RESUMEN

Exposure to various chemicals found in the environment and in the context of drug development can cause acute toxicity. To provide an alternative to in vivo animal toxicity testing, the U.S. Tox21 consortium developed in vitro assays to test a library of approximately 10,000 drugs and environmental chemicals (Tox21 10 K compound library) in a quantitative high-throughput screening (qHTS) approach. In this study, we assessed the utility of Tox21 assay data in comparison with chemical structure information in predicting acute systemic toxicity. Prediction models were developed using four machine learning algorithms, namely Random Forest, Naïve Bayes, eXtreme Gradient Boosting, and Support Vector Machine, and their performance was assessed using the area under the receiver operating characteristic curve (AUC-ROC). The chemical structure-based models as well as the Tox21 assay data demonstrated good predictive power for acute toxicity, achieving AUC-ROC values ranging from 0.83 to 0.93 and 0.73 to 0.79, respectively. We applied the models to predict the acute toxicity potential of the compounds in the Tox21 10 K compound library, most of which were found to be non-toxic. In addition, we identified the Tox21 assays that contributed the most to acute toxicity prediction, such as acetylcholinesterase (AChE) inhibition and p53 induction. Chemical features including organophosphates and carbamates were also identified to be significantly associated with acute toxicity. In conclusion, this study underscores the utility of in vitro assay data in predicting acute toxicity.

RESUMEN

The facile development of a sustainable and durable flame-retardant approach for protein silk is of interest. Inspired by silk tin-weighting technology, this study developed a novel and sustainable in-situ deposition strategy based on biomass phytic acid to impart durable flame-retardant performance to silk fabrics. The chemical structure of insoluble chelating precipitation, and the surface morphology, thermal stability, combustion behavior, flame-retardant capacity, laundering resistance, and flame-retardant mode of action of the tin-weighting silk samples, were explored. The Sn-, P-, Si-containing insoluble chelating precipitation formed within the fiber interior and combined with silk fibers through electrostatic attraction and metal salt chelation. As a result, the tin-weighting silk displayed excellent self-extinguishing capacity, with the damaged length reduced to 9.2 cm and the LOI increased to 31.6 %; it also achieved self-extinguishing after 30 washing cycles, demonstrating high flame-retardant efficacy and laundering resistance. Moreover, the tin-weighting silk also showed the obvious suppression in smoke and heat generation by 55.6 % and 35.7 %, respectively. The synergistic charring action of phosphate groups, tin metal salts, and silicates was beneficial for enhancing the fire safety of silk. The tin-weighting treatment also displayed a minor impact on mechanical performance of silk fabrics.

RESUMEN

Background: There is a shortage of reliable predictive models to provide valuable prognostic information for early esophageal squamous cell carcinoma (ESCC) without lymph node metastasis (LNM). We aimed to develop and validate a nomogram using the prognostic factors in T1N0 ESCC patients. Methods: Patients with pathological T1N0 ESCC who underwent esophagectomy between 2014 and 2021 at three institutes were reviewed. The prognostic factors were evaluated by Cox proportional hazards model and a nomogram was developed. Patients were divided into high- and low-risk groups based on cut-off value of total points in the nomogram. Overall survival (OS) was estimated by the Kaplan-Meier method and compared using the log-rank test. Results: A total of 275 patients were included and split into training (n=180) and external validation (n=95) cohorts. In the training cohort, multivariable analysis showed that the surgical approach, T1 substage, and carcinoembryonic antigen (CEA) level were independent prognostic factors. The developed nomogram had relatively high performance, with the area under the receiver operating characteristic (ROC) curve (AUC) of 0.783, 0.711 and 0.612 for 1-, 3-, and 5-year OS, respectively. The calibration curves showed that the predicted probability was in good agreement with the actual probability. Forty-seven was determined as cut-off value of total points. High-risk group (n=148) showed a significant poor OS than low-risk group (n=127) (P<0.001). Conclusions: Left surgical approach, stage T1b, and higher CEA were associated with poorer prognosis in T1N0 ESCC patients. The nomogram demonstrated a good performance to predict the individual survival.

RESUMEN

Background: Few data are available on metastatic colorectal cancer (mCRC) treated with late-line regorafenib monotherapy or combined with other therapies. This study thus aimed to examine regorafenib combined with immune checkpoint inhibitors (ICIs) compared with regorafenib monotherapy in patients with advanced CRC. Methods: This single-center retrospective cohort study included patients with advanced CRC who experienced recurrence and progression after standard first- and second-line treatments treatment from November 2018 to December 2021. The patients received regorafenib plus ICIs or regorafenib monotherapy. Treatment response was evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST). Overall survival (OS) and progression-free survival (PFS) were analyzed via multivariate analysis. Results: The combined group and the monotherapy group included 30 and 43 patients, respectively. The median OS (13.7 vs. 10.1 months; P=0.10) and PFS (4 vs. 3.6 months; P=0.32) were not significantly different between the two groups. In males, the median OS was significantly longer in the combined group compared with the monotherapy group (not reached vs. 8.03 months; P=0.02), but the median PFS showed no significant difference (7.23 vs. 3.90 months; P=0.16). There was no significant difference in OS (P=0.71) or PFS (P=0.89) in females. Eastern Cooperative Oncology Group performance status (ECOG PS) 1 [vs. 0; hazard ratio (HR) =3.13, 95% confidence interval (CI): 1.61-6.10; P<0.001] was independently associated with PFS. ECOG PS 1 (vs. 0; HR =3.63, 95% CI: 1.54-8.56; P=0.003) and combined therapy (vs. monotherapy; HR =0.47, 95% CI: 0.22-0.99; P=0.048) were associated with OS. Conclusions: Regorafenib combined with ICIs led to numerically longer PFS and significantly prolonged OS in patients with mCRC compared to regorafenib monotherapy, especially in male patients.

RESUMEN

Fibronectin (FN) is an essential component of the extracellular matrix (ECM) that protects the integrity of the microvascular endothelial barrier (MEB). However, Treponema pallidum subsp. pallidum (Tp) breaches this barrier through elusive mechanisms and rapidly disseminates throughout the host. We aimed to understand the impact of Tp on the surrounding FN matrix of MEB and the underlying mechanisms of this effect. In this study, immunofluorescence assays (IF) were conducted to assess the integrity of the FN matrix surrounding human microvascular endothelial cell-1 (HMEC-1) with/without Tp co-culture, revealing that only live Tp exhibited the capability to mediate FN matrix disaggregation in HMEC-1. Western blotting and IF were employed to determine the protein levels associated with the FN matrix during Tp infection, which showed the unaltered protein levels of total FN and its receptor integrin α5ß1, along with reduced insoluble FN and increased soluble FN. Simultaneously, the integrin α5ß1-binding protein-intracellular vimentin maintained a stable total protein level while exhibiting an increase in the soluble form, specifically mediated by the phosphorylation of its 39th residue (pSer39-vimentin). Besides, this process of vimentin phosphorylation, which could be hindered by a serine-to-alanine mutation or inhibition of phosphorylated-AKT1 (pAKT1), promoted intracellular vimentin rearrangement and FN matrix disaggregation. Moreover, within the introduction of additional cellular FN rather than other Tp-adhered ECM protein, in vitro endothelial barrier traversal experiment and in vivo syphilitic infectivity test demonstrated that viable Tp was effectively prevented from penetrating the in vitro MEB or disseminating in Tp-challenged rabbits. This investigation revealed the active pAKT1/pSer39-vimentin signal triggered by live Tp to expedite the disaggregation of the FN matrix and highlighted the importance of FN matrix stability in syphilis, thereby providing a novel perspective on ECM disruption mechanisms that facilitate Tp dissemination across the MEB.

Asunto(s)

RESUMEN

BACKGROUND: This study aimed to develop a comprehensive model based on five GLIM variables to predict the individual survival and provide more appropriate patient counseling. METHODS: This retrospective cohort study included 301 gastric cancer (GC) patients undergoing radical resection. C-reactive protein (CRP) as an inflammatory marker was included in GLIM criteria and a nomogram for predicting 5-year overall survival (OS) in GC patients was established. The Bootstrap repeated sampling for 1000 times was used for internal validation. RESULTS: Of the total 301 patients, 20 (6.64%) died within 5 years. CRP improved the sensitivity and accuracy of the survival prediction model (AUC = 0.782, 0.694 to 0.869 for the model without CRP; AUC = 0.880, 0.809 to 0.950 for the model adding CRP). Besides, a GLIM-based nomogram was established with an AUC of 0.889. The C-index for predicting OS was 0.878 (95% CI: 0.823 to 0.934), and the calibration curve fitted well. Decision curve analysis (DCA) showed the clinical utility of the nomogram based on GLIM. CONCLUSION: The addition of CRP improved the sensitivity and accuracy of the survival prediction model. The 5-year survival probability of GC patients undergoing radical resection can be reliably predicted by the nomogram presented in this study.

Asunto(s)

RESUMEN

Historical chlor-alkali production has led to substantial concentrations of persistent organic pollutant residues in the environment. This study systematically investigated the distribution of polycyclic aromatic hydrocarbons (PAHs), chlorinated/brominated-PAHs (Cl/Br-PAHs), polychlorinated naphthalenes (PCNs), and hexachlorobutadiene (HCBD) in sediment, lotus (Nelumbo nucifera), and fish samples from Ya-Er Lake, which is a site in China with historical chlor-alkali contamination. The average concentrations [(4.97-1.47) × 103 ng/g dry weight (dw)] of these pollutants in backfill sediments, which were dredged from the lake after chlor-alkali production stopped, were 2.68-70.87 times those in fresh lake sediments (0.622-218 ng/g dw) and reported concentrations in other areas. Correlation analyses indicated that Cl-PAHs, Br-PAHs, and PCNs likely originated from halogenation of parent PAHs in the study area, and the chlorination ratios were larger than those of bromination. The Cl(1/2/3)-PAHs/PAHs and Br(1)-PAHs/PAHs ratios were higher than those for PAHs with more halogen atoms. This contamination extended into the biota, with notable pollutant burdens found in lotus (Nelumbo nucifera, 0.305-77.3 ng/g dw) and even higher concentrations in fish (2.20-345 ng/g lipid weight). Estimated biological soil accumulation factors revealed significant enrichment in lotus organs (mean: 7.19) and fish muscle (mean: 10.65), especially the latter, which highlighted bioaccumulation and potential food chain transfer risks. The estimated daily intakes of PAHs, Cl/Br-PAHs, and HCBD through fish consumption currently pose negligible risks, while dietary intake of PCNs may present health concerns. Continuous monitoring and impact assessments are crucial for developing appropriate risk management strategies to safeguard public health.

RESUMEN

Diabetic peripheral neuropathy (DPN) is a complication of diabetes mellitus that lacks specific treatment, its high prevalence and disabling neuropathic pain greatly affects patients' physical and mental health. Schwann cells (SCs) are the major glial cells of the peripheral nervous system, which play an important role in various inflammatory and metabolic neuropathies by providing nutritional support, wrapping axons and promoting repair and regeneration. Increasingly, high glucose (HG) has been found to promote the progression of DPN pathogenesis by targeting SCs death regulation, thus revealing the specific molecular process of programmed cell death (PCD) in which SCs are disrupted is an important link to gain insight into the pathogenesis of DPN. This paper is the first to review the recent progress of HG studies on apoptosis, autophagy, pyroptosis, ferroptosis and necroptosis pathways in SCs, and points out the crosstalk between various PCDs and the related therapeutic perspectives, with the aim of providing new perspectives for a deeper understanding of the mechanisms of DPN and the exploration of effective therapeutic targets.

Asunto(s)

RESUMEN

The type VI secretion system 2 (T6SS2) gene cluster of Vibrio parahaemolyticus comprises three operons: VPA1027-1024, VPA1043-1028, and VPA1044-1046. AcsS is a LysR-like transcriptional regulator that play a role in activating flagella-driven motility in V. parahaemolyticus. However, its potential roles in other cellular pathways remain poorly understood. In this study, we conducted a series of experiments to investigate the regulatory effects of AcsS on the transcription of VPA1027 (hcp2), VPA1043, and VPA1044. The findings revealed that AcsS indirectly inhibits the transcription of these genes. Additionally, deletion of acsS resulted in enhanced adhesion of V. parahaemolyticus to HeLa cells. However, disruption of T6SS2 alone or in conjunction with AcsS significantly diminished the adhesion capacity of V. parahaemolyticus to HeLa cells. Therefore, it is suggested that AcsS suppresses cell adhesion in V. parahaemolyticus by downregulating the transcription of T6SS2 genes.

Asunto(s)

RESUMEN

BACKGROUND: Our previous study synthesized the analgesic effects of repetitive Transcranial Magnetic Stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) trials up to 2019. There has been a significant increase in pain trials in the past few years, along with methodological variabilities such as sample size, stimulation intensity, and rTMS paradigms. OBJECTIVES/METHODS: This study therefore updated the effects of DLPFC-rTMS on chronic pain and quantified the impact of methodological differences across studies. RESULTS: A total of 36 studies were included. Among them, 26 studies were clinical trials (update = 9, 307/711 patients), and 10 (update = 1, 34/249 participants) were provoked pain studies. The updated meta-analysis does not support an effect on neuropathic pain after including the additional trials (pshort-term = 0.20, pmid-term = 0.50). However, there is medium-to-large analgesic effect in migraine trials extending up to six weeks follow-up (SMDmid-term = -0.80, SMDlong-term = -0.51), that was not previously reported. Methodological differences wthine the studies were considered. DLPFC-rTMS also induces potential improvement in the emotional aspects of pain (SMDshort-term = -0.28). CONCLUSIONS: The updated systematic meta-analysis continues to support analgesic effects for chronic pain overall. However, the updated results no longer support DLPFC-rTMS for pain relief in neuropathic pain, and do supports DLPFC-rTMS in the management of migraine. There is also evidence for DLPFC-rTMS to improve emotional aspects of pain.

Asunto(s)

RESUMEN

INTRODUCTION: Premature ovarian insufficiency [POI] is a disease characterized by a premature decline in ovarian function before the age of 40. In China, Ligustrum lucidum [FLL] has long been used to improve ovarian function and treat POI. METHODS: This study aims to verify the effect of FLL on POI through network pharmacology, molecular docking, and in-vitro cell experiments. RESULTS: A total of 13 active substances were screened in FLL, including including quercetin, taxifolin, luteolin, kaempferol, and beta-sitosterol. Then, network analysis found that FLL may exert effects on POI through 10 targets, including AR, ESR1, ESR2, KDR, CYP19A1, CLPP, GC, MMP3, PPARG, and STS. According to GO and KEGG enrichment analysis, FLL is associated with mechanisms related to estrogen, including steroid hormone biosynthesis, ovarian steroidogenesis, and the estrogen signaling pathway. Molecular docking confirms the interaction between the active ingredients of FLL and CYP19A1, which encodes aromatase. CCK8 experiment confirmed that quercetin and taxifolin can enhance the proliferation of KGN granulosa cells, while quercetin, taxifolin, and kaempferol can inhibit the apoptosis of KGN granulosa cells. ELISA experiments have confirmed that quercetin, taxifolin, luteolin, and kaempferol can increase the synthesis of estradiol in KGN granulosa cells. WB confirms that quercetin can increase the expression level of CYP19A1 in KGN cells. CONCLUSION: FLL can improve the proliferation, apoptosis, and synthesis of estradiol in ovarian granulosa cells, and has the potential to treat POI.

RESUMEN

High-performance n-type organic mixed ionic-electronic conductors (OMIECs) are essential for advancing complementary circuits based on organic electrochemical transistors (OECTs). Despite significant progress, current n-type OMIECs often exhibit lower transconductance and slower response times compared to their p-type counterparts, limiting the development of OECT-based complementary circuits. Optimizing the conjugated backbone and side chain structures of OMIECs is critical for enhancing both ion and electron transport efficiencies while maintaining a delicate balance between the two. In this study, hydrophilic polyethylene glycol (PEG) side chains were incorporated into the highly conductive n-type polymer poly(3,7-dihydrobenzo[1,2-b:4,5-b']difuran-2,6-dione) (PBFDO) backbone to achieve this goal. The incorporation of PEG chains improved ion accessibility, and by adjusting the PEG content, the electronic and ionic transport properties were fine-tuned, ultimately enhancing the performance of OECTs and related p-n complementary circuits. The n-type OECTs based on PBFDO-PEG50wt% demonstrated exceptional transfer characteristics, including a transient response time (τON) as low as 72 µs, a high geometry-normalized transconductance exceeding 400 S cm-1, and an impressive µC* value surpassing 720 F cm-1 V-1 s-1. Notably, the use of PBFDO-PEG50wt% in a complementary inverter resulted in a voltage gain of 20 V/V, more than five times higher than that achieved with unmodified PBFDO (<4 V/V). These findings highlight the importance of balancing electron and ion transport characteristics in OMIECs to achieve high performance in OECTs and their associated circuits, and they validate PEG decoration as an effective approach.

RESUMEN

The trophoblast lineage differentiation represents a rate-limiting step in successful embryo implantation. Adhesion, invasion and migration processes within the trophoblast are governed by several transcription factors. Among them, CDX2 is a critical regulator shaping the destiny of the trophoblast. While its altered expression is a linchpin initiating embryo implantation in mice, the precise influence of CDX2 on the functionality and lineage differentiation of early human trophoblast remains unclear. In this study, we employed well-established human trophoblast stem cell (hTSC) lines with CDX2 overexpression coupled with a 3D in vitro culture system for early human embryos. We revealed that the downregulation of CDX2 is a prerequisite for syncytialization during human embryo implantation based on immunofluorescence, transcriptome analysis, CUT-tag sequencing and the construction of 3D human trophoblast organoids. While CDX2 overexpression inhibited syncytialization, it propelled hTSC proliferation and invasive migration. CDX2 exerted its influence by interacting with CGA, PTGS2, GCM1, LEF1 and CDH2, thereby hindering premature differentiation of the syncytiotrophoblast. CDX2 overexpression enhanced the epithelial-mesenchymal transition of human trophoblast organoids. In summary, our study provides insights into the molecular characteristics of trophoblast differentiation and development in humans, laying a theoretical foundation for advancing research in embryo implantation.

RESUMEN

Due to the swift advancement of the Internet of Things (IoT), there has been a significant surge in the quantity of interconnected IoT devices that send and exchange vital data across the network. Nevertheless, the frequency of attacks on the Internet of Things is steadily rising, posing a persistent risk to the security and privacy of IoT data. Therefore, it is crucial to develop a highly efficient method for detecting cyber threats on the Internet of Things. Nevertheless, several current network attack detection schemes encounter issues such as insufficient detection accuracy, the curse of dimensionality due to excessively high data dimensions, and the sluggish efficiency of complex models. Employing metaheuristic algorithms for feature selection in network data represents an effective strategy among the myriad of solutions. This study introduces a more comprehensive metaheuristic algorithm called GQBWSSA, which is an enhanced version of the Salp Swarm Algorithm with several strategy improvements. Utilizing this algorithm, a threshold voting-based feature selection framework is designed to obtain an optimized set of features. This procedure efficiently decreases the number of dimensions in the data, hence preventing the negative effects of having a high number of dimensions and effectively extracting the most significant and crucial information. Subsequently, the extracted feature data is combined with the LightGBM algorithm to form a lightweight and efficient ensemble learning scheme for IoT attack detection. The proposed enhanced metaheuristic algorithm has superior performance in feature selection compared to the recent metaheuristic algorithms, as evidenced by the experimental evaluation conducted using the NSLKDD and CICIoT2023 datasets. Compared to current popular ensemble learning solutions, the proposed overall solution exhibits excellent performance on multiple key indicators, including accuracy, precision, as well as training and detection time. Especially on the large-scale dataset CICIoT2023, the proposed scheme achieves an accuracy rate of 99.70% in binary classification and 99.41% in multi classification.

RESUMEN

The aim of this study was to investigate the prevalence of Vibrionaceae family in retail seafood products available in the Qidong market during the summer of 2023 and to characterize Vibrio parahaemolyticus isolates, given that this bacterium is the leading cause of seafood-associated food poisoning. We successfully isolated a total of 240 Vibrionaceae strains from a pool of 718 seafood samples. The breakdown of the isolates included 146 Photobacterium damselae, 59 V. parahaemolyticus, 18 V. campbellii, and 11 V. alginolyticus. Among these, P. damselae and V. parahaemolyticus were the predominant species, with respective prevalence rates of 20.3% and 8.2%. Interestingly, all 59 isolates of V. parahaemolyticus were identified as non-pathogenic. They demonstrated proficiency in swimming and swarming motility and were capable of forming biofilms across a range of temperatures. In terms of antibiotic resistance, the V. parahaemolyticus isolates showed high resistance to ampicillin, intermediate resistance to cefuroxime and cefazolin, and were sensitive to the other antibiotics evaluated. The findings of this study may offer valuable insights and theoretical support for enhancing seafood safety measures in Qidong City.

Asunto(s)

RESUMEN

This research focused on utilizing banana peel as the primary material for producing mesoporous biomass charcoal through one-step potassium hydroxide activation. Subsequently, the biomass charcoal underwent high-temperature calcination with varying impregnation ratios of KOH : BC for different durations in tubular furnaces set at different temperatures. The resultant biomass charcoal was then subjected to hydrothermal treatment with FeCl3·6H2O to produce biochar/iron oxide composites. The adsorption capabilities of these composites towards methylene blue (MB) were examined under various conditions, including pH (ranging from 3 to 12), temperature variations, and initial MB concentrations (ranging from 50 to 400 mg L-1). The adsorption behavior aligned with the Langmuir model and demonstrated quasi-secondary kinetics. After five adsorption cycles, the capacity decreased from 618.64 mg g-1 to 497.18 mg g-1, indicating considerable stability. Notably, Fe3O4-N-BC exhibited exceptional MB adsorption performance.

Asunto(s)

RESUMEN

As an emergent pollutant, microplastics (MPs) are becoming prevalent in the soil environment. However, the characteristics of MPs and the response of microbial communities to the abundance of MPs in agricultural soils in West China still need to be elucidated in detail. This study utilized the Agilent 8700 Laser Direct Infrared (LDIR) to analyze the characteristics of small-sized MPs (20-1000 µm) in soils from un-mulched and mulched agricultural fields in West China, and illustrated their correlation with microbial diversity. The results revealed a higher abundance of MPs in mulched soil ((4.12 ± 2.13) × 105 items kg-1) than that in un-mulched soil ((1.04 ± 0.26) × 105 items kg-1). The detected MPs were dominated by fragments, 20-50 µm and Polyamide (PA). High-throughput sequencing analysis indicated that alpha diversity (Chao1 and Shannon indices) in the plastisphere was lower compared to that in soil, and varied significantly with MPs abundance in soil. As the abundance of MPs increased, the proportion of soil about the degradation of organic matte and photoautotrophic taxa increased, which showed enrichment in the plastisphere. Functional predictions further indicated that MPs abundance affected potential soil functions, such as metabolic pathways associated with the C and N cycling. The plastisphere showed higher functional abundance associated with organic matter degradation, indicating higher potential health risks compared to soil environments. Based on the RDA analyses, it was determined that environmental physicochemical properties and MPs abundance had a greater impact on fungal communities than on bacterial communities. In general, the abundance of MPs affected the microbial diversity composition and potentially influenced the overall performance of soil ecosystems. This study offers empirical data on the abundance of MPs in long-term mulched agricultural fields and new insights for exploring the ecological risk issues associated with MPs.

Asunto(s)

RESUMEN

Recent research has revealed that N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) constitutes a significant risk factor in the development of esophageal cancer. Several investigations have elucidated the beneficial impact of folic acid (FA) in safeguarding esophageal epithelial cells against MNNG-induced damage. Therefore, we hypothesized that FA might prevent MNNG-induced proliferation of esophageal epithelial cells by interfering with the PI3K/AKT/mTOR signaling pathway. In vivo experiments, we found that FA antagonized MNNG-induced proliferation of rat esophageal mucosal epithelial echinocytes and activation of the PI3K/AKT/mTOR signaling pathway. In our in vitro experiments, it was observed that acute exposure to MNNG for 24 h led to a decrease in proliferative capacity and inhibition of the PI3K/AKT/mTOR signaling pathway in an immortalized human normal esophageal epithelial cell line (Het-1A), which was also ameliorated by supplementation with FA. We successfully established a Het-1A-T-cell line by inducing malignant transformation in Het-1A cells through exposure to MNNG. Notably, the PI3K/AKT2/mTOR pathway showed early suppression followed by activation during this transition. Next, we observed that FA inhibited cell proliferation and activation of the PI3K/AKT2/mTOR signaling pathway in Het-1A-T malignantly transformed cells. We further investigated the impact of 740Y-P, a PI3K agonist, and LY294002, a PI3K inhibitor, on Het-1A-T-cell proliferation. Overall, our findings show that FA supplementation may be beneficial in safeguarding normal esophageal epithelial cell proliferation and avoiding the development of esophageal cancer by decreasing the activation of the MNNG-induced PI3K/AKT2/mTOR signaling pathway.

Asunto(s)

RESUMEN

High salt (HS) consumption is a risk factor for multiple autoimmune disorders via disturbing immune homeostasis. Nevertheless, the exact mechanisms by which HS exacerbates rheumatoid arthritis (RA) pathogenesis remain poorly defined. Herein, we found that heightened phosphorylation of PDPK1 and SGK1 upon HS exposure attenuated FoxO1 expression to enhance the glycolytic capacity of CD4 T cells, resulting in strengthened Th17 but compromised Treg program. GSK2334470 (GSK), a dual PDPK1/SGK1 inhibitor, effectively mitigated the HS-induced enhancement in glycolytic capacity and the overproduction of IL-17A. Therefore, administration of GSK markedly alleviated HS-exacerbated RA progression in collagen-induced arthritis (CIA) model. Collectively, our data indicate that HS consumption subverts Th17/Treg homeostasis through the PDPK1-SGK1-FoxO1 signaling, while GSK could be a viable drug against RA progression in clinical settings.