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Frontiers in Genetics 2024N4-acetylcysteine (ac4C) is a chemical modification in mRNAs that alters the structure and function of mRNA by adding an acetyl group to the N4 position of cytosine....
STM-ac4C: a hybrid model for identification of N4-acetylcytidine (ac4C) in human mRNA based on selective kernel convolution, temporal convolutional network, and multi-head self-attention.
N4-acetylcysteine (ac4C) is a chemical modification in mRNAs that alters the structure and function of mRNA by adding an acetyl group to the N4 position of cytosine. Researchers have shown that ac4C is closely associated with the occurrence and development of various cancers. Therefore, accurate prediction of ac4C modification sites on human mRNA is crucial for revealing its role in diseases and developing new diagnostic and therapeutic strategies. However, existing deep learning models still have limitations in prediction accuracy and generalization ability, which restrict their effectiveness in handling complex biological sequence data. This paper introduces a deep learning-based model, STM-ac4C, for predicting ac4C modification sites on human mRNA. The model combines the advantages of selective kernel convolution, temporal convolutional networks, and multi-head self-attention mechanisms to effectively extract and integrate multi-level features of RNA sequences, thereby achieving high-precision prediction of ac4C sites. On the independent test dataset, STM-ac4C showed improvements of 1.81%, 3.5%, and 0.37% in accuracy, Matthews correlation coefficient, and area under the curve, respectively, compared to the existing state-of-the-art technologies. Moreover, its performance on additional balanced and imbalanced datasets also confirmed the model's robustness and generalization ability. Various experimental results indicate that STM-ac4C outperforms existing methods in predictive performance. In summary, STM-ac4C excels in predicting ac4C modification sites on human mRNA, providing a powerful new tool for a deeper understanding of the biological significance of mRNA modifications and cancer treatment. Additionally, the model reveals key sequence features that influence the prediction of ac4C sites through sequence region impact analysis, offering new perspectives for future research. The source code and experimental data are available at https://github.com/ymy12341/STM-ac4C.
PubMed: 38873109
DOI: 10.3389/fgene.2024.1408688 -
Redox Biology Aug 2024The ABCC1 gene belongs to the ATP-binding cassette membrane transporter superfamily, which plays a crucial role in the efflux of various endogenous and exogenous...
The ABCC1 gene belongs to the ATP-binding cassette membrane transporter superfamily, which plays a crucial role in the efflux of various endogenous and exogenous substances. Mutations in ABCC1 can result in autosomal dominant hearing loss. However, the specific roles of ABCC1 in auditory function are not fully understood. Through immunofluorescence, we found that ABCC1 was expressed in microvascular endothelial cells (ECs) of the stria vascularis (StV) in the murine cochlea. Then, an Abcc1 knockout mouse model was established by using CRISPR/Cas9 technology to elucidate the role of ABCC1 in the inner ear. The ABR threshold did not significantly differ between WT and Abcc1 mice at any age studied. After noise exposure, the ABR thresholds of the WT and Abcc1 mice were significantly elevated. Interestingly, after 14 days of noise exposure, ABR thresholds largely returned to pre-exposure levels in WT mice but not in Abcc1 mice. Our subsequent experiments showed that microvascular integrity in the StV was compromised and that the number of outer hair cells and the number of ribbons were significantly decreased in the cochleae of Abcc1 mice post-exposure. Besides, the production of ROS and the accumulation of 4-HNE significantly increased. Furthermore, StV microvascular ECs were cultured to elucidate the role of ABCC1 in these cells under glucose oxidase challenge. Notably, 30 U/L glucose oxidase (GO) induced severe oxidative stress damage in Abcc1 cells. Compared with WT cells, the ROS and 4-HNE levels and the apoptotic rate were significantly elevated in Abcc1 cells. In addition, the reduced GSH/GSSG ratio was significantly decreased in Abcc1 cells after GO treatment. Taken together, Abcc1 mice are more susceptible to noise-induced hearing loss, possibly because ABCC1 knockdown compromises the GSH antioxidant system of StV ECs. The exogenous antioxidant N-acetylcysteine (NAC) may protect against oxidative damage in Abcc1 murine cochleae and ECs.
Topics: Animals; Mice; Multidrug Resistance-Associated Proteins; Cochlea; Hearing Loss, Noise-Induced; Mice, Knockout; Antioxidants; Oxidative Stress; Disease Models, Animal; Reactive Oxygen Species; Endothelial Cells
PubMed: 38870779
DOI: 10.1016/j.redox.2024.103218 -
PloS One 2024There is a consistent association between exposure to air pollution and elevated rates of cardiopulmonary illnesses. As public health activities emphasize the paramount...
BACKGROUND
There is a consistent association between exposure to air pollution and elevated rates of cardiopulmonary illnesses. As public health activities emphasize the paramount need to reduce exposure, it is crucial to examine strategies like the antioxidant diet that could potentially protect individuals who are unavoidably exposed.
METHODS
A systematic search was performed in PubMed/Medline, EMBASE, CENTRAL, and ClinicalTrials.gov up to March 31, 2023, for clinical trials assessing dietary supplements against cardiovascular (blood pressure, heart rate, heart rate variability, brachial artery diameter, flow-mediated dilation, and lipid profile) or pulmonary outcomes (pulmonary function and airway inflammation) attributed to air pollution exposure.
RESULTS
After reviewing 4681 records, 18 studies were included. There were contradictory findings on the effects of fish oil and olive oil supplementations on cardiovascular outcomes. Although with limited evidence, fish oil offered protection against pulmonary dysfunction induced by pollutants. Most studies on vitamin C did not find protective cardiovascular effects; however, the combination of vitamin C and E offered protective effects against pulmonary dysfunction but showed conflicting results for cardiovascular outcomes. Other supplements like sulforaphane, L-arginine, n-acetylcysteine, and B vitamins showed potential beneficial effects but need further research due to the limited number of existing trials.
CONCLUSIONS
Although more research is needed to determine the efficacy and optimal dose of anti-inflammatory and antioxidant dietary supplements against air pollution toxicity, this low-cost preventative strategy has the potential to offer protection against outcomes of air pollution exposure.
Topics: Humans; Dietary Supplements; Air Pollution; Antioxidants; Cardiovascular Diseases; Clinical Trials as Topic; Fish Oils; Ascorbic Acid
PubMed: 38870164
DOI: 10.1371/journal.pone.0304402 -
Functional & Integrative Genomics Jun 2024With advances in radioactive particle implantation in clinical practice, Iodine-125 (I) seed brachytherapy has emerged as a promising treatment for cholangiocarcinoma...
With advances in radioactive particle implantation in clinical practice, Iodine-125 (I) seed brachytherapy has emerged as a promising treatment for cholangiocarcinoma (CCA), showing good prognosis; however, the underlying molecular mechanism of the therapeutic effect of I seed is unclear. To study the effects of I seed on the proliferation and apoptosis of CCA cells. CCA cell lines, RBE and HCCC-9810, were treated with reactive oxygen species (ROS) scavenger acetylcysteine (NAC) or the p53 functional inhibitor, pifithrin-α hydrobromide (PFTα). Cell counting kit-8 (CCK-8) assay, 5-bromo-2-deoxy-uridine (BrdU) staining, and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay and flow cytometry assay were performed to test the radiation-sensitivity of I seed toward CCA cells at different radiation doses (0.4 mCi and 0.8 mCi). 2,7-dichlorofluorescein diacetate (DCF-DA) assay, real-time quantitative polymerase chain reaction (RT-qPCR), and western blot analysis were performed to assess the effect of I seed on the ROS/p53 axis. A dose-dependent inhibitory effect of I seeds on the proliferation of CCA cells was observed. The I seed promoted apoptosis of CCA cells and induced the activation of the ROS/p53 pathway in a dose-dependent manner. NAC or PFTα treatment effectively reversed the stimulatory effect of I seed on the proliferation of CCA cells. NAC or PFTα suppressed apoptosis and p53 protein expression induced by the I seed. I seed can inhibit cell growth mainly through the apoptotic pathway. The mechanism may involve the activation of p53 and its downstream apoptotic pathway by up-regulating the level of ROS in cells.
Topics: Cholangiocarcinoma; Tumor Suppressor Protein p53; Iodine Radioisotopes; Reactive Oxygen Species; Apoptosis; Cell Proliferation; Humans; Cell Line, Tumor; Bile Duct Neoplasms; Acetylcysteine; Benzothiazoles; Signal Transduction
PubMed: 38862667
DOI: 10.1007/s10142-024-01392-1 -
Journal of Translational Medicine Jun 2024Astragaloside IV (AST-IV), as an effective active ingredient of Astragalus membranaceus (Fisch.) Bunge. It has been found that AST-IV inhibits the replication of dengue...
BACKGROUND
Astragaloside IV (AST-IV), as an effective active ingredient of Astragalus membranaceus (Fisch.) Bunge. It has been found that AST-IV inhibits the replication of dengue virus, hepatitis B virus, adenovirus, and coxsackievirus B3. Enterovirus 71 (EV71) serves as the main pathogen in severe hand-foot-mouth disease (HFMD), but there are no specific drugs available. In this study, we focus on investigating whether AST-IV can inhibit EV71 replication and explore the potential underlying mechanisms.
METHODS
The GES-1 or RD cells were infected with EV71, treated with AST-IV, or co-treated with both EV71 and AST-IV. The EV71 structural protein VP1 levels, the viral titers in the supernatant were measured using western blot and 50% tissue culture infective dose (TCID), respectively. Network pharmacology was used to predict possible pathways and targets for AST-IV to inhibit EV71 replication. Additionally, ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) was used to investigate the potential targeted metabolites of AST-IV. Associations between metabolites and apparent indicators were performed via Spearman's algorithm.
RESULTS
This study illustrated that AST-IV effectively inhibited EV71 replication. Network pharmacology suggested that AST-IV inhibits EV71 replication by targeting PI3K-AKT. Metabolomics results showed that AST-IV achieved these effects by elevating the levels of hypoxanthine, 2-ketobutyric acid, adenine, nicotinic acid mononucleotide, prostaglandin H2, 6-hydroxy-1 H-indole-3- acetamide, oxypurinol, while reducing the levels of PC (14:0/15:0). Furthermore, AST-IV also mitigated EV71-induced oxidative stress by reducing the levels of MDA, ROS, while increasing the activity of T-AOC, CAT, GSH-Px. The inhibition of EV71 replication was also observed when using the ROS inhibitor N-Acetylcysteine (NAC). Additionally, AST-IV exhibited the ability to activate the PI3K-AKT signaling pathway and suppress EV71-induced apoptosis.
CONCLUSION
This study suggests that AST-IV may activate the cAMP and the antioxidant stress response by targeting eight key metabolites, including hypoxanthine, 2-ketobutyric acid, adenine, nicotinic acid mononucleotide, prostaglandin H2, 6-Hydroxy-1 H-indole-3-acetamide, oxypurinol and PC (14:0/15:0). This activation can further stimulate the PI3K-AKT signaling to inhibit EV71-induced apoptosis and EV71 replication.
Topics: Virus Replication; Saponins; Proto-Oncogene Proteins c-akt; Signal Transduction; Triterpenes; Humans; Phosphatidylinositol 3-Kinases; Network Pharmacology; Metabolomics; Enterovirus A, Human
PubMed: 38858642
DOI: 10.1186/s12967-024-05355-9 -
European Review For Medical and... May 2024
Topics: Humans; Acetylcysteine; Mucus; Administration, Intravenous; Respiratory Tract Diseases; Expectorants
PubMed: 38856122
DOI: 10.26355/eurrev_202405_36281 -
Cureus May 2024Non-Hodgkin's lymphoma (NHL) involving skeletal muscle is generally found to be a secondary metastasis and extremely rarely as a primary site of malignancy. Furthermore,...
Non-Hodgkin's lymphoma (NHL) involving skeletal muscle is generally found to be a secondary metastasis and extremely rarely as a primary site of malignancy. Furthermore, in HIV patients, an increased incidence of lymphomas may be identified within the first six months of highly active antiretroviral therapy (HAART) initiation unmasked by immune reconstitution inflammatory syndrome (IRIS). We illustrate an extremely rare instance of NHL of the skeletal muscle in a young immunocompromised male with HIV/AIDS presenting as necrotizing myofasciitis complicated by compartment syndrome and hemodialysis-refractory type B lactic acidosis. A young Hispanic male with AIDS was admitted for acute left thigh pain and was soon found to have abscess formation with compartment syndrome requiring thigh fasciotomy. During the course of the ICU stay, the patient's clinical status acutely worsened with sepsis-induced multiorgan failure, including acute renal and acute liver failure requiring N-acetylcysteine and severe refractory metabolic acidosis requiring renal replacement therapy. Repeat imaging demonstrated diffuse myonecrosis. Left thigh muscle biopsy confirmed aggressive NHL of skeletal muscle. Despite months of arduous medical management in ICU, doxorubicin, vincristine, cyclophosphamide chemotherapy with concurrent high-dose prednisone for the vented patient, and intermittent curves of improvement, our patient succumbed to the nature of the disease and subsequently died from severe sepsis from the immunocompromised state. Interestingly, our patient's initial CD4 count was 1, which improved to 96 after five months of HAART, raising concerns for IRIS lymphoma. Given such rapid improvement with chemotherapy, the possibility of IRIS-related lymphoma, and the surprising dearth of data for chemotherapy use in critically ill patients on mechanical ventilation, more research is needed in these topics to better approach such complicated patients.
PubMed: 38854279
DOI: 10.7759/cureus.59888 -
Cureus May 2024Acute liver failure (ALF) exemplifies a rapid decline in liver function among individuals with previously healthy livers, often manifesting through symptoms such as...
Acute liver failure (ALF) exemplifies a rapid decline in liver function among individuals with previously healthy livers, often manifesting through symptoms such as jaundice, confusion, and potentially life-threatening complications. Timely medical intervention, and, in severe instances, liver transplantation, are essential for enhancing outcomes and averting further deterioration. While the causes of ALF are multifaceted, in developed nations, it predominantly arises from drug-induced liver injury. Treatment primarily revolves around supportive measures, with severe cases necessitating liver transplantation. In instances where acute overdose with acetaminophen serves as the instigating factor, N-acetylcysteine (NAC) emerges as a pivotal component of management, as indicated by the Rumack-Matthew nomogram. The Rumack-Matthew nomogram guides treatment for acetaminophen overdose by correlating serum levels with the risk of liver damage. If levels exceed a set threshold, NAC is administered to prevent toxicity by replenishing glutathione. The decision to administer NAC is typically guided by this clinical tool, which aids healthcare providers in determining the appropriate course of action. NAC assumes a critical role in ameliorating the detrimental effects of acetaminophen overdose, particularly in averting liver damage, thus holding significant importance in patient care and recovery. While chronic acetaminophen overdose cases leading to ALF may also benefit from NAC, the supporting evidence remains weak. In this context, we present a case of ALF stemming from chronic acetaminophen ingestion, managed with NAC when liver transplantation was not a viable option.
PubMed: 38854233
DOI: 10.7759/cureus.59883 -
Frontiers in Human Neuroscience 2024This study aims to determine if pretreating with enteral N-acetylcysteine (NAC) improves CNS oxidative stress and facilitates improvement in oromotor skills during...
Transcutaneous auricular vagus nerve stimulation may benefit from the addition of N-acetylcysteine to facilitate motor learning in infants of diabetic mothers failing oral feeds.
OBJECTIVE
This study aims to determine if pretreating with enteral N-acetylcysteine (NAC) improves CNS oxidative stress and facilitates improvement in oromotor skills during transcutaneous auricular nerve stimulation (taVNS) paired with oral feedings in infants of diabetic mothers (IDMs) who are failing oral feeds.
METHODS
We treated 10 IDMs who were gastrostomy tube candidates in an open-label trial of NAC and taVNS paired with oral feeding. NAC (75 or 100 mg/kg/dose) was given by nasogastric (NG) administration every 6 h for 4 days, then combined with taVNS paired with 2 daily feeds for another 14 days. NAC pharmacokinetic (PK) parameters were determined from plasma concentrations at baseline and at steady state on day 4 of treatment in conjunction with magnetic resonance spectroscopic (MRS) quantification of CNS glutathione (GSH) as a marker of oxidative stress. We compared increases in oral feeding volumes before and during taVNS treatment and with a prior cohort of 12 IDMs who largely failed to achieve full oral feeds with taVNS alone.
RESULTS
NAC 100 mg/kg/dose every 6 h NG resulted in plasma [NAC] that increased [GSH] in the basal ganglia with a mean of 0.13 ± 0.08 mM ( = 0.01, compared to baseline). Mean daily feeding volumes increased over 14 days of NAC + taVNS compared to the 14 days before treatment and compared to the prior cohort of 12 IDMs treated with taVNS alone. Seven IDMs reached full oral feeds sufficient for discharge, while three continued to have inadequate intake.
CONCLUSION
In IDM failing oral feeds, NAC 100 mg/kg/dose every 6 h NG for 4 days before and during taVNS paired with oral feeding increased CNS GSH, potentially mitigating oxidative stress, and was associated with improving functional feeding outcomes compared to taVNS alone in a prior cohort. This represents a novel approach to neuromodulation and supports the concept that mitigation of ongoing oxidative stress may increase response to taVNS paired with a motor task.
PubMed: 38841121
DOI: 10.3389/fnhum.2024.1373543 -
Ecotoxicology and Environmental Safety Jul 2024Benzyl butyl phthalate (BBP) is a widely used plasticizer that poses various potential health hazards. Although BBP has been extensively studied, the direct mechanism...
Benzyl butyl phthalate (BBP) is a widely used plasticizer that poses various potential health hazards. Although BBP has been extensively studied, the direct mechanism underlying its toxicity in male germ cells remains unclear. Therefore, we investigated BBP-mediated male germ cell toxicity in GC-1 spermatogonia (spg), a differentiated mouse male germ cell line. This study investigated the impact of BBP on reactive oxygen species (ROS) generation, apoptosis, and autophagy regulation, as well as potential protective measures against BBP-induced toxicity. A marked dose-dependent decrease in GC-1 spg cell proliferation was observed following treatment with BBP at 12.5 μM. Exposure to 50 μM BBP, approximating the IC of 53.9 μM, markedly increased cellular ROS generation and instigated apoptosis, as evidenced by augmented protein levels of both intrinsic and extrinsic apoptosis-related markers. An amount of 50 μM BBP induced marked upregulation of autophagy regulator proteins, p38 MAPK, and extracellular signal-regulated kinase and substantially downregulated the phosphorylation of key kinases involved in regulating cell proliferation, including phosphoinositide 3-kinase, protein kinase B, mammalian target of rapamycin (mTOR), c-Jun N-terminal kinase. The triple combination of N-acetylcysteine, parthenolide, and 3-methyladenine markedly restored cell proliferation, decreased BBP-induced apoptosis and autophagy, and restored mTOR phosphorylation. This study provides new insights into BBP-induced male germ cell toxicity and highlights the therapeutic potential of the triple inhibitors in mitigating BBP toxicity.
Topics: Male; Animals; Mice; Phthalic Acids; Autophagy; Apoptosis; Reactive Oxygen Species; Sesquiterpenes; Acetylcysteine; Adenine; Cell Proliferation; Cell Line; Plasticizers; Spermatogonia
PubMed: 38838463
DOI: 10.1016/j.ecoenv.2024.116544