Relationship between Sjogren's syndrome and gastroesophageal reflux: A bidirectional Mendelian randomization study.

The clinical incidence of sjogren's syndrome combined with gastroesophageal reflux disease is high. Existing observational studies have shown inconsistent results in the association between gastroesophageal reflux disease (GERD) and Sjogren's syndrome (SS).We observed that the symptoms of SS patients also improved after receiving GERD-related treatment. Therefore, we aimed to investigate the relationship between GERD and SS through a bidirectional two-sample Mendelian randomization (MR) study. Independent SNPs associated with GERD and SS were selected from a genome-wide association study (GWAS) as instrumental variables to conduct a bidirectional two-sample Mendelian analysis of GERD and SS. Genetic data were obtained from two databases for the following two outcomes: Gastroesophageal reflux (IEU Open GWAS) [sample size = 602,604 (patients = 129,080; nonpatients = 473,524)] and SS (FinnGen) [sample size = 392,423 (patients = 2,495; nonpatients = 389,928)]. Statistical methods for the MR analysis included the inverse-variance weighting method, weighted median, simple mode and weighted mode, as well as heterogeneity and sensitivity analyses using the Cochran Q statistic, MR‒Egger regression, outlier detection methods (MR-PRESSO). In addition, Steiger Test was conducted to test the direction of causality. MR analysis showed a positive correlation between GERD and SS risk [odds ratio (OR) = 1.3279 (95% confidence interval 1.0312-1.7099, P = 0.0280)]. However, in contrast, no significant causal effect of SS on GERD was observed [OR = 1.0024 (95% CI 0.9651-1.0412; P = 0.8995)]. This bidirectional two-sample Mendelian randomization study confirmed a causal relationship between SS and GERD, and suggested that GERD is a risk factor for SS, while SS does not affect GERD.

Tris(triazolo)triazine-based Covalent Organic Frameworks for Efficiently Photocatalytic Hydrogen Peroxide Production.

Two-dimensional covalent organic frameworks (2D-COFs) have recently emerged as fascinating scaffolds for solar-to-chemical energy conversion because of their customizable structures and functionalities. Herein, two tris(triazolo)triazine-based COF materials (namely COF-JLU51 and COF-JLU52) featuring large surface area, high crystallinity, excellent stability and photoelectric properties were designed and constructed for the first time. Remarkably, COF-JLU51 gave an outstanding H2O2 production rate of over 4200 µmol g-1 h-1 with excellent reusability in pure water and O2 under one standard sun light, that higher than its isomorphic COF-JLU52 and most of the reported metal-free materials, owing to its superior generation, separation and transport of photogenerated carriers. Experimental and theoretical researches prove that the photocatalytic process undergoes a combination of indirect 2e- O2 reduction reaction (ORR) and 4e- H2O oxidation reaction (WOR). Specifically, an ultrahigh yield of 7624.7 µmol g-1 h-1 with apparent quantum yield of 18.2% for COF-JLU52 was achieved in a 1:1 ratio of benzyl alcohol and water system. This finding contributes novel, nitrogen-rich and high-quality tris(triazolo)triazine-based COF materials, and also designate their bright future in photocatalytic solar transformations.

MTHFR as a Novel Candidate Marker for Litter Size in Rabbits.

Litter size is a significant economic trait during animal reproduction. This current study attempted to decipher whether MTHFR promotes the apoptosis of granulosa cells (GCs) and inhibits their proliferation by investigating the effects of the MTHFR gene using flow cytometry and a Cell Counting Kit-8 (CCK-8) assay. MTHFR is linked with ovarian follicle development in the reproductive performance of 104 female New Zealand rabbits. We observed that MTHFR could regulate the mRNA of follicular development-related genes (TIMP1, CITED1, FSHR, GHR, HSD17B1, and STAR) with a qRT-PCR, and we observed the protein expression of CITED1 and GHR using a western blot (WB) analysis. The dual luciferase activity assays helped identify the core promoter region of the MTHFR gene, and the polymorphism of the MTHFR promoter region was studied using Sanger sequencing. The results indicated four single nucleotide polymorphisms (SNPs) within the core promoter region, among which the g.-680C>A locus was significantly associated with both the total and alive litter sizes. Additionally, the CC genotype was associated with the largest total and alive litter sizes, compared to the CA and AA genotypes (p < 0.05). In conclusion, this study investigated the effects of MTHFR on ovarian granulosa cells and its association with selected reproductive parameters in rabbits. The results provide a theoretical foundation for the use of MTHFR as a molecular marker in rabbits.

Modulation of dlPFC function and decision-making capacity by repetitive transcranial magnetic stimulation in methamphetamine use disorder.

This study explores the impact of repetitive transcranial magnetic stimulation (rTMS) on decision-making capabilities in individuals with methamphetamine use disorder (MUD), alongside potential underlying psychological mechanisms. Employing the Iowa Gambling Task (IGT) and computational modeling techniques, we assessed the decision-making processes of 50 male MUD participants (24 underwent rTMS treatment, 26 received no treatment) and 39 healthy controls (HC). We compared pre- and post-rTMS treatment alterations in the left dorsolateral prefrontal cortex (dlPFC). Results revealed inferior performance in the IGT among the MUD group, characterized by aberrant model parameters in the Value-Plus-Perseverance (VPP) model, including heightened learning rate, outcome sensitivity, and reinforcement learning weight, alongside diminished response consistency and loss aversion. RTMS treatment demonstrated efficacy in reducing craving scores, enhancing decision-making abilities, and partially restoring normalcy to certain model parameters in the MUD cohort. Nonetheless, no linear relationship between changes in model parameters and craving was observed. These findings lend support to the somatic marker hypothesis, implicating the dlPFC in the decision-making deficits observed in MUD, with rTMS potentially ameliorating these deficits by modulating the function of these brain regions. This study not only offers novel insights and methodologies for MUD rehabilitation but also underscores the necessity for further research to corroborate and refine these findings. Trial Registration www.chictr.org.cn Identifier: No. ChiCTR17013610.

An interpretable ensemble trees method with joint analysis of static and dynamic features for myocardial infarction detection.

OBJECTIVE: In recent years, artificial intelligence-based electrocardiogram (ECG) methods have been massively applied to myocardial infarction (MI). However, the joint analysis of static and dynamic features to achieve accurate and interpretable MI detection has not been comprehensively addressed. Approach. This paper proposes a simplified ensemble tree method with a joint analysis of static and dynamic features to solve this issue for MI detection. Initially, the dynamic features are extracted by modeling the intrinsic dynamics of ECG via dynamic learning in addition to extracting classical static features. Secondly, a two-stage feature selection strategy is designed to identify a few significant features, which substitute the original variables that are employed in constructing the ensemble tree. This approach enhances the discriminative ability by selecting significant static and dynamic features. Subsequently, this paper presents an interpretable classification method named StackTree by introducing a stacked ensemble scheme to modify the ensemble tree simplification algorithm. The representative rules of the raw ensemble trees are selected as the intermediate training data that is used to retrain a decision tree with performance close to that of the source ensemble model. Using this scheme, the significant precision and interpretability of MI detection are thus comprehensively addressed. Main results. The effectiveness of our method in detecting MI is evaluated using the PTB and clinical database. The findings suggest that our algorithm outperforms the traditional methods based on a single type of feature. Additionally, it is comparable to the conventional random forest, achieving 97.1% accuracy under the inter-patient framework on the PTB database. Furthermore, feature subsets trained on PTB are validated using the clinical database, resulting in an accuracy of 84.5%. The chosen important features demonstrate that both static and dynamic information have crucial roles in MI detection. Crucially, the proposed method provides clear internal workings in an easy-to-understand visual manner. .

Distribution, risk evaluation, and source allocation of cesium and strontium in surface soil in a mining city.

Radioactive nuclides cesium (Cs) and strontium (Sr) possess long half-lives, with 135Cs at approximately 2.3 million years and 87Sr at about 49 billion years. Their persistent accumulation can result in long-lasting radioactive contamination of soil ecosystems. This study employed geo-accumulation index (Igeo), pollution load index (PLI), potential ecological risk index (PEPI), health risk assessment model (HRA), and Monte Carlo simulation to evaluate the pollution and health risks of Cs and Sr in the surface soil of different functional areas in a typical mining city in China. Positive matrix factorization (PMF) model was used to elucidate the potential sources of Cs and Sr and the respective contribution rates of natural and anthropogenic sources. The findings indicate that soils in the mining area exhibited significantly higher levels of Cs and Sr pollution compared to smelting factory area, agricultural area, and urban residential area. Strontium did not pose a potential ecological risk in any studied functional area. The non-carcinogenic health risk of Sr to the human body in the study area was relatively low. Because of the lack of parameters for Cs, the potential ecological and human health risks of Cs was not calculated. The primary source of Cs in the soil was identified as the parent material from which the soil developed, while Sr mainly originated from associated contamination caused by mining activities. This research provides data for the control of Cs and Sr pollution in the surface soil of mining city.

Advances in Aptamer-Based Conjugate Recognition Techniques for the Detection of Small Molecules in Food.

Small molecules are significant risk factors for causing food safety issues, posing serious threats to human health. Sensitive screening for hazards is beneficial for enhancing public security. However, traditional detection methods are unable to meet the requirements for the field screening of small molecules. Therefore, it is necessary to develop applicable methods with high levels of sensitivity and specificity to identify the small molecules. Aptamers are short-chain nucleic acids that can specifically bind to small molecules. By utilizing aptamers to enhance the performance of recognition technology, it is possible to achieve high selectivity and sensitivity levels when detecting small molecules. There have been several varieties of aptamer target recognition techniques developed to improve the ability to detect small molecules in recent years. This review focuses on the principles of detection platforms, classifies the conjugating methods between small molecules and aptamers, summarizes advancements in aptamer-based conjugate recognition techniques for the detection of small molecules in food, and seeks to provide emerging powerful tools in the field of point-of-care diagnostics.

Europium Nanoparticle-Based Lateral Flow Strip Biosensors for the Detection of Quinoxaline Antibiotics and Their Main Metabolites in Fish Feeds and Tissues.

Olaquindox (OLA) and quinocetone (QCT) have been prohibited in aquatic products due to their significant toxicity and side effects. In this study, rapid and visual europium nanoparticle (EuNP)-based lateral flow strip biosensors (LFSBs) were developed for the simultaneous quantitative detection of OLA, QCT, and 3-methyl-quinoxaline-2-carboxylic acid (MQCA) in fish feed and tissue. The EuNP-LFSBs enabled sensitive detection for OLA, QCT, and MQCA with a limit of detection of 0.067, 0.017, and 0.099 ng/mL (R2 ≥ 0.9776) within 10 min. The average recovery of the EuNP-LFSBs was 95.13%, and relative standard deviations were below 9.38%. The method was verified by high-performance liquid chromatography (HPLC), and the test results were consistent. Therefore, the proposed LFSBs serve as a powerful tool to monitor quinoxalines in fish feeds and their residues in fish tissues.

Seasonal dynamics of the microbiota and nutritional composition in bee bread from Apis cerana and Apis mellifera colonies.

Bee bread is a product of honeybees, which collect and ferment pollen, that contains highly nutritious and easily digestible active substances. However, its nutritional composition varies significantly with fermentation strains and seasonal changes. To unveil the patterns of microbial community and nutritional component changes in bee bread across seasons, we employed high-throughput techniques to assess the diversity of bacteria and fungi in bee bread. The results indicated that the compositions of bacteria and fungi in bee bread undergo significant seasonal variation, with noticeable changes in the microbial diversity of bee bread from different bee species. Subsequently, metabolomic analysis revealed high activity of glycerophospholipid metabolism in bee bread. Furthermore, our analysis identifaied noteworthy differences in nutritional components, including pH values, sugar content, and free amino acid levels, in bee bread across different seasons.

Label-Free and DNAzyme-Mediated Biosensor with a High Signal-to-Noise Ratio for a Lumpy Skin Disease Virus Assay.

Lumpy skin disease virus (LSDV) is a severe and highly contagious form of cowpox. As LSDV continues to mutate and there is no vaccine and treatment in nonendemic countries, early detection of LSDV becomes an important basis for epidemic prevention and control, especially for detection of conserved sequences. A new label-free and sensitive fluorescence method was developed based on a light-up RNA aptamer for detecting LSDV. The method integrated recombinase polymerase amplification (RPA), CRISPR/Cas12a, 10-23 DNAzyme, and Baby Spinach RNA aptamer for triple cascade signal amplification. Based on highly sensitive and specific RPA and CRISPR/Cas12a, DNAzyme achieved a third signal amplification. Additionally, the Baby Spinach RNA aptamer had stronger fluorescence signals and higher quantum yields. The label-free method had ultrahigh sensitivity with the actual detection limit as 1.29 copies·µL-1. The method was 100-fold more sensitive compared to RPA with Cas12a. Moreover, it had no cross-reactivity with viruses belonging to the Capripoxvirus, such as sheep pox virus and goat pox virus with genetic homology as 97%. Furthermore, the method displayed 100% accuracy in 50 actual samples. Therefore, the method based on RPA, Cas12a, and 10-23 DNAzyme had advantages in LSDV detection and provided a new solution for LSD prevention and control.

Selenomethionine Inhibited HADV-Induced Apoptosis Mediated by ROS through the JAK-STAT3 Signaling Pathway.

Adenovirus (HAdV) can cause severe respiratory infections in children and immunocompromised patients. There is a lack of specific therapeutic drugs for HAdV infection, and the study of anti-adenoviral drugs has far-reaching clinical implications. Elemental selenium can play a specific role as an antioxidant in the human immune cycle by non-specifically binding to the amino acid methionine in body proteins. Methods: The antiviral mechanism of selenomethionine was explored by measuring cell membrane status, intracellular DNA status, cytokine secretion, mitochondrial membrane potential, and ROS production. Conclusions: Selenomethionine improved the regulation of ROS-mediated apoptosis by modulating the expression of Jak1/2, STAT3, and BCL-XL, which led to the inhibition of apoptosis. It is anticipated that selenomethionine will offer a new anti-adenoviral therapeutic alternative.

Early effectiveness and safety analysis of belimumab in addition to standard treatment in patients with systemic lupus erythematosus.

Objectives: This study aimed to evaluate the early effectiveness and safety of belimumab in addition to standard therapy in patients with systemic lupus erythematosus (SLE) for 24 weeks. Patients and methods: This retrospective study was conducted with 60 adult patients with active SLE between June 2020 and August 2022. The patients either received intravenous belimumab in addition to standard therapy (n=31; 24 females, 7 males; mean age: 33.7±14.1 years; range, 18 to 52 years) or only standard therapy (n=29; 22 females, 7 males; mean age: 34.1±13.4 years; range, 19 to 66 years) for 24 weeks. Outcome measures, including safety and effectiveness (Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index [SELENA-SLEDAI]), changes in biomarkers (double-stranded DNA [deoxyribonucleic acid]), serum complement levels, and immunoglobin G (IgG) were recorded. Adverse events were recorded. Results: Baseline demographic and clinical characteristics were similar between the two groups. More patients in the belimumab group achieved a reduction of ≥4 points in SELENA-SLEDAI at weeks 12 and 24 (week 12, 77.4% vs. 41.4%, p=0.008; week 24, 87.1% vs. 48.3%, p=0.002). The mean score of SELENA-SLEDAI was significantly lower in the belimumab group compared to the standard therapy group at week 12. However, a significant difference was not reached at week 24. Moreover, mean levels of serum C3 and C4 in the belimumab group were significantly higher than those in the standard therapy group at weeks 12 and 24. A higher proportion of patients in the belimumab group had a normal C3 level than in the standard therapy group. In addition, belimumab treatment resulted in a significant decrease in IgG levels at both weeks 12 and 24. At week 24, the belimumab group had a higher reduction in prednisone dose than the standard therapy group. Furthermore, the percentages of patients with more than 50% reduction in prednisone over baseline were significantly greater for belimumab versus standard therapy at week 12 (p=0.002). The occurrence of adverse events was similar between the two groups (standard therapy group, 44.8%; belimumab group, 51.6%). Conclusion: Intravenous belimumab was well tolerated and significantly improved disease activity in Chinese patients with SLE at the early stage of treatment. More importantly, belimumab treatment could result in a rapid reduction in prednisone dose as early as week 12.

Gum arabic coating alleviates chilling injury of cold-stored peach by regulating reactive oxygen species, phenolic, and sugar metabolism.

In this study, gum arabic (GA) coating was employed to mitigate chilling injury in peach fruit, and it was observed that 10% GA coating exhibited the most favorable effect. GA coating significantly inhibited the decline of AsA content and enhanced antioxidant enzyme activity in peach fruit, thereby enhancing reactive oxygen species (ROS) scavenging rate while reducing its accumulation. Simultaneously, GA coating inhibited the activity of oxidative degradation enzymes for phenolics and enhanced synthase activity, thus maintaining higher levels of total phenolics and flavonoids in fruits. Additionally, compared to the control fruit, GA-coated fruits demonstrated higher concentrations of sucrose and sorbitol, accompanied more robust activity of sucrose synthase and sucrose phosphate synthase, as well as reduced activity of acid invertase and neutral invertase. Our study demonstrates that GA coating can effectively enhance the cold resistance of peach fruit by regulating ROS, phenolics, and sugar metabolism, maintaining high levels of phenolics and sucrose while enhancing antioxidant activity.

Mitochondrial DNA evidence reflects high genetic divergence of Amynthas aspergillum (Oligochaeta: Megascolecidae) in southern China.

Amynthas aspergillum (Perrier, 1872), a natural resource used in traditional Chinese medicine (Guang-dilong) with high economic value, is widely distributed in forests and farmland habitats in the hilly areas of southern China. To investigate the extent of genetic differentiation and diversity in A. aspergillum, a population genetic structure study was performed on 157 samples from 75 locations in southern China using the mitochondrial genes COI, COII, 12S rRNA, 16S rRNA, and NDI. The results indicated that A. aspergillum had a high level of genetic diversity, and variation within populations was the main source of the total variation. Six deeply divergent mitochondrial clades (I-VI) were detected using both phylogenetic tree and haplotype network analyses. This finding was supported by the high Kimura two-parameter genetic distance and the pairwise fixation index value obtained based on the COI gene. No significant phylogeographic structures were observed. The widespread geographic distribution of clades II, IV, and VI suggested a recent demographic expansion based on multiple analysis results. These results include a high level of Hd and low π, star-shaped haplotype network structures with a high number of less frequent haplotypes, significantly negative neutrality test values, and a unimodal mismatch distribution pattern. The divergence time estimates and reconstruction of the ancestral area revealed that A. aspergillum originated in Guangxi Province and underwent initial intraspecific diversification in the early Pliocene to generate clade I. Then, it gradually dispersed eastward and rapidly differentiated into clades II-V during the Pleistocene. The Yunnan-Guizhou Plateau and Nanling and Wuyi Mountains might act as geographical barriers for the spread of A. aspergillum to the west and north.

Cathelicidin-HG Alleviates Sepsis-Induced Platelet Dysfunction by Inhibiting GPVI-Mediated Platelet Activation.

Platelet activation contributes to sepsis development, leading to microthrombosis and increased inflammation, which results in disseminated intravascular coagulation and multiple organ dysfunction. Although Cathelicidin can alleviate sepsis, its role in sepsis regulation remains largely unexplored. In this study, we identified Cath-HG, a novel Cathelicidin from Hylarana guentheri skin, and analyzed its structure using nuclear magnetic resonance spectroscopy. The modulatory effect of Cath-HG on the symptoms of mice with sepsis induced by cecal ligation and puncture was evaluated in vivo, and the platelet count, degree of organ damage, and microthrombosis were measured. The antiplatelet aggregation activity of Cath-HG was studied in vitro, and its target was verified. Finally, we further investigated whether Cath-HG could regulate thrombosis in vivo in a FeCl3 injury-induced carotid artery model. The results showed that Cath-HG exhibited an α-helical structure in sodium dodecyl sulfate solution and effectively reduced organ inflammation and damage, improving survival in septic mice. It alleviated sepsis-induced thrombocytopenia and microthrombosis. In vitro, Cath-HG specifically inhibited collagen-induced platelet aggregation and modulated glycoprotein VI (GPVI) signaling pathways. Dot blotting, enzyme-linked immunosorbent assay, and pull-down experiments confirmed GPVI as the target of Cath-HG. Molecular docking and amino acid residue truncations/mutations identified crucial sites of Cath-HG. These findings suggest that GPVI represents a promising therapeutic target for sepsis, and Cath-HG may serve as a potential treatment for sepsis-related thrombocytopenia and thrombotic events. Additionally, identifying Cath-HG as a GPVI inhibitor provides insights for developing novel antithrombotic therapies targeting platelet activation mediated by GPVI.

Corrigendum: Fat fraction quantification with MRI estimates tumor proliferation of hepatocellular carcinoma.

[This corrects the article DOI: 10.3389/fonc.2024.1367907.].

Translational selenium nanoparticles boost GPx1 activation to reverse HAdV-14 virus-induced oxidative damage.

Human adenovirus (HAdV) can cause severe respiratory infections in immunocompromised patients, but its clinical treatment is seriously limited by side effects of drugs such as poor efficacy, low bioavailability and severe nephrotoxicity. Trace element selenium (Se) has been found will affect the disease progression of pneumonia, but its antivirus efficacy could be improved by speciation optimization. Therefore, herein we performed anti-HAdV effects of different Se speciation and found that lentinan (LNT)-decorated selenium nanoparticles (SeNPs) exhibited low cytotoxicity and excellent anti-HAdV antiviral activity. Furthermore, SeNPs@LNT reduced the HAdV infection-induced mitochondrial damage and excessive production of reactive oxygen species (ROS). It was also involved in the repair of host cell DNA damage and inhibition of viral DNA replication. SeNPs@LNT inhibited HAdV-induced apoptosis mainly by modulating the p53/Bcl-2 apoptosis signaling pathway. In vivo, SeNPs@LNT replenished Se by targeting the infected site through the circulatory system and was involved in the synthesis of Glutathione peroxidase 1 (GPx1). More importantly, GPx1 played an antioxidant and immunomodulatory role in alleviating HAdV-induced inflammatory cytokine storm and alleviating adenovirus pneumonia in Se-deficient mice. Collectively, this study provides a Se speciation of SeNPs@LNT with anti-HAdV activity, and demonstrate that SeNPs@LNT is a promising pharmaceutical candidate for the treatment of HAdV.

Androcin 18-1, a novel scorpion-venom peptide, shows a potent antitumor activity against human U87 cells via inducing mitochondrial dysfunction.

Scorpion venom is a potent natural source for antitumor drug development due to the multiple action modes of anticancer components. Although the sequence of Androcin 18-1 has been identified from the transcriptome profile of the scorpion venom Androctonus bicolor, its bioactivity remains unclear. In this study, we described the antitumor mechanism whereby Androcin 18-1 inhibits the proliferation and induces apoptosis by inducing cell membrane disruption, ROS accumulation, and mitochondrial dysfunction in human U87 glioblastoma cells. Moreover, Androcin 18-1 could suppress cell migration via the mechanisms associated with cytoskeleton disorganization and MMPs/TIMPs expression regulation. The discovery of this work highlights the potential application of Androcin 18-1 in drug development for glioblastoma treatment.

Therapeutic targeting of TNIK in papillary thyroid carcinoma: a novel approach for tumor growth suppression.

Papillary thyroid carcinoma (PTC) is a common endocrine malignancy. The pathology of PTC is far from clear. As a kinase that can be targeted, the role of TNIK in PTC has not been investigated. This study was focused on the effects and molecular mechanisms of TNIK in PTC. Both public datasets and clinical specimens were used to verify TNIK expression. The effects of TNIK were investigated in both cell lines and mice models. Transcriptome analysis was used to explore the underlying mechanism of TNIK. Immunofluorescence, wound healing, and qRT-PCR assays were used to validate the mechanism of TNIK in PTC. The therapeutic effects of TNIK inhibitor NCB-0846 were evaluated by flow cytometry, western blot, and subcutaneous xenografts mice. TNIK expression was upregulated in PTC tissues. TNIK knockdown could suppress cell proliferation and tumor growth in no matter cell models or nude mice. The transcriptome analysis, GO enrichment analysis, and GSEA analysis results indicated TNIK was highly correlated with cytoskeleton, cell motility, and Wnt pathways. The mechanistic studies demonstrated that TNIK regulated cytoskeleton remodeling and promoted cell migration. NCB-0846 significantly inhibited TNIK kinase activity, induced cell apoptosis, and activated apoptosis-related proteins in a dose-dependent manner. In addition, NCB-0846 inhibited tumor growth in tumor-bearing mice. In summary, we proposed a novel regulatory mechanism in which TNIK-mediated cytoskeleton remodeling and cell migration to regulate tumor progression in PTC. TNIK is a therapeutic target in PTC and NCB-0846 would act as a novel targeted drug for PTC therapy.

Proton pump inhibitors stabilize the expression of PD-L1 on cell membrane depending on the phosphorylation of GSK3ß.

BACKGROUND: Preclinical and clinical evidence indicates that proton pump inhibitors (PPIs) may indirectly diminish the microbiome diversity, thereby reducing the effectiveness of immune checkpoint inhibitors (ICIs). Conversely, recent publications have shown that PPIs could potentially enhance the response to ICIs. The precise mechanism through which PPIs modulate the ICIs remains unclear. In this study, we discovered a novel molecular function of PPIs in regulating immune invasion, specifically through inducing PD-L1 translocation in various tumor cells. METHODS: C57BL/6 mice subcutaneous transplantation model is used to verify the potential efficacy of PPIs and PD-L1 antibody. Western blotting analysis and phosphorylated chip are used to verify the alteration of PD-L1-related pathways after being treated with PPIs. The related gene expression is performed by qRT-PCR and luciferase reporter analysis. We also collected 60 clinical patients diagnosed with esophageal cancer or reflux esophagitis and then detected the expression of PD-L1 in the tissue samples by immunohistochemistry. RESULTS: We observed that the IC50 of tumor cells in response to PPIs was significantly higher than that of normal epithelial cells. PPIs significantly increased the expression of PD-L1 on cell membrane at clinically relevant concentrations. Furthermore, pre-treatment with PPIs appeared to synergize the efficiency of anti-PD-L1 antibodies in mouse models. However, PPI administration did not alter the transcription or total protein level of PD-L1 in multiple tumor cells. Using a phosphorylated protein chip, we identified that PPIs enhanced the phosphorylation of GSK3ß, then leading to PD-L1 protein translocation to the cell membranes. The capacity of PPIs to upregulate PD-L1 was negated following GSK3ß knockout. Furthermore, our clinical data showed that the PPIs use resulted in increased PD-L1 expression in esophageal cancer patients. CONCLUSION: We mainly address a significant and novel mechanism that the usage of PPIs could directly induce the expression of PD-L1 by inducing GSK3ß phosphorylation and facilitate primary tumor progression and metastasis.