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Molecular Insights into the Developmental Origins of Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 6155

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Guest Editor
Asper Clinical Research Institute, St. Boniface Hospital, Department of Pharmacology and Therapeutics Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R2H 2A6, Canada
Interests: oncology; research; pharmacology; ethics; cancer; cardiology; diabetes; innovation; regulatory
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Special Issue Information

Dear Colleagues,

Many lines of epidemiological, clinical, and experimental evidence have concluded that the risk of developing chronic, noncommunicable diseases in adulthood may be influenced by molecular and genetic aspects as well as lifestyle and environmental experiences during early life. Fetal development and infancy are characterized by the rapid growth, development, and maturation of organ systems. It has now become increasingly evident that several pathophysiological conditions, including diabetes and cardiovascular disease, that occur in adolescence and adulthood may have their origins during fetal or postnatal development. While maternal nutrition (poor quality and quantity) is the most examined aspect in terms of influencing the development of fetal organ systems, paternal stressors have also recently emerged as critical developmental and molecular elements that can increase offspring’s predisposition to adverse health outcomes in later life.

This Special Issue will bring together global experts in the field of developmental and molecular programming to provide an overview of as well as recent advances in the understanding of the long-term consequences of the programming of gene expression and the modification of the molecular biology of organ systems during fetal and postnatal development. Since nutritional exposure during fetal development can also be transmitted to further generations, the impact of heritable epigenetic modifications on nutritional programming and increased risk for disease in postnatal life will be described. Furthermore, the potential importance and molecular aspects of normal fetal nutrition, growth, and development through efficient maternal nutrition before and during pregnancy will be highlighted as a novel strategy for the primary prevention of disease in later life.

Dr. Paramjit S. Tappia
Dr. Bram Ramjiawan
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Developmental Origins of Health and Disease (DOHaD)
  • fetal development
  • maternal nutrition
  • molecular programming
  • epigenetic modifications
  • environmental exposures
  • genetic factors

Published Papers (5 papers)

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Research

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20 pages, 3185 KiB  
Article
Regulation of Neuronal Chloride Homeostasis by Pro- and Mature Brain-Derived Neurotrophic Factor (BDNF) via KCC2 Cation–Chloride Cotransporters in Rat Cortical Neurons
by Mira Hamze, Cathy Brier, Emmanuelle Buhler, Jinwei Zhang, Igor Medina and Christophe Porcher
Int. J. Mol. Sci. 2024, 25(11), 6253; https://doi.org/10.3390/ijms25116253 - 6 Jun 2024
Viewed by 271
Abstract
The strength of inhibitory neurotransmission depends on intracellular neuronal chloride concentration, primarily regulated by the activity of cation–chloride cotransporters NKCC1 (Sodium–Potassium–Chloride Cotransporter 1) and KCC2 (Potassium–Chloride Cotransporter 2). Brain-derived neurotrophic factor (BDNF) influences the functioning of these co-transporters. BDNF is synthesized from precursor [...] Read more.
The strength of inhibitory neurotransmission depends on intracellular neuronal chloride concentration, primarily regulated by the activity of cation–chloride cotransporters NKCC1 (Sodium–Potassium–Chloride Cotransporter 1) and KCC2 (Potassium–Chloride Cotransporter 2). Brain-derived neurotrophic factor (BDNF) influences the functioning of these co-transporters. BDNF is synthesized from precursor proteins (proBDNF), which undergo proteolytic cleavage to yield mature BDNF (mBDNF). While previous studies have indicated the involvement of BDNF signaling in the activity of KCC2, its specific mechanisms are unclear. We investigated the interplay between both forms of BDNF and chloride homeostasis in rat hippocampal neurons and in utero electroporated cortices of rat pups, spanning the behavioral, cellular, and molecular levels. We found that both pro- and mBDNF play a comparable role in immature neurons by inhibiting the capacity of neurons to extrude chloride. Additionally, proBDNF increases the endocytosis of KCC2 while maintaining a depolarizing shift of EGABA in maturing neurons. Behaviorally, proBDNF-electroporated rat pups in the somatosensory cortex exhibit sensory deficits, delayed huddling, and cliff avoidance. These findings emphasize the role of BDNF signaling in regulating chloride transport through the modulation of KCC2. In summary, this study provides valuable insights into the intricate interplay between BDNF, chloride homeostasis, and inhibitory synaptic transmission, shedding light on the underlying cellular mechanisms involved. Full article
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21 pages, 4142 KiB  
Article
Retinoic Acid-Mediated Control of Energy Metabolism Is Essential for Lung Branching Morphogenesis
by Hugo Fernandes-Silva, Marco G. Alves, Marcia R. Garcez, Jorge Correia-Pinto, Pedro F. Oliveira, Catarina C. F. Homem and Rute S. Moura
Int. J. Mol. Sci. 2024, 25(9), 5054; https://doi.org/10.3390/ijms25095054 - 6 May 2024
Viewed by 890
Abstract
Lung branching morphogenesis relies on intricate epithelial–mesenchymal interactions and signaling networks. Still, the interplay between signaling and energy metabolism in shaping embryonic lung development remains unexplored. Retinoic acid (RA) signaling influences lung proximal–distal patterning and branching morphogenesis, but its role as a metabolic [...] Read more.
Lung branching morphogenesis relies on intricate epithelial–mesenchymal interactions and signaling networks. Still, the interplay between signaling and energy metabolism in shaping embryonic lung development remains unexplored. Retinoic acid (RA) signaling influences lung proximal–distal patterning and branching morphogenesis, but its role as a metabolic modulator is unknown. Hence, this study investigates how RA signaling affects the metabolic profile of lung branching. We performed ex vivo lung explant culture of embryonic chicken lungs treated with DMSO, 1 µM RA, or 10 µM BMS493. Extracellular metabolite consumption/production was evaluated by using 1H-NMR spectroscopy. Mitochondrial respiration and biogenesis were also analyzed. Proliferation was assessed using an EdU-based assay. The expression of crucial metabolic/signaling components was examined through Western blot, qPCR, and in situ hybridization. RA signaling stimulation redirects glucose towards pyruvate and succinate production rather than to alanine or lactate. Inhibition of RA signaling reduces lung branching, resulting in a cystic-like phenotype while promoting mitochondrial function. Here, RA signaling emerges as a regulator of tissue proliferation and lactate dehydrogenase expression. Furthermore, RA governs fatty acid metabolism through an AMPK-dependent mechanism. These findings underscore RA’s pivotal role in shaping lung metabolism during branching morphogenesis, contributing to our understanding of lung development and cystic-related lung disorders. Full article
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12 pages, 2548 KiB  
Article
Perinatal Use of Citrulline Rescues Hypertension in Adult Male Offspring Born to Pregnant Uremic Rats
by You-Lin Tain, Chih-Yao Hou, Guo-Ping Chang-Chien, Sufan Lin and Chien-Ning Hsu
Int. J. Mol. Sci. 2024, 25(3), 1612; https://doi.org/10.3390/ijms25031612 - 28 Jan 2024
Cited by 1 | Viewed by 960
Abstract
The growing recognition of the association between maternal chronic kidney disease (CKD) and fetal programming highlights the increased vulnerability of hypertension in offspring. Potential mechanisms involve oxidative stress, dysbiosis in gut microbiota, and activation of the renin–angiotensin system (RAS). Our prior investigation showed [...] Read more.
The growing recognition of the association between maternal chronic kidney disease (CKD) and fetal programming highlights the increased vulnerability of hypertension in offspring. Potential mechanisms involve oxidative stress, dysbiosis in gut microbiota, and activation of the renin–angiotensin system (RAS). Our prior investigation showed that the administration of adenine to pregnant rats resulted in the development of CKD, ultimately causing hypertension in their adult offspring. Citrulline, known for enhancing nitric oxide (NO) production and possessing antioxidant and antihypertensive properties, was explored for its potential to reverse high blood pressure (BP) in offspring born to CKD dams. Male rat offspring, both from normal and adenine-induced CKD models, were randomly assigned to four groups (8 animals each): (1) control, (2) CKD, (3) citrulline-treated control rats, and (4) citrulline-treated CKD rats. Citrulline supplementation successfully reversed elevated BP in male progeny born to uremic mothers. The protective effects of perinatal citrulline supplementation were linked to an enhanced NO pathway, decreased expression of renal (pro)renin receptor, and changes in gut microbiota composition. Citrulline supplementation led to a reduction in the abundance of Monoglobus and Streptococcus genera and an increase in Agothobacterium Butyriciproducens. Citrulline’s ability to influence taxa associated with hypertension may be linked to its protective effects against maternal CKD-induced offspring hypertension. In conclusion, perinatal citrulline treatment increased NO availability and mitigated elevated BP in rat offspring from uremic mother rats. Full article
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Review

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22 pages, 1363 KiB  
Review
The Impact of the Aryl Hydrocarbon Receptor on Antenatal Chemical Exposure-Induced Cardiovascular–Kidney–Metabolic Programming
by You-Lin Tain and Chien-Ning Hsu
Int. J. Mol. Sci. 2024, 25(9), 4599; https://doi.org/10.3390/ijms25094599 - 23 Apr 2024
Viewed by 736
Abstract
Early life exposure lays the groundwork for the risk of developing cardiovascular–kidney–metabolic (CKM) syndrome in adulthood. Various environmental chemicals to which pregnant mothers are commonly exposed can disrupt fetal programming, leading to a wide range of CKM phenotypes. The aryl hydrocarbon receptor (AHR) [...] Read more.
Early life exposure lays the groundwork for the risk of developing cardiovascular–kidney–metabolic (CKM) syndrome in adulthood. Various environmental chemicals to which pregnant mothers are commonly exposed can disrupt fetal programming, leading to a wide range of CKM phenotypes. The aryl hydrocarbon receptor (AHR) has a key role as a ligand-activated transcription factor in sensing these environmental chemicals. Activating AHR through exposure to environmental chemicals has been documented for its adverse impacts on cardiovascular diseases, hypertension, diabetes, obesity, kidney disease, and non-alcoholic fatty liver disease, as evidenced by both epidemiological and animal studies. In this review, we compile current human evidence and findings from animal models that support the connection between antenatal chemical exposures and CKM programming, focusing particularly on AHR signaling. Additionally, we explore potential AHR modulators aimed at preventing CKM syndrome. As the pioneering review to present evidence advocating for the avoidance of toxic chemical exposure during pregnancy and deepening our understanding of AHR signaling, this has the potential to mitigate the global burden of CKM syndrome in the future. Full article
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64 pages, 5766 KiB  
Review
Review of Eukaryote Cellular Membrane Lipid Composition, with Special Attention to the Fatty Acids
by Omeralfaroug Ali and András Szabó
Int. J. Mol. Sci. 2023, 24(21), 15693; https://doi.org/10.3390/ijms242115693 - 28 Oct 2023
Cited by 6 | Viewed by 2478
Abstract
Biological membranes, primarily composed of lipids, envelop each living cell. The intricate composition and organization of membrane lipids, including the variety of fatty acids they encompass, serve a dynamic role in sustaining cellular structural integrity and functionality. Typically, modifications in lipid composition coincide [...] Read more.
Biological membranes, primarily composed of lipids, envelop each living cell. The intricate composition and organization of membrane lipids, including the variety of fatty acids they encompass, serve a dynamic role in sustaining cellular structural integrity and functionality. Typically, modifications in lipid composition coincide with consequential alterations in universally significant signaling pathways. Exploring the various fatty acids, which serve as the foundational building blocks of membrane lipids, provides crucial insights into the underlying mechanisms governing a myriad of cellular processes, such as membrane fluidity, protein trafficking, signal transduction, intercellular communication, and the etiology of certain metabolic disorders. Furthermore, comprehending how alterations in the lipid composition, especially concerning the fatty acid profile, either contribute to or prevent the onset of pathological conditions stands as a compelling area of research. Hence, this review aims to meticulously introduce the intricacies of membrane lipids and their constituent fatty acids in a healthy organism, thereby illuminating their remarkable diversity and profound influence on cellular function. Furthermore, this review aspires to highlight some potential therapeutic targets for various pathological conditions that may be ameliorated through dietary fatty acid supplements. The initial section of this review expounds on the eukaryotic biomembranes and their complex lipids. Subsequent sections provide insights into the synthesis, membrane incorporation, and distribution of fatty acids across various fractions of membrane lipids. The last section highlights the functional significance of membrane-associated fatty acids and their innate capacity to shape the various cellular physiological responses. Full article
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