Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer.

Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial antitumor activity followed by recurrence due to cancer cell-intrinsic and immune-mediated paracrine mechanisms. Here, we explored the potential role of cancer-associated fibroblasts (CAFs) in enabling KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2 and ERBB3 receptor tyrosine kinases as a mechanism by which KRAS*-independent growth is supported. Genetic extinction or pharmacological inhibition of KRAS* resulted in up-regulation of ERBB2 and ERBB3 expression in human and murine models, which prompted cancer cell utilization of CAF-derived NRG1 as a survival factor. Genetic depletion or pharmacological inhibition of ERBB2/3 or NRG1 abolished KRAS* bypass and synergized with KRASG12D inhibitors in combination treatments in mouse and human PDAC models. Thus, we found that CAFs can contribute to KRAS* inhibitor therapy resistance via paracrine mechanisms, providing an actionable therapeutic strategy to improve the effectiveness of KRAS* inhibitors in PDAC patients.

NRF2 regulates EGF stability through OTUD4 in lung adenocarcinoma.

NRF2 (NFE2L2) is a transcription factor mainly for regulating cellular antioxidant response and therefore promotes tumor progression. The target genes of NRF2 also play important roles in cellular processes including glucose metabolism, de novo serine synthesis, iron metabolism, etc. Here, by modulating NRF2 expression in lung adenocarcinoma (LUAD) cells, we showed that NRF2 regulated EGF expression at protein level. Furthermore, EGF was identified as a ubiquitinated protein. We predicted three deubiquitinases of EGF, and OTUD4 had the highest correlation with NRF2 in LUAD among the three. OTUD4 expression was reduced upon NRF2 knocking-down and recovered upon NRF2 rescuing in A549 cells. Then a potential binding site for NRF2 in OTUD4 promoter was searched out. By binding with OTUD4 promoter, NRF2 transcriptionally activated OTUD4, thus promoted EGF deubiquitination and enhanced its stability. More importantly, OTUD4 and NRF2 expression was found being correlated in LUAD patients. The data collectively revealed a novel mechanism of NRF2 regulating on EGF stability through OTUD4 in LUAD.

Comparison of Different Competitive Proteome Profiling Approaches in Target Identification of Covalent Inhibitors.

Competitive proteome profiling is a powerful approach for the identification of targets of small molecules. This approach usually employs an inhibitor-derived probe or a cysteine-reactive probe such as an IA-alkyne in a comparison between inhibitor-treated and untreated samples, thus enabling distinction between genuine targets and nonspecific labeling. We have developed an active probe derived from an EGFR inhibitor, afatinib, and a cysteine reactive probe, an alkyne-containing α,ß-unsaturated amide, to compare their characterization of cellular targets. In both approaches, myosin heavy chain 9 (MYH9) was identified as an off-target. Subsequent functional validation experiments suggested that MYH9 might be involved in the function of afatinib.

Anticoagulation for coexisting bioprosthetic aortic valve thrombosis and anticoagulant-related bleeding: "A double edge sword".

The choice of anticoagulant agents for newly implanted bioprosthetic valve varies significantly, particularly in the presence of postoperative atrial fibrillation with increasing use of nonvitamin K oral anticoagulation (NOACs) in recent years. We reported a challenging case with a coexisting bioprosthetic aortic valve thrombosis and significant anticoagulant-related bleeding. Clinical management strategy and brief literature review were presented.

5-Caffeoylquinic acid ameliorates oxidative stress-mediated cell death via Nrf2 activation in hepatocytes.

CONTEXT: 5-Caffeoylquinic acid (5-CQA) is one of the most abundant compounds found in natural foods including coffee. OBJECTIVE: We investigated whether 5-CQA had a cytoprotective effect through the NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) signalling pathway. MATERIALS AND METHODS: Nrf2 activation in response to 5-CQA treatment at the concentration of 10-100 µM is evaluated by Western blotting of Nrf2 and ARE reporter gene assay as well as its target gene expression in HepG2 cells. Intracellular reactive oxygen species (ROS) and glutathione (GSH) levels were measured in the tert-butyl hydroperoxide-induced hepatocytes to examined cytoprotective effect of 5-CQA (10-100 µM). The specific role of 5-CQA on Nrf2 activation was examined using Nrf2 knockout cells or Nrf2 specific inhibitor, ML-385. RESULTS: Nuclear translocation of Nrf2 is increased by 5-CQA in HepG2 cells which peaked at 6 h. Consequently, 5-CQA significantly increases the ARE reporter gene activity and downstream antioxidant proteins, including glutamate cysteine ligase (GCL), hemeoxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1, and Sestrin2. Nrf2 deficiency or inhibition completely antagonized ability of 5-CQA to induce HO-1 and GCL expression. Cells pre-treated with 5-CQA were rescued from tert-butyl hydroperoxide-induced ROS production and GSH depletion. Nrf2 activation by 5-CQA was due to increased phosphorylation of MAPKs, AMPK and PKCδ. DISCUSSION AND CONCLUSIONS: Taken together, our results demonstrate that as a novel Nrf2 activator, 5-CQA, may be a promising candidate against oxidative stress-mediated liver injury. Additional efforts are needed to assess 5-CQA, as a potential therapeutic in liver diseases in vivo and in humans.

Coronary artery assessment using self-navigated free-breathing radial whole-heart magnetic resonance angiography in patients with congenital heart disease.

OBJECTIVES: To evaluate a self-navigated free-breathing three-dimensional (SNFB3D) radial whole-heart MRA technique for assessment of main coronary arteries (CAs) and side branches in patients with congenital heart disease (CHD). METHODS: SNFB3D-MRA datasets of 109 patients (20.1±11.8 years) were included. Three readers assessed the depiction of CA segments, diagnostic confidence in determining CA dominance, overall image quality and the ability to freeze cardiac and respiratory motion. Vessel sharpness was quantitatively measured. RESULTS: The percentages of cases with excellent CA depiction were as follows (mean score): left main, 92.6 % (1.92); left anterior descending (LAD), 88.3 % (1.88); right (RCA), 87.8 % (1.85); left circumflex, 82.8 % (1.82); posterior descending, 50.2 % (1.50) and first diagonal, 39.8 % (1.39). High diagnostic confidence for the assessment of CA dominance was achieved in 56.2 % of MRA examinations (mean score, 1.56). Cardiac motion freezing (mean score, 2.18; Pearson's r=0.73, P<0.029) affected image quality more than respiratory motion freezing (mean score, 2.20; r=0.58, P<0.029). Mean quantitative vessel sharpness of the internal thoracic artery, RCA and LAD were 53.1, 52.5 and 48.7 %, respectively. CONCLUSIONS: Most SNFB3D-MRA examinations allow for excellent depiction of the main CAs in young CHD patients; visualisation of side branches remains limited. KEY POINTS: • Self-navigated free-breathing three-dimensional magnetic resonance angiography (SNFB3D-MRA) sufficiently visualises coronary arteries (CAs). • Depiction of main CAs in patients with congenital heart disease is excellent. • Visualisation of CA side branches using SNFB3D-MRA is limited. • SNFB3D-MRA image quality is especially correlated to cardiac motion freezing ability.

Radiology research in mainland China in the past 10 years: a survey of original articles published in Radiology and European Radiology.

PURPOSE: To evaluate the features and trends of Radiology research in Mainland China through bibliometric analysis of the original articles published in Radiology and European Radiology (ER) between 2006 and 2015. MATERIALS AND METHODS: We reviewed the original articles published in Radiology and ER between 2006 and 2015. The following information was abstracted: imaging subspecialty, imaging technique(s) used, research type, sample size, study design, statistical analysis, study results, funding declarations, international collaborations, number of authors, department and province of the first author. All variables were examined longitudinally over time. RESULTS: Radiology research in Mainland China saw a substantial increase in original research articles published, especially in the last 5 years (P < 0.001). Within Mainland China's Radiology research, neuroradiology, vascular/interventional Radiology, and abdominal Radiology were the most productive fields; MR imaging was the most used modality, and a distinct geographic provenience was observed for articles published in Radiology and ER. CONCLUSION: Radiology research in Mainland China has seen substantial growth in the past 5 years with neuroradiology, vascular/interventional Radiology, and abdominal Radiology as the most productive fields. MR imaging is the most used modality. Article provenience shows a distinct geographical pattern. KEY POINTS: • Radiology research in Mainland China saw a substantial increase. • Neuroradiology, vascular/interventional Radiology, and abdominal Radiology are the most productive fields. • MRI is the most used modality in Mainland China's Radiology research. • Guangdong, Shanghai, and Beijing are the most productive provinces.

Speech recognition interference by the temporal and spectral properties of a single competing talker.

This study investigated how speech recognition during speech-on-speech masking may be impaired due to the interaction between amplitude modulations of the target and competing talker. Young normal-hearing adults were tested in a competing talker paradigm where the target and/or competing talker was processed to primarily preserve amplitude modulation cues. Effects of talker sex and linguistic interference were also examined. Results suggest that performance patterns for natural speech-on-speech conditions are largely consistent with the same masking patterns observed for signals primarily limited to temporal amplitude modulations. However, results also suggest a role for spectral cues in talker segregation and linguistic competition.

Modulation masking and glimpsing of natural and vocoded speech during single-talker modulated noise: Effect of the modulation spectrum.

Compared to notionally steady-state noise, modulated maskers provide a perceptual benefit for speech recognition, in part due to preserved speech information during the amplitude dips of the masker. However, overlap in the modulation spectrum between the target speech and the competing modulated masker may potentially result in modulation masking, and thereby offset the release from energetic masking. The current study investigated masking release provided by single-talker modulated noise. The overlap in the modulation spectra of the target speech and the modulated noise masker was varied through time compression or expansion of the competing masker. Younger normal hearing adults listened to sentences that were unprocessed or noise vocoded to primarily limit speech recognition to the preserved temporal envelope cues. For unprocessed speech, results demonstrated improved performance with masker modulation spectrum shifted up or down compared to the target modulation spectrum, except for the most extreme time expansion. For vocoded speech, significant masking release was observed with the slowest masker rate. Perceptual results combined with acoustic analyses of the preserved glimpses of the target speech suggest contributions of modulation masking and cognitive-linguistic processing as factors contributing to performance.

Correlation study of functional magnetic resonance index and clinicopathological features of rectal cancer.

PURPOSE: To investigate the correlation between DCE-MRI, R2*, IVIM, and clinicopathological features of rectal cancer. METHODS: This was a prospective study, enrolling 42 patients with rectal cancer, 20 of whom underwent rectal mesorectal excision. Dynamic contrast-enhanced magnetic resonance imaging scanning was performed preoperatively in all patients, and additional preoperative scanning of R2* imaging and intravoxel incoherent motion was performed in those who underwent surgery. Artificially delineate the ROI around the tumor. Functional magnetic resonance index parameters Ktrans, Ve, R2*, D, D*, and f were estimated by computer software to analyze postoperative pathological reports of patients undergoing total mesenteric resection. Correlation and significance analyses of imaging metrics and pathologic features were performed by GraphPad Prism 9 to assess statistical significance. RESULTS: DEC-MRI, R2*, and IVIM have certain application values in the distance from the lower margin of the tumor to the anorectal ring, imaging T stage and N stage, tumor markers CEA and CA199, immunohistochemical indexes Ki-76 and P53, lymph node cancer metastasis, and rectal fascia status (P < 0.05). CONCLUSION: DEC-MRI, R2*, and IVIM provide reliable quantitative parameters for preoperative clinicopathological evaluation of patients with rectal cancer.

Evaluate the groundwater quality and human health risks for sustainable drinking and irrigation purposes in mountainous region of Chongqing, Southwest China.

Groundwater is crucial for agriculture and domestic consumption. This research investigated the hydrogeochemical properties and contaminant sources of groundwater within the mountainous terrain of northern Chongqing, with the objective of evaluating its appropriateness for irrigation and potable use. The hydrochemical type of the groundwater was HCO3 - Ca, dominated by silicate and calcite dissolutions. High NO3- (29.03% exceeds 10 mg/L) were attributed to the overuse of agricultural fertilizers. A comprehensive evaluation was conducted to determine the groundwater suitability for agricultural and potable uses. The results showed that groundwater in the southwestern region, particularly within the Yangtze River mainstem watershed, exhibited less suitability for irrigation owing to its lower mineralization, in contrast to the northeastern region near the Daning River watershed. But this trend is reversed for drinking purposes. Overall, the groundwater was appropriate for both drinking (93.55% were classified as excellent) and irrigation (70.98% were classified as low restriction) purposes in the study area. Deterministic and probabilistic noncarcinogenic health risk analyses centered on nitrate exposure revealed that infants (with 13.79% of samples >1) were at greater risk than children (8.58%), adult males (6.98%), and adult females (5.24%). This underscores the urgency to reduce nitrogen fertilizer usage and improve water management in the region. This research will provide guidance for the sustainable groundwater management in mountainous regions.

PD-L1-expressing natural killer cells predict favorable prognosis and response to PD-1/PD-L1 blockade in neuroblastoma.

T/NK cell-based immunotherapy has achieved remarkable success in adult cancers but has limited efficacy in pediatric malignancies including high-risk neuroblastoma (NB). Immune defects of NB tumor microenvironment are poorly understood compared with adults. Here, we described the unique characteristics of NB immune contexture and determined the phenotype signatures of PD-L1-expressing CD8+ T and NK cells in NB tumors by systemically analyzing the spatial distribution of T and NK cells and the distinct expression of programmed death 1 (PD-1) and its ligand (PD-L1) in patients with NB. We found that PD-L1-expressing CD8+ T and NK cells in NB tumors were highly activated and functionally competent and associated with better clinical outcomes. Intratumoral NK cells were a favorable prognostic biomarker independent of CD8+ T cells, PD-1/PD-L1 expression, tumor stage, MYCN amplification, and risk classification. NK cells combined with anti-PD-1/PD-L1 antibodies showed potent antitumor activity against both MYCN-amplified and non-amplified NBs in vitro and in vivo, and PD-L1-expressing NK cells associated with improved antitumor efficacy. Collectively, we raise novel insights into the role of PD-L1 expression on CD8+ T-cell and NK-cell activation. We highlight the great potential of intratumoral NK cells in better defining risk stratification, and predicting survival and response to anti-PD-1/PD-L1 therapy in NB. These findings explain why single anti-PD-1/PD-L1 therapy may not be successful in NB, suggesting its combination with NK cell-adoptive cellular therapy as a promising strategy for relapsing/refractory NB. This study provides a potential prospect that patients with PD-L1-expressing NK cells may respond to anti-PD-1/PD-L1 therapy.

Relationships between sarcopenia, nutrient intake, and gut microbiota in Chinese community-dwelling older women.

BACKGROUND: The relationship among gut microbiota, sarcopenia components, and influencing factors in female sarcopenic patients has been poorly investigated. METHODS: Female participants completed questionnaires of physical activity and dietary frequency and were assessed for the presence of sarcopenia by the Asian Working Group of Sarcopenia 2019 (AWGS 2019) criteria. Fecal samples were collected from 17 sarcopenia and 30 non-sarcopenia subjects for 16S sequencing and short chain fatty acid (SCFA) detection. RESULTS: The prevalence of sarcopenia was 19.20% among 276 participants. The dietary protein, fat, dietary fiber, vitamin B1, niacin, vitamin E, phosphorus, magnesium, iron, zinc, and cooper intake of sarcopenia were all remarkably low. In addition, the richness of gut microbiota (Chao1 and ACE indexes) was considerably reduced in sarcopenic patients, and the sarcopenic gut microbiota and its metabolite were decreased in Firmicutes/Bacteroidetes, Agathobacter, Dorea and Butyrate and were enriched in Shigella and Bacteroides. Correlation analysis showed that Agathobacter and Acetate were positively correlated with grip strength and gait speed, respectively, and Bifidobacterium was negatively correlated with grip strength and appendicular skeletal muscle index (ASMI). Moreover, the protein intake was positively related to Bifidobacterium. CONCLUSIONS: This cross-sectional study revealed the alterations of gut microbiota composition, SCFA, and nutrient intake in women with sarcopenia and their relation to sarcopenic components. These results provide insights into further studies on the role of nutrition and gut microbiota in sarcopenia and its use as a therapeutic approach.

Safety and clinical efficacy of sintilimab (anti-PD-1) in pediatric patients with advanced or recurrent malignancies in a phase I study.

The aim of this phase I study is to evaluate, for the first time, the safety and efficacy of sintilimab in pediatric patients diagnosed with advanced or recurrent malignancies. During the dose escalation phase, patients received a single intravenous infusion of sintilimab at varying doses of 1, 3, and 10 mg/kg. The primary endpoints included the identification of dose-limiting toxicities (DLTs) as well as the evaluation of safety and tolerance. Secondary endpoints focused on assessing objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A total of 29 patients were enrolled, including 10 individuals diagnosed with Hodgkin lymphoma (HL) and 19 patients with various other tumor categories. Notably, diverse pathological types such as thymoma, choroid plexus carcinoma, and NK/T-cell lymphoma were also included in the study cohort. By the safety data cutoff, most adverse events were grade 1 or 2, with grade 3 or higher treatment-related adverse events (TRAE) occurring in 10% of patients. Among the 27 evaluated subjects, four achieved confirmed complete response (CR) while seven patients exhibited confirmed partial response (PR). Additionally, seven patients maintained disease (SD) during the study period. Notably, sintilimab demonstrated remarkable tolerability without DLTs and exhibited promising anti-tumor effects in pediatric HL. Whole-exome sequencing (WES) was conducted in 15 patients to assess the mutational landscape and copy number variation (CNV) status. The completion of this phase I study establishes the foundation for potential combination regimens involving sintilimab in childhood cancer treatment. The trial is registered on ClinicalTrials.gov with the identifier NCT04400851.

Efficacy and safety of programmed cell death receptor 1 inhibition-based regimens in patients with pediatric malignancies: the real-world study in China.

Background: Programmed death receptor 1 (PD-1) inhibition has shown durable response and mild adverse events (AEs) in adult malignancies. However, data on the clinical activity of PD-1 inhibition in pediatric patients are lacking. We comprehensively assessed the efficacy and safety of PD-1 inhibitor-based regimens for pediatric malignancies. Methods: We conducted a real-world, multi-institutional, retrospective analysis of pediatric malignancies treated with PD-1 inhibitor-based regimens. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints included disease control rate (DCR), duration of response (DOR), and AEs. The Kaplan-Meier method was used to calculate PFS and DOR. The National Cancer Institute Common Toxicity Criteria for AEs (version 5.0) were used to grade toxicity. Results: A total of 93 and 109 patients were evaluated for efficacy and safety, respectively. For all efficacy-evaluable patients, PD-1 inhibitor monotherapy, combined chemotherapy, combined histone deacetylase inhibitor, and combined vascular endothelial growth factor receptor tyrosine kinase inhibitor cohorts, the ORR and DCR were 53.76%/81.72%, 56.67%/83.33%, 54.00%/80.00%, 100.00%/100.00%, and 12.50%/75.00%, respectively; the median PFS and DOR were 17.6/31.2 months, not achieved/not achieved, 14.9/31.2 months, 17.6/14.9 months, and 3.7/1.8 months, respectively; the incidence rate of AEs were 83.49%, 55.26%, 100.00%, 80.00%, and 100.00%, respectively. One patient in the PD-1 inhibitor-combined chemotherapy cohort discontinued treatment due to diabetic ketoacidosis. Conclusions: This largest retrospective analysis demonstrate that PD-1 inhibitor-based regimens are potentially effective and tolerable in pediatric malignancies. Our findings provide references for future clinical trials and practice of PD-1 inhibitors in pediatric cancer patients.

The RSL3 Induction of KLK Lung Adenocarcinoma Cell Ferroptosis by Inhibition of USP11 Activity and the NRF2-GSH Axis.

Antioxidant transcription factor NRF2 plays a pivotal role in cell ferroptosis. KLK lung adenocarcinoma (LUAD) is a specific molecular subtype of Kras-mutant LUAD. The activation of mutant Kras in combination with the inactivation of Lkb1 and Keap1 abnormally increases NRF2 expression, while high NRF2 confers KLK LUAD cell resistance to ferroptosis. This study assessed the inhibition of NRF2-GSH axis to sensitize a small molecule RSL3 to induce KLK LUAD cell ferroptosis and then explored the underlying molecular mechanisms. The data showed that the NRF2-GSH inhibition sensitized RSL3 induction of KLK LUAD cell ferroptosis in vitro, while RSL3 treatment reduced level of NRF2 protein in KLK LUAD during ferroptosis. Moreover, RSL3 treatment inhibited activity of the NRF2-GSH signaling during in KLK LUAD cell ferroptosis in vitro and in vivo. Mechanistically, the RSL3 reduction of NRF2 expression was through the promotion of NRF2 ubiquitination in KLK LUAD cells. In addition, RSL3 was able to directly bind to USP11, a recently identified de-ubiquitinase of NRF2, and inactivate USP11 protein to induce NRF2 protein ubiquitination and degradation in KLK LUAD cells. These data revealed a novel mechanism of RSL3 induction in KLK LUAD cell ferroptosis by suppression of the USP11-NRF2-GSH signaling. Future study will confirm RSL3 as a novel therapeutic approach in control of KLK lung adenocarcinoma.

Expression and Regulation of pde6h by Thyroid Hormone During Metamorphosis in Paralichthys olivaceus.

PDE6H is a cone cell-specific inhibitory subunit that plays a critical role in the adaptation of the photosensitive system to bright and dark phases of the light environment. Thyroid hormone (TH) is one of the most important factors that control development and metabolism in animals, composed mainly of triiodothyronine (T3), and thyroxine (T4). TH also plays a key role in the metamorphosis of the flounder (Paralichthys olivaceus), wherein exogenous TH can accelerate the behavioral changes of larvae from the pelagic to benthic type accompanying changes in the light environment from bright to dark. In this study, transcriptional analysis showed that pde6h is expressed in adult eye, that its expression peaks at the climax of metamorphosis, and that it can be significantly up-regulated to the highest level by exogenous T4 in the early stages of metamorphosis but is inhibited by thiourea (TU). The rescue experiment showed that metamorphic inhibition of larvae and expression inhibition of pde6h gene in TU groups can be rescued by removing TU. Further, dual-luciferase reporter assay indicated the putative regulatory effect of TH on pde6h expression, mediated directly on the gene promoter by the TRαA gene. Together, we speculated that TH may control physiological adaptation of the photosensitive system to light changes during metamorphosis by acting directly on pde6h. This study can help us further study the physiological function of pde6h during flounder metamorphosis in the future.

Applications of Activity-Based Protein Profiling (ABPP) and Bioimaging in Drug Discovery.

Activity-based protein profiling (ABPP) and bioimaging have been developed in recent years as powerful technologies in drug discovery. Specifically, both approaches can be applied in critical steps of drug development, such as therapy target discovery, high-throughput drug screening and target identification of bioactive molecules. We have been focused on the development of various strategies that enable simultaneous activity-based protein profiling and bioimaging studies, thus facilitating an understanding of drug actions and potential toxicities. In this Minireview, we summarize these novel strategies and applications, with the aim of promoting these technologies in drug discovery.

ß-glucosidase from Hevea brasiliensis seeds: Purification, homology modeling, and insights into the substrate-binding model.

The isolation of ß-glucosidase from Hevea brasiliensis (Hbglu) seeds was investigated and a homology model was built on the MODELLER software to understand the structure feature. The quality of the model was evaluated on PROCHEK. The refined model was used for molecular docking on AutoDock 4.2 to determine the substrate- binding sites and potential substrates based on their calculated binding affinities. The substrate specificity of Hbglu was verified through the kinetic measurement of hydrolytic activities. Molecular dynamic simulations of cyanogenic ß-glucosidase and ligand-bound complex showed that the free energy (ΔG) for the binding of p-nitrophenyl-ß-D-glucopyranoside and daidzein-7-O-ß-D-glucoside were -8.6 and -7.92 kcal/mol, respectively. Thus, daidzein-7-O-ß-D-glucoside is a potential substrate. Future studies on the physicochemical properties and catalytic mechanisms will provide information on the molecular biological properties of Hbglu. PRACTICAL APPLICATIONS: This study reported the 3D structural simulation of ß-glucosidase from Hbglu. The docking condition between Hbglu and various different substrates were assessed on Autodock. The results can be used as reference in designing enzymes, and improving the utilization of ß-glucosidases for the hydrolysis of flavor precursors from fruits, teas, and wines and for the production of flavonoid compounds and cyanogenic glycoside degradation.

Mild Oxidative Stress Reduces NRF2 SUMOylation to Promote Kras/Lkb1/Keap1 Mutant Lung Adenocarcinoma Cell Migration and Invasion.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a crucial transcription factor for cell adaptation and defense against oxidative stress. NRF2 activation confers Kras/Lkb1/Keap1 (KLK) mutant tumor cells with greater resistance to oxidative insults. We previously reported that SUMOylation at lysine residue 110 is important for the ability of NRF2 to promote reactive oxygen species (ROS) clearance in hepatocellular carcinoma. In this study, we investigated whether SUMOylation is necessary for the ability of NRF2 to inhibit KLK lung adenocarcinoma (LUAD) cell migration and invasion. Our experiments showed that mild oxidative stress reduced NRF2 SUMOylation, which promoted KLK LUAD cell migration and invasion. Mechanistically, NRF2 SUMOylation increased the antioxidant ability of NRF2 and reduced cellular ROS levels, mainly by transcriptionally activating Cat in KLK LUAD cells. With reduced NRF2 SUMOylation, increased ROS acted as signaling molecules to activate the JNK/c-Jun axis, which enhanced cell mobility and cell adhesion, to promote LUAD cell migration and invasion. Taken together, the results of this study reveal a novel signaling process in which reduced NRF2 SUMOylation permits increased KLK LUAD cell migration and invasion under mild oxidative stress.