Properties Promotes Infected Wound Healing.

Damaged skin is susceptible to invasion by harmful microorganisms, especially Staphylococcus aureus and Escherichia coli, which can delay healing. Epigallocatechin-3-gallate (EGCG) is a natural compound known for effectively promoting wound healing and its potent anti-inflammatory effects. However, its application is limited due to its susceptibility to oxidation and isomerization, which alter its structure. The use of zeolitic imidazolate framework-8 (ZIF-8) can effectively tackle these issues. This study introduces an oxygen (O2) and hydrogen peroxide (H2O2) self-supplying ZIF-8 nanoplatform designed to enhance the bioavailability of EGCG, combining photodynamic therapy (PDT) and chemodynamic therapy (CDT) to improve antibacterial properties and ultimately accelerate wound healing. For this purpose, EGCG and indocyanine green (ICG), a photosensitizer, were successively integrated into a ZIF-8, and coated with bovine serum albumin (BSA) to enhance biocompatibility. The outer layer of this construct was further modified with manganese dioxide (MnO2) to promote CDT and calcium peroxide (CaO2) to supply H2O2 and O2, resulting in the final nanoplatform EGCG-ICG@ZIF-8/BSA-MnO2/CaO2 (EIZBMC). In in vitro experiments under 808 nm laser, EIZBMC exhibited synergistic antibacterial effects through PDT and CDT. This combination effectively released reactive oxygen species (ROS), which mediated oxidative stress to inhibit the bacteria. Subsequently, in a murine model of wound infection, EIZBMC not only exerted antibacterial effects through PDT and CDT but also alleviated the inflammatory condition and promoted the regeneration of collagen fibers, which led to accelerated wound healing. Overall, this research presents a promising approach to enhancing the therapeutic efficacy of EGCG by leveraging the synergistic antibacterial effects of PDT and CDT. This multifunctional nanoplatform maximizes EGCG's anti-inflammatory properties, offering a potent solution for promoting infected wound healing.

Anti-tumor withanolides as signal transducers and activators of transcription 3 (STAT3)-inhibition from Withania obtusifolia.

The Solanaceae family and the Withania genus specifically are rich sources of medicinal plants. Liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS/MS) revealed a predominance of withanolides from an organic extract of Withania obtusifolia. A constructed molecular network uncovered the presence of potentially novel withanolides. A series of withanolides were then isolated and structurally characterized from the extract including two new withanolides (withafolia A and withafolia B) and seven previously reported metabolites. Of the isolated compounds, cytotoxicity of withanolide J, physaperuvin G, and a commercial STAT3 inhibitor (S3I-201) were assessed against a human leukemia HL-60 cell line resulting in IC50 values of 26, 29, and 120 µM, respectively. In silico molecular docking simulations indicate that withanolide J and physaperuvin G can bind as an inhibitor in the active site of STAT3 with docking scores comparable to the selective STAT3 inhibitor, S3I-201.

Magnetically controlled quantum thermal devices via three nearest-neighbor coupled spin-1/2 systems.

A quantum thermal device based on three nearest-neighbor coupled spin-1/2 systems controlled by the magnetic field is proposed. We systematically study the steady-state thermal behaviors of the system. When the two terminals of our system are in contact with two thermal reservoirs, respectively, the system behaves as a perfect thermal modulator that can manipulate heat current from zero to specific values by adjusting magnetic-field direction over different parameter ranges, since the longitudinal magnetic field can completely block the heat transport. Significantly, the modulator can also be achieved when a third thermal reservoir perturbs the middle spin. We also find that the transverse field can induce the system to separate into two subspaces in which neither steady-state heat current vanishes, thus providing an extra level of control over the heat current through the manipulation of the initial state. In addition, the performance of this device as a transistor can be enhanced by controlling the magnetic field, achieving versatile amplification behaviors, in particular substantial amplification factors.

Quantum heat valve and diode of strongly coupled defects in amorphous material.

The mechanical strain can control the frequency of two-level atoms in amorphous material. In this work, we would like to employ two coupled two-level atoms to manipulate the magnitude and direction of heat transport by controlling mechanical strain to realize the function of a thermal switch and valve. It is found that a high-performance heat diode can be realized in the wide piezo voltage range at different temperatures. We also discuss the dependence of the rectification factor on temperatures and couplings of heat reservoirs. We find that the higher temperature differences correspond to the larger rectification effect. The asymmetry system-reservoir coupling strength can enhance the magnitude of heat transfer, and the impact of asymmetric and symmetric coupling strength on the performance of the heat diode is complementary. It may provide an efficient way to modulate and control heat transport's magnitude and flow preference. This work may give insight into designing and tuning quantum heat machines.

In vitro and in vivo antimicrobial effects of domiphen combined with itraconazole against Aspergillus fumigatus.

Aspergillus fumigatus, a prevalent saprophytic fungus in the atmosphere, is known to rapidly induce severe invasive aspergillosis (IA) upon inhalation of its conidia by humans or animals. The mortality rate associated with IA exceeds 50%. The misuse of antifungal agents has contributed to the emergence of numerous highly pathogenic drug-resistant strains of A. fumigatus. Our study found that the combination of domiphen and itraconazole had sound synergistic antimicrobial effects against wild-type and itraconazole-resistant A. fumigatus in vivo and in vitro through MIC, FIC, plate inoculation, growth curve experiments, and Galleria mellonella infection model. Drug cytotoxicity and pharmacological tests for acute toxicity assays demonstrated that both itraconazole and domiphen showed minimal cytotoxicity and good biocompatibility. The transcriptome sequencing experiment demonstrated that domiphen exerted a suppressive effect on the expression of various genes, including those involved in drug efflux, redox regulation, and cellular membrane and cell wall remodeling. The present investigation explores the synergistic antimicrobial mechanisms of domiphen and itraconazole, encompassing three key aspects: (i) domiphen inhibited the efflux of itraconazole by reducing the expression of drug efflux-related genes, (ii) the combination has good ability to disrupt the cell membrane and cell wall, (iii) the combination also can remove biofilm more effectively. In summary, the utilization of domiphen as a synergist of itraconazole exhibited disruptive effects on the biofilm, cell wall, and cell membrane of A. fumigatus. This subsequently led to a modified distribution of itraconazole within the fungal organism, ultimately resulting in enhanced antifungal efficacy. The results of this study may provide a new therapeutic strategy for the treatment of IA caused by drug-resistant A. fumigatus.

Dose-Response Meta-Analysis on Risk of Diabetes in Relation to Red and Processed Meat Consumption - Asian Populations, 2006-2021.

What is already known about this topic?: Red and processed meat consumption has been positively related to an increased risk of diabetes in Western populations. However, the results remain inconclusive within Asian populations. What is added by this report?: This dose-response meta-analysis of prospective cohort studies conducted in East Asian populations reveals a positive relation between the consumption of processed meat and increased risk of diabetes. Furthermore, a U-shaped association was identified between the consumption of unprocessed red meat and the risk of diabetes. What are the implications for public health practice?: This research presents substantive evidence advocating for the reduction of processed and unprocessed red meat consumption as a viable strategy for mitigating the risk of diabetes in East Asian populations.

Measurement of carbon effect in land consolidation projects and evaluation of low-carbon promotion paths: a case study of Wudi County, Shandong Province, China.

Against the backdrop of China's "double carbon" objective, the exploration of low-carbon land consolidation has become a prominent area of focus for enhancing the development of ecological civilization. In this study, three typical projects at different time points (2016, 2019, and 2022) in Wudi County were selected to measure the carbon effect of land consolidation from four perspectives: artificial and industrial materials, mechanical shift consumption, land use structure, and farmland ecosystem. Based on the calculation of carbon effect of land consolidation by using carbon emission coefficient method, the changes of land use structure and carbon storage of farmland ecosystem before and after land consolidation were corrected by using GIS tools and net ecosystem productivity (NEP) model based on remote sensing technology, and the carbon emission intensity of each land consolidation project was finally obtained. The study summarized the influencing factors of carbon emissions through the above analysis and uses the fuzzy interpretation structure (FISM) model to provide the hierarchy of influencing factors of carbon emissions, thus proposing a low-carbon promotion path for land consolidation. The findings of this study can serve as a useful reference for low-carbon land consolidation efforts. The results showed that (1) the first, second, and third projects emitted 6140.06 t, 1243.78 t, and 17,604.62 t of carbon, respectively. Among them, the largest contributors to these emissions were labor and industrial materials, followed by mechanical shift; land use structure and farmland ecosystem were the main sources of carbon sinks and have a positive impact on the carbon cycle. (2) The carbon emission intensity of project one, project two, and project three after standardization is 0.26, 0.49, and 0.25, respectively, which are all at a high level. (3) According to the FISM model categorized 15 low-carbon upgrading paths, it was recommended that the government take a leading role in Wudi County by developing a scientific and rational construction plan. Additionally, efforts were made to actively protect farmland and forest land from destruction, reduce energy and material consumption, increase carbon storage in the farmland ecosystem, and promote low carbonization of land consolidation to the fullest extent possible.

Combined CD25, CD64, and CD69 Biomarker in 3D-Printed Multizone Millifluidic Device for Sepsis Detection in Clinical Samples.

Sepsis is a serious medical condition that arises from a runaway response to an infection, which triggers the immune system to release chemicals into the bloodstream. This immune response can result in widespread inflammation throughout the body, which may cause harm to vital organs and, in more severe cases, lead to organ failure and death. Timely and accurate diagnosis of sepsis remains a challenge in analytical diagnostics. In this work, we have developed and validated a sepsis detection device, utilizing 3D printing technology, which incorporates multiple affinity separation zones. Our device requires minimal operator intervention and utilizes CD64, CD69, and CD25 as the biomarker targets for detecting sepsis in liquid biopsies. We assessed the effectiveness of our 3D-printed multizone cell separation device by testing it on clinical samples obtained from both septic patients (n = 35) and healthy volunteers (n = 8) and validated its performance accordingly. Unlike previous devices using poly(dimethyl siloxane), the 3D-printed device had reduced nonspecific binding for anti-CD25 capture, allowing this biomarker to be assayed for the first time in cell separations. Our results showed a statistically significant difference in cell capture between septic and healthy samples (with p values of 0.0001 for CD64, CD69, and CD25), suggesting that 3D-printed multizone cell capture is a reliable method for distinguishing sepsis. A receiver operator characteristic (ROC) analysis was performed to determine the accuracy of the captured cell counts for each antigen in detecting sepsis. The ROC area under the curve (AUC) values for on-chip detection of CD64+, CD69+, and CD25+ leukocytes were 0.96, 0.92, and 0.88, respectively, indicating our diagnostic test matches clinical outcomes. When combined for sepsis diagnosis, the AUC value for CD64, CD69, and CD25 was 0.99, indicating an improved diagnostic performance due to the use of multiple biomarkers.

Quantum thermal diode dominated by pure classical correlation via three triangular-coupled qubits.

A quantum thermal diode is designed based on three pairwise coupled qubits, two connected to a common reservoir and the other to an independent reservoir. It is found that the internal couplings between qubits can enhance heat currents. If the two identical qubits uniformly couple with the common reservoir, the crossing dissipation will occur, leading to the initial-state-dependent steady state, which can be decomposed into the mixture of two particular steady states: the heat-conducting state generating maximum heat current and the heat-resisting state not transporting heat. However, the rectification factor doesn't depend on the initial state. In particular, we find that neither quantum entanglement nor quantum discord is present in the steady state, but the pure classical correlation shows a remarkably consistent behavior as the heat rectification factor, which reveals the vital role of classical correlation in the system.

Isolation of Cancer Cells from Liquid Biopsies Using 3D-Printed Affinity Devices.

Liquid biopsies are examination procedures for deciding the grouping of malignant growth cells tracked down in samples of blood and other body fluids. Liquid biopsies are likewise significantly less intrusive than tissue biopsies as they just require small amount of blood or body fluids from the patient. With the utilization of microfluidics, cancer cells can be isolated from the fluid biopsy and achieve early diagnosis. 3D printing is turning out to be progressively well known for microfluidic devices creation. 3D printing has shown multiple advantages compared to traditional microfluidic devices production, including effortless large-scale manufacturing of precise copies, the fuse of new materials, and execution of additional complicated or drawn-out plans that are hard to execute in conventional microfluidic devices. Combining 3D printing with microfluidics makes for a relatively inexpensive analysis of liquid biopsies with a chip that can be more advantageous to use over traditional microfluidic chips. In this chapter, a method for affinity-based separation of cancer cells in a liquid biopsy using a 3D microfluidic chip will be discussed, along with the rationale behind the method.

Quantum heat diode versus light emission in circuit quantum electrodynamical system.

Precisely controlling heat transfer in a quantum mechanical system is particularly significant for designing quantum thermodynamical devices. With the technology of experiment advances, circuit quantum electrodynamics (circuit QED) has become a promising system due to controllable light-matter interactions as well as flexible coupling strengths. In this paper, we design a thermal diode in terms of the two-photon Rabi model of the circuit QED system. We find that the thermal diode can not only be realized in the resonant coupling but also achieve better performance, especially for the detuned qubit-photon ultrastrong coupling. We also study the photonic detection rates and their nonreciprocity, which indicate similar behaviors with the nonreciprocal heat transport. This provides the potential to understand thermal diode behavior from the quantum optical perspective and could shed new insight into the relevant research on thermodynamical devices.

Analysis of the implementation effects of ecological restoration projects based on carbon storage and eco-environmental quality: A case study of the Yellow River Delta, China.

As an important means to address global climate change and land-use/land-cover (LULC) change, ecological restoration projects (ERPs) have a large effect on carbon storage functions and eco-environmental quality. However, the various ERPs carried out in the Yellow River Delta region have important implications for ecological security strategies in China. Therefore, based on land-use data and remote sensing image data, with the help of ArcGIS and Google Earth Engine (GEE) platforms, this study uses the Integrated Valuation of Ecosystem Services and Trade-offs (InVEST) model, an improved remote sensing ecological index (RSEI) model and other methods to deeply examine the evolutionary trends of eco-environmental quality and carbon storage during the implementation of ERPs in the Yellow River Delta and selects key implementation areas for in-depth analysis to determine the implementation effects of ERPs. Our findings suggested that the RSEI and carbon storage levels in the study area had opposite evolutionary trends from 2001 to 2020. Among them, the RSEI showed a fluctuating upwards trend (0.4461 (2001) and 0.5185 (2020)), while the total carbon stock showed a fluctuating downwards trend (30.67 Tg (2001) and 26.40 Tg (2020)). However, from 2015 to 2020, the RSEI and carbon storage were at a relatively stable level, which indirectly indicated that the ERPs carried out during the period from 2015 to 2020 had achieved a good comprehensive implementation effect. In addition, the areas with better improvement effects from 2015 to 2020 were primarily located in the mouth of the Yellow River Delta (Areas C and D), and their RSEI and the total carbon stock showed a certain upwards trend. This research can promote the formulation of the management strategy of ERPs in the Yellow River Delta, which is of tremendous importance to the ecological environmental preservation and high-quality development of the Yellow River Basin.

High-recovery sorting of cancer cells from whole blood via periodic-focusing inertial microchip.

Inertial microfluidic devices continue to show promise for label-free separation of cells from liquid biopsies and other biological samples. Serpentine-channel microfluidic devices capitalizing on inertial forces such as Dean flow have been demonstrated for cell separation, but are limited in performance due to the magnitude of the inertial lift and drag force gradients across the separation channel. We have developed a new flow design that uses periodic channel contractions to enhance the magnitude of the force gradient. Separation recover was 97% with the final sorter output consisting of 78% target cells. Separation efficiency was 87% for whole blood, which could be increased to 97% if the sample was diluted prior to sorting. The enrichment of cancer cells was over 1000-fold, and sorted cancer cells maintained a viability of 93.8% for 96 hours after sorting. In the analysis of blood plasma, breast cancer cells from a clinical patient were enriched 20×. The incorporation of periodic channel contractions in a Dean flow circuit resulted in an increase in Dean flow gradient according to simulation, resulting in sorting of small-diameter cancer cells in blood samples.

Monitoring spatiotemporal characteristics of land-use carbon emissions and their driving mechanisms in the Yellow River Delta: A grid-scale analysis.

Comprehensive and accurate grasp of land-use carbon emissions (LCE) level and its driving mechanism is key to success in China's pursuit of low-carbon development, and it is also the scientific basis for the formulation and implementation of regional carbon emissions strategies. Based on fossil fuel carbon emissions raster data (published by the Open-Data Inventory for Anthropogenic Carbon dioxide (ODIAC) platform) and land use data, this manuscript selects the Yellow River Delta as the study area and uses an improved LCE measurement model, exploratory spatial data analysis, multiscale geographical weighting regression (MGWR), and other models to explore the spatiotemporal heterogeneity and driving mechanisms of LCE at the grid level. The results showed the following: ① The total amount of LCE in the study area continued to increase from 2000 to 2019, the growth rate decreased, but the peak of LCE had not yet been reached. ② The LCE of the study area showed a significant positive global autocorrelation. The H-H aggregation region showed a relatively stable spatial distribution range; the L-L aggregation region showed wide distribution characteristics that covered the entire study area; and the aggregation regions of H-L and L-H, which have not yet reached the scale. ③ At the global dimension, the mean correlation coefficients between LCE and driving factors (net primary productivity (NPP), nighttime light (NTL), and population density (PD)) from 2000 to 2019 were -0.11, 0.28, and 0.12; at the local dimension, the strength (from strong to weak) of the effect of each factor on LCE was PD, NTL, NPP (2000) and NTL, PD, NPP (2019). The research results provide a scientific basis and basic guarantee for the development, and implementation of regional carbon emission strategies.

Piperlongumine Inhibits Thioredoxin Reductase 1 by Targeting Selenocysteine Residues and Sensitizes Cancer Cells to Erastin.

Piperlongumine, a natural alkaloid substance extracted from the fruit of the long pepper (Piper longum Linn.), is known to inhibit the cytosolic thioredoxin reductase (TXNRD1 or TrxR1) and selectively kill cancer cells. However, the details and mechanism of the inhibition by piperlongumine against TXNRD1 remain unclear. In this study, based on the classical DTNB reducing assay, irreversible inhibition of recombinant TXNRD1 by piperlongumine was found and showed an apparent kinact value of 0.206 × 10-3 µM-1 min-1. Meanwhile, compared with the wild-type TXNRD1 (-GCUG), the UGA-truncated form (-GC) of TXNRD1 was resistant to piperlongumine, suggesting the preferential target of piperlongumine is the selenol (-SeH) at the C-terminal redox motif of the enzyme. Interestingly, the high concentration of piperlongumine-inhibited TXNRD1 showed that its Sec-dependent activity is decayed but its intrinsic NADPH oxidase activity is retained. Furthermore, piperlongumine did not induce ferroptosis in HCT116 cells at 10 µM, whereas significantly promoted erastin-induced lipid oxidation, which could be alleviated by supplying glutathione (GSH) or N-acetyl L-cysteine (NAC). However, restricting GSH synthesis by inhibiting glutaminase (GLS) using the small molecule inhibitor CB-839 only slightly enhanced erastin-induced cell death. Taken together, this study elucidates the molecular mechanism of the antitumor capacity of piperlongumine by targeting TXNRD1 and reveals the potential possibility of inhibiting TXNRD1 to strengthen cancer cells' ferroptosis.

Microfluidic technology and its application in the point-of-care testing field.

Since the outbreak of the coronavirus disease 2019 (COVID-19), countries around the world have suffered heavy losses of life and property. The global pandemic poses a challenge to the global public health system, and public health organizations around the world are actively looking for ways to quickly and efficiently screen for viruses. Point-of-care testing (POCT), as a fast, portable, and instant detection method, is of great significance in infectious disease detection, disease screening, pre-disease prevention, postoperative treatment, and other fields. Microfluidic technology is a comprehensive technology that involves various interdisciplinary disciplines. It is also known as a lab-on-a-chip (LOC), and can concentrate biological and chemical experiments in traditional laboratories on a chip of several square centimeters with high integration. Therefore, microfluidic devices have become the primary implementation platform of POCT technology. POCT devices based on microfluidic technology combine the advantages of both POCT and microfluids, and are expected to shine in the biomedical field. This review introduces microfluidic technology and its applications in combination with other technologies.

Thioredoxin reductase 1 inhibitor shikonin promotes cell necroptosis via SecTRAPs generation and oxygen-coupled redox cycling.

Shikonin, a naturally occurring naphthoquinone with potent anti-tumor activity, has been reported to induce cancer cell death via targeting selenoenzyme thioredoxin reductase 1 (TrxR1; TXNRD1). However, the interaction between shikonin and TrxR1 remains unclear, and the roles of the cellular antioxidant system in shikonin induced cell death are obscure. Here, we found that shikonin modified the Sec498 residue of TrxR1 to fully inhibit its antioxidant activity, however, the shikonin-modified TrxR1 still remained intrinsic NADPH oxidase activity, which promotes superoxide anions production. Besides, TrxR1 efficiently reduced shikonin in both selenocysteine dependent and selenocysteine independent manners, and the oxygen-coupled redox cycling of shikonin also generates excessive superoxide anions. The inhibitory effects and the redox cycling of shikonin towards TrxR1 caused cancer cell ROS-dependent necroptosis. Interestingly, as we evaluated, some cancer cell lines were insensitive to shikonin, especially kelch-like ECH associated protein 1 (KEAP1)-mutant non-small cell lung cancer (NSCLC) cells, which harbor constitutive activation of the nuclear factor-erythroid 2-related factor 2 (NRF2). NADPH bankruptcy caused by glucose starvation or glucose limitation (inhibiting glucose transporter 1 by BAY-876) could efficiently overcome the resistance of KEAP1-mutant NSCLC cells to shikonin. Glucose-6-phosphate dehydrogenase (G6PD), was known as a rate-limiting enzyme in the pentose phosphate pathway, however, the pharmacological inhibition of G6PD by 6-aminonicotinamide (6-AN), enhanced the shikonin-induced cytotoxicity but has no selectivity on KEAP1-mutant NSCLC cells. This study will be helpful in applying shikonin for potential chemotherapy, and in combinational treatment of KEAP1-mutant NSCLC.

Plumbagin reduction by thioredoxin reductase 1 possesses synergy effects with GLUT1 inhibitor on KEAP1-mutant NSCLC cells.

Thioredoxin reductase 1 (TrxR1 or TXNRD1) is a major enzyme in cellular redox regulation and is considered as a drug target for cancer therapy. Previous studies have reported that plumbagin caused reactive oxygen species (ROS)-dependent apoptosis via inhibiting TrxR1 activity or being reduced by TrxR1, leading to selectively cancer cell death. However, the mechanism of TrxR1-mediated redox cycling of plumbagin is obscure and the evidence for plumbagin targeting TrxR1 is still lacking. Herein, we demonstrated that TrxR1 catalyzed plumbagin reduction in both selenocysteine (Sec)-dependent and independent manners, and its activity relied on the intact N-terminal motif of TrxR1, but a high-efficiency reduction was supported by the C-terminal thiols. During the redox cycling of plumbagin, excessive ROS production was observed coupled with oxygen. Using LC-MS and TrxR1 mutants, we found that the Sec residue of TrxR1 was modified by plumbagin, which converted the enzyme from antioxidant to pro-oxidant. Furthermore, we evaluated the therapeutic potential of plumbagin in non-small cell lung cancer (NSCLC), and found that Kelch-like ECH-associated protein 1 (KEAP1)-mutant NSCLC cells, which possess constitutive nuclear factor erythroid 2-related factor 2 (NRF2) activity, were insensitive to plumbagin; however, inhibition of glucose transporter 1 (GLUT1) by small-molecule BAY-876 or inhibiting glucose-6-phosphate dehydrogenase (G6PD) by 6-aminonicotinamide (6-AN) overcame the plumbagin-resistance of KEAP1-mutant NSCLC cells. Taken together, this study elucidated the pharmacological mechanism of plumbagin by targeting TrxR1 and revealed the synergy effect of plumbagin and BAY-876, which may be helpful for applying naphthoquinone compounds to chemotherapy, particularly for treating KEAP1-mutant NSCLC cells.