Red Blood Cell Metabolism In Vivo and In Vitro

Metabolites, Journal Year: 2023, Volume and Issue: 13(7), P. 793 - 793

Published: June 27, 2023

Red blood cells (RBC) are the most abundant cell in human body, with a central role oxygen transport and its delivery to tissues. However, omics technologies recently revealed unanticipated complexity of RBC proteome metabolome, paving way for reinterpretation mechanisms by which metabolism regulates systems biology beyond transport. The new data analytical tools also informed dissection changes that RBCs undergo during refrigerated storage under bank conditions, logistic necessity makes >100 million units available life-saving transfusions every year worldwide. In this narrative review, we summarize last decade advances field vivo vitro, largely influenced authors’ own journeys field. We hope review will stimulate further research interesting medically important area or, at least, serve as testament our fascination simple, yet complex, cell.

Language: Английский

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De novo design of allosterically switchable protein assemblies

Nature, Journal Year: 2024, Volume and Issue: 632(8026), P. 911 - 920

Published: Aug. 14, 2024

Allosteric modulation of protein function, wherein the binding an effector to a triggers conformational changes at distant functional sites, plays central part in control metabolism and cell signalling1–3. There has been considerable interest designing allosteric systems, both gain insight into mechanisms underlying such 'action distance' create synthetic proteins whose functions can be regulated by effectors4–7. However, emulating subtle distributed across many residues, characteristic natural proteins, is significant challenge8,9. Here, inspired classic Monod–Wyman–Changeux model cooperativity10, we investigate de novo design allostery through rigid-body coupling peptide-switchable hinge modules11 interfaces12 that direct formation alternative oligomeric states. We find this approach used generate wide variety allosterically switchable including cyclic rings incorporate or eject subunits response peptide dihedral cages undergo effector-induced disassembly. Size-exclusion chromatography, mass photometry13 electron microscopy reveal these designed assemblies closely resemble models presence absence effectors have ligand-binding cooperativity comparable systems as haemoglobin14. Our results indicate arise from global energetics substructures without optimized side-chain–side-chain communication pathways provide roadmap for generating triggerable delivery nanomachines cellular feedback circuitry. suggest it pathways, providing molecular systems.

Language: Английский

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Serum protein-based nanoparticles for cancer diagnosis and treatment

Journal of Controlled Release, Journal Year: 2020, Volume and Issue: 329, P. 997 - 1022

Published: Oct. 19, 2020

Language: Английский

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Controllable Self‐Assembly of Peptide‐Cyanine Conjugates In Vivo as Fine‐Tunable Theranostics

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 60(14), P. 7809 - 7819

Published: Jan. 15, 2021

Abstract The fabrication of functional assemblies with defined structures through controllable molecular packing under physiological conditions is challenging. Here, modularly designed peptide‐cyanine conjugates that intracellularly self‐assembly into 1D columnar superstructures controlled cyanine aggregation were designed, and they exhibit distinct imaging or photothermal properties. peptide backbone cleaved by caspase‐3/7 after entering the cells. Then self‐assembled residue, a double substitution ( Pr‐2Cy ), forms P helical column in which H‐aggregated dyes show 3.4‐fold conversion efficiency compared to free ones. residue single Pr‐1Cy ) loose column, undefined structure have fluorescence quantum yield up 9.5 % (emission at 819 nm H 2 O). This work provides simple way modify vivo peptides molecules for achieving desired bio‐applications.

Language: Английский

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The Role of Acidosis in the Pathogenesis of Severe Forms of COVID-19

Biology, Journal Year: 2021, Volume and Issue: 10(9), P. 852 - 852

Published: Aug. 31, 2021

COVID-19 has specific characteristics that distinguish this disease from many other infections. We suggest the pathogenesis of severe forms can be associated with acidosis. This review article discusses several mechanisms potentially linking damaging effects acidosis and shows existence a vicious cycle between development hypoxia in patients. At early stages disease, inflammation, difficulty gas exchange lungs thrombosis collectively contribute to onset In accordance Verigo-Bohr effect, decrease blood pH leads oxygen saturation, which contributes exacerbation results deterioration patient’s condition. A also cause conformational changes S-protein virus thus lead affinity avidity protective antibodies. Hypoxia dysregulation immune system multidirectional pro- anti-inflammatory reactions, resulting “cytokine storm”. review, we highlight potential importance supporting normal as an approach therapy.

Language: Английский

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Nanoparticle Effects on Stress Response Pathways and Nanoparticle–Protein Interactions

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(14), P. 7962 - 7962

Published: July 19, 2022

Nanoparticles (NPs) are increasingly used in a wide variety of applications and products; however, NPs may affect stress response pathways interact with proteins biological systems. This review article will provide an overview the beneficial detrimental effects on focus NP–protein interactions. Depending upon particular NP, experimental model system, dose exposure conditions, introduction have either positive or negative effects. Cellular processes such as development oxidative stress, initiation inflammatory response, mitochondrial function, detoxification, alterations to signaling all affected by NPs. In terms tissue-specific effects, local microenvironment can profound effect whether NP is harmful cells. Interactions metal-binding (zinc, copper, iron calcium) both their structure function. insights into current knowledge protein-based nanotoxicology closely examines targets specific

Language: Английский

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Carbon Monoxide Signaling: Examining Its Engagement with Various Molecular Targets in the Context of Binding Affinity, Concentration, and Biologic Response

Pharmacological Reviews, Journal Year: 2022, Volume and Issue: 74(3), P. 825 - 875

Published: June 23, 2022

Carbon monoxide (CO) has been firmly established as an endogenous signaling molecule with a variety of pathophysiological and pharmacological functions, including immunomodulation, organ protection, circadian clock regulation, among many others. In terms its molecular mechanism(s) action, CO is known to bind large number hemoproteins at least 25 identified targets, hemoglobin, myoglobin, neuroglobin, cytochrome c oxidase, P450, soluble guanylyl cyclase, myeloperoxidase, some ion channels dissociation constant values spanning the range sub-nM high μM. Although CO's binding affinity targets extensively studied established, there pressing need incorporate such information into analysis biologic response in context dosage. Especially important understand reservoir role hemoglobin storage, transport, distribution, transfer. We critically review literature inject sense quantitative assessment our analyses various relationships affinity, concentration, target occupancy level, anticipated actions. hope that this presents picture overall landscape engagement stimulates additional research, helps move field direction examining individual all concentration available CO. believe work will help further understanding relationship functions eventual development CO-based therapeutics.

Significance Statement

The carbon therapeutic agent significantly rely on therapeutically relevant varying affinity. This examines by quantitatively analyzing intricate for CO, state carboxyhemoglobin provide holistic approach action

Language: Английский

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Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors and Iron Metabolism

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 3037 - 3037

Published: Feb. 3, 2023

The production of erythropoietin (EPO), the main regulator erythroid differentiation, is regulated by hypoxia-inducible factor (HIF). HIF2α seems to be principal EPO transcription, but HIF1α and 3α also may have additional influences on maturation. HIF involved in regulation iron, an essential component erythropoiesis. Iron for organism highly toxic, so its absorption retention are strictly controlled. induces synthesis proteins iron regulation, thereby ensuring availability necessary hematopoiesis. a major hemoglobin erythrocyte differentiation proliferation HIF. Renal anemia condition which there lack stimulation due decreased expression. prolyl hydroxylase inhibitors (HIF-PHIs) stabilize allow it potent under normoxic conditions. Therefore, unlike erythropoiesis-stimulating agents, HIF-PHI enhance from intestinal tract supply reticuloendothelial macrophages hepatocytes into plasma, thus facilitating only currently market worldwide roxadustat, Japan, five products available. Clinical studies date Japan shown that HIF-PHIs not promote hematopoiesis, decrease hepcidin, metabolism, increase total iron-binding capacity (TIBC), indicates transport capacity. However, concerns about systemic effects been completely dispelled, warranting further careful monitoring.

Language: Английский

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CRISPR-Based Gene Therapies: From Preclinical to Clinical Treatments

Cells, Journal Year: 2024, Volume and Issue: 13(10), P. 800 - 800

Published: May 8, 2024

In recent years, clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas) protein have emerged as a revolutionary gene editing tool to treat inherited disorders affecting different organ systems, such blood muscles. Both hematological neuromuscular genetic benefit from genome approaches but face challenges in their clinical translation. The ability of CRISPR/Cas9 technologies modify hematopoietic stem cells ex vivo has greatly accelerated the development therapies for disorders. last decade, many trials were initiated are now delivering encouraging results. FDA approval Casgevy, first CRISPR/Cas9-based drug severe sickle cell disease transfusion-dependent β-thalassemia, represents significant milestone field highlights great potential this technology. Similar preclinical efforts currently expanding CRISPR other hematologic primary immunodeficiencies. field, versatility been instrumental generation new cellular animal models Duchenne muscular dystrophy (DMD), offering innovative platforms speed up therapeutic solutions. Several corrective interventions proposed genetically restore dystrophin production using toolbox demonstrated promising results DMD models. Although these advances represent step forward translation DMD, there still hurdles overcome, delivery methods associated with high viral vector doses, together safety immunological concerns. Collectively, obtained fields emphasize transformative impact patients affected by debilitating conditions. As each suffers specific challenges, may progress differentially depending on disorder. Ongoing investigations will address risks limitations therapies, including long-term efficacy, genotoxicity, adverse immune reactions. This review provides insights into diverse applications CRISPR-based both settings monogenic compare while highlighting current trends, difficulties, overcome.

Language: Английский

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Biological and genetic determinants of glycolysis: Phosphofructokinase isoforms boost energy status of stored red blood cells and transfusion outcomes

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(9), P. 1979 - 1997.e13

Published: July 3, 2024

Language: Английский

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