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American Journal of Physiology. Renal... Dec 2023The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been... (Review)
Review
The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been crucial in explaining the cardinal manifestations of human minimal change nephrotic syndrome (MCNS). Recently, uncovered genomic defects upstream of induce a hypomorph state that makes podocytes inherently susceptible to mild cytokine storms resulting from a common cold. In hypomorph podocytes, ZHX proteins are redistributed away from normal transmembrane partners like aminopeptidase A (APA) toward alternative binding partners like IL-4Rα. During disease relapse, high plasma soluble IL-4Rα (sIL-4Rα) associated with chronic atopy complements the cytokine milieu of a common cold to displace ZHX1 from podocyte transmembrane IL-4Rα toward the podocyte nucleus. Nuclear ZHX1 induces severe upregulation of , resulting in incomplete sialylation of part of the ANGPTL4 protein, secretion of hyposialylated ANGPTL4, and hyposialylation-related injury in the glomerulus. This pattern of injury induces many of the classic manifestations of human minimal change disease (MCD), including massive and selective proteinuria, podocyte foot process effacement, and loss of glomerular basement membrane charge. Administration of glucocorticoids reduces upregulation, which reduces hyposialylation injury to improve the clinical phenotype. Improving sialylation of podocyte-secreted ANGPTL4 also reduces proteinuria and improves experimental MCD. Neutralizing circulating TNF-α, IL-6, or sIL-4Rα after the induction of the cytokine storm in hypomorph mice reduces albuminuria, suggesting potential new therapeutic targets for clinical trials to prevent MCD relapse. These studies collectively lay to rest prior suggestions of a role of single cytokines or soluble proteins in triggering MCD relapse.
Topics: Mice; Humans; Animals; Nephrosis, Lipoid; Podocytes; Common Cold; Proteinuria; Glomerular Basement Membrane; Recurrence; Nephrotic Syndrome; Transcription Factors; Homeodomain Proteins
PubMed: 37795536
DOI: 10.1152/ajprenal.00219.2023 -
Best Practice & Research. Clinical... Aug 2023The increase in caesarean sections (CS) has resulted in an increase in women with a uterine niche. The exact aetiology of niche development has yet to be elucidated but... (Review)
Review
The increase in caesarean sections (CS) has resulted in an increase in women with a uterine niche. The exact aetiology of niche development has yet to be elucidated but is likely multifactorial. This study aimed to give a systematic overview of the available literature on histopathological features, risk factors and results of preventive strategies on niche development to gain more insight into the underlying mechanisms. Based on current published data histopathological findings associated with niche development were necrosis, fibrosis, inflammation, adenomyosis and insufficient approximation. Patient-related risk factors included multiple CS, BMI and smoking. Labour-related factors were CS before onset of labour, extended cervical dilatation, premature rupture of membranes and presenting part of the fetus at CS below the pelvic inlet. Preventive strategies should focus on the optimal level of incision, training of surgeons and full-thickness closure of the myometrium (single or double-layer) using non-locking sutures. Conflicting data exist concerning the effect of endometrial inclusion. Future studies without heterogeneity in population, using standardized performance of the CS after proper training and using standardized niche evaluation with a relevant core outcome set are required to allow meta-analyses and to develop evidence-based preventive strategies. These studies are needed to reduce the prevalence of niches and prevent complications in subsequent pregnancies such as caesarean scar pregnancies.
Topics: Pregnancy; Female; Humans; Cicatrix; Uterus; Cesarean Section; Myometrium; Risk Factors
PubMed: 37385157
DOI: 10.1016/j.bpobgyn.2023.102363 -
Cell Communication and Signaling : CCS Aug 2023Macrophages are immune cells with high plasticity that are widely distributed in all tissues and organs of the body. Under the influence of the immune microenvironment... (Review)
Review
Macrophages are immune cells with high plasticity that are widely distributed in all tissues and organs of the body. Under the influence of the immune microenvironment of breast tumors, macrophages differentiate into various germline lineages. They exert pro-tumor or tumor-suppressive effects by secreting various cytokines. Pyroptosis is mediated by Gasdermin family proteins, which form holes in cell membranes and cause a violent inflammatory response and cell death. This is an important way for the body to fight off infections. Tumor cell pyroptosis can activate anti-tumor immunity and inhibit tumor growth. At the same time, it releases inflammatory mediators and recruits tumor-associated macrophages (TAMs) for accumulation. Macrophages act as "mediators" of cytokine interactions and indirectly influence the pyroptosis pathway. This paper describes the mechanism of action on the part of TAM in affecting the pyroptosis process of breast tumor cells, as well as its key role in the tumor microenvironment. Additionally, it provides the basis for in-depth research on how to use immune cells to affect breast tumors and guide anti-tumor trends, with important implications for the prevention and treatment of breast tumors. Video Abstract.
Topics: Humans; Female; Pyroptosis; Tumor-Associated Macrophages; Breast Neoplasms; Macrophages; Cytokines; Tumor Microenvironment
PubMed: 37542283
DOI: 10.1186/s12964-023-01208-y -
ACS Nano Jun 2024We have evolved the nanopore-forming macrolittin peptides from the bee venom peptide melittin using successive generations of synthetic molecular evolution. Despite...
We have evolved the nanopore-forming macrolittin peptides from the bee venom peptide melittin using successive generations of synthetic molecular evolution. Despite their sequence similarity to the broadly membrane permeabilizing cytolytic melittin, the macrolittins have potent membrane selectivity. They form nanopores in synthetic bilayers made from 1-palmitoyl, 2-oleoyl-phosphatidylcholine (POPC) at extremely low peptide concentrations and yet have essentially no cytolytic activity against any cell membrane, even at high concentration. Here, we explore the structural determinants of macrolittin nanopore stability in POPC bilayers using atomistic molecular dynamics simulations and experiments on macrolittins and single-site variants. Simulations of macrolittin nanopores in POPC bilayers show that they are stabilized by an extensive, cooperative hydrogen bond network comprised of the many charged and polar side chains interacting with each other via bridges of water molecules and lipid headgroups. Lipid molecules with unusual conformations participate in the H-bond network and are an integral part of the nanopore structure. To explore the role of this H-bond network on membrane selectivity, we swapped three critical polar residues with the nonpolar residues found in melittin. All variants have potency, membrane selectivity, and cytotoxicity that were intermediate between a cytotoxic melittin variant called MelP5 and the macrolittins. Simulations showed that the variants had less organized H-bond networks of waters and lipids with unusual structures. The membrane-spanning, cooperative H-bond network is a critical determinant of macrolittin nanopore stability and membrane selectivity. The results described here will help guide the future design and optimization of peptide nanopore-based applications.
Topics: Nanopores; Melitten; Molecular Dynamics Simulation; Phosphatidylcholines; Lipid Bilayers; Hydrogen Bonding; Peptides; Humans
PubMed: 38844421
DOI: 10.1021/acsnano.4c02824 -
The Journal of Cell Biology Oct 2023Myosins are required for clathrin-mediated endocytosis, but their precise molecular roles in this process are not known. This is, in part, because the biophysical...
Myosins are required for clathrin-mediated endocytosis, but their precise molecular roles in this process are not known. This is, in part, because the biophysical properties of the relevant motors have not been investigated. Myosins have diverse mechanochemical activities, ranging from powerful contractility against mechanical loads to force-sensitive anchoring. To better understand the essential molecular contribution of myosin to endocytosis, we studied the in vitro force-dependent kinetics of the Saccharomyces cerevisiae endocytic type I myosin called Myo5, a motor whose role in clathrin-mediated endocytosis has been meticulously studied in vivo. We report that Myo5 is a low-duty-ratio motor that is activated ∼10-fold by phosphorylation and that its working stroke and actin-detachment kinetics are relatively force-insensitive. Strikingly, the in vitro mechanochemistry of Myo5 is more like that of cardiac myosin than that of slow anchoring myosin-1s found on endosomal membranes. We, therefore, propose that Myo5 generates power to augment actin assembly-based forces during endocytosis in cells.
Topics: Actins; Clathrin; Myosin Type I; Myosins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 37549220
DOI: 10.1083/jcb.202303095 -
Brain Sciences Aug 2023The concept of migraine with aura (MwA) is a widespread condition that can affect up to 30% of migraine patients and manifests itself as a temporary visual illusion... (Review)
Review
The concept of migraine with aura (MwA) is a widespread condition that can affect up to 30% of migraine patients and manifests itself as a temporary visual illusion followed by a prolonged headache. It was initially pitched as a neurological disease, and observed that the spread of accompanying electrophysiological waves as part of the condition, which came to be known as cortical spreading depression (CSD). A strong theoretical basis for a link between MwA and CSD has eventually led to knowledge of the dynamics between the pair. In addition to experiment-based observations, mathematical models make an important contribution towards a numerical means of expressing codependent neural-scale manifestations. This provides alternate means of understanding and observing the phenomena while helping to visualize the links between the variables and their magnitude in contributing towards the emanation and dynamic pulsing of the condition. A number of biophysical mechanisms are believed to contribute to the MwA-CSD, spanning ion diffusion, ionic currents of membranes, osmosis, spatial buffering, neurotransmission, gap junctions, metabolic pumping, and synapse connections. As part of this review study, the various mathematical models for the description of the condition are expressed, reviewed, and contrasted, all of which vary in their depth, perspective, and level of information presented. Subsequent to this, the review looked into links between electrophysiological data-driven manifestations from measurements such as EEG and fMRI. While concluding remarks forged a structured pathway in the area on sub-themes that need to be investigated in order to strengthen and robustify the existing models, they include an accounting for inter-personal variability in models, sex and hormonal factors, and age groups, i.e., pediatrics vs. adults.
PubMed: 37759842
DOI: 10.3390/brainsci13091241 -
The Journal of Allergy and Clinical... May 2024Airway hyperresponsiveness (AHR) is a key clinical feature of asthma. The presence of AHR in people with asthma provides the substrate for bronchoconstriction in... (Review)
Review
Airway hyperresponsiveness (AHR) is a key clinical feature of asthma. The presence of AHR in people with asthma provides the substrate for bronchoconstriction in response to numerous diverse stimuli, contributing to airflow limitation and symptoms including breathlessness, wheeze, and chest tightness. Dysfunctional airway smooth muscle significantly contributes to AHR and is displayed as increased sensitivity to direct pharmacologic bronchoconstrictor stimuli, such as inhaled histamine and methacholine (direct AHR), or to endogenous mediators released by activated airway cells such as mast cells (indirect AHR). Research in in vivo human models has shown that the disrupted airway epithelium plays an important role in driving inflammation that mediates indirect AHR in asthma through the release of cytokines such as thymic stromal lymphopoietin and IL-33. These cytokines upregulate type 2 cytokines promoting airway eosinophilia and induce the release of bronchoconstrictor mediators from mast cells such as histamine, prostaglandin D, and cysteinyl leukotrienes. While bronchoconstriction is largely due to airway smooth muscle contraction, airway structural changes known as remodeling, likely mediated in part by epithelial-derived mediators, also lead to airflow obstruction and may enhance AHR. In this review, we outline the current knowledge of the role of the airway epithelium in AHR in asthma and its implications on the wider disease. Increased understanding of airway epithelial biology may contribute to better treatment options, particularly in precision medicine.
Topics: Humans; Asthma; Animals; Respiratory Mucosa; Cytokines; Respiratory Hypersensitivity; Bronchial Hyperreactivity; Mast Cells; Bronchoconstriction
PubMed: 38395082
DOI: 10.1016/j.jaci.2024.02.011 -
The Journal of Cell Biology Jul 2023Trafficking of cell-surface proteins from endosomes to the plasma membrane is a key mechanism to regulate synaptic function. In non-neuronal cells, proteins recycle to...
Trafficking of cell-surface proteins from endosomes to the plasma membrane is a key mechanism to regulate synaptic function. In non-neuronal cells, proteins recycle to the plasma membrane either via the SNX27-Retromer-WASH pathway or via the recently discovered SNX17-Retriever-CCC-WASH pathway. While SNX27 is responsible for the recycling of key neuronal receptors, the roles of SNX17 in neurons are less understood. Here, using cultured hippocampal neurons, we demonstrate that the SNX17 pathway regulates synaptic function and plasticity. Disruption of this pathway results in a loss of excitatory synapses and prevents structural plasticity during chemical long-term potentiation (cLTP). cLTP drives SNX17 recruitment to synapses, where its roles are in part mediated by regulating the surface expression of β1-integrin. SNX17 recruitment relies on NMDAR activation, CaMKII signaling, and requires binding to the Retriever and PI(3)P. Together, these findings provide molecular insights into the regulation of SNX17 at synapses and define key roles for SNX17 in synaptic maintenance and in regulating enduring forms of synaptic plasticity.
Topics: Cell Membrane; Long-Term Potentiation; Membrane Proteins; Neuronal Plasticity; Protein Transport; Synapses; Sorting Nexins; Cells, Cultured; Neurons
PubMed: 37141105
DOI: 10.1083/jcb.202207025 -
Membranes Jan 2024Direct air capture (DAC) is an emerging negative CO emission technology that aims to introduce a feasible method for CO capture from the atmosphere. Unlike carbon... (Review)
Review
Direct air capture (DAC) is an emerging negative CO emission technology that aims to introduce a feasible method for CO capture from the atmosphere. Unlike carbon capture from point sources, which deals with flue gas at high CO concentrations, carbon capture directly from the atmosphere has proved difficult due to the low CO concentration in ambient air. Current DAC technologies mainly consider sorbent-based systems; however, membrane technology can be considered a promising DAC approach since it provides several advantages, e.g., lower energy and operational costs, less environmental footprint, and more potential for small-scale ubiquitous installations. Several recent advancements in validating the feasibility of highly permeable gas separation membrane fabrication and system design show that membrane-based direct air capture (m-DAC) could be a complementary approach to sorbent-based DAC, e.g., as part of a hybrid system design that incorporates other DAC technologies (e.g., solvent or sorbent-based DAC). In this article, the ongoing research and DAC application attempts via membrane separation have been reviewed. The reported membrane materials that could potentially be used for m-DAC are summarized. In addition, the future direction of m-DAC development is discussed, which could provide perspective and encourage new researchers' further work in the field of m-DAC.
PubMed: 38392657
DOI: 10.3390/membranes14020030