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Purpose: Mitochondrial damage may lead to uncontrolled oxidative stress and massive apoptosis, and thus plays a pivotal role in the pathological processes of myocardial ischemia-reperfusion (I/R) injury. However, it is difficult for the drugs such as puerarin (PUE) to reach the mitochondrial lesion due to lack of targeting ability, which seriously affects the expected efficacy of drug therapy for myocardial I/R injury. Methods: We prepared triphenylphosphonium (TPP) cations and ischemic myocardium-targeting peptide (IMTP) co-modified puerarin-loaded liposomes (PUE@T/I-L), which effectively deliver the drug to mitochondria and improve the effectiveness of PUE in reducing myocardial I/R injury. Results: In vitro test results showed that PUE@T/I-L had sustained release and excellent hemocompatibility. Fluorescence test results showed that TPP cations and IMTP double-modified liposomes (T/I-L) enhanced the intracellular uptake, escaped lysosomal capture and promoted drug targeting into the mitochondria. Notably, PUE@T/I-L inhibited the opening of the mitochondrial permeability transition pore, reduced intracellular reactive oxygen species (ROS) levels and increased superoxide dismutase (SOD) levels, thereby decreasing the percentage of Hoechst-positive cells and improving the survival of hypoxia-reoxygenated (H/R)-injured H9c2 cells. In a mouse myocardial I/R injury model, PUE@T/I-L showed a significant myocardial protective effect against myocardial I/R injury by protecting mitochondrial integrity, reducing myocardial apoptosis and decreasing infarct size. Conclusion: This drug delivery system exhibited excellent mitochondrial targeting and reduction of myocardial apoptosis, which endowed it with good potential extension value in the precise treatment of myocardial I/R injury.
Subject(s)
Isoflavones , Liposomes , Myocardial Reperfusion Injury , Organophosphorus Compounds , Animals , Liposomes/chemistry , Myocardial Reperfusion Injury/drug therapy , Isoflavones/chemistry , Isoflavones/pharmacology , Isoflavones/administration & dosage , Isoflavones/pharmacokinetics , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Organophosphorus Compounds/administration & dosage , Organophosphorus Compounds/pharmacokinetics , Male , Mice , Apoptosis/drug effects , Reactive Oxygen Species/metabolism , Cations/chemistry , Myocardium/pathology , Myocardium/metabolism , Oxidative Stress/drug effects , Peptides/chemistry , Peptides/pharmacology , Peptides/administration & dosage , Drug Delivery Systems/methodsABSTRACT
Atopic dermatitis (AD) is a chronic inflammatory disease with a complex and heterogeneous clinical presentation, leading to treatment limitations. Therefore, there is an urgent demand for new therapeutic drug targets. This study utilized Summary-data-based Mendelian randomization (SMR) to identify potential drug targets for AD. Summary statistics for 2,940 human plasma proteins were obtained from the UK Biobank, while AD statistics came from the Early Genetics and Epidemiology of Life Processes consortium and the FinnGen consortium. Furthermore, subsequent colocalization analyses confirmed the causal roles of candidate proteins. Moreover, Phenome-Wide Association Studies (PheWAS), protein-protein interaction (PPI), enrichment analysis, and single cell-type expression analysis provided additional insights. Additionally, drug prediction, druggability prediction, and molecular docking informed the discovery of novel drug targets. SMR analysis showed that eight plasma proteins were causally associated with AD: PVALB and TST were associated with a reduced risk of AD, while CA14, ECM1, IL22, IL6R, IL18R1, and MMP12 were associated with an increased risk of AD. Colocalization analysis confirmed significant associations for TST, IL22, and CA14. PheWAS further revealed that candidate drug targets were mainly linked to other allergic diseases. The corresponding protein-coding genes are predominantly expressed in melanocytes, T cells, and macrophages in skin tissue. Importantly, these proteins were identified to be involved in cytokine-cytokine receptor interaction, Th17 cell differentiation, and the JAK-STAT signaling pathway. All of these proteins are druggable, and six of them show great potential as drug targets. In conclusion, this study identified eight plasma proteins causally associated with AD and provided new insights into the etiology and potential drug targets for AD.
Subject(s)
Blood Proteins , Dermatitis, Atopic , Proteome , Humans , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/blood , Dermatitis, Atopic/genetics , Dermatitis, Atopic/immunology , Blood Proteins/metabolism , Blood Proteins/genetics , Genome-Wide Association Study , Mendelian Randomization Analysis , Molecular Docking Simulation , Protein Interaction Maps , Molecular Targeted Therapy/methods , Genetic Predisposition to DiseaseABSTRACT
The present study focused on the efficacy and role of triptolide (TPL) in relieving symptoms of acute gouty arthritis (AGA) in vivo and in vitro. The effects of TPL in AGA were investigated in monosodium urate (MSU)-treated rat ankles, RAW264.7 macrophages, and neutrophils isolated from mouse peritoneal cavity. Observation of pathological changes in the ankle joint of rats. Enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction (RT-qPCR) were performed to detect the expression levels of inflammatory factors and chemokines. The levels of the indicators of macrophage M1/M2 polarization, and the mechanistic targets of Akt and rapamycin complex 2, were determined via western blotting and RT-qPCR. The expression levels of CD86 and CD206 were detected using immunohistochemistry. Neutrophil migration was observed via air pouch experiments in vivo and Transwell cell migration assay in vitro. Myeloperoxidase (MPO) and Neutrophil elastase (NE) release was analyzed by via immunohistochemistry and immunofluorescence. The expression levels of beclin-1, LC3B, Bax, Bcl-2, and cleaved caspase-3 in neutrophils were determined via western blotting and immunofluorescence. Neutrophil apoptosis was detected using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Our results suggest that TPL inhibited inflammatory cell infiltration in rat ankle joints and inflammatory factor and chemokine secretion in rat serum, regulated macrophage polarization through the PI3K/AKT signaling pathway, suppressed inflammatory factor and chemokine expression in neutrophils, and inhibited neutrophil migration, neutrophil extracellular trap formation, transitional autophagy, and apoptosis. This suggests that TPL can prevent and treat MSU-induced AGA by regulating macrophage polarization through the PI3K/Akt pathway and modulating neutrophil activity.
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The determination of vitamin B6 (VB6) in food is of great significance due to its vital role in maintaining health and its necessity for ingestion through dietary sources. Therefore, based on ionic liquid-based yellow-emitting carbon dots (Y-CDs), a novel fluorescence-smartphone dual-mode method was first developed. The present method was applied to the detection of VB6 in milk. In the fluorescence method, the formation of complexes between VB6 and Y-CDs results in a significant decrease of the fluorescence intensity of Y-CDs. VB6 in milk samples was successfully determined according to this method, which exhibited a low detection limit (5 × 10-5 mg/mL) and excellent recoveries (98.80%-103.80%), demonstrating its feasibility in real sample analysis. In addition, the smartphone-based analysis method was established by researching the correlation between different VB6 concentrations and the (R + B) values of Y-CDs. When this method was applied, the detection process of VB6 was simplified. By combining the two methods, the possibility of incorrect analysis results can be effectively reduced, and the reliability of detection results can be improved through cross-validation of the two methods. Compared with traditional chromatography and electrochemical methods, the dual-mode method was more rapid, convenient, accurate, and suitable for the detection of VB6.
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Background: Traumatic brain injury (TBI) is a condition characterized by structural and physiological disruptions in brain function caused by external forces. However, as the highly complex and heterogenous nature of TBI, effective treatments are currently lacking. Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) has shown notable antinociceptive and anti-inflammatory effects, yet its detailed neuroprotective effects and mode of action remain incompletely understood. This study investigated the neuroprotective effects and the underlying mechanisms of MOTS-c. Methods: Adult male C57BL/6 mice were randomly divided into three groups: control (CON) group, MOTS-c group and TBI group. Enzyme-linked immunosorbent assay (ELISA) kit method was used to measure the expression levels of MOTS-c in different groups. Behavioral tests were conducted to assess the effects of MOTS-c. Then, transcriptomics and metabolomics were performed to search Differentially Expressed Genes (DEGs) and Differentially Expressed Metabolites (DEMs), respectively. Moreover, the integrated transcriptomics and metabolomics analysis were employed using R packages and online Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results: ELISA kit method showed that TBI resulted in a decrease in the expression of MOTS-c. and peripheral administration of MOTS-c could enter the brain tissue after TBI. Behavioral tests revealed that MOTS-c improved memory, learning, and motor function impairments in TBI mice. Additionally, transcriptomic analysis screened 159 differentially expressed genes. Metabolomic analysis identified 491 metabolites with significant differences. Integrated analysis found 14 KEGG pathways, primarily related to metabolic pathways. Besides, several signaling pathways were enriched, including neuroactive ligand-receptor interaction and retrograde endocannabinoid signaling. Conclusion: TBI reduced the expression of MOTS-c. MOTS-c reduced inflammatory responses, molecular damage, and cell death by down-regulating macrophage migration inhibitory factor (MIF) expression and activating the retrograde endocannabinoid signaling pathway. In addition, MOTS-c alleviated the response to hypoxic stress and enhanced lipid ß-oxidation to provide energy for the body following TBI. Overall, our study offered new insights into the neuroprotective mechanisms of MOTS-c in TBI mice.
Subject(s)
Brain Injuries, Traumatic , Neuroprotective Agents , Transcriptome , Animals , Male , Mice , Brain Injuries, Traumatic/metabolism , Metabolomics , Mice, Inbred C57BL , Neuroprotective Agents/pharmacologyABSTRACT
BACKGROUND: Cetuximab is extensively used in the treatment of metastatic colorectal cancer (mCRC). However, resistance poses a significant challenge to successful therapy. Recently, paraptosis, a non-classical programmed cell death, has garnered increased attention for its potential application value in antitumor treatments. We aimed to identify the essential pathways and signaling molecules involved in paraptosis inhibition and select them as therapeutic targets in cetuximab resistance. Additionally, engineered exosome technology is used as a drug delivery system with both targeted and effector properties. RESULTS: By comparing the differential expression of paraptosis-related genes between drug-resistant colon cancer cells and sensitive cells, it was observed that the paraptosis level induced by cetuximab was significantly downregulated in drug-resistant cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified the focal adhesion kinase (FAK) signaling pathway as a key pathway involved in the suppression of paraptosis. The biological function of FAK in cetuximab-resistant cells was investigated through cell morphology observation, CCK-8 assay, colony formation assay, RT-qPCR, Western Blot, and loss-of-function experiments. The results showed that the FAK signaling pathway was significantly upregulated in cetuximab-resistant colon cancer cells, and siRNA interference targeting FAK could notably inhibit cell proliferation while upregulating the paraptosis level. Based on this, engineered colon cancer cells targeted and FAK siRNA loaded exosomes (CT-Exo-siFAK1) were constructed. In vitro experiments, CT-Exo-siFAK1 could effectively activate paraptosis and inhibit the proliferation of drug-resistant colon cancer cells. In vivo experiments also confirmed that CT-Exo-siFAK1 significantly suppressed tumor growth and metastasis while upregulating the paraptosis level. CONCLUSION: This study suggests that FAK signaling pathway-mediated inhibition of paraptosis levels is crucial in the sensitivity of cetuximab targeted therapy in colon cancer, and the use of engineered exosomes to deliver FAK siRNA may be an effective strategy to reverse cetuximab resistance.
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BACKGROUND: The fractures of patients with osteoporosis represent a major health care burden that requires efficient prevention. OBJECTIVE: To analyze the efficacy and significance of diverse interventions for preventing falls or fractures in patients with osteoporosis, and to establish a foundation for clinical interventions. METHODS: Ten databases were searched for studies published before January 30, 2024. Screening, data extraction, and risk of bias assessment were independently conducted by two researchers using Stata 14.0 software. A network meta-analysis using the frequentist framework was then performed to determine the effectiveness of various interventions for preventing and managing falls and fractures in patients with osteoporosis. The findings were used as basis for the prioritization of interventions. RESULTS: The initial search yielded 3894 studies. After 3878 studies were excluded, 16 studies were finally included. For the prevention of falls in patients with osteoporosis, effective interventions include exercise and exercise plus medication. A combination of exercise, assessment and modifications, quality improvement strategies, social engagement, basic falls risk assessment, and assistive technology may be the preferred recommended intervention. For the prevention of fractures in patients with osteoporosis, no statistically significant disparities were observed among the compared interventions, exercise may be the preferred recommended intervention. CONCLUSION: Exercise and exercise plus medication are effective in reducing the number of falls in patients with osteoporosis. Although exercise may be the optimal intervention for fracture prevention, the quality of current evidence remains inadequate. Large-scale high-quality randomized controlled trials are necessary to substantiate these findings. TRIAL REGISTRATION: PROSPERO CRD42024507487.
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Epidermal growth factor receptor (EGFR)-targeted therapy is an important treatment for RAS wild-type metastatic colorectal cancer (mCRC), but the resistance mechanism remains unclear. Here, the differential expression of circRNAs between Cetuximab sensitive and resistant cell lines was analyzed using whole-transcriptome sequencing. We identified that the expression of circHIF1A was significantly higher in LIM1215-R than in LIM1215. When treated with Cetuximab, downregulation of circHIF1A level weakened the proliferation and clonal formation ability of LIM1215-R, caused more cells to enter G0-G1 phase, and significantly reduced the basal respiration, ATP production, and maximal respiration, as well as the glycolytic capacity and glycolytic reserve. The response rate and prognosis of circHIF1A-positive patients were inferior to those of negative patients. Mechanistically, circHIF1A can upregulate the level of hypoxia-inducible factor 1 A (HIF1A) by competitively binding to miR-361-5p, inducing the overexpression of enzymes such as glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). In a xenograft model, inhibition of circHIF1A expression increased the sensitivity to Cetuximab treatment. In conclusion, circHIF1A can promote HIF1α-mediated glycometabolism alteration to induce Cetuximab resistance in CRC. It has the potential to become a screening indicator for the Cetuximab beneficial population in mCRC and a new therapeutic target for enhancing treatment efficacy.
Subject(s)
Cetuximab , Colorectal Neoplasms , Drug Resistance, Neoplasm , Hypoxia-Inducible Factor 1, alpha Subunit , Cetuximab/pharmacology , Humans , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/drug therapy , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Cell Line, Tumor , Mice , Animals , RNA, Circular/genetics , RNA, Circular/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Gene Expression Regulation, Neoplastic , Mice, Nude , Antineoplastic Agents, Immunological/pharmacology , Glycolysis , Cell Proliferation/drug effectsABSTRACT
Purpose: The study investigates the value of the BRAFV600E mutation in determining the aggressiveness of papillary thyroid cancer (PTC) and its correlation with ultrasound features. Methods: The study selected 176 patients with BRAFV600E mutation and 80 without the mutation who underwent surgery at Guangxi Medical University Cancer Hospital. Clinical and pathological data were collected, focusing on BRAFV600E mutations and associated ultrasonic features. Correlation analysis, as well as univariate and multivariate logistic regression analysis, were conducted to identify independent risk factors for BRAFV600E mutation. The results were verified using a nomogram model. Results: The analysis results indicate that the BRAFV600E mutation correlates with tumor size, nodule size, taller-than-wide shape, margin, and shape of papillary thyroid cancer. The receiver operating characteristic curve was used to analyze the diagnostic effect of these features on BRAFV600E mutation. The results showed that nodule size had the most significant area under the curve (AUC = 0.665). Univariate and multivariate logistic regression analyses revealed that taller-than-wide shape ≥1, ill-defined margin, irregular shape, nodule size (≤1.40 cm), TT4 (>98.67 nmol/L), and FT3 (<4.14 pmol/L) were independent risk factors for BRAFV600E mutation. While considering all these factors in the nomogram, the Concordance index (C-index) remained high at 0.764. This suggests that the model has a good predictive effect. Conclusion: Ultrasound features including nodule size, taller-than-wide shape ≥1, ill-defined margins, irregular shape, higher TT4 levels, and lower FT3 levels were associated with papillary thyroid cancer aggressiveness and BRAFV600E mutation.
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Objective: Bioinformatics methods were applied to investigate the pivotal genes and regulatory networks associated with atherosclerotic carotid artery stenosis (ACAS) and provide new insights for the treatment of this disease. Methods: The study utilized five ACAS datasets (GSE100927, GSE11782, GESE28829, GSE41571, and GSE43292) downloaded from the NCBI GEO database. The first four datasets were combined as the training set (n = 99), while GSE43292 (n = 64) was used as the validation set. Difference analysis and functional enrichment analysis were then performed on the training set. The pathogenic targets of ACAS were screened by protein-protein interaction networks and MCODE analyses, combined with three machine learning algorithms. The results were next verified by analysis of inter-group differences and ROC curve analysis. Next, immune-related function and immune cell correlation analyses were performed, and plaques of human ACAS were applied to verify the results via immunohistochemistry (IH) and immunofluorescence (IF). Finally, the competing endogenous RNAs (ceRNA) and transcription factors (TFs) regulatory networks of the characterized genes were constructed. Results: A total of 177 differentially expressed genes were identified, including 67 genes downregulated and 110 genes upregulated. Gene set enrichment analysis revealed that five pathways were active in the experimental group, including xenograft rejection, autoimmune thyroid disease, graft-versus-host disease, leishmaniasis infection, and lysosomes. Four key genes were identified, with C3AR1 being upregulated and FBLN5, PPP1R12A, and TPM1 being downregulated. The analysis of inter-group differences demonstrated that the four characterized genes were differentially expressed in both the control and experimental groups. The ROC analysis showed that they had high AUC values in both the training and validation sets. Therefore, a predictive ACAS patient nomogram model based on the screened genes was established. Correlation analysis revealed a positive correlation between C3AR1 expression and neutrophils, which was further validated in IH and IF. One or multiple lncRNAs may compete with the characterized genes for binding miRNAs. Additionally, each characterized gene interacts with multiple TFs. Conclusion: Four pivotal genes were screened, and relevant ceRNA and TFs were predicted. These molecules may exert a crucial role in ACAS and serve as potential biomarkers and therapeutic targets.
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OBJECTIVE: Carotid atherosclerosis is a chronic progressive vascular disease that can be complicated by stroke in severe cases. Prompt diagnosis and treatment of high-risk patients are quite difficult due to the lack of reliable clinical biomarkers. This study aimed to explore potential plaque metabolic markers of stroke-prone risk and relevant targets for pharmacological intervention. METHOD: Carotid intima and plaque sample tissues were obtained from 20 patients with cerebrovascular symptoms of carotid origin. An untargeted metabolomics approach based on liquid chromatography-tandem mass spectrometry was utilized to characterize the metabolic profiles of the tissues. Multivariate and univariate analysis tools were used. RESULTS: A total of 154 metabolites were significantly altered in carotid plaque when compared with thickened intima. Of these, 62 metabolites were upregulated, whereas 92 metabolites were downregulated. Support vector machines identified the 15 most important metabolites, such as N-(cyclopropylmethyl)-N'-phenylurea, 9(S)-HOTrE, ACar 12:2, quinoxaline-2,3-dithiol, and l-thyroxine, as biomarkers for high-risk plaques. Metabolic pathway analysis showed that abnormal purine and nucleotide metabolism, amino acid metabolism, glutathione metabolism, and vitamin metabolism may contribute to the occurrence and progression of carotid atherosclerotic plaque. CONCLUSIONS: Our study identifies the biomarkers and related metabolic mechanisms of carotid plaque, which is stroke-prone, and provides insights and ideas for the precise prevention and targeted intervention of the disease.
Subject(s)
Biomarkers , Metabolomics , Plaque, Atherosclerotic , Tandem Mass Spectrometry , Humans , Tandem Mass Spectrometry/methods , Male , Female , Biomarkers/analysis , Biomarkers/metabolism , Middle Aged , Aged , Plaque, Atherosclerotic/chemistry , Plaque, Atherosclerotic/metabolism , Metabolomics/methods , Chromatography, Liquid/methods , Carotid Artery Diseases/metabolism , MetabolomeABSTRACT
Microbial-based therapeutics in clinical practice are of considerable interest, and a recent study demonstrated fecal microbial transplantation (FMT) followed by dietary fiber supplements improved glucose homeostasis. Previous evidence suggests that donor and recipient compatibility and FMT protocol are key determinants, but little is known about the involvement of specific recipient factors. Using data from our recent randomized placebo-control phase 2 clinical trial in adults with obesity and metabolic syndrome, we grouped participants that received FMT from one of 4 donors with either fiber supplement into HOMA-IR responders (n = 21) and HOMA-IR non-responders (n = 8). We further assessed plasma bile acids using targeted metabolomics and performed subgroup analyzes to evaluate the effects of recipient parameters and gastrointestinal factors on microbiota engraftment and homeostatic model assessment of insulin resistance (HOMA2-IR) response. The baseline fecal microbiota composition at genus level of recipients could predict the improvements in HOMA2-IR at week 6 (ROC-AUC = 0.70). Prevotella was identified as an important predictor, with responders having significantly lower relative abundance than non-responders (p = .02). In addition, recipients displayed a highly individualized degree of microbial engraftment from donors. Compared to the non-responders, the responders had significantly increased bacterial richness (Chao1) after FMT and a more consistent engraftment of donor-specific bacteria ASVs (amplicon sequence variants) such as Faecalibacillus intestinalis (ASV44), Roseburia spp. (ASV103), and Christensenellaceae spp. (ASV140) (p < .05). Microbiota engraftment was strongly associated with recipients' factors at baseline including initial gut microbial diversity, fiber and nutrient intakes, inflammatory markers, and bile acid derivative levels. This study identified that responders to FMT therapy had a higher engraftment rate in the transplantation of specific donor-specific microbes, which were strongly correlated with insulin sensitivity improvements. Further, the recipient baseline gut microbiota and related factors were identified as the determinants for responsiveness to FMT and fiber supplementation. The findings provide a basis for the development of precision microbial therapeutics for the treatment of metabolic syndrome.
Subject(s)
Bacteria , Bile Acids and Salts , Fecal Microbiota Transplantation , Feces , Gastrointestinal Microbiome , Metabolic Syndrome , Humans , Metabolic Syndrome/therapy , Metabolic Syndrome/microbiology , Male , Female , Adult , Middle Aged , Feces/microbiology , Bile Acids and Salts/metabolism , Bile Acids and Salts/blood , Bacteria/classification , Bacteria/isolation & purification , Bacteria/genetics , Bacteria/metabolism , Obesity/therapy , Obesity/microbiology , Dietary Fiber/administration & dosage , Dietary Fiber/metabolism , Insulin Resistance , Treatment OutcomeABSTRACT
Trastuzumab-induced cardiotoxicity (TIC) is a common and serious disease with abnormal cardiac function. Accumulating evidence has indicated certain non-coding RNAs (ncRNAs), functioning as competing endogenous RNAs (ceRNAs), impacting the progression of cardiovascular diseases. Nonetheless, the specific involvement of ncRNA-mediated ceRNA regulatory mechanisms in TIC remains elusive. The present research aims to comprehensively investigate changes in the expressions of all ncRNA using whole-transcriptome RNA sequencing. The sequencing analysis unveiled significant dysregulation, identifying a total of 43 circular RNAs (circRNAs), 270 long noncoding RNAs (lncRNAs), 12 microRNAs (miRNAs), and 4131 mRNAs in trastuzumab-treated mouse hearts. Subsequently, circRNA-based ceRNA networks consisting of 82 nodes and 91 edges, as well as lncRNA-based ceRNA networks comprising 111 nodes and 112 edges, were constructed. Using the CytoNCA plugin, pivotal genes-miR-31-5p and miR-644-5p-were identified within these networks, exhibiting potential relevance in TIC treatment. Additionally, KEGG and GO analyses were conducted to explore the functional pathways associated with the genes within the ceRNA networks. The outcomes of the predicted ceRNAs and bioinformatics analyses elucidated the plausible involvement of ncRNAs in TIC pathogenesis. This insight contributes to a better understanding of underlying mechanisms and aids in identifying promising targets for effective prevention and treatment strategies.
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INTRODUCTION: The incidence of breast cancer has steadily risen over the years owing to changes in lifestyle and environment. Presently, breast cancer is one of the primary causes of cancer-related deaths among women, making it a crucial global public health concern. Thus, the creation of an automated diagnostic system for breast cancer bears great importance in the medical community. OBJECTIVES: This study analyses the Wisconsin breast cancer dataset and develops a machine learning algorithm for accurately classifying breast cancer as benign or malignant. METHODS: Our research is a retrospective study, and the main purpose is to develop a high-precision classification algorithm for benign and malignant breast cancer. To achieve this, we first preprocessed the dataset using standard techniques such as feature scaling and handling missing values. We assessed the normality of the data distribution initially, after which we opted for Spearman correlation analysis to examine the relationship between the feature subset data and the labeled data, considering the normality test results. We subsequently employed the Wilcoxon rank sum test to investigate the dissimilarities in distribution among various breast cancer feature data. We constructed the feature subset based on statistical results and trained 7 machine learning algorithms, specifically the decision tree, stochastic gradient descent algorithm, random forest algorithm, support vector machine algorithm, logistics algorithm, and AdaBoost algorithm. RESULTS: The results of the evaluation indicated that the AdaBoost-Logistic algorithm achieved an accuracy of 99.12%, outperforming the other 6 algorithms and previous techniques. CONCLUSION: The constructed AdaBoost-Logistic algorithm exhibits significant precision with the Wisconsin breast cancer dataset, achieving commendable classification performance for both benign and malignant breast cancer cases.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/diagnosis , Breast Neoplasms/epidemiology , Retrospective Studies , Algorithms , Machine Learning , Support Vector MachineABSTRACT
Oxidative stress and neuronal dysfunction caused by intracerebral haemorrhage (ICH) can lead to secondary injury. The m6A modification has been implicated in the progression of ICH. This study aimed to investigate the role of the m6A reader YTHDC2 in ICH-induced secondary injury. ICH models were established in rats using autologous blood injection, and neuronal cell models were induced with Hemin. Experiments were conducted to overexpress YTH domain containing 2 (YTHDC2) and examine its effects on neuronal dysfunction, brain injury, and neuronal ferritinophagy. RIP-qPCR and METTL3 silencing were performed to investigate the regulation of YTHDC2 on nuclear receptor coactivator 4 (NCOA4). Finally, NCOA4 overexpression was used to validate the regulatory mechanism of YTHDC2 in ICH. The study found that YTHDC2 expression was significantly downregulated in the brain tissues of ICH rats. However, YTHDC2 overexpression improved neuronal dysfunction and reduced brain water content and neuronal death after ICH. Additionally, it reduced levels of ROS, NCOA4, PTGS2, and ATG5 in the brain tissues of ICH rats, while increasing levels of FTH and FTL. YTHDC2 overexpression also decreased levels of MDA and Fe2+ in the serum, while promoting GSH synthesis. In neuronal cells, YTHDC2 overexpression alleviated Hemin-induced injury, which was reversed by Erastin. Mechanistically, YTHDC2-mediated m6A modification destabilized NCOA4 mRNA, thereby reducing ferritinophagy and alleviating secondary injury after ICH. However, the effects of YTHDC2 were counteracted by NCOA4 overexpression. Overall, YTHDC2 plays a protective role in ICH-induced secondary injury by regulating NCOA4-mediated ferritinophagy.
Subject(s)
Adenine , Brain Injuries , Hemin , Animals , Rats , Adenine/analogs & derivatives , Brain Injuries/genetics , Brain Injuries/metabolism , Cerebral Hemorrhage/genetics , Cerebral Hemorrhage/metabolism , DNA Methylation , Hemin/pharmacology , Hemin/metabolism , Oxidative Stress , Transcription Factors/metabolismABSTRACT
The skeletal system is crucial for supporting bodily functions, protecting vital organs, facilitating hematopoiesis, and storing essential minerals. Skeletal homeostasis, which includes aspects such as bone density, structural integrity, and regenerative processes, is essential for normal skeletal function. Autophagy, an intricate intracellular mechanism for degrading and recycling cellular components, plays a multifaceted role in bone metabolism. It involves sequestering cellular waste, damaged proteins, and organelles within autophagosomes, which are then degraded and recycled. Autophagy's impact on bone health varies depending on factors such as regulation, cell type, environmental cues, and physiological context. Despite being traditionally considered a cytoplasmic process, autophagy is subject to transcriptional and epigenetic regulation within the nucleus. However, the precise influence of epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNA expression, on cellular fate remains incompletely understood. The interplay between autophagy and epigenetic modifications adds complexity to bone cell regulation. This article provides an in-depth exploration of the intricate interplay between these two regulatory paradigms, with a focus on the epigenetic control of autophagy in bone metabolism. Such an understanding enhances our knowledge of bone metabolism-related disorders and offers insights for the development of targeted therapeutic strategies.
Subject(s)
Bone Diseases, Metabolic , Epigenesis, Genetic , Humans , Autophagy/genetics , Homeostasis , Autophagosomes , Bone DensityABSTRACT
Chemical investigation of the culture extract of an endophyte Xylaria curta YSJ-5 from Alpinia zerumbet (Pers.) Burtt. et Smith resulted in the isolation of eight previously undescribed compounds including five eremophilane sesquiterpenes xylarcurenes A-E, one norsesquiterpene xylarcurene F, and two α-pyrone derivatives xylarpyrones A-B together with eight known related derivatives. Their chemical structures were extensively established based on the 1D- and 2D-NMR spectroscopic analysis, modified Mosher's method, electronic circular dichroism calculations, single-crystal X-ray diffraction experiments, and the comparison with previous literature data. All these compounds were tested for in vitro cytotoxic, anti-inflammatory, α-glucosidase inhibitory, and antibacterial activities. As a result, 6-pentyl-4-methoxy-pyran-2-one was disclosed to display significant antibacterial activity against Staphylococcus aureus and methicillin-resistant S. aureus with minimal inhibitory concentration value of 6.3 µg/mL.
Subject(s)
Ascomycota , Methicillin-Resistant Staphylococcus aureus , Sesquiterpenes , Pyrones/chemistry , Molecular Structure , Sesquiterpenes/chemistry , Anti-Bacterial Agents/chemistryABSTRACT
An undescribed cytotoxic cyclopeptide named phomopamide A (1) was isolated from Diaporthe sp., which is an endophytic fungus from Artemisia argyi. Phomopamide A (1) featured an pentadepsipeptide skeleton and composed of two Phe, one Val, one Leu, and one 2-hydroxyoctanoic acid units. The structure of this new compound was fully characterised on the basis of extensive spectroscopic analysis. Moreover, phomopamide A was evaluated for in vitro cyctotoxic and α-glucosidase inhibitory activity. As a result, phomopaminde A exhibited no cytotoxic activity against four tumour cell lines, while it showed a potent α-glucosidase inhibition effect with IC50 value of 62.35 µM.
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Doxorubicin (DOX) is an effective anticancer drug with potent antitumour activity. However, the application of DOX is limited by its adverse reactions, such as depression. Taurine can alleviate depression induced by multiple factors. However, it is still unclear whether and how taurine improves DOX-induced depression. To address this question, the aim of this study was to explore the potential mechanism by which taurine protects against DOX-induced depression. Mice were randomly divided into three groups (n = 8): (1) the control group, (2) the DOX group, and (3) the DOX + taurine group. The open field test (OFT), elevated plus maze test, and forced swim test (FST) were first performed to assess the effects of DOX and taurine on the behaviour of mice. Next, a combined transcriptomic and metabolomic analysis was performed to analyse the possible antidepressive effect of taurine. Taurine pretreatment increased the total distance travelled and speed of mice in the OFT, increased the number of entries into the open arm and the time spent in the open arm, and reduced the immobility time in the FST. In addition, 179 differential genes and 51 differentially abundant metabolites were detected in the DOX + taurine group compared to the DOX group. Furthermore, differential genes and differentially abundant metabolites were found to be jointly involved in 21 pathways, which may be closely related to the antidepressant effect of taurine. Taurine alleviated DOX-induced depressive behaviour. The various pathways identified in this study, such as the serotonergic synapse and the inflammatory mediator regulation of TRP channels, may be key regulatory pathways related to depression and antidepressant effects.
Subject(s)
Depression , Taurine , Mice , Animals , Depression/chemically induced , Depression/drug therapy , Depression/genetics , Taurine/metabolism , Doxorubicin/toxicity , Antidepressive Agents/pharmacology , Gene Expression ProfilingABSTRACT
Presently, most fluorescent probes for amino acid enantiomers detection require metal ions participation, which greatly increases the detection steps and costs, and affects the accuracy of detection results. To solve this problem, a dual pattern recognition sensor of chiral carbon dots (L-Try-Thr-CDs) with a quantum yield of 36.23 % was prepared by a one-step solvothermal method for the highly selective detection of lysine (Lys) enantiomers. Under optimal experimental conditions, the fluorescence and circular dichroism (CD) signals of the obtained L-Try-Thr-CDs could rapidly and effectively responded to L-Lys with limits of detection (LOD) of 16.51 nM and 24.38 nM, respectively, much lower than previously reported sensors. Importantly, the L-Try-Thr-CDs as a dual-mode sensor could not only detect amino acid enantiomers and simplify the steps, but also avoid inaccurate detection results due to unstable metal ions. Furthermore, the L-Try-Thr-CDs could detect L-Lys in living cells via a fluorescence microscope because of their excellent fluorescence characteristics and low toxicity. These results indicated that the dual-mode sensor not only provided a practical strategy for the design of new fluorescent probes, but also possessed outstanding application prospects in the accurate detection of lysine enantiomers.