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BACKGROUND: Toxoplasmosis, caused by Toxoplasma gondii , poses serious health issues for humans and animals. Individuals with impaired immune systems are more susceptible to severe toxoplasmosis. Pregnant women infected by T. gondii can face the possibility of birth defects and miscarriages. While pyrimethamine and sulfadiazine are commonly used drugs in clinical practice, concerns over their side effects and resistance are on the rise. A spider peptide XYP1 isolated from Lycosa coelestis had potent anti-T. gondii effects, but it had a high synthesis cost and strong cytotoxicity. METHODS: This study intended to modify XYP1 for producing derived peptides via amino acid truncation and substitution. The anti-T. gondii effect was evaluated by trypan blue staining assay and killing experiment of RH strain tachyzoites. The CCK8 and hemolysis assays were used to compare their safeties. The morphological changes of T. gondii were observed by scanning electron microscope and transmission electron microscope. In addition, the mechanism of XYP1 against T. gondii through RNA-sequencing was further explored. RESULTS: In vivo and in vitro experiments revealed that XYP1-18 and XYP1-18-1 had excellent anti-T. gondii activity with lower cytotoxicity and hemolysis activity than XYP1. XYP1, XYP1-18, and XYP1-18-1 were able to disrupt the surface membrane integrity of T. gondii tachyzoites, forming pores and causing the disruption of organelles. Furthermore, RNA-sequencing analysis indicated that XYP1 could stimulate the host immune response to effectively eliminate T. gondii and lessen the host's inflammatory reaction. CONCLUSIONS: XYP1-18 had lower cytotoxicity and hemolysis activity than XYP1, as well as significantly extending the survival time of the mice. XYP1 played a role in host inflammation and immune responses, revealing its potential mechanism. Our research provided valuable insights into the development and application of peptide-based drugs, offering novel strategies and directions for treating toxoplasmosis.

Asunto(s)

Toxoplasma , Toxoplasma/efectos de los fármacos , Animales , Ratones , Femenino , Péptidos/farmacología , Toxoplasmosis/parasitología , Antiprotozoarios/farmacología , Hemólisis/efectos de los fármacos , Humanos

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This study aimed to determine changes in the hydrolysis of vicagrel, a substrate drug of arylacetamide deacetylase (Aadac) and carboxylesterase 2 (Ces2), in P-glycoprotein (P-gp)-deficient or P-gp-inhibited mice and to elucidate the mechanisms involved.Male wild-type (WT) and P-gp knock-out (KO) mice were used to investigate the systemic exposure of vicagrel thiol active metabolite H4 and platelet response to vicagrel, and the mRNA and protein expression levels of intestinal Aadac and Ces2. Moreover, WT mice were administered vicagrel alone or in combination with elacridar (a potent P-gp inhibitor) to determine drug-drug interactions.Compared with WT mice, P-gp KO mice exhibited significant increases in the systemic exposure of H4, the protein expression levels of intestinal Aadac and Ces2, and inhibition of ADP-induced platelet aggregation by vicagrel. Further, the H4 exposure was positively correlated with intestinal Aadac protein expression levels but did not vary with short-term inhibition of P-gp efflux activity by elacridar.P-gp-deficient mice, rather than elacridar-treated mice, exhibited significant upregulation of intestinal Aadac and Ces2 and thus, enhanced metabolic activation of and platelet response to vicagrel, suggesting that the metabolic activation of vicagrel may vary with P-gp deficiency, not P-gp inhibition, in mice.

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BACKGROUND: Serum lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) in the general population, its association with ASCVD incidence in Chinese maintenance hemodialysis (MHD) patients remains unclear. We aimed to evaluate the relationship between Lp(a) levels and ASCVD incidence among MHD patients in Beijing, China. METHODS: This retrospective, observational cohort study included MHD patients at Beijing Tongren Hospital from January 1, 2013 to December 1, 2020, and followed until December 1,2023. The primary outcome was ASCVD occurrence. Kaplan-Meier survival analysis was used to evaluate ASCVD-free survival in MHD patients, with stratification based on Lp(a) levels. Cox regression analyses were conducted to assess the association between Lp(a) levels and the occurrence of ASCVD. RESULTS: A total of 265 patients were enrolled in the study. The median follow-up period were 71 months.78 (29.4%) participants experienced ASCVD events, and 118 (47%) patients died, with 58 (49.1%) deaths attributed to ASCVD. Spearman rank correlation analyses revealed positive correlations between serum Lp(a) levels and LDL-c levels, and negative correlations with hemoglobin, triglyceride, serum iron, serum creatinine, and albumin levels. Multivariate Cox regression analysis showed that Lp(a) levels ≥ 30 mg/L, increased age, decreased serum albumin levels, and a history of diabetes mellitus were significantly associated with ASCVD incidence. CONCLUSIONS: This study demonstrated an independent and positive association between serum Lp(a) levels and the risk of ASCVD in MHD patients, suggesting that serum Lp(a) could potentially serve as a clinical biomarker for estimating ASCVD risk in this population.

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Aterosclerosis , Lipoproteína(a) , Diálisis Renal , Humanos , Masculino , Femenino , Estudios Retrospectivos , Lipoproteína(a)/sangre , Persona de Mediana Edad , Aterosclerosis/sangre , Aterosclerosis/epidemiología , Anciano , Beijing/epidemiología , Factores de Riesgo , Incidencia , Estudios de Cohortes

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To address issues of global energy sustainability, it is essential to develop highly efficient bifunctional transition metal-based electrocatalysts to accelerate the kinetics of both the hydrogen evolution reaction (HER) and the oxygen evolution reaction (OER). Herein, the heterogeneous molybdenum and vanadium codoped cobalt carbonate nanosheets loaded on nickel foam (VMoCoCOx@NF) are fabricated by facile hydrothermal deposition. Firstly, the mole ratio of V/Mo/Co in the composite is optimized by response surface methodology (RSM). When the optimized composite serves as a bifunctional catalyst, the water-splitting current density achieves 10 mA cm-2 and 100 mA cm-2 at cell voltages of 1.54 V and 1.61 V in a 1.0 M KOH electrolyte with robust stability. Furthermore, characterization is carried out using field emission scanning electron microscopy-energy dispersive spectroscopy (FESEM-EDS), high-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). Density functional theory (DFT) calculations reveal that the fabricated VMoCoCOx@NF catalyst synergistically decreases the Gibbs free energy of hydrogen and oxygen-containing intermediates, thus accelerating OER/HER catalytic kinetics. Benefiting from the concerted advantages of porous NF substrates and clustered VMoCoCOx nanosheets, the fabricated catalyst exhibits superior electrocatalytic performance. This work presents a novel approach to developing transition metal catalysts for overall water splitting.

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Mitochondrial Pyruvate Carrier 1 (MPC1) is localized on mitochondrial outer membrane to mediate the transport of pyruvate from cytosol to mitochondria. It is also well known to act as a tumor suppressor. Hexavalent chromium (Cr (VI)) contamination poses a global challenge due to its high toxicity and carcinogenesis. This research was intended to probe the potential mechanism of MPC1 in the effect of Cr (VI)-induced carcinogenesis. First, Cr (VI)-treatments decreased the expression of MPC1 in vitro and in vivo. Overexpression of MPC1 inhibited Cr (VI)-induced glycolysis and migration in A549 cells. Then, high mobility group A2 (HMGA2) protein strongly suppressed the transcription of MPC1 by binding to its promoter, and HMGA2/MPC1 axis played an important role in oxidative phosphorylation (OXPHOS), glycolysis and cell migration. Furthermore, endoplasmic reticulum (ER) stress made a great effect on the interaction between HMGA2 and MPC1. Finally, the mammalian target of the rapamycin (mTOR) was determined to mediate MPC1-regulated OXPHOS, aerobic glycolysis and cell migration. Collectively, our data revealed a novel HMGA2/MPC-1/mTOR signaling pathway to promote cell growth via facilitating the metabolism reprogramming from OXPHOS to aerobic glycolysis, which might be a potential therapy for cancers.

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Movimiento Celular , Proliferación Celular , Cromo , Glucólisis , Proteína HMGA2 , Transportadores de Ácidos Monocarboxílicos , Transducción de Señal , Serina-Treonina Quinasas TOR , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Glucólisis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Proteína HMGA2/metabolismo , Proteína HMGA2/genética , Movimiento Celular/efectos de los fármacos , Cromo/farmacología , Proliferación Celular/efectos de los fármacos , Animales , Transportadores de Ácidos Monocarboxílicos/metabolismo , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Células A549 , Ratones , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ratones Desnudos , Proteínas de Transporte de Membrana/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Ratones Endogámicos BALB C , Línea Celular Tumoral , Proteínas de Transporte de Membrana Mitocondrial

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Neurodegenerative diseases like Alzheimer's and Parkinson's disease (AD and PD) are well-known, yet their underlying causes remain unclear. Recent studies have suggested that disruption of ion channels contribute to their pathogenesis. Among these channels, the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, encoded by HCN1-4 genes, are of particular interest due to their role in generating hyperpolarization-activated current (Ih), which is crucial in various neural activities impacting memory and motor functions. A growing body of evidence underscores the pivotal role of HCN in Aß generation, glial cell function, and ischemia-induced dementia; while HCN is expressed in various regions of the basal ganglia, modulating their functions and influencing motor disorders in PD; neuroinflammation triggered by microglial activation represents a shared pathological mechanism in both AD and PD, in which HCN also plays a significant part. This review delves into the neuronal functions governed by HCN, its roles in the aforementioned pathogenesis, its expression patterns in AD and PD, and discusses potential therapeutic drugs targeting HCN for the treatment of these diseases, aiming to offer a novel perspective and inspire future research endeavors.

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Enfermedad de Alzheimer , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización , Enfermedad de Parkinson , Humanos , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Parkinson/metabolismo , Animales

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Background and Aims: Hepatocellular carcinoma (HCC) cases with small nodules are commonly treated with radiofrequency ablation (RFA), but the recurrence rate remains high. This study aimed to establish a blood signature for identifying HCC with metastatic traits pre-RFA. Methods: Data from HCC patients treated between 2010 and 2017 were retrospectively collected. A blood signature for metastatic HCC was established based on blood levels of alpha-fetoprotein and des-γ-carboxy-prothrombin, cell-free DNA (cfDNA) mutations, and methylation changes in target genes in frozen-stored plasma samples that were collected before RFA performance. The HCC blood signature was validated in patients prospectively enrolled in 2021. Results: Of 251 HCC patients in the retrospective study, 33.9% experienced recurrence within 1 year post-RFA. The HCC blood signature identified from these patients included des-γ-carboxy-prothrombin ≥40 mAU/mL with cfDNA mutation score, where cfDNA mutations occurred in the genes of TP53, CTNNB1, and TERT promoter. This signature effectively predicted 1-year post-RFA recurrence of HCC with 92% specificity and 91% sensitivity in the retrospective dataset, and with 87% specificity and 76% sensitivity in the prospective dataset (n=32 patients). Among 14 cases in the prospective study with biopsy tissues available, positivity for the HCC blood signature was associated with a higher HCC tissue score and shorter distance between HCC cells and microvasculature. Conclusions: This study established an HCC blood signature in pre-RFA blood that potentially reflects HCC with metastatic traits and may be valuable for predicting the disease's early recurrence post-RFA.

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Remote ischemic preconditioning (RIPC) exerts a protective role on myocardial ischemia/reperfusion (I/R) injury by the release of various humoral factors. Lactate is a common metabolite in ischemic tissues. Nevertheless, little is known about the role lactate plays in myocardial I/R injury and its underlying mechanism. This investigation revealed that RIPC elevated the level of lactate in blood and myocardium. Furthermore, AZD3965, a selective monocarboxylate transporter 1 inhibitor, and 2-deoxy-d-glucose, a glycolysis inhibitor, mitigated the effects of RIPC-induced elevated lactate in the myocardium and prevented RIPC against myocardial I/R injury. In an in vitro hypoxia/reoxygenation model, lactate markedly mitigated hypoxia/reoxygenation-induced cell damage in H9c2 cells. Meanwhile, further studies suggested that lactate contributed to RIPC, rescuing I/R-induced autophagy deficiency by promoting transcription factor EB (TFEB) translocation to the nucleus through activating the AMPK-mammalian target of rapamycin (mTOR) pathway without influencing the phosphatidylinositol 3-kinase-Akt pathway, thus reducing cardiomyocyte damage. Interestingly, we also found that lactate up-regulated the mRNA and protein expression of connexin 43 (CX43) by facilitating the binding of TFEB to CX43 promoter in the myocardium. Functionally, silencing of TFEB attenuated the protective effect of lactate on cell damage, which was reversed by overexpression of CX43. Further mechanistic studies suggested lactate facilitated CX43-regulated autophagy via the AMPK-mTOR-TFEB signaling pathway. Collectively, our research demonstrates that RIPC protects against myocardial I/R injury through lactate-mediated myocardial autophagy via the AMPK-mTOR-TFEB-CX43 axis.

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Cardiac myosin-binding protein C (cMyBP-C) is a novel cardiac marker of acute myocardial infarction (AMI) and acute cardiac injuries (ACI). Construction of point-of-care testing techniques capable of sensing cMyBP-C with high sensitivity and precision is urgently needed. Herein, we synthesized an Au@NGQDs@Au/Ag multi-shell nanoUrchins (MSNUs), and then applied it in a colorimetric/SERS dual-mode immunoassay for detection of cMyBP-C. The MSNUs displayed superior stability, colorimetric brightness, and SERS enhancement ability with an enhanced factor of 5.4 × 109, which were beneficial to improve the detection capability of test strips. The developed MSNU-based test strips can achieve an ultrasensitive immunochromatographic assay of cMyBP-C in both colorimetric and SERS modes with the limits of detection as low as 19.3 and 0.77 pg/mL, respectively. Strikingly, this strip was successfully applied to analyze actual plasma samples with significantly better sensitivity, negative predictive value, and accuracy than commercially available gold test strips. Notably, this method possessed a wide range of application scenarios via combining with a color recognizer application named Color Grab on the smartphone, which can meet various needs of different users. Overall, our MSNU-based test strip as a mobile health monitoring tool shows excellent sensitivity, reproducibility, and rapid detection of the cMyBP-C, which holds great potential for the early clinic diagnosis of AMI and ACI.

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Proteínas Portadoras , Oro , Humanos , Inmunoensayo/métodos , Proteínas Portadoras/sangre , Oro/química , Límite de Detección , Colorimetría/métodos , Nanopartículas del Metal/química , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/sangre , Espectrometría Raman/métodos

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Agriculture receives approximately 25 % of the annual global nitrogen input, 37 % of which subsequently runs off into adjacent low-order streams and surface water, where it may contribute to high nitrification and nitrous oxide (N2O). However, the mechanisms of nitrification and the pathways controlling N2O production in agricultural streams remain unknown. Here, we report that the third microbial ammonia oxidation process, complete ammonia oxidation (comammox), is widespread and contributes to important ammonia oxidation with low ammonia-N2O conversion in both basin- and continental-scale agricultural streams. The contribution of comammox to ammonia oxidation (21.5 ± 2.3 %) was between that of bacterial (68.6 ± 2.7 %) and archaeal (9.9 ± 1.8 %) ammonia oxidation. Interestingly, N2O production by comammox (18.5 ± 2.1 %) was higher than archaeal (10.5 ± 1.9 %) but significantly lower than bacterial (70.2 ± 2.6 %) ammonia oxidation. The first metagenome-assembled genome (MAG) of comammox bacteria from agricultural streams further revealed their potential extensive diverse and specific metabolism. Their wide habitats might be attributed to the diverse metabolism, i.e. harboring the functional gene of nitrate reduction to ammonia, while the lower N2O would be attributed to their lacking biological function to produce N2O. Our results highlight the importance of widespread comammox in agricultural streams, both for the fate of ammonia fertilizer and for climate change. However, it has not yet been routinely included in Earth system models and IPCC global assessments. Synopsis Widespread but overlooked comammox contributes to important ammonia oxidation but low N2O production, which were proved by the first comammox MAG found in agricultural streams.

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Agricultura , Amoníaco , Archaea , Bacterias , Óxido Nitroso , Oxidación-Reducción , Ríos , Amoníaco/metabolismo , Óxido Nitroso/metabolismo , Óxido Nitroso/análisis , Archaea/metabolismo , Bacterias/metabolismo , Nitrificación

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RATIONALE AND OBJECTIVES: to develop a deep learning radiomics graph network (DLRN) that integrates deep learning features extracted from gray scale ultrasonography, radiomics features and clinical features, for distinguishing parotid pleomorphic adenoma (PA) from adenolymphoma (AL) MATERIALS AND METHODS: A total of 287 patients (162 in training cohort, 70 in internal validation cohort and 55 in external validation cohort) from two centers with histologically confirmed PA or AL were enrolled. Deep transfer learning features and radiomics features extracted from gray scale ultrasound images were input to machine learning classifiers including logistic regression (LR), support vector machines (SVM), KNN, RandomForest (RF), ExtraTrees, XGBoost, LightGBM, and MLP to construct deep transfer learning radiomics (DTL) models and Rad models respectively. Deep learning radiomics (DLR) models were constructed by integrating the two features and DLR signatures were generated. Clinical features were further combined with the signatures to develop a DLRN model. The performance of these models was evaluated using receiver operating characteristic (ROC) curve analysis, calibration, decision curve analysis (DCA), and the Hosmer-Lemeshow test. RESULTS: In the internal validation cohort and external validation cohort, comparing to Clinic (AUC=0.767 and 0.777), Rad (AUC=0.841 and 0.748), DTL (AUC=0.740 and 0.825) and DLR (AUC=0.863 and 0.859), the DLRN model showed greatest discriminatory ability (AUC=0.908 and 0.908) showed optimal discriminatory ability. CONCLUSION: The DLRN model built based on gray scale ultrasonography significantly improved the diagnostic performance for benign salivary gland tumors. It can provide clinicians with a non-invasive and accurate diagnostic approach, which holds important clinical significance and value. Ensemble of multiple models helped alleviate overfitting on the small dataset compared to using Resnet50 alone.

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BACKGROUND: Terpenes are important components of plant aromas, and terpene synthases (TPSs) are the key enzymes driving terpene diversification. In this study, we characterized the volatile terpenes in five different Chrysanthemum nankingense tissues. In addition, genome-wide identification and expression analysis of TPS genes was conducted utilizing an improved chromosome-scale genome assembly and tissue-specific transcriptomes. The biochemical functions of three representative TPSs were also investigated. RESULTS: We identified tissue-specific volatile organic compound (VOC) and volatile terpene profiles. The improved Chrysanthemum nankingense genome assembly was high-quality, including a larger assembled size (3.26 Gb) and a better contig N50 length (3.18 Mb) compared to the old version. A total of 140 CnTPS genes were identified, with the majority representing the TPS-a and TPS-b subfamilies. The chromosomal distribution of these TPS genes was uneven, and 26 genes were included in biosynthetic gene clusters. Closely-related Chrysanthemum taxa were also found to contain diverse TPS genes, and the expression profiles of most CnTPSs were tissue-specific. The three investigated CnTPS enzymes exhibited versatile activities, suggesting multifunctionality. CONCLUSIONS: We systematically characterized the structure and diversity of TPS genes across the Chrysanthemum nankingense genome, as well as the potential biochemical functions of representative genes. Our results provide a basis for future studies of terpene biosynthesis in chrysanthemums, as well as for the breeding of improved chrysanthemum varieties.

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Transferasas Alquil y Aril , Chrysanthemum , Genoma de Planta , Familia de Multigenes , Terpenos , Transferasas Alquil y Aril/genética , Transferasas Alquil y Aril/metabolismo , Chrysanthemum/genética , Chrysanthemum/enzimología , Terpenos/metabolismo , Filogenia , Compuestos Orgánicos Volátiles/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Transcriptoma

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Background: The segmentation of prostates from transrectal ultrasound (TRUS) images is a critical step in the diagnosis and treatment of prostate cancer. Nevertheless, the manual segmentation performed by physicians is a time-consuming and laborious task. To address this challenge, there is a pressing need to develop computerized algorithms capable of autonomously segmenting prostates from TRUS images, which sets a direction and form for future development. However, automatic prostate segmentation in TRUS images has always been a challenging problem since prostates in TRUS images have ambiguous boundaries and inhomogeneous intensity distribution. Although many prostate segmentation methods have been proposed, they still need to be improved due to the lack of sensibility to edge information. Consequently, the objective of this study is to devise a highly effective prostate segmentation method that overcomes these limitations and achieves accurate segmentation of prostates in TRUS images. Methods: A three-dimensional (3D) edge-aware attention generative adversarial network (3D EAGAN)-based prostate segmentation method is proposed in this paper, which consists of an edge-aware segmentation network (EASNet) that performs the prostate segmentation and a discriminator network that distinguishes predicted prostates from real prostates. The proposed EASNet is composed of an encoder-decoder-based U-Net backbone network, a detail compensation module (DCM), four 3D spatial and channel attention modules (3D SCAM), an edge enhancement module (EEM), and a global feature extractor (GFE). The DCM is proposed to compensate for the loss of detailed information caused by the down-sampling process of the encoder. The features of the DCM are selectively enhanced by the 3D spatial and channel attention module. Furthermore, an EEM is proposed to guide shallow layers in the EASNet to focus on contour and edge information in prostates. Finally, features from shallow layers and hierarchical features from the decoder module are fused through the GFE to predict the segmentation prostates. Results: The proposed method is evaluated on our TRUS image dataset and the open-source µRegPro dataset. Specifically, experimental results on two datasets show that the proposed method significantly improved the average segmentation Dice score from 85.33% to 90.06%, Jaccard score from 76.09% to 84.11%, Hausdorff distance (HD) score from 8.59 to 4.58 mm, Precision score from 86.48% to 90.58%, and Recall score from 84.79% to 89.24%. Conclusions: A novel 3D EAGAN-based prostate segmentation method is proposed. The proposed method consists of an EASNet and a discriminator network. Experimental results demonstrate that the proposed method has achieved satisfactory results on 3D TRUS image segmentation for prostates.

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BACKGROUND: Patients who have been treated with mechanical ventilation for more than 72 hours are susceptible to symptoms such as hypoxia and respiratory muscle fatigue after weaning, which may result in weaning difficulty and delay, as well as an increased incidence of negative emotions such as anxiety and depression. Correct pulmonary rehabilitation exercise technique and timing can improve the weaning success rate, reduce the disability rate, and reduce the incidence of pulmonary infection, as well as reduce medical expenses. OBJECTIVE: This article provides a review of pulmonary rehabilitation interventions for mechanically ventilated patients, searching relevant literature through databases such as CNKI and PubMed, aiming to provide guidance for the successful weaning of mechanically ventilated patients. METHODS: We selected articles related to pulmonary rehabilitation interventions for mechanically ventilated patients from CNKI (China National Knowledge Infrastructure) and PubMed over the years. RESULTS: This article provides a comprehensive review of the research on lung rehabilitation for patients who are mechanically ventilated during the weaning process in an effort to serve as a guide for a successful transition from mechanical ventilation. CONCLUSION: Early pulmonary rehabilitation training can effectively increase the pulmonary function level and ventilation function of patients and reduce the duration of mechanical ventilation and hospitalization, and is an effective, safe, and feasible treatment method.

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Glioma is the most common and aggressive type of primary malignant brain tumor. The N6-methyladenosine (m6A) modification widely exists in eukaryotic cells and plays an important role in the occurrence and development of human tumors. However, the function and mechanism of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an RNA-binding protein and m6A reader in gliomas remains to be comprehensively and extensively explored. Herein, we found that HNRNPC mRNA and protein overexpression were associated with a poor prognosis for patients with gliomas, based on the data from TCGA, the CGGA, and the TMAs. Biologically, HNRNPC knockdown markedly repressed malignant phenotypes of glioma in vitro and in vivo, whereas ectopic HNRNPC expression had the opposite effect. Integrative RNA sequencing and MeRIP sequencing analyses identified interleukin-1 receptor-associated kinase 1 (IRAK1) as a downstream target of HNRNPC. The glioma public datasets and tissue microarrays (TMAs) data indicated that IRAK1 overexpression was associated with poor prognosis, and IRAK1 knockdown significantly repressed malignant biological behavior in vitro. Mechanistically, HNRNPC maintains the mRNA stability of IRAK1 in an m6A-dependent manner, resulting in activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which was necessary for the malignant behavior of glioma. Our findings demonstrate the HNRNPC-IRAK1-MAPK axis as a crucial carcinogenic factor for glioma and the novel underlying mechanism of IRAK1 upregulation, which provides a rationale for therapeutically targeting epitranscriptomic modulators in glioma.

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Progresión de la Enfermedad , Glioma , Ribonucleoproteína Heterogénea-Nuclear Grupo C , Quinasas Asociadas a Receptores de Interleucina-1 , Sistema de Señalización de MAP Quinasas , ARN Mensajero , Humanos , Glioma/genética , Glioma/patología , Glioma/metabolismo , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Quinasas Asociadas a Receptores de Interleucina-1/genética , ARN Mensajero/metabolismo , ARN Mensajero/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo C/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo C/genética , Línea Celular Tumoral , Sistema de Señalización de MAP Quinasas/genética , Ratones , Estabilidad del ARN/genética , Ratones Desnudos , Animales , Regulación Neoplásica de la Expresión Génica , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Femenino , Masculino , Adenosina/análogos & derivados , Adenosina/metabolismo , Pronóstico

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Patulin (PAT), the most common mycotoxin, is widespread in foods and beverages which poses a serious food safety issue to human health. Our previous research confirmed that exposure to PAT can lead to acute kidney injury (AKI). Curcumin is the most abundant active ingredient in turmeric rhizome with various biological activities. The aim of this study is to investigate whether curcumin can prevent the renal injury caused by PAT, and to explore potential mechanisms. In vivo, supplementation with curcumin attenuated PAT-induced ferroptosis. Mechanically, curcumin inhibited autophagy, led to the accumulation of p62 and its interaction with Keap1, promoted the nuclear translocation of nuclear factor E2 related factor 2 (Nrf2), and increased the expression of antioxidant stress factors in the process of ferroptosis. These results have also been confirmed in HKC cell experiments. Furthermore, knockdown of Nrf2 in HKC cells abrogated the protective effect of curcumin on ferroptosis. In conclusion, we confirmed that curcumin mitigated PAT-induced AKI by inhibiting ferroptosis via activation of the p62/Keap1/Nrf2 pathway. This study provides new potential targets and ideas for the prevention and treatment of PAT.

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Curcumina , Ferroptosis , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2 , Patulina , Transducción de Señal , Factor 2 Relacionado con NF-E2/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Curcumina/farmacología , Ferroptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Humanos , Masculino , Patulina/toxicidad , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Proteína Sequestosoma-1/metabolismo , Línea Celular , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Ratones , Ratones Endogámicos C57BL

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The incidence of nonalcoholic steatohepatitis (NASH) is related with perfluorooctane sulfonate (PFOS), yet the mechanism remains ill-defined. Mounting evidence suggests that ferroptosis plays a crucial role in the initiation of NASH. In this study, we used mice and human hepatocytes L-02 to investigate the role of ferroptosis in PFOS-induced NASH and the effect and molecular mechanism of PFOS on liver ferroptosis. We found here that PFOS caused NASH in mice, and lipid accumulation and inflammatory response in the L-02 cells. PFOS induced hepatic ferroptosis in vivo and in vitro, as evidenced by the decrease in glutathione peroxidase 4 (GPX4), and the increases in cytosolic iron, acyl-CoA synthetase long-chain family member 4 (ACSL4) and lipid peroxidation. In the PFOS-treated cells, the increases in the inflammatory factors and lipid contents were reversed by ferroptosis inhibitor. PFOS-induced ferroptosis was relieved by autophagy inhibitor. The expression of mitochondrial calcium uniporter (MCU) was accelerated by PFOS, leading to subsequent mitochondrial calcium accumulation, and inhibiting autophagy reversed the increase in MCU. Inhibiting mitochondrial calcium reversed the variations in GPX4 and cytosolic iron, without influencing the change in ACSL4, induced by PFOS. MCU interacted with ACSL4 and the siRNA against MCU reversed the changes in ACSL4，GPX4 and cytosolic iron systemically. This study put forward the involvement of hepatic ferroptosis in PFOS-induced NASH and identified MCU as the mediator of the autophagy-dependent ferroptosis.

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Ácidos Alcanesulfónicos , Autofagia , Calcio , Coenzima A Ligasas , Ferroptosis , Fluorocarburos , Enfermedad del Hígado Graso no Alcohólico , Ferroptosis/efectos de los fármacos , Fluorocarburos/toxicidad , Animales , Ácidos Alcanesulfónicos/toxicidad , Ratones , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/patología , Autofagia/efectos de los fármacos , Coenzima A Ligasas/metabolismo , Humanos , Calcio/metabolismo , Canales de Calcio/metabolismo , Masculino , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Línea Celular , Hepatocitos/efectos de los fármacos

RESUMEN

Pancreatic cancer (PC) is among the deadliest malignancies, with an extremely poor diagnosis and prognosis. Gemcitabine (GEM) remains the first-line drug for treating PC; however, only a small percentage of patients benefit from current immunotherapies or targeted therapies. Resistance to GEM is prevalent and affects long-term survival. We found that ubiquitin-protein ligase E3 module N-recognition 5 (UBR5) is a therapeutic target against GEM resistance. UBR5 was markedly upregulated in clinical GEM-resistant PC samples and GEM-resistant PC cells. UBR5 knockdown markedly increased GEM sensitivity in GEM-resistant PC cell lines. UBR5-mediated GEM resistance was accompanied by activation of epithelial-mesenchymal transition (EMT) and could be mitigated by inhibiting EMT. Further analysis revealed that UBR5 promoted GEM resistance in PC cells by enhancing O-GlcNAcylation-mediated EMT. In addition, UBR5 knockdown resulted in increased O-GlcNAase (OGA) levels, an essential negatively regulated enzyme in the O-GlcNAcylation process. We identified a negative association between OGA and UBR5 levels, which further supported the hypothesis that O-GlcNAcylation-mediated GEM resistance induced by UBR5 is OGA-dependent in PC cells. Mechanistic studies revealed that UBR5 acts as an E3 ubiquitin ligase of OGA and regulates O-GlcNAcylation by binding and modulating OGA, facilitating its degradation and ubiquitination. Additionally, high-throughput compound library screening using three-dimensional protein structure analysis and drug screening identified a Food and Drug Administration drug, Y-39983 dihydrochloride, as a potent GEM sensitiser and UBR5 inhibitor. The combination of Y-39983 dihydrochloride and GEM attenuated tumour growth in a mouse xenograft tumour model. Collectively, these data demonstrated that UBR5 plays a pivotal role in the sensitisation of PC to GEM and provides a potential therapeutic strategy to overcome GEM resistance.

Asunto(s)

Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Gemcitabina , Histona Acetiltransferasas , Hialuronoglucosaminidasa , Neoplasias Pancreáticas , Ubiquitina-Proteína Ligasas , Animales , Humanos , Ratones , Línea Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Gemcitabina/farmacología , Gemcitabina/uso terapéutico , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación , Hialuronoglucosaminidasa/efectos de los fármacos , Hialuronoglucosaminidasa/genética , Hialuronoglucosaminidasa/metabolismo , Histona Acetiltransferasas/efectos de los fármacos , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/farmacocinética , Antígenos de Neoplasias

RESUMEN

This study aimed to explore the brain network characteristics in elderly patients with Parkinson's disease (PD) with depressive symptoms. Thirty elderly PD patients with depressive symptoms (PD-D) and 26 matched PD patients without depressive symptoms (PD-NOD) were recruited based on HAMD-24 with a cut-off of 7. The resting-state functional connectivity (RSFC) was conducted by 53-channel functional near-infrared spectroscopy (fNIRS). There were no statistically significant differences in MMSE scores, disease duration, Hoehn-Yahr stage, daily levodopa equivalent dose, and MDS-UPDRS III between the two groups. However, compared to the PD-NOD group, the PD-D group showed significantly higher MDS-UPDRS II, HAMA-14, and HAMD-24. The interhemispheric FC strength and the FC strength between the left dorsolateral prefrontal cortex (DLPFC-L) and the left frontal polar area (FPA-L) was significantly lower in the PD-D group (FDR p < 0.05). As for graph theoretic metrics, the PD-D group had significantly lower degree centrality (aDc) and node efficiency (aNe) in the DLPFC-L and the FPA-L (FDR, p < 0.05), as well as decreased global efficiency (aEg). Pearson correlation analysis indicated moderate negative correlations between HAMD-24 scores and the interhemispheric FC strength, FC between DLPFC-L and FPA-L, aEg, aDc in FPA-L, aNe in DLPFC-L and FPA-L. In conclusion, PD-D patients show decreased integration and efficiency in their brain networks. Furthermore, RSFC between DLPFC-L and FPA-L regions is negatively correlated with depressive symptoms. These findings propose that targeting DLPFC-L and FPA-L regions via non-invasive brain stimulation may be a potential intervention for alleviating depressive symptoms in elderly PD patients.

RESUMEN

The human eye is susceptible to various disorders that affect its structure or function, including glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR). Mitochondrial dysfunction has been identified as a critical factor in the pathogenesis and progression of eye disorders, making it a potential therapeutic target in the clinic. Natural products have been used in traditional medicine for centuries and continue to play a significant role in modern drug development and clinical therapeutics. Recently, there has been a surge in research exploring the efficacy of natural products in treating eye disorders and their underlying physiological mechanisms. This review aims to discuss the involvement of mitochondrial dysfunction in eye disorders and summarize the recent advances in the application of natural products targeting mitochondria. In addition, we describe the future perspective and challenges in the development of mitochondria-targeting natural products.