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International Journal of Biological... 2024Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the critical pathological mechanisms of pulmonary hypertension (PH), and therefore is...
Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the critical pathological mechanisms of pulmonary hypertension (PH), and therefore is gradually being adopted as an important direction for the treatment of PH. Metallothioneins (MTs) have been reported to be associated with PH, but the underlying mechanisms are not fully understood. Here, we demonstrated that the expression level of metallothionein 3 (MT3) was significantly increased in pulmonary arterioles from PH patients and chronic hypoxia-induced rat and mouse PH models, as well as in hypoxia-treated human PASMCs. Knockdown of MT3 significantly inhibited the proliferation of human PASMCs by arresting the cell cycle in the G1 phase, while overexpression of MT3 had the opposite effect. Mechanistically, we found that MT3 increased the intracellular zinc (Zn) concentration to enhance the transcriptional activity of metal-regulated transcription factor 1 (MTF1), which promoted the expression of autophagy-related gene 5 (ATG5), facilitating autophagosome formation. More importantly, MT3-induced autophagy and proliferation of human PASMCs were largely prevented by knockdown of MTF1 and ATG5. Therefore, in this study, we identified MT3-Zinc-MTF1-ATG5 as a novel pathway that affects PASMC proliferation by regulating autophagosome formation, suggesting that MT3 may be a novel target for the treatment of PH.
Topics: Pulmonary Artery; Animals; Cell Proliferation; Humans; Zinc; Mice; Rats; Myocytes, Smooth Muscle; Metallothionein 3; Male; Autophagosomes; Autophagy-Related Protein 5; Rats, Sprague-Dawley; Transcription Factors; Autophagy; Hypertension, Pulmonary; Mice, Inbred C57BL; DNA-Binding Proteins; Transcription Factor MTF-1; Metallothionein
PubMed: 38904023
DOI: 10.7150/ijbs.92992 -
Nature Communications Jun 2024Aerobic life is powered by membrane-bound redox enzymes that shuttle electrons to oxygen and transfer protons across a biological membrane. Structural studies suggest...
Aerobic life is powered by membrane-bound redox enzymes that shuttle electrons to oxygen and transfer protons across a biological membrane. Structural studies suggest that these energy-transducing enzymes operate as higher-order supercomplexes, but their functional role remains poorly understood and highly debated. Here we resolve the functional dynamics of the 0.7 MDa IIIIV obligate supercomplex from Mycobacterium smegmatis, a close relative of M. tuberculosis, the causative agent of tuberculosis. By combining computational, biochemical, and high-resolution (2.3 Å) cryo-electron microscopy experiments, we show how the mycobacterial supercomplex catalyses long-range charge transport from its menaquinol oxidation site to the binuclear active site for oxygen reduction. Our data reveal proton and electron pathways responsible for the charge transfer reactions, mechanistic principles of the quinone catalysis, and how unique molecular adaptations, water molecules, and lipid interactions enable the proton-coupled electron transfer (PCET) reactions. Our combined findings provide a mechanistic blueprint of mycobacterial supercomplexes and a basis for developing drugs against pathogenic bacteria.
Topics: Mycobacterium smegmatis; Electron Transport; Cryoelectron Microscopy; Oxidation-Reduction; Bacterial Proteins; Protons; Electron Transport Complex III; Oxygen; Electron Transport Complex IV; Catalytic Domain; Models, Molecular
PubMed: 38902248
DOI: 10.1038/s41467-024-49628-9 -
Journal of Chemical Information and... Jun 2024In this study, we introduce a novel approach to enhance the accuracy of molecular dynamics simulations by refining the force fields (FFs) through a combination of...
In this study, we introduce a novel approach to enhance the accuracy of molecular dynamics simulations by refining the force fields (FFs) through a combination of transferable parameters and molecule-specific characteristics derived from quantum mechanical (QM) calculations. Traditional FFs often prioritize generality over precision, leading to limitations in the accuracy of accurately capturing intra- and intermolecular interactions. To address this, we present an open-source toolkit, called HessFit, designed to integrate QM-derived bonded parameters and atomic charges into existing FFs. In combination with bond, angle, torsional, and nonbonded parameters derivation, HessFit can easily extract multiple barrier terms of dihedrals from QM Hessian and gradient or return all terms through a fitting procedure scheme of QM potential energy surface. We showcase the effectiveness of HessFit through comprehensive evaluations of vibrational properties across a diverse set of small molecules and demonstrate that experimental results support its ability in predicting thermodynamic properties of organic molecules compared to previous state-of-the-art approaches. We further explore its application to Zn metalloprotein models, which are hard systems to treat with automatic approaches. Our results demonstrate that HessFit parameters compete with GAFF2 and OPLS parameters to describing small organic molecules, and its feasibility is also comparable to current FFs used to modeling nonstandard residues in Zn proteins for molecular dynamics simulations. The effectiveness of the HessFit protocol makes it a valuable tool for deriving or extending force field parameters for novel compounds in several molecular modeling applications.
PubMed: 38897917
DOI: 10.1021/acs.jcim.4c00540 -
Human Brain Mapping Jun 2024Quantitative susceptibility mapping (QSM) is an MRI modality used to non-invasively measure iron content in the brain. Iron exhibits a specific anatomically varying...
Quantitative susceptibility mapping (QSM) is an MRI modality used to non-invasively measure iron content in the brain. Iron exhibits a specific anatomically varying pattern of accumulation in the brain across individuals. The highest regions of accumulation are the deep grey nuclei, where iron is stored in paramagnetic molecule ferritin. This form of iron is considered to be what largely contributes to the signal measured by QSM in the deep grey nuclei. It is also known that QSM is affected by diamagnetic myelin contents. Here, we investigate spatial gene expression of iron and myelin related genes, as measured by the Allen Human Brain Atlas, in relation to QSM images of age-matched subjects. We performed multiple linear regressions between gene expression and the average QSM signal within 34 distinct deep grey nuclei regions. Our results show a positive correlation (p < .05, corrected) between expression of ferritin and the QSM signal in deep grey nuclei regions. We repeated the analysis for other genes that encode proteins thought to be involved in the transport and storage of iron in the brain, as well as myelination. In addition to ferritin, our findings demonstrate a positive correlation (p < .05, corrected) between the expression of ferroportin, transferrin, divalent metal transporter 1, several gene markers of myelinating oligodendrocytes, and the QSM signal in deep grey nuclei regions. Our results suggest that the QSM signal reflects both the storage and active transport of iron in the deep grey nuclei regions of the brain.
Topics: Humans; Iron; Magnetic Resonance Imaging; Male; Female; Myelin Sheath; Adult; Homeostasis; Ferritins; Brain; Gene Expression; Middle Aged; Cation Transport Proteins; Young Adult; Brain Mapping
PubMed: 38896001
DOI: 10.1002/hbm.26688 -
Nutrients Jun 2024In pregnant women with multiple infections, nutrient deficiencies, and inflammation (MINDI), the study of anemia and iron status is limited. For this cross-sectional...
In pregnant women with multiple infections, nutrient deficiencies, and inflammation (MINDI), the study of anemia and iron status is limited. For this cross-sectional study ( = 213 Panamanian indigenous women), we investigated if hemoglobin, anemia (Hb < 110 g/L), ferritin, serum iron, serum transferrin receptor, and hepcidin were associated with (1) maternal nutritional status and supplementation practices, (2) biomarkers of inflammation, and (3) presence/absence of infections. Hierarchical generalized linear and logistic regression models and dominance analyses identified the relative importance of these predictors. Anemia (38%), which was likely underestimated due to low plasma volume (95%), was associated with lower ferritin, vitamin A, and weight-for-height, suggesting anemia of undernutrition. Inflammation was not associated with Hb or anemia; nevertheless, higher CRP was associated with increased odds of low serum iron and higher ferritin and hepcidin, indicating iron restriction due to inflammation. The length of iron supplementation did not enter models for anemia or iron indicators, but a multiple nutrient supplement was associated with higher ferritin and hepcidin. Moreover, iron supplementation was associated with higher odds of vaginal trichomoniasis but lower odds of caries and bacterial vaginosis. The complex pathogenesis of anemia and iron deficiency in MINDI settings may require other interventions beyond iron supplementation.
Topics: Humans; Female; Pregnancy; Inflammation; Adult; Cross-Sectional Studies; Iron; Nutritional Status; Anemia, Iron-Deficiency; Ferritins; Hepcidins; Dietary Supplements; Biomarkers; Young Adult; Iron Deficiencies; Hemoglobins; Cohort Studies; Anemia; Receptors, Transferrin; Maternal Nutritional Physiological Phenomena
PubMed: 38892681
DOI: 10.3390/nu16111748 -
Synthesis and Antioxidant Activity of -Benzyl-2-[4-(aryl)-1-1,2,3-triazol-1-yl]ethan-1-imine Oxides.International Journal of Molecular... May 2024The synthesis, antioxidant capacity, and anti-inflammatory activity of four novel -benzyl-2-[4-(aryl)-1-1,2,3-triazol-1-yl]ethan-1-imine oxides - are reported herein....
The synthesis, antioxidant capacity, and anti-inflammatory activity of four novel -benzyl-2-[4-(aryl)-1-1,2,3-triazol-1-yl]ethan-1-imine oxides - are reported herein. The nitrones - were tested for their antioxidant properties and their ability to inhibit soybean lipoxygenase (LOX). Four diverse antioxidant tests were used for in vitro antioxidant assays, namely, interaction with the stable free radical DPPH (1,1-diphenyl-2-picrylhydrazyl radical) as well as with the water-soluble azo compound AAPH (2,2'-azobis(2-amidinopropane) dihydrochloride), competition with DMSO for hydroxyl radicals, and the scavenging of cationic radical ABTS (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) radical cation). Nitrones , and , having the 4-fluorophenyl, 2,4-difluorophenyl, and 4-fluoro-3-methylphenyl motif, respectively, exhibited high interaction with DPPH (64.5-81% after 20 min; 79-96% after 60 min), whereas nitrone with unfunctionalized phenyl group showed the lowest inhibitory potency (57% after 20 min, 78% after 60 min). Nitrones and , decorated with phenyl and 4-fluoro-3-methylphenyl motif, respectively, appeared the most potent inhibitors of lipid peroxidation. The results obtained from radical cation ABTS were not significant, since all tested compounds - showed negligible activity (8-46%), much lower than Trolox (91%). Nitrone , bearing the 2,4-difluorophenyl motif, was found to be the most potent LOX inhibitor (IC = 10 μM).
Topics: Antioxidants; Lipoxygenase; Glycine max; Lipoxygenase Inhibitors; Triazoles; Imines; Biphenyl Compounds; Picrates; Nitrogen Oxides; Free Radical Scavengers
PubMed: 38892102
DOI: 10.3390/ijms25115908 -
International Journal of Molecular... May 2024In wounded leaves, four 13-lipoxygenases (AtLOX2, AtLOX3, AtLOX4, AtLOX6) act in a hierarchical manner to contribute to the jasmonate burst. This leads to defense...
In wounded leaves, four 13-lipoxygenases (AtLOX2, AtLOX3, AtLOX4, AtLOX6) act in a hierarchical manner to contribute to the jasmonate burst. This leads to defense responses with LOX2 playing an important role in plant resistance against caterpillar herb-ivory. In this study, we sought to characterize the impact of AtLOX2 on wound-induced phytohormonal and transcriptional responses to foliar mechanical damage using wildtype (WT) and mutant plants. Compared with WT, the mutant had higher constitutive levels of the phytohormone salicylic acid (SA) and enhanced expression of SA-responsive genes. This suggests that AtLOX2 may be involved in the biosynthesis of jasmonates that are involved in the antagonism of SA biosynthesis. As expected, the jasmonate burst in response to wounding was dampened in plants. Generally, 1 h after wounding, genes linked to jasmonate biosynthesis, jasmonate signaling attenuation and abscisic acid-responsive genes, which are primarily involved in wound sealing and healing, were differentially regulated between WT and mutants. Twelve h after wounding, WT plants showed stronger expression of genes associated with plant protection against insect herbivory. This study highlights the dynamic nature of jasmonate-responsive gene expression and the contribution of AtLOX2 to this pathway and plant resistance against insects.
Topics: Arabidopsis; Gene Expression Regulation, Plant; Arabidopsis Proteins; Lipoxygenase; Oxylipins; Cyclopentanes; Transcriptome; Salicylic Acid; Plant Growth Regulators; Plant Leaves; Mutation; Gene Expression Profiling; Lipoxygenases
PubMed: 38892085
DOI: 10.3390/ijms25115898 -
International Journal of Molecular... May 2024Friedreich's Ataxia (FRDA) stands out as the most prevalent form of hereditary ataxias, marked by progressive movement ataxia, loss of vibratory sensitivity, and...
Friedreich's Ataxia (FRDA) stands out as the most prevalent form of hereditary ataxias, marked by progressive movement ataxia, loss of vibratory sensitivity, and skeletal deformities, severely affecting daily functioning. To date, the only medication available for treating FRDA is Omaveloxolone (Skyclarys), recently approved by the FDA. Missense mutations within the human frataxin (FXN) gene, responsible for intracellular iron homeostasis regulation, are linked to FRDA development. These mutations induce FXN dysfunction, fostering mitochondrial iron accumulation and heightened oxidative stress, ultimately triggering neuronal cell death pathways. This study amalgamated 226 FXN genetic variants from the literature and database searches, with only 18 previously characterized. Predictive analyses revealed a notable prevalence of detrimental and destabilizing predictions for FXN mutations, predominantly impacting conserved residues crucial for protein function. Additionally, an accurate, comprehensive three-dimensional model of human FXN was constructed, serving as the basis for generating genetic variants I154F and W155R. These variants, selected for their severe clinical implications, underwent molecular dynamics (MD) simulations, unveiling flexibility and essential dynamic alterations in their N-terminal segments, encompassing FXN42, FXN56, and FXN78 domains pivotal for protein maturation. Thus, our findings indicate potential interaction profile disturbances in the FXN42, FXN56, and FXN78 domains induced by I154F and W155R mutations, aligning with the existing literature.
Topics: Humans; Frataxin; Friedreich Ataxia; Iron-Binding Proteins; Molecular Dynamics Simulation; Mutation, Missense; Computer Simulation; Genetic Variation
PubMed: 38891993
DOI: 10.3390/ijms25115796 -
Scientific Reports Jun 2024Lipid metabolism is an important part of the heart's energy supply. The expression pattern and molecular mechanism of lipid metabolism-related genes (LMRGs) in acute...
Lipid metabolism is an important part of the heart's energy supply. The expression pattern and molecular mechanism of lipid metabolism-related genes (LMRGs) in acute myocardial infarction (AMI) are still unclear, and the link between lipid metabolism and immunity is far from being elucidated. In this study, 23 Common differentially expressed LMRGs were discovered in the AMI-related mRNA microarray datasets GSE61144 and GSE60993. These genes were mainly related to "leukotriene production involved in inflammatory response", "lipoxygenase pathway", "metabolic pathways", and "regulation of lipolysis in adipocytes" pathways. 12 LMRGs (ACSL1, ADCY4, ALOX5, ALOX5AP, CCL5, CEBPB, CEBPD, CREB5, GAB2, PISD, RARRES3, and ZNF467) were significantly differentially expressed in the validation dataset GSE62646 with their AUC > 0.7 except for ALOX5AP (AUC = 0.699). Immune infiltration analysis and Pearson correlation analysis explored the immune characteristics of AMI, as well as the relationship between these identified LMRGs and immune response. Lastly, the up-regulation of ACSL1, ALOX5AP, CEBPB, and GAB2 was confirmed in the mouse AMI model. Taken together, LMRGs ACSL1, ALOX5AP, CEBPB, and GAB2 are significantly upregulated in AMI patients' blood, peripheral blood of AMI mice, myocardial tissue of AMI mice, and therefore might be new potential biomarkers for AMI.
Topics: Myocardial Infarction; Lipid Metabolism; Humans; 5-Lipoxygenase-Activating Proteins; Gene Expression Profiling; Animals; Arachidonate 5-Lipoxygenase; Gene Expression Regulation; Mice; Male; Coenzyme A Ligases
PubMed: 38890389
DOI: 10.1038/s41598-024-65022-3 -
Journal of Molecular Modeling Jun 2024The coherent electron/spin transport in azurin, a species of copper protein, was calculated based on the Landauer model. The research is motivated by the fast electron...
CONTEXT
The coherent electron/spin transport in azurin, a species of copper protein, was calculated based on the Landauer model. The research is motivated by the fast electron transport and spin selectivity/polarization in azurin, which have been reported in relation to the chiral-induced spin selectivity of the peptide structure. The calculated spin polarization of copper proteins was large. This phenomenon was strongly influenced by the spin density of the atoms in the ligand group, whereas the contribution of copper was negligible. The results suggest that spin polarization in copper proteins is enhanced by that of the ligand groups. The predicted spin polarization aligns primarily with the scanning tunneling microscope-based break-junction technique to study the electronic properties of single-molecule junctions.
METHODS
Computational techniques employed in this study are nonequilibrium Green's functions (NEGF) and density functional theory (DFT) based on the Landauer model, implemented using the QuantumATK software (Synopsys Inc.). The Perdew-Burke-Ernzerhof (PBE) exchange-correlation functional was adopted for spin-polarized generalized gradient approximation (SGGA). The valence atomic orbitals were constructed using the wavefunctions of the SIESTA package, which was based on the norm-conserving Troullier-Martins relativistic pseudopotentials for describing core electrons. The mesh used for real-space integration was 150 Ha.
Topics: Azurin; Copper; Models, Molecular; Electron Transport; Density Functional Theory
PubMed: 38890154
DOI: 10.1007/s00894-024-06025-9