scholarly journals An Examination of the Putative Role of Melatonin in Exosome Biogenesis

2021 ◽  
Vol 9 ◽  
Author(s):  
Hassan Amini ◽  
Aysa Rezabakhsh ◽  
Morteza Heidarzadeh ◽  
Mehdi Hassanpour ◽  
Shahriar Hashemzadeh ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Target Cells ◽  
Secretory Vesicles ◽  
Melatonin Treatment ◽  
Exosome Biogenesis ◽  
Intracellular Organelles ◽  
The Subject ◽  
Original Cell ◽  
Cargo Sorting

During the last two decades, melatonin has been found to have pleiotropic effects via different mechanisms on its target cells. Data are abundant for some aspects of the signaling pathways within cells while other casual mechanisms have not been adequately addressed. From an evolutionary perspective, eukaryotic cells are equipped with a set of interrelated endomembrane systems consisting of intracellular organelles and secretory vesicles. Of these, exosomes are touted as cargo-laden secretory vesicles that originate from the endosomal multivesicular machinery which participate in a mutual cross-talk at different cellular interfaces. It has been documented that cells transfer various biomolecules and genetic elements through exosomes to sites remote from the original cell in a paracrine manner. Findings related to the molecular mechanisms between melatonin and exosomal biogenesis and cargo sorting are the subject of the current review. The clarification of the interplay between melatonin and exosome biogenesis and cargo sorting at the molecular level will help to define a cell’s secretion capacity. This review precisely addresses the role and potential significance of melatonin in determining the efflux capacity of cells via the exosomal pathway. Certain cells, for example, stem cells actively increase exosome efflux in response to melatonin treatment which accelerates tissue regeneration after transplantation into the injured sites.

scholarly journals The Aging Vasculature: Glucose Tolerance, Hypoglycemia and the Role of the Serum Response Factor

2021 ◽  
Vol 8 (5) ◽  
pp. 58
Author(s):  
Hazel Aberdeen ◽  
Kaela Battles ◽  
Ariana Taylor ◽  
Jeranae Garner-Donald ◽  
Ana Davis-Wilson ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Molecular Mechanisms ◽  
Serum Response Factor ◽  
Response Factor ◽  
Homeostatic Control ◽  
Older Americans ◽  
The Subject ◽  
Serum Response

The fastest growing demographic in the U.S. at the present time is those aged 65 years and older. Accompanying advancing age are a myriad of physiological changes in which reserve capacity is diminished and homeostatic control attenuates. One facet of homeostatic control lost with advancing age is glucose tolerance. Nowhere is this more accentuated than in the high proportion of older Americans who are diabetic. Coupled with advancing age, diabetes predisposes affected subjects to the onset and progression of cardiovascular disease (CVD). In the treatment of type 2 diabetes, hypoglycemic episodes are a frequent clinical manifestation, which often result in more severe pathological outcomes compared to those observed in cases of insulin resistance, including premature appearance of biomarkers of senescence. Unfortunately, molecular mechanisms of hypoglycemia remain unclear and the subject of much debate. In this review, the molecular basis of the aging vasculature (endothelium) and how glycemic flux drives the appearance of cardiovascular lesions and injury are discussed. Further, we review the potential role of the serum response factor (SRF) in driving glycemic flux-related cellular signaling through its association with various proteins.

Microglia in cerebral ischemia: molecular actions and interactionsThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigator's Forum.

2006 ◽  
Vol 84 (1) ◽  
pp. 49-59 ◽  
Author(s):  
Aaron Y. Lai ◽  
Kathryn G. Todd
Keyword(s):  
Cerebral Ischemia ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Extracellular Signals ◽  
Messenger Molecules ◽  
Membrane Bound ◽  
The Subject ◽  
Survey Review ◽  
Selection Of

The precise role of microglia in stroke and cerebral ischemia has been the subject of debate for a number of years. Microglia are capable of synthesizing numerous soluble and membrane-bound biomolecules, some known to be neuroprotective, some neurotoxic, whereas others have less definitive bioactivities. The molecular mechanisms through which microglia activate these molecules have thus become an important area of ischemia research. Here we provide a survey review that summarizes the key actions of microglial factors in cerebral ischemia including complement proteins, chemokines, pro-inflammatory cytokines, neurotrophic factors, hormones, and proteinases, as well several important messenger molecules that play a part in how these factors respond to extracellular signals during ischemic injuries. We also provide some new perspectives on how microglial intracellular signaling may contribute to the seemingly contradictory roles of several microglial effector molecules.

scholarly journals Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 979 ◽  
Author(s):  
Valeria De Pasquale ◽  
Anna Moles ◽  
Luigi Michele Pavone
Keyword(s):  
Molecular Mechanisms ◽  
Protein Processing ◽  
Lysosomal Storage ◽  
Therapeutic Approaches ◽  
Kidney Dysfunction ◽  
Nuclear Membranes ◽  
Intracellular Organelles ◽  
Primary Focus ◽  
Storage Disorders

Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases.

Elevated venous thromboembolism risk in preeclampsia: molecular mechanisms and clinical impact

2015 ◽  
Vol 43 (4) ◽  
pp. 696-701 ◽  
Author(s):  
Karl Egan ◽  
Barry Kevane ◽  
Fionnuala Ní Áinle
Keyword(s):  
Venous Thromboembolism ◽  
Molecular Mechanisms ◽  
Endothelial Activation ◽  
Extracellular Traps ◽  
Increased Risk ◽  
Consensus Statements ◽  
Maternal Hypertension ◽  
The Subject ◽  
Developed World

Venous thromboembolism (VTE) remains a leading cause of maternal death and morbidity in the developed world. Strategies for prevention of VTE in pregnancy have been the subject of recent guidelines and consensus statements. These guidelines recommend thrombosis prevention in women who have risk factors associated with an elevated VTE risk. Preeclampsia is characterized by maternal hypertension and proteinuria developing after 20 weeks gestation, complicating up to 7% of pregnancies and is associated with a massive annual morbidity and mortality burden. Women with preeclampsia have been shown to be at increased risk of VTE with studies to date suggesting that this risk may be up to 5-fold greater than the risk of pregnancy-associated VTE in the general population. Despite the fact that preeclampsia is so common and potentially devastating, our understanding of its pathogenesis and potential therapeutic strategies remain poor. In addition, the mechanisms underlying the prothrombotic phenotype in preeclampsia are also poorly characterized although a number of potential mechanisms have been postulated. Derangements of platelet and endothelial activation and impairment of endogenous anti-coagulant pathways have been reported and may contribute to the observed VTE risk. Recently, evidence for the role of neutrophil extracellular traps (NETs) and cell-free DNA in the pathogenesis of VTE has emerged and some evidence exists to suggest that this may be of relevance in preeclampsia. Future studies aimed at understanding the diagnostic and potential therapeutic relevance of this procoagulant state are likely to be of enormous clinical benefit for pregnant women affected with this potentially devastating condition.

scholarly journals ECM deposition is driven by caveolin-1–dependent regulation of exosomal biogenesis and cargo sorting

2020 ◽  
Vol 219 (11) ◽  
Author(s):  
Lucas Albacete-Albacete ◽  
Inmaculada Navarro-Lérida ◽  
Juan Antonio López ◽  
Inés Martín-Padura ◽  
Alma M. Astudillo ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Communication ◽  
Tumor Stroma ◽  
Cholesterol Content ◽  
Deposition Mechanism ◽  
Caveolin 1 ◽  
Exosome Biogenesis ◽  
Exosomal Sorting ◽  
Cargo Sorting

The composition and physical properties of the extracellular matrix (ECM) critically influence tumor progression, but the molecular mechanisms underlying ECM layering are poorly understood. Tumor–stroma interaction critically depends on cell communication mediated by exosomes, small vesicles generated within multivesicular bodies (MVBs). We show that caveolin-1 (Cav1) centrally regulates exosome biogenesis and exosomal protein cargo sorting through the control of cholesterol content at the endosomal compartment/MVBs. Quantitative proteomics profiling revealed that Cav1 is required for exosomal sorting of ECM protein cargo subsets, including Tenascin-C (TnC), and for fibroblast-derived exosomes to efficiently deposit ECM and promote tumor invasion. Cav1-driven exosomal ECM deposition not only promotes local stromal remodeling but also the generation of distant ECM-enriched stromal niches in vivo. Cav1 acts as a cholesterol rheostat in MVBs, determining sorting of ECM components into specific exosome pools and thus ECM deposition. This supports a model by which Cav1 is a central regulatory hub for tumor–stroma interactions through a novel exosome-dependent ECM deposition mechanism.

scholarly journals Actin and Myosin in Non-Neuronal Exocytosis

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1455 ◽  
Author(s):  
Pika Miklavc ◽  
Manfred Frick
Keyword(s):  
Molecular Motors ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cell Cortex ◽  
Secretory Cells ◽  
Secretory Vesicles ◽  
Cortical Actin ◽  
Myosin V ◽  
Myosin I

Cellular secretion depends on exocytosis of secretory vesicles and discharge of vesicle contents. Actin and myosin are essential for pre-fusion and post-fusion stages of exocytosis. Secretory vesicles depend on actin for transport to and attachment at the cell cortex during the pre-fusion phase. Actin coats on fused vesicles contribute to stabilization of large vesicles, active vesicle contraction and/or retrieval of excess membrane during the post-fusion phase. Myosin molecular motors complement the role of actin. Myosin V is required for vesicle trafficking and attachment to cortical actin. Myosin I and II members engage in local remodeling of cortical actin to allow vesicles to get access to the plasma membrane for membrane fusion. Myosins stabilize open fusion pores and contribute to anchoring and contraction of actin coats to facilitate vesicle content release. Actin and myosin function in secretion is regulated by a plethora of interacting regulatory lipids and proteins. Some of these processes have been first described in non-neuronal cells and reflect adaptations to exocytosis of large secretory vesicles and/or secretion of bulky vesicle cargoes. Here we collate the current knowledge and highlight the role of actomyosin during distinct phases of exocytosis in an attempt to identify unifying molecular mechanisms in non-neuronal secretory cells.

scholarly journals Elucidation of signaling pathways that regulate ethylene-induced leaf and flower abscission of agriculturally important plants

2012 ◽  
Author(s):  
Mark L. Tucker ◽  
Shimon Meir ◽  
Amnon Lers ◽  
Sonia Philosoph-Hadas ◽  
Cai-Zhong Jiang
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Regulatory Proteins ◽  
Target Cells ◽  
Specific Gene ◽  
Gene Promoters ◽  
Tomato Plants ◽  
Stage Of Development ◽  
Flower Abscission

The Problem: Abscission is a highly regulated process, occurring as a natural terminal stage of development, in which various organs are separated from the parent plant. In most plant species, the process is initiated by a decrease in active auxin in the abscission zone (AZ) and an increase in ethylene, and may be accelerated by postharvest or environmental stresses. Another potential key regulator in abscission is IDA (Inflorescence Deficient in Abscission), which was identified as an essential peptide signal for floral organ abscission in Arabidopsis. However, information is still lacking regarding the molecular mechanisms integrating all these regulators. In our previous BARD funded research we made substantial progress towards understanding these molecular events in tomato, and the study is still in progress. We established a powerful platform for analysis of genes for regulatory proteins expressed in AZ. We identified changes in gene expression for several transcription factors (TFs) directly linked to ethylene and auxin signaling and several additional regulatory proteins not so obviously linked to these hormones. Moreover, we demonstrated using a virus-induced gene silencing (VIGS) assay that several play a functional role in the onset of abscission. Based on these results we have selected 14 genes for further analysis in stably transformed tomato plants. All 14 genes were suppressed by RNA interference (RNAi) using a constitutive promoter, and 5 of them were also suppressed using an abscission-specific promoter. Transformations are currently at different stages of progress including some lines that already display an abscission phenotype. Objectives: We propose here to (1) complete the functional analysis of the stably transformed tomato plants with T2 lines and perform transcriptome analysis using custom abscission-specific microarrays; (2) conduct an indepth analysis of the role of IDA signaling in tomato leaf and flower abscission; (3) perform transcriptome and proteome analyses to extend the earlier gene expression studies to identify transcripts and proteins that are highly specific to the separation layer (i.e., target cells for cell separation) prior to the onset of abscission; (4) extend and compliment the work in tomato using a winnowed set of genes in soybean. Methodology: Next Generation Sequencing (NGS) of mRNA will be used to further increase the list of abscission-associated genes, and for preparation of a custom tomato abscission microarray to test altered gene expression in transgenic plants. Tandem mass spectrometry (LC-MS/MS) of protein extracts from leaf petiole, flower pedicel and their AZ tissues will be used to identify the proteome of the AZ before and during abscission. AZ-specific gene promoters will be used in stably transformed tomato plants to reduce non-target phenotypes. The bean pod mottle virus (BPMV) plasmid vectors will be used for VIGS analysis in soybean. Expected Contribution: Our study will provide new insights into the regulation of ethylene-induced abscission by further revealing the role of key regulators in the process. This will permit development of novel techniques for manipulating leaf and flower abscission, thereby improving the postharvest performance of agriculturally important crops.

scholarly journals Functional role of a glycolipid in directional movements of neurons

2001 ◽  
Vol 73 (2) ◽  
pp. 221-229 ◽  
Author(s):  
ROSALIA MENDEZ-OTERO ◽  
MARCELO F. SANTIAGO
Keyword(s):  
Nervous System ◽  
Neuronal Migration ◽  
Functional Role ◽  
Molecular Mechanisms ◽  
Complex Structure ◽  
Final Destination ◽  
Extracellular Signaling ◽  
The Subject ◽  
Migratory Process

Migration of neurons from their site of origin to their final destination is a critical and universal step in the formation of the complex structure of the nervous system. The migratory process is thought to be governed in part by genetically and epigenetically defined sequences of signals which are interpreted by migrating cells. The molecular mechanisms that underlie neuronal migration have been the subject of intense investigation. As in other developmental processes, many molecules must participate in neuronal migration. Some molecules, such as cell adhesion molecules and motor proteins, may contribute to discrete steps in the migration act; others, like extracellular signaling molecules, may regulate the activation and/or termination of the migration program. In this article we review findings from our group that demonstrate the functional role(s) of a specific glycolipid in neuronal migration and neurite outgrowth in the developing and adult nervous system.

scholarly journals Local control of thyroid hormone action: role of type 2 deiodinase

2011 ◽  
Vol 209 (3) ◽  
pp. 261-272 ◽  
Author(s):  
Graham R Williams ◽  
J H Duncan Bassett
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Nuclear Receptors ◽  
Molecular Mechanisms ◽  
Target Cells ◽  
Hormone Action ◽  
Iodothyronine Deiodinase ◽  
Thyroid Hormone Action

The thyroid gland predominantly secretes the pro-hormone thyroxine (T4) that is converted to the active hormone 3,5,3′-l-triiodothyronine (T3) in target cells. Conversion of T4 to T3 is catalyzed by the type 2 iodothyronine deiodinase enzyme (DIO2), and T3 action in target tissues is determined by DIO2-regulated local availability of T3 to its nuclear receptors, TRα and TRβ. Studies of Dio2 knockout mice have revealed new and important roles for the enzyme during development and in adulthood in diverse tissues including the cochlea, skeleton, brown fat, pituitary, and hypothalamus. In this review, we discuss the molecular mechanisms by which DIO2 controls intracellular T3 availability and action.

How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

2020 ◽  
Vol 48 (3) ◽  
pp. 1019-1034 ◽  
Author(s):  
Rachel M. Woodhouse ◽  
Alyson Ashe
Keyword(s):  
Histone Modifications ◽  
Molecular Mechanisms ◽  
Epigenetic Inheritance ◽  
Nematode Caenorhabditis Elegans ◽  
Histone Methyltransferases ◽  
Transgenerational Epigenetic Inheritance ◽  
C Elegans ◽  
Recent Developments ◽  
Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

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