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Frontiers in Bioscience (Landmark... May 2024Ubiquitination is a crucial post-translational modification of proteins that regulates diverse cellular functions. Accurate identification of ubiquitination sites in...
BACKGROUND
Ubiquitination is a crucial post-translational modification of proteins that regulates diverse cellular functions. Accurate identification of ubiquitination sites in proteins is vital for understanding fundamental biological mechanisms, such as cell cycle and DNA repair. Conventional experimental approaches are resource-intensive, whereas machine learning offers a cost-effective means of accurately identifying ubiquitination sites. The prediction of ubiquitination sites is species-specific, with many existing models being tailored for () and (). However, these models have shortcomings in sequence window selection and feature extraction, leading to suboptimal performance.
METHODS
This study initially employed the chi-square test to determine the optimal sequence window. Subsequently, a combination of six features was assessed: Binary Encoding (BE), Composition of K-Spaced Amino Acid Pair (CKSAAP), Enhanced Amino Acid Composition (EAAC), Position Weight Matrix (PWM), 531 Properties of Amino Acids (AA531), and Position-Specific Scoring Matrix (PSSM). Comparative evaluation involved three feature selection methods: Minimum Redundancy-Maximum Relevance (mRMR), Elastic net, and Null importances. Alongside these were four classifiers: Support Vector Machine (SVM), Decision Tree (DT), Random Forest (RF), and Extreme Gradient Boosting (XGBoost). The Null importances combined with the RF model exhibited superior predictive performance, and was denoted as UbNiRF (: ArUbNiRF; : HoUbNiRF).
RESULTS
A comprehensive assessment indicated that UbNiRF is superior to existing prediction tools across five performance metrics. It notably excelled in the Matthews Correlation Coefficient (MCC), with values of 0.827 for the dataset and 0.781 for the dataset. Feature analysis underscores the significance of integrating six features and demonstrates their critical role in enhancing model performance.
CONCLUSIONS
UbNiRF is a valuable predictive tool for identifying ubiquitination sites in both and . Its robust performance and species-specific discovery capabilities make it extremely useful for elucidating biological processes and disease mechanisms associated with ubiquitination.
Topics: Arabidopsis; Humans; Ubiquitination; Computational Biology; Machine Learning; Arabidopsis Proteins; Algorithms; Support Vector Machine; Random Forest
PubMed: 38812315
DOI: 10.31083/j.fbl2905197 -
Frontiers in Bioscience (Landmark... May 2024The F-box protein (FBXO) family plays a key role in the malignant progression of tumors. However, the biological functions and clinical value of the FBXO family in liver...
OBJECTIVE
The F-box protein (FBXO) family plays a key role in the malignant progression of tumors. However, the biological functions and clinical value of the FBXO family in liver cancer remain unclear. Our study comprehensively assessed the clinical value of the FBXO family in hepatocellular carcinoma (HCC) and constructed a novel signature based on the FBXO family to predict prognosis and guide precision immunotherapy.
METHODS
The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases were utilized to investigate the expression characteristics and prognostic value of the FBXO family in HCC. A predictive model based on the FBXO family using TCGA database; and its predictive ability was validated using the ICGC database. Further analyses revealed that this predictive model can independently predict the overall survival (OS) rate of patients with HCC. We further analyzed the association of this predictive model with signaling pathways, clinical pathological features, somatic mutations, and immune therapy responses. Finally, we validated the biological functions of cyclin F () through experiments.
RESULTS
A predictive model involving three genes (, , and ) was constructed, effectively identifying high and low-risk patients with differences in OS, clinicopathological characteristics, somatic mutations, and immune cell infiltration status. Additionally, knock-down of in HCC cell lines reduced cell proliferation , suggesting that may be a potential therapeutic target for HCC.
CONCLUSIONS
The predictive model based on the FBXO family can effectively predict OS and the immune therapy response in HCC. Additionally, is a potential therapeutic target for HCC.
Topics: Humans; Liver Neoplasms; Carcinoma, Hepatocellular; F-Box Proteins; Prognosis; Male; Female; Cell Line, Tumor; Middle Aged; Gene Expression Regulation, Neoplastic; Cyclins; Biomarkers, Tumor; Cell Proliferation; Databases, Genetic
PubMed: 38812312
DOI: 10.31083/j.fbl2905202 -
Frontiers in Bioscience (Landmark... May 2024Changes in myocardial mitochondrial morphology and function in premature ventricular contractions (PVCs)-induced cardiomyopathy (PVCCM) remain poorly studied. Here, we...
AIMS
Changes in myocardial mitochondrial morphology and function in premature ventricular contractions (PVCs)-induced cardiomyopathy (PVCCM) remain poorly studied. Here, we investigated the effects of PVCs with different coupling intervals (CIs) on myocardial mitochondrial remodelling in a canine model of PVCCM.
METHODS AND RESULTS
Twenty-one beagles underwent pacemaker implantation and were randomised into the sham (n = 7), short-coupled PVCs (SCP, n = 7), and long-coupled PVCs (LCP, n = 7) groups. Right ventricular (RV) apical bigeminy was produced for 12-week to induce PVCCM in the SCP (CI, 250 ms) and LCP (CI, 350 ms) groups. Echocardiography was performed at baseline and biweekly thereafter to evaluate cardiac function. Masson's trichrome staining measured ventricular interstitial fibrosis. The ultrastructural morphology of the myocardial mitochondria was analysed using transmission electron microscopy. Mitochondrial Ca2+ concentration, reactive oxygen species (ROS) levels, adenosine triphosphate (ATP) content, membrane potential, and electron transport chain (ETC) complex activity were measured to assess myocardial mitochondrial function. Twelve-week-PVCs led to left ventricular (LV) enlargement with systolic dysfunction, disrupted mitochondrial morphology, increased mitochondrial Ca2+ concentration and ROS levels, decreased mitochondrial ATP content and membrane potential, and impaired ETC complex activity in both the SCP and LCP groups (all < 0.01 the sham group). Ventricular fibrosis was observed only in canines with LCP. Worse cardiac function and more pronounced abnormalities in mitochondrial morphology and function were observed in the LCP group than to the SCP group (all < 0.05).
CONCLUSION
We demonstrated myocardial mitochondrial abnormalities in dogs with PVCCM, characterised by abnormal mitochondrial morphology, mitochondrial Ca2+ overload, oxidative stress, and impaired mitochondrial energy metabolism. Compared to SCP, long-term LCP exposure resulted in more severe mitochondrial remodelling and cardiac dysfunction in dogs.
Topics: Animals; Dogs; Mitochondria, Heart; Cardiomyopathies; Disease Models, Animal; Ventricular Premature Complexes; Reactive Oxygen Species; Calcium; Male; Adenosine Triphosphate; Membrane Potential, Mitochondrial; Echocardiography
PubMed: 38812311
DOI: 10.31083/j.fbl2905200 -
Frontiers in Bioscience (Landmark... May 2024Neointimal hyperplasia (NIH) is the pathological basis of vascular injury disease. Vascular cells are the dominant cells in the process of NIH, but the extent of...
BACKGROUND
Neointimal hyperplasia (NIH) is the pathological basis of vascular injury disease. Vascular cells are the dominant cells in the process of NIH, but the extent of heterogeneity amongst them is still unclear.
METHODS
A mouse model of NIH was constructed by inducing carotid artery ligation. Single-cell sequencing was then used to analyze the transcriptional profile of vascular cells. Cluster features were determined by functional enrichment analysis, gene set scoring, pseudo-time analysis, and cell-cell communication analysis. Additionally, immunofluorescence staining was conducted on vascular tissues from fibroblast lineage-traced (PdgfraDreER-tdTomato) mice to validate the presence of cells.
RESULTS
The left carotid arteries (ligation) were compared to right carotid arteries (sham) from ligation-induced NIH C57BL/6 mice. Integrative analyses revealed a high level of heterogeneity amongst vascular cells, including fourteen clusters and seven cell types. We focused on three dominant cell types: endothelial cells (ECs), vascular smooth muscle cells (vSMCs), and fibroblasts. The major findings were: (1) four subpopulations of ECs, including ECs4, mesenchymal-like ECs (ECs1 and ECs2), and fibro-like ECs (ECs3); (2) four subpopulations of fibroblasts, including pro-inflammatory Fibs-1, Fibs-2, collagen-producing Fibs-3, and mesenchymal-like Fibs-4; (3) four subpopulations of vSMCs, including vSMCs-1, vSMCs-2, vSMCs-3, and vSMCs-3-derived vSMCs; (4) ECs3 express genes related to extracellular matrix (ECM) remodeling and cell migration, and fibro-like vSMCs showed strong chemokine secretion and relatively high levels of proteases; (5) fibro-like vSMCs that secrete Vegfa interact with ECs mainly through vascular endothelial growth factor receptor 2 (Vegfr2).
CONCLUSIONS
This study presents the dynamic cellular landscape within NIH arteries and reveals potential relationships between several clusters, with a specific focus on ECs3 and fibro-like vSMCs. These two subpopulations may represent potential target cells for the treatment of NIH.
Topics: Animals; Neointima; Single-Cell Analysis; Hyperplasia; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Mice; Gene Expression Profiling; Endothelial Cells; Carotid Arteries; Myocytes, Smooth Muscle; Male; Fibroblasts; Disease Models, Animal; Single-Cell Gene Expression Analysis
PubMed: 38812305
DOI: 10.31083/j.fbl2905173 -
Frontiers in Bioscience (Landmark... May 2024Osteosarcoma (OS) is the most prevalent orthopedic malignancy with a dismal prognosis. Disulfidptosis-related lncRNAs (DRLncs) may be related to the progression of OS,...
BACKGROUND
Osteosarcoma (OS) is the most prevalent orthopedic malignancy with a dismal prognosis. Disulfidptosis-related lncRNAs (DRLncs) may be related to the progression of OS, but their potential molecular regulatory role is still unclear.
METHODS
Based on the data collected from The Cancer Genome Atlas (TCGA), we conducted correlation analysis and the univariate Cox analysis to screen prognosis-related DRLncs, followed by developing genotyping patterns and corresponding classifier. Subsequently, the survival analysis, enrichment analysis, drug sensitivity analysis and immune infiltration analysis were performed. Afterward, multivariate Cox regression was used to construct a risk model, which was further validated by the receiver operating characteristic (ROC) curve. The aberrant expression of hub DRLncs in OS was validated using the Reverse Transcription Polymerase Chain Reaction (RT-qPCR) assay.
RESULTS
We identified 262 DRLncs and eleven prognosis-related DRLncs through filtering. We then constructed two distinct expression patterns of prognosis-related DRLncs and developed a classifier. We obtained 393 differentially expressed genes (DEGs) between different subtypes, which were significantly enriched in biological processes related to the extracellular matrix, integrin binding, focal adhesion, and Wnt signaling pathways. Through immune infiltration analysis, the activated CD4 memory T cells, resting natural killer (NK) cells, M1 macrophages, and resting dendritic cells (DC) were observed to exhibit different abundance in distinct subtypes. In the drug sensitivity analysis, tamoxifen showed a promising effect for drug-resistant OS. Furthermore, we identified five hub DRLncs and constructed a risk model. The RT-qPCR confirmed the aberrant expression of five hub DRLncs in OS.
CONCLUSIONS
The present study identified DRLncs in OS, and conducted a comprehensive investigation of DRLncs-related expression patterns, survival status, immune landscape and drug sensitivity to reveal the difference in prognostic, pharmacological and immunological phenotype characteristics between distinct subtypes. Additionally, we developed a risk model to predict the prognosis, and constructed a genotyping classifier to predict the above phenotype characteristics in OS.
Topics: Humans; Osteosarcoma; RNA, Long Noncoding; Prognosis; Bone Neoplasms; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor; Genotype; Gene Expression Profiling; Tumor Microenvironment; Female; Male
PubMed: 38812298
DOI: 10.31083/j.fbl2905193 -
CPT: Pharmacometrics & Systems... May 2024Sotatercept is a breakthrough, first-in-class biologic, that is FDA-approved for the treatment of pulmonary arterial hypertension (PAH). A population pharmacokinetic...
Sotatercept is a breakthrough, first-in-class biologic, that is FDA-approved for the treatment of pulmonary arterial hypertension (PAH). A population pharmacokinetic (PopPK) model was developed using data from two phase 1 studies in healthy participants, and two phase 2 studies and one phase 3 study in participants with PAH. The pooled sotatercept PK data encompassed single intravenous (IV) or subcutaneous (SC) doses ranging from 0.01 to 3.0 mg/kg, as well as multiple SC doses ranging from 0.03 to 1.0 mg/kg, with PK samples collected up to a maximum of ~150 weeks following Q3W and Q4W dosing regimens. The final PopPK analysis included 350 participants, with 30 and 320 participants receiving sotatercept IV and SC, respectively. A two-compartment model with a first-order absorption rate constant and a linear disposition from central compartment well-described sotatercept PK. The estimated bioavailability is ~66%; bioavailability, clearance (CL), and central volume (VC) have low to moderate inter-individual variability. Time-varying body weight and baseline albumin concentration were statistically significant predictors of PK; CL and VC were predicted to increase with increasing body weight, while CL was predicted to decrease with increasing baseline albumin concentration. However, the magnitude of covariate effects is not predicted to meaningfully alter the disposition of sotatercept. Altogether, the PopPK modeling results demonstrate favorable PK characteristics (low to moderate variability and typical bioavailability), supporting sotatercept as a SC biological agent for the treatment of patients with PAH.
PubMed: 38812074
DOI: 10.1002/psp4.13166 -
Biological Research May 2024Studies have suggested that endoplasmic reticulum stress (ERS) is involved in neurological dysfunction and that electroacupuncture (EA) attenuates neuropathic pain (NP)...
Studies have suggested that endoplasmic reticulum stress (ERS) is involved in neurological dysfunction and that electroacupuncture (EA) attenuates neuropathic pain (NP) via undefined pathways. However, the role of ERS in the anterior cingulate cortex (ACC) in NP and the effect of EA on ERS in the ACC have not yet been investigated. In this study, an NP model was established by chronic constriction injury (CCI) of the left sciatic nerve in rats, and mechanical and cold tests were used to evaluate behavioral hyperalgesia. The protein expression and distribution were evaluated using western blotting and immunofluorescence. The results showed that glucose-regulated protein 78 (BIP) and inositol-requiring enzyme 1α (IRE-1α) were co-localized in neurons in the ACC. After CCI, BIP, IRE-1α, and phosphorylation of IRE-1α were upregulated in the ACC. Intra-ACC administration of 4-PBA and Kira-6 attenuated pain hypersensitivity and downregulated phosphorylation of IRE-1α, while intraperitoneal injection of 4-PBA attenuated hyperalgesia and inhibited the activation of P38 and JNK in ACC. In contrast, ERS activation by intraperitoneal injection of tunicamycin induced behavioral hyperalgesia in naive rats. Furthermore, EA attenuated pain hypersensitivity and inhibited the CCI-induced overexpression of BIP and pIRE-1α. Taken together, these results demonstrate that EA attenuates NP by suppressing BIP- and IRE-1α-mediated ERS in the ACC. Our study presents novel evidence that ERS in the ACC is implicated in the development of NP and provides insights into the molecular mechanisms involved in the analgesic effect of EA.
Topics: Animals; Electroacupuncture; Gyrus Cinguli; Neuralgia; Male; Rats, Sprague-Dawley; Endoplasmic Reticulum Stress; Disease Models, Animal; Rats; Blotting, Western; Heat-Shock Proteins; Protein Serine-Threonine Kinases; Hyperalgesia; Endoplasmic Reticulum Chaperone BiP
PubMed: 38812057
DOI: 10.1186/s40659-024-00511-3 -
Skeletal Muscle May 2024Intramuscular fat (IMAT) infiltration, pathological adipose tissue that accumulates between muscle fibers, is a shared hallmark in a diverse set of diseases including... (Comparative Study)
Comparative Study
Intramuscular fat (IMAT) infiltration, pathological adipose tissue that accumulates between muscle fibers, is a shared hallmark in a diverse set of diseases including muscular dystrophies and diabetes, spinal cord and rotator cuff injuries, as well as sarcopenia. While the mouse has been an invaluable preclinical model to study skeletal muscle diseases, they are also resistant to IMAT formation. To better understand this pathological feature, an adequate pre-clinical model that recapitulates human disease is necessary. To address this gap, we conducted a comprehensive in-depth comparison between three widely used mouse strains: C57BL/6J, 129S1/SvlmJ and CD1. We evaluated the impact of strain, sex and injury type on IMAT formation, myofiber regeneration and fibrosis. We confirm and extend previous findings that a Glycerol (GLY) injury causes significantly more IMAT and fibrosis compared to Cardiotoxin (CTX). Additionally, females form more IMAT than males after a GLY injury, independent of strain. Of all strains, C57BL/6J mice, both females and males, are the most resistant to IMAT formation. In regard to injury-induced fibrosis, we found that the 129S strain formed the least amount of scar tissue. Surprisingly, C57BL/6J of both sexes demonstrated complete myofiber regeneration, while both CD1 and 129S1/SvlmJ strains still displayed smaller myofibers 21 days post injury. In addition, our data indicate that myofiber regeneration is negatively correlated with IMAT and fibrosis. Combined, our results demonstrate that careful consideration and exploration are needed to determine which injury type, mouse model/strain and sex to utilize as preclinical model especially for modeling IMAT formation.
Topics: Animals; Male; Female; Mice, Inbred C57BL; Regeneration; Muscle, Skeletal; Mice; Adipose Tissue; Fibrosis; Disease Models, Animal; Sex Characteristics; Species Specificity; Glycerol; Mice, 129 Strain
PubMed: 38812056
DOI: 10.1186/s13395-024-00344-4 -
European Journal of Medical Research May 2024Exosomes (Exos) are involved in the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) on heart failure (HF). We investigated the molecular mechanisms...
BACKGROUND
Exosomes (Exos) are involved in the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) on heart failure (HF). We investigated the molecular mechanisms underlying the involvement of BMSC-Exos in ferroptosis on HF.
METHODS
A rat model of HF and cellular model of hypoxia were established. BMSC-Exos were injected into model rats or co-cultured with model cells. In model rats, the cardiac function (echocardiography), oxidative stress (commercial kits), pathological damage (HE staining), fibrosis (MASSON staining), iron deposition (Prussian blue staining), and cell apoptosis (TUNEL staining) were examined. Viability (cell counting kit-8; CCK-8), cell cycle (flow cytometry), oxidative stress, and Fe levels were detected in the model cells. GAS5, UL3, YAP, and TAZ expression were detected using qRT-PCR, western blotting, and immunohistochemistry analyses.
RESULTS
BMSC-Exos restored cardiac function and inhibited oxidative stress, apoptosis, pathological damage, fibrosis, and iron deposition in myocardial tissues of HF rats. In hypoxic cells, BMSC-Exos increased cell viability, decreased the number of G1 phase cells, decreased Fe levels, and inhibited oxidative stress. Ferrostatin-1 (a ferroptosis inhibitor) exhibited a synergistic effect with BMSC-Exos. Additionally, GAS5 was upregulated in BMSC-Exos, further upregulating its target UL3 and Hippo pathway effectors (YAP and TAZ). The relieving effects of BMSC-Exos on HF or hypoxia-induced injury were enhanced by GAS5 overexpression, but weakened by UL3 silencing or verteporfin (a YAP inhibitor).
CONCLUSIONS
GAS5-harbouring BMSC-Exos inhibited ferroptosis by regulating the UL3/Hippo pathway, contributing to HF remission in vivo and in vitro.
Topics: Ferroptosis; Animals; Rats; Heart Failure; Mesenchymal Stem Cells; Exosomes; RNA, Long Noncoding; Male; Hippo Signaling Pathway; Rats, Sprague-Dawley; Protein Serine-Threonine Kinases; Signal Transduction; Oxidative Stress; Apoptosis; Disease Models, Animal
PubMed: 38812041
DOI: 10.1186/s40001-024-01880-x -
Cardiovascular Diabetology May 2024Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. Recently, ferroptosis has been recognised as a novel therapeutic target for...
BACKGROUND
Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. Recently, ferroptosis has been recognised as a novel therapeutic target for cardiovascular diseases. Although an association between ferroptosis and vascular calcification has been reported, the role and mechanism of iron overload in vascular calcification are still poorly understood. Specifically, further in-depth research is required on whether metalloproteins SLC39a14 and SLC39a8 are involved in ferroptosis induced by iron overload.
METHODS
R language was employed for the differential analysis of the dataset, revealing the correlation between ferroptosis and calcification. The experimental approaches encompassed both in vitro and in vivo studies, incorporating the use of iron chelators and models of iron overload. Additionally, gain- and loss-of-function experiments were conducted to investigate iron's effects on vascular calcification comprehensively. Electron microscopy, immunofluorescence, western blotting, and real-time polymerase chain reaction were used to elucidate how Slc39a14 and Slc39a8 mediate iron overload and promote calcification.
RESULTS
Ferroptosis was observed in conjunction with vascular calcification (VC); the association was consistently confirmed by in vitro and in vivo studies. Our results showed a positive correlation between iron overload in VSMCs and calcification. Iron chelators are effective in reversing VC and iron overload exacerbates this process. The expression levels of the metal transport proteins Slc39a14 and Slc39a8 were significantly upregulated during calcification; the inhibition of their expression alleviated VC. Conversely, Slc39a14 overexpression exacerbates calcification and promotes intracellular iron accumulation in VSMCs.
CONCLUSIONS
Our research demonstrates that iron overload occurs during VC, and that inhibition of Slc39a14 and Slc39a8 significantly relieves VC by intercepting iron overload-induced ferroptosis in VSMCs, providing new insights into the VC treatment.
Topics: Ferroptosis; Vascular Calcification; Animals; Cation Transport Proteins; Myocytes, Smooth Muscle; Disease Models, Animal; Muscle, Smooth, Vascular; Mice, Inbred C57BL; Iron Chelating Agents; Signal Transduction; Male; Humans; Iron; Iron Overload
PubMed: 38812011
DOI: 10.1186/s12933-024-02224-z