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1.
Toxicol Lett ; 2024 Jul 03.
Article in English | MEDLINE | ID: mdl-38969027

ABSTRACT

2-Methyl-4-nitroaniline (MNA), an intermediate in the synthesis of azo dyes, is widely distributed in various environmental media and organisms. Although there is speculation regarding MNA's potential to be hepatotoxic, the underlying mechanisms of its hepatotoxicity and its definitive diagnostic process remain largely unexplored. In this research. In the present study, we initially predicted the toxicity and possible toxic effect pathways of MNA using ProTox-II, and found that MNA binds to the PPARγ receptor (binding energy -6.118kcal/mol) with a potential PPARγ agonist effect. Subsequently, in vivo exposure evaluation was conducted on Wistar rats to assess the impact of MNA after a 90-day exposure period, by detecting serum biochemical indexes, hematological indexes, urinary indexes, inflammatory factors, liver histopathological observations and liver tissue PPARγ mRNA expression. The results showed that MNA causes liver function abnormalities, liver histopathological changes and inflammatory response, along with a pronounced increase in PPARγ mRNA levels. This study suggests that the hepatotoxic mechanism of MNA may be related to its possible upregulation of PPARγ expression, increased liver dysfunction and inflammatory responses. Based on these results, the benchmark dose lower limit (BMDL) of 1.503mg/kg for male Wistar rats was also established, providing a vital benchmark for determining the safety threshold of MNA. Our data highlight the hepatotoxic mechanism of MNA and contribute to a better understanding of its potential etiological diagnosis.

2.
J Nephrol ; 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38965198

ABSTRACT

BACKGROUND: Chronic kidney disease (CKD) may affect women of childbearing age and may lead to substantial maternal and foetal morbidity and mortality in pregnancy. There is a lack of prediction models for  preeclampsia and adverse pregnancy outcomes in pregnant women with CKD. This study aimed to create a prediction nomogram for these issues. METHODS: This retrospective cohort study included clinical data from 627 women with CKD and their 627 pregnancies at Peking University First Hospital between January 1, 2009, and December 31, 2022. Multivariate logistic regression analysis was conducted to identify independent prognostic factors and develop a nomogram for predicting the occurrence of preeclampsia. The identified risk factors were utilised to construct the nomogram, which was subsequently internally validated using receiver operating characteristic (ROC) analysis and calibration curve assessment. RESULTS: According to our multivariate analysis, age, blood urea nitrogen (BUN), serum creatinine (Scr), mean arterial pressure (MAP), 24-h proteinuria, and CKD stage were identified as predictors of preeclampsia. Additionally, Scr, MAP, BUN, and 24-h proteinuria were found to be predictors of adverse pregnancy outcomes. The nomogram for predicting preeclampsia had an area under the ROC curve of 0.910, while the nomogram for predicting adverse pregnancy outcomes had an area under the ROC curve of 0.906. Both models demonstrated excellent discriminatory ability. CONCLUSIONS: A nomogram based on 24-h proteinuria, serum creatinine, serum urea and age, and MAP allows predicting the occurrence of preeclampsia and other adverse pregnancy-related outcomes in CKD patients.

3.
J Gene Med ; 26(7): e3715, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38962887

ABSTRACT

BACKGROUND: The present study aimed to dissect the cellular complexity of Crohn's disease (CD) using single-cell RNA sequencing, focusing on identifying key cell populations and their transcriptional profiles in inflamed tissue. METHODS: We applied scRNA-sequencing to compare the cellular composition of CD patients with healthy controls, utilizing Seurat for clustering and annotation. Differential gene expression analysis and protein-protein interaction networks were constructed to identify crucial genes and pathways. RESULTS: Our study identified eight distinct cell types in CD, highlighting crucial fibroblast and T cell interactions. The analysis revealed key cellular communications and identified significant genes and pathways involved in the disease's pathology. The role of fibroblasts was underscored by elevated expression in diseased samples, offering insights into disease mechanisms and potential therapeutic targets, including responses to ustekinumab treatment, thus enriching our understanding of CD at a molecular level. CONCLUSIONS: Our findings highlight the complex cellular and molecular interplay in CD, suggesting new biomarkers and therapeutic targets, offering insights into disease mechanisms and treatment implications.


Subject(s)
Crohn Disease , Single-Cell Analysis , Ustekinumab , Crohn Disease/genetics , Crohn Disease/drug therapy , Humans , Ustekinumab/therapeutic use , Single-Cell Analysis/methods , Gene Expression Profiling/methods , Protein Interaction Maps , Fibroblasts/metabolism , Biomarkers , Female , Transcriptome , Adult , Male , T-Lymphocytes/metabolism , T-Lymphocytes/immunology , Treatment Outcome , Sequence Analysis, RNA/methods , Gene Regulatory Networks
4.
ACS Nano ; 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38963059

ABSTRACT

The abuse or misuse of antibiotics in clinical and agricultural settings severely endangers human health and ecosystems, which has raised profound concerns for public health worldwide. Trace detection and reliable discrimination of commonly used fluoroquinolone (FQ) antibiotics and their analogues have consequently become urgent to guide the rational use of antibiotic medicines and deliver efficient treatments for associated diseases. Herein, we report a wearable eye patch integrated with a quadruplex nanosensor chip for noninvasive detection and discrimination of primary FQ antibiotics in tears during routine eyedrop treatment. A set of dual-mode fluorescent nanoprobes of red- or green-emitting CdTe quantum dots integrated with lanthanide ions and a sensitizer, adenosine monophosphate, were constructed to provide an enhanced fluorescence up to 45-fold and nanomolar sensitivity toward major FQs owing to the aggregation-regulated antenna effect. The aggregation-driven, CdTe-Ln(III)-based microfluidic sensor chip is highly specific to FQ antibiotics against other non-FQ counterparts or biomolecular interfering species and is able to accurately discriminate nine types of FQ or non-FQ eyedrop suspensions using linear discriminant analysis. The prototyped wearable sensing detector has proven to be biocompatible and nontoxic to human tissues, which integrates the entire optical imaging modules into a miniaturized, smartphone-based platform for field use and reduces the overall assay time to ∼5 min. The practicability of the wearable eye patch was demonstrated through accurate quantification of antibiotics in a bactericidal event and the continuous profiling of FQ residues in tears after using a typical prescription antibiotic eyedrop. This technology provides a useful supplement to the toolbox for on-site and real-time examination and regulation of inappropriate daily drug use that might potentially lead to long-term antibiotic abuse and has great implications in advancing personal healthcare techniques for the regulation of daily medication therapy.

5.
Org Biomol Chem ; 2024 Jul 02.
Article in English | MEDLINE | ID: mdl-38953741

ABSTRACT

An efficient method for the construction of 5-arylpyrazolo[1,5-a]pyrimidines using calcium carbide as a solid alkyne source instead of flammable and explosive gaseous acetylene, pyrazole-3-amine and (hetero)aromatic aldehydes as starting materials in the presence of a copper mediator is described. Meanwhile, 2-arylpyrimido[1,2-b]indazoles are also synthesized under similar conditions using indazole-3-amine as a substitute for pyrazole-3-amine as a starting material. The method has salient features such as the use of an inexpensive and easy-to-handle alkyne source, commercially available substrates, wide functional group tolerance, a low-cost mediator, and simple workup procedures. This protocol can also be extended to gram-scale synthesis.

6.
J Biotechnol ; 392: 96-102, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38960098

ABSTRACT

In eukaryotes, the localization of small ribosomal subunits to mRNA transcripts requires the translation of Kozak elements at the starting site. The sequence of Kozak elements affects the translation efficiency of protein synthesis. However, whether the upstream nucleotide of Kozak sequence affects the expression of recombinant proteins in Chinese hamster ovary (CHO) cells remains unclear. In order to find the optimal sequence to enhance recombinant proteins expression in CHO cells, -10 to +4 sequences around ATG in 100 CHO genes were compared, and the extended Kozak elements with different translation intensities were constructed. Using the classic Kozak element as control, the effects of optimized extended Kozak elements on the secreted alkaline phosphatase (SEAP) and human serum albumin (HSA) gene were studied. The results showed that the optimized extended Kozak sequence can enhance the stable expression level of recombinant proteins in CHO cells. Furthermore, it was found that the increased expression level of the recombinant protein was not related with higher transcription level. In summary, optimizing extended Kozak elements can enhance the expression of recombinant proteins in CHO cells, which contributes to the construction of an efficient expression system for CHO cells.

7.
Mol Pharm ; 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38949095

ABSTRACT

Claudin18.2 (CLDN18.2), due to its high expression in various gastric cancer tissues, is considered an optimal target for antitumor drug molecules. In this study, we obtained the labeled compounds of [125I]I-zolbetuximab using the Iodogen method. Under the optimum labeling conditions, the molar activity of [125I]I-zolbetuximab was 1.75 × 102 GBq/µmol, and the labeling efficiency was more than 99%. The labeled compounds exhibited excellent in vitro stability in both phosphate buffer saline (PBS, pH = 7.4) and fetal bovine serum systems (FBS) (radiochemical purity >90% at 72 h). The uptake percentage of [125I]I-zolbetuximab in MKN45-CLDN18.2 cells is 24.69 ± 0.84% after 6 h. The saturation binding assay and specificity assay further demonstrated the high specificity of [125I]I-zolbetuximab for CLDN18.2. The long retention at the tumor site and rapid metabolic clearance at other organ sites of [125I]I-zolbetuximab were observed in small-animal SPECT-CT imaging. The same trend was also observed in the biodistribution study. Due to the excellent targeting ability of zolbetuximab for CLDN18.2, [125I]I-zolbetuximab exhibits strong specific binding and retention with cells and tumors highly expressing CLDN18.2. However, the balance between mAb's longer cycle time in vivo and targeting binding and retention ability should be intensively considered for using this kind of radiopharmaceutical in the diagnosis and treatment of CLDN18.2-positive gastric cancer.

8.
Environ Sci Technol ; 2024 Jul 09.
Article in English | MEDLINE | ID: mdl-38980177

ABSTRACT

There has been widespread concern about the health hazards of per- and polyfluoroalkyl substances (PFAS), which may be the risk factor for hyperuricemia with evidence still insufficient in the general population in China. Here, we conducted a nationwide study involving 9,580 adults aged 18 years or older from 2017 to 2018, measured serum concentrations of uric acid and PFAS (PFOA, PFOS, 6:2 Cl-PFESA, PFNA, PFHxS) in participants, to assess the associations of individual PFAS with hyperuricemia, and estimated a joint effect of PFAS mixtures. We found positive associations of higher serum PFAS with elevated odds of hyperuricemia in Chinese adults, with the greatest contribution from PFOA (69.37%). The nonmonotonic dose-response (NMDR) relationships were observed for 6:2 Cl-PFESA and PFHxS with hyperuricemia. Participants with less marine fish consumption, overweight, and obesity may be the sensitive groups to the effects of PFAS on hyperuricemia. We highlight the potential health hazards of legacy long-chain PFAS (PFOA) once again because of the higher weights of joint effects. This study also provides more evidence about the NMDR relationships in PFAS with hyperuricemia and emphasizes a theoretical basis for public health planning to reduce the health hazards of PFAS in sensitive groups.

9.
Front Med (Lausanne) ; 11: 1378846, 2024.
Article in English | MEDLINE | ID: mdl-38978778

ABSTRACT

Sarcopenia is a condition characterized by age-related loss of muscle mass and strength. Increasing evidence suggests that patients with sarcopenia have higher rates of coronavirus 2019 (COVID-19) infection and poorer post-infection outcomes. However, the exact mechanism and connections between the two is unknown. In this study, we used high-throughput data from the GEO database for sarcopenia (GSE111016) and COVID-19 (GSE171110) to identify common differentially expressed genes (DEGs). We conducted GO and KEGG pathway analyses, as well as PPI network analysis on these DEGs. Using seven algorithms from the Cytoscape plug-in cytoHubba, we identified 15 common hub genes. Further analyses included enrichment, PPI interaction, TF-gene and miRNA-gene regulatory networks, gene-disease associations, and drug prediction. Additionally, we evaluated immune cell infiltration with CIBERSORT and assessed the diagnostic accuracy of hub genes for sarcopenia and COVID-19 using ROC curves. In total, we identified 66 DEGs (34 up-regulated and 32 down-regulated) and 15 hub genes associated with sarcopenia and COVID-19. GO and KEGG analyses revealed functions and pathways between the two diseases. TF-genes and TF-miRNA regulatory network suggest that FOXOC1 and hsa-mir-155-5p may be identified as key regulators, while gene-disease analysis showed strong correlations with hub genes in schizophrenia and bipolar disorder. Immune infiltration showed a correlation between the degree of immune infiltration and the level of infiltration of different immune cell subpopulations of hub genes in different datasets. The ROC curves for ALDH1L2 and KLF5 genes demonstrated their potential as diagnostic markers for both sarcopenia and COVID-19. This study suggests that sarcopenia and COVID-19 may share pathogenic pathways, and these pathways and hub genes offer new targets and strategies for early diagnosis, effective treatment, and tailored therapies for sarcopenia patients with COVID-19.

10.
Ann Hematol ; 2024 Jul 11.
Article in English | MEDLINE | ID: mdl-38990294

ABSTRACT

The MEF2D rearrangement is a recurrent chromosomal abnormality detected in approximately 2.4-5.3% of patients with acute B-cell lymphoblastic leukemia (B-ALL). Currently, MEF2D-rearranged B-ALL is not classified as an independent subtype in the WHO classification. Consequently, the clinical significance of MEF2D rearrangement in B-ALL remains largely unexplored. In this study, we retrospectively screened 260 B-ALL patients with RNA sequencing data collected between November 2018 and December 2022. Among these, 10 patients were identified with MEF2D rearrangements (4 with MEF2D::HNRNPUL1, 3 with MEF2D::BCL9, 1 with MEF2D::ARID1B, 1 with MEF2D::DAZAP1 and 1 with MEF2D::HNRNPM). Notably, HNRNPM and ARID1B are reported as MEF2D fusion partners for the first time. The patient with the MEF2D::HNRNPM fusion was resistant to chemotherapy and chimeric antigen receptor T-cell therapy and relapsed early after allogenic stem cell transplantation. The patient with MEF2D::ARID1B experienced early extramedullary relapse after diagnosis. All 10 patients achieved complete remission after induction chemotherapy. However, 9/10 (90%) of whom experienced relapse. Three of the 9 patients relapsed with aberrant expression of myeloid antigens. The median overall survival of these patients was only 11 months. This small cohort showed a high incidence of early relapse and short survival in patients with MEF2D rearrangements.

11.
RSC Adv ; 14(30): 21307-21317, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38979459

ABSTRACT

Lithium extraction from salt lake brine is still challenging due to the existence of similar elements, e.g. sodium. In the present work, polysulfone (PSF) microcapsules containing 1-phenylazo-2-naphthol (HS) and trioctylphosphine oxide (TOPO) as extractants were successfully prepared by microfluidic technology for the separation of Li+ from brine with Li+ and Na+. The morphology, composition, and structure of HS-TOPO-based microcapsules were characterized systematically. The results showed that microcapsules consisting of 20 wt% (m m-1) polysulfone and 80 wt% (m m-1) 1-phenylazo-2-naphthol-trioctylphosphine oxide as the extractant, which was labeled as PSF/HS-TOPO-2/8, exhibited the best performance for Li+ adsorption. The separation factor (SF) of Li+ over Na+ is up to 653 and the adsorption capacity for Li+ in the simulated brine could reach 3.67 mg g-1 for microcapsules PSF/HS-TOPO-2/8, which demonstrated that Li+ can be separated with high selectivity. Besides, the kinetic results demonstrated that the adsorption followed quasi-secondary adsorption kinetic models, indicating that the adsorption mechanism of lithium by microcapsules involved chemisorption. After ten cycles of adsorption-elution, the maximum equilibrium adsorption capacity still remained at 87%. All these results demonstrate that PSF/HS-TOPO-2/8 microcapsules can be used as an efficient adsorber for the adsorption of Li+ from brine with high selectivity and stability.

12.
J Chem Phys ; 161(2)2024 Jul 14.
Article in English | MEDLINE | ID: mdl-38984963

ABSTRACT

Electron-phonon coupling is an important energy transfer mechanism in solids after ultrafast laser excitation. In this study, we present an extreme ultraviolet (EUV) and infrared (IR) pump-probe photoemission experiment to investigate the electron-phonon coupling in nonequilibrium gold. The energy of IR-laser-emitted photoelectrons is shifted due to the EUV photoemission and oscillates with a ∼4THz frequency. Such oscillation is considered as the effective excitation of the longitudinal acoustic phonon mode in gold through the spectral-dependent electron-phonon coupling. Our study showcases the capability of time-resolved photoemission electron microscopy to monitor the non-equilibrium lattice vibrations with ultrahigh spatial and temporal resolution.

13.
Phys Rev Lett ; 132(24): 240801, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38949366

ABSTRACT

Quantum networks promise unprecedented advantages in information processing and open up intriguing new opportunities in fundamental research, where network topology and network nonlocality fundamentally underlie these applications. Hence, the detections of network topology and nonlocality are crucial, which, however, remain an open problem. Here, we conceive and experimentally demonstrate to determine the network topology and network nonlocality hosted by a triangle quantum network comprising three parties, within and beyond Bell theorem, with a general witness operator for the first time. We anticipate that this unique approach may stimulate further studies toward the efficient characterization of large complex quantum networks so as to better harness the advantage of quantum networks for quantum information applications.

14.
Proc Natl Acad Sci U S A ; 121(28): e2403143121, 2024 Jul 09.
Article in English | MEDLINE | ID: mdl-38959041

ABSTRACT

Currently, the nanofluidic synapse can only perform basic neuromorphic pulse patterns. One immediate problem that needs to be addressed to further its capability of brain-like computing is the realization of a nanofluidic spiking device. Here, we report the use of a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate membrane to achieve bionic ionic current-induced spiking. In addition to the simulation of various electrical pulse patterns, our synapse could produce transmembrane ionic current-induced spiking, which is highly analogous to biological action potentials with similar phases and excitability. Moreover, the spiking properties could be modulated by ions and neurochemicals. We expect that this work could contribute to biomimetic spiking computing in solution.


Subject(s)
Action Potentials , Polystyrenes , Synapses , Action Potentials/physiology , Synapses/physiology , Polystyrenes/chemistry , Nanotechnology/methods , Nanotechnology/instrumentation
15.
World J Gastrointest Surg ; 16(6): 1618-1628, 2024 Jun 27.
Article in English | MEDLINE | ID: mdl-38983338

ABSTRACT

BACKGROUND: Patients with resectable gastric adenocarcinoma accompanied by vascular cancer thrombus (RGAVCT) have a poor prognosis, with a 5-year survival rate ranging from 18.42%-53.57%. These patients need a reasonable postoperative treatment plan to improve their prognosis. AIM: To determine the most effective postoperative chemotherapy regimen for patients with RGAVCT. METHODS: We retrospectively collected the clinicopathological data of 530 patients who underwent radical resection for gastric cancer between January 2017 and January 2022 and who were pathologically diagnosed with gastric adenocarcinoma with a choroidal cancer embolus. Furthermore, we identified the high-risk variables that can influence the prognosis of patients with RGAVCT by assessing the clinical and pathological features of the patients who met the inclusion criteria. We also assessed the significance of survival outcomes using Mantel-Cox univariate and multivariate analyses. The subgroups of patients with stages I, II, and III disease who received single-, dual-, or triple-drug regimens following surgery were analyzed using SPSS 25.0 and the ggplot2 package in R 4.3.0. RESULTS: In all, 530 eligible individuals with RGAVCT were enrolled in this study. The median overall survival (OS) of patients with RGAVCT was 24 months, and the survival rates were 80.2%, 62.5%, and 42.3% at 12, 24, and 59 months, respectively. Preoperative complications, tumor size, T stage, and postoperative chemotherapy were identified as independent factors that influenced OS in patients with RGAVCT according to the Cox multivariate analysis model. A Kaplan-Meier analysis revealed that chemotherapy had no effect on OS of patients with stage I or II RGAVCT; however, chemotherapy did have an effect on OS of stage III patients. Stage III patients who were treated with chemotherapy consisting of dual- or triple-agent regimens had better survival than those treated with single-agent regimens, and no significant difference was observed in the survival of patients treated with chemotherapy consisting of dual- or triple-agent regimens. CONCLUSION: For patients with stage III RGAVCT, a dual-agent regimen of postoperative chemotherapy should be recommended rather than a triple-agent treatment, as the latter is associated with increased frequency of adverse events.

16.
Org Lett ; 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38967298

ABSTRACT

Current methods for the asymmetric α-sulfenylation of carbonyls cannot be applied to acyclic carbonyls that have two similar substituents at the α-position. This research demonstrated that the electrophilic sulfenylation of geometry-defined acyclic ß,ß-disubstituted enesulfinamides using S-aryl or S-alkyl benzenethiosulfonates can be highly stereoselective. This process results in enantioenriched α,α-disubstituted α-sulfenylated ketone surrogates with sulfur-containing acyclic tetrasubstituted carbon stereocenters bearing two electronically and sterically similar substituents (e.g., methyl and ethyl). Furthermore, by employing the corresponding stereoisomers of enensulfinamides, any of the four stereoisomers of α-sulfenylated ketimines can be selectively accessed.

17.
Biosens Bioelectron ; 262: 116530, 2024 Jun 26.
Article in English | MEDLINE | ID: mdl-38943854

ABSTRACT

The progression of gastric cancer involves a complex multi-stage process, with gastroscopy and biopsy being the standard procedures for diagnosing gastric diseases. This study introduces an innovative non-invasive approach to differentiate gastric disease stage using gastric fluid samples through machine-learning-assisted surface-enhanced Raman spectroscopy (SERS). This method effectively identifies different stages of gastric lesions. The XGBoost algorithm demonstrates the highest accuracy of 96.88% and 91.67%, respectively, in distinguishing chronic non-atrophic gastritis from intestinal metaplasia and different subtypes of gastritis (mild, moderate, and severe). Through blinded testing validation, the model can achieve more than 80% accuracy. These findings offer new possibilities for rapid, cost-effective, and minimally invasive diagnosis of gastric diseases.

18.
J Neurosurg ; : 1-13, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38941649

ABSTRACT

OBJECTIVE: The highly intricate nature of the cervical spinal cord can cause arteriovenous shunts in these segments that may be associated with heightened clinical risks and treatment complexities. In this article, the authors aimed to provide a comprehensive analysis of the detailed natural course, treatment, and clinical outcomes of cervical spinal cord arteriovenous shunts (SCAVSs) based on the largest cohort to date. METHODS: Two hundred forty consecutive patients were included. Data on clinical presentation, angioarchitecture, treatment, and follow-up were retrospectively reviewed. RESULTS: The cohort demonstrated a greater prevalence of acute onset (63.3% vs 36.7%). Spontaneous recovery was observed in 63.7% of patients after onset, with a significantly elevated recovery rate observed among patients experiencing acute onset (72.4% vs 48.9%, p < 0.001). The risks of acute and gradual clinical deterioration after onset was 11.9%/year and 13.4%/year, respectively. Microsurgery was performed in 39.6% of patients, while the remaining 60.4% exclusively underwent embolization. The complete obliteration rate was 65.3% after microsurgery and 21.4% after embolization. The rate of treatment-related deterioration was 14.7% after microsurgery and 6.2% after embolization. After partial treatment, the acute and gradual deterioration rates were 4.1%/year and 6.6%/year, respectively. Lack of spontaneous recovery after onset was an independent predictor of embolization-related deterioration (OR 17.905, p = 0.007) and long-term gradual deterioration after partial treatment (HR 2.325, p = 0.021). After a median follow-up period of 32.55 months, prognosis was unfavorable in 16.7% of patients, with the sole independent risk factor being the absence of spontaneous recovery after onset (OR 2.476, p = 0.018). CONCLUSIONS: The outcomes of patients with cervical SCAVS were generally favorable, even in patients with only partial obliteration of the lesions. However, patients who did not show a trend toward spontaneous recovery after onset had a significantly elevated risk of unfavorable prognosis, highlighting the need for prompt clinical intervention.

20.
J Zhejiang Univ Sci B ; 25(6): 485-498, 2024 May 15.
Article in English, Chinese | MEDLINE | ID: mdl-38910494

ABSTRACT

End-stage liver diseases, such as cirrhosis and liver cancer caused by hepatitis B, are often combined with hepatic encephalopathy (HE); ammonia poisoning is posited as one of its main pathogenesis mechanisms. Ammonia is closely related to autophagy, but the molecular mechanism of ammonia's regulatory effect on autophagy in HE remains unclear. Sialylation is an essential form of glycosylation. In the nervous system, abnormal sialylation affects various physiological processes, such as neural development and synapse formation. ST3 ß|-galactoside α2,|3-sialyltransferase 6 (ST3GAL6) is one of the significant glycosyltransferases responsible for adding α2,3-linked sialic acid to substrates and generating glycan structures. We found that the expression of ST3GAL6 was upregulated in the brains of mice with HE and in astrocytes after ammonia induction, and the expression levels of α2,3-sialylated glycans and autophagy-related proteins microtubule-associated protein light chain 3 (LC3) and Beclin-1 were upregulated in ammonia-induced astrocytes. These findings suggest that ST3GAL6 is related to autophagy in HE. Therefore, we aimed to determine the regulatory relationship between ST3GAL6 and autophagy. We found that silencing ST3GAL6 and blocking or degrading α2,3-sialylated glycans by way of Maackia amurensis lectin-II (MAL-II) and neuraminidase can inhibit autophagy. In addition, silencing the expression of ST3GAL6 can downregulate the expression of heat shock protein ß8 (HSPB8) and Bcl2-associated athanogene 3 (BAG3). Notably, the overexpression of HSPB8 partially restored the reduced autophagy levels caused by silencing ST3GAL6 expression. Our results indicate that ST3GAL6 regulates autophagy through the HSPB8-BAG3 complex.


Subject(s)
Apoptosis Regulatory Proteins , Autophagy , Brain , Hepatic Encephalopathy , Polysaccharides , Sialyltransferases , Sialyltransferases/metabolism , Sialyltransferases/genetics , Animals , Mice , Polysaccharides/metabolism , Hepatic Encephalopathy/metabolism , Apoptosis Regulatory Proteins/metabolism , Brain/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Ammonia/metabolism , Astrocytes/metabolism , Male , beta-Galactoside alpha-2,3-Sialyltransferase , Molecular Chaperones/metabolism , Heat-Shock Proteins/metabolism , Humans , Gene Silencing , Microtubule-Associated Proteins/metabolism , Mice, Inbred C57BL
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