scholarly journals Mac-1 Receptor Clustering Initiates Production of Pro-Inflammatory, Antibacterial Extracellular Vesicles From Neutrophils

2021 ◽  
Vol 12 ◽  
Author(s):  
Viktória Szeifert ◽  
Ferenc Kolonics ◽  
Balázs Bartos ◽  
Delaram Khamari ◽  
Pál Vági ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Total Internal Reflection ◽  
Molecular Mechanisms ◽  
Cluster Formation ◽  
Calcium Signal ◽  
Complement Receptor 3 ◽  
Coated Surfaces ◽  
Necessary And Sufficient ◽  
Stimulation Of ◽  
Inflammatory Effect

Depending on the prevailing environmental conditions, neutrophilic granulocytes release extracellular vesicles (EV) which have either anti-inflammatory effects on other neutrophils or pro-inflammatory and antibacterial effects. In the present study we investigated the molecular mechanisms underlying the biogenesis of functionally heterogenic EVs. We show that selective stimulation of Mac-1 integrin (complement receptor 3) by specific ligands initiates the generation of EVs which are able to impair bacterial growth and to induce the secretion of the pro-inflammatory cytokine IL-8 (aEV). However, direct Mac-1 stimulation results in aEV release only if neutrophils were activated on ligand coated surfaces whereas soluble ligands are ineffective. Using total internal reflection fluorescence (TIRF) microcopy, an increased clustering of Mac-1 molecules could be visualized in neutrophils added to C3bi coated surfaces; moreover antibody induced cluster formation triggers aEV release as well. Mac-1 induced production of aEV apparently necessitates a strong calcium signal as it fully depends on the presence of extracellular calcium. However, initiation of a strong calcium signal by an ionophore only results the generation of EV devoid of any antibacterial or pro-inflammatory effect. Our results thus demonstrate that stimulation and clustering of Mac-1 is necessary and sufficient for initiation of aEV biogenesis. In contrast, an intracellular calcium signal is necessary but by itself not sufficient for the production of antibacterial and pro-inflammatory EVs.

scholarly journals Inactivation of EMILIN-1 by Proteolysis and Secretion in Small Extracellular Vesicles Favors Melanoma Progression and Metastasis

2021 ◽  
Vol 22 (14) ◽  
pp. 7406
Author(s):  
Ana Amor López ◽  
Marina S. Mazariegos ◽  
Alessandra Capuano ◽  
Pilar Ximénez-Embún ◽  
Marta Hergueta-Redondo ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Cell Viability ◽  
Extracellular Vesicles ◽  
Primary Tumor ◽  
Molecular Mechanisms ◽  
Primary Tumor Growth ◽  
Node Metastasis ◽  
Metastatic Cells ◽  
Tumor Growth And Metastasis

Several studies have demonstrated that melanoma-derived extracellular vesicles (EVs) are involved in lymph node metastasis; however, the molecular mechanisms involved are not completely defined. Here, we found that EMILIN-1 is proteolyzed and secreted in small EVs (sEVs) as a novel mechanism to reduce its intracellular levels favoring metastasis in mouse melanoma lymph node metastatic cells. Interestingly, we observed that EMILIN-1 has intrinsic tumor and metastasis suppressive-like properties reducing effective migration, cell viability, primary tumor growth, and metastasis. Overall, our analysis suggests that the inactivation of EMILIN-1 by proteolysis and secretion in sEVs reduce its intrinsic tumor suppressive activities in melanoma favoring tumor progression and metastasis.

scholarly journals The Emerging Role of Extracellular Vesicles in Endocrine Resistant Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1160
Author(s):  
Giusi La Camera ◽  
Luca Gelsomino ◽  
Amanda Caruso ◽  
Salvatore Panza ◽  
Ines Barone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Endocrine Resistance ◽  
Disease Recurrence ◽  
Estrogen Receptor Α ◽  
Research Area ◽  
Tumor Evolution

Breast cancer is the most common solid malignancy diagnosed in females worldwide, and approximately 70% of these tumors express estrogen receptor α (ERα), the main biomarker of endocrine therapy. Unfortunately, despite the use of long-term anti-hormone adjuvant treatment, which has significantly reduced patient mortality, resistance to the endocrine treatments often develops, leading to disease recurrence and limiting clinical benefits. Emerging evidence indicates that extracellular vesicles (EVs), nanosized particles that are released by all cell types and responsible for local and systemic intercellular communications, might represent a newly identified mechanism underlying endocrine resistance. Unraveling the role of EVs, released by transformed cells during the tumor evolution under endocrine therapy, is still an open question in the cancer research area and the molecular mechanisms involved should be better defined to discover alternative therapeutic approaches to overcome resistance. In this review, we will provide an overview of recent findings on the involvement of EVs in sustaining hormonal resistance in breast cancer and discuss opportunities for their potential use as biomarkers to monitor the therapeutic response and disease progression.

Cellular and molecular basis of increased ammoniagenesis in potassium deprivation

2011 ◽  
Vol 301 (5) ◽  
pp. F969-F978 ◽  
Author(s):  
Shaikh Abu Hossain ◽  
Farrukh A. Chaudhry ◽  
Kamyar Zahedi ◽  
Faraaz Siddiqui ◽  
Hassane Amlal
Keyword(s):  
Phosphoenolpyruvate Carboxykinase ◽  
Molecular Mechanisms ◽  
Intracellular Acidosis ◽  
Deficient Diet ◽  
Proximal Tubule Cells ◽  
Glutamine Transporter ◽  
Additive Increase ◽  
Acid Base Status ◽  
Low K ◽  
Stimulation Of

Hypokalemia is associated with increased ammoniagenesis and stimulation of net acid excretion by the kidney in both humans and experimental animals. The molecular mechanisms underlying these effects remain unknown. Toward this end, rats were placed in metabolic cages and fed a control or K+-deficient diet (KD) for up to 6 days. Rats subjected to KD showed normal acid-base status and serum electrolytes composition. Interestingly, urinary NH4+ excretion increased significantly and correlated with a parallel decrease in urine K+ excretion in KD vs. control animals. Molecular studies showed a specific upregulation of the glutamine transporter SN1, which correlated with the upregulation of glutaminase (GA), glutamate dehydrogenase (GDH), and phosphoenolpyruvate carboxykinase. These effects occurred as early as day 2 of KD. Rats subjected to a combined KD and 280 mM NH4Cl loading (to induce metabolic acidosis) for 2 days showed an additive increase in NH4+ excretion along with an additive increment in the expression levels of ammoniagenic enzymes GA and GDH compared with KD or NH4Cl loading alone. The incubation of cultured proximal tubule cells NRK 52E or LLC-PK1 in low-K+ medium did not affect NH4+ production and did not alter the expression of SN1, GA, or GDH in NRK cells. These results demonstrate that K+ deprivation stimulates ammoniagenesis through a coordinated upregulation of glutamine transporter SN1 and ammoniagenesis enzymes. This effect is developed before the onset of hypokalemia. The signaling pathway mediating these events is likely independent of KD-induced intracellular acidosis. Finally, the correlation between increased NH4+ production and decreased K+ excretion indicate that NH4+ synthesis and transport likely play an important role in renal K+ conservation during hypokalemia.

Microglia extracellular vesicles: focus on molecular composition and biological function

2021 ◽  
Vol 49 (4) ◽  
pp. 1779-1790 ◽  
Author(s):  
Lorenzo Ceccarelli ◽  
Chiara Giacomelli ◽  
Laura Marchetti ◽  
Claudia Martini
Keyword(s):  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Biological Function ◽  
Biological Effects ◽  
Genetic Material ◽  
Cell Communication ◽  
Molecular Composition ◽  
Cargo Proteins ◽  
A Cell ◽  
The Central Nervous System

Extracellular vesicles (EVs) are a heterogeneous family of cell-derived lipid bounded vesicles comprising exosomes and microvesicles. They are potentially produced by all types of cells and are used as a cell-to-cell communication method that allows protein, lipid, and genetic material exchange. Microglia cells produce a large number of EVs both in resting and activated conditions, in the latter case changing their production and related biological effects. Several actions of microglia in the central nervous system are ascribed to EVs, but the molecular mechanisms by which each effect occurs are still largely unknown. Conflicting functions have been ascribed to microglia-derived EVs starting from the neuronal support and ending with the propagation of inflammation and neurodegeneration, confirming the crucial role of these organelles in tuning brain homeostasis. Despite the increasing number of studies reported on microglia-EVs, there is also a lot of fragmentation in the knowledge on the mechanism at the basis of their production and modification of their cargo. In this review, a collection of literature data about the surface and cargo proteins and lipids as well as the miRNA content of EVs produced by microglial cells has been reported. A special highlight was given to the works in which the EV molecular composition is linked to a precise biological function.

scholarly journals Rare variants in axonogenesis genes connect three families with sound–color synesthesia

2018 ◽  
Vol 115 (12) ◽  
pp. 3168-3173 ◽  
Author(s):  
Amanda K. Tilot ◽  
Katerina S. Kucera ◽  
Arianna Vino ◽  
Julian E. Asher ◽  
Simon Baron-Cohen ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Rare Variants ◽  
Autism Spectrum ◽  
Sensory Experiences ◽  
Limited Success ◽  
Whole Exome ◽  
Rare Genetic Variants ◽  
Sound Color ◽  
Stimulation Of

Synesthesia is a rare nonpathological phenomenon where stimulation of one sense automatically provokes a secondary perception in another. Hypothesized to result from differences in cortical wiring during development, synesthetes show atypical structural and functional neural connectivity, but the underlying molecular mechanisms are unknown. The trait also appears to be more common among people with autism spectrum disorder and savant abilities. Previous linkage studies searching for shared loci of large effect size across multiple families have had limited success. To address the critical lack of candidate genes, we applied whole-exome sequencing to three families with sound–color (auditory–visual) synesthesia affecting multiple relatives across three or more generations. We identified rare genetic variants that fully cosegregate with synesthesia in each family, uncovering 37 genes of interest. Consistent with reports indicating genetic heterogeneity, no variants were shared across families. Gene ontology analyses highlighted six genes—COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2—associated with axonogenesis and expressed during early childhood when synesthetic associations are formed. These results are consistent with neuroimaging-based hypotheses about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences.

scholarly journals Extracellular Vesicles Derived From Canine Mesenchymal Stromal Cells in Serum Free Culture Medium Have Anti-inflammatory Effect on Microglial Cells

2021 ◽  
Vol 8 ◽  
Author(s):  
Yukina Kuwahara ◽  
Karin Yoshizaki ◽  
Hidetaka Nishida ◽  
Hiroaki Kamishina ◽  
Sadatoshi Maeda ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Culture Medium ◽  
Serum Free ◽  
Naturally Occurring ◽  
Serum Free Condition ◽  
Cell Sources ◽  
Fetal Bovine ◽  
Inflammatory Effect

Mesenchymal stem/stromal cells (MSCs) have been used as cell sources for treating dogs with naturally-occurring diseases. Extracellular vesicles (EVs) derived from MSCs are now recognized as pivotal to modulating the immune response and supporting tissue repair. Manufacture of MSC-EVs for clinical application mandates removal of the xeno-proteins, including fetal bovine serum. The objective of this study was to examine whether canine MSCs survived and secreted EVs in serum-free medium (SFM) conditions and to assess the immunomodulatory effect of EVs in vitro. Canine MSCs were found to survive and secrete EVs under SFM conditions. The surface markers of MSCs in the SFM were similar to MSCs in complete culture medium. Canine MSC-EVs had a diameter of ~300 nm and were positive for EV markers. MSC-derived EVs from the serum-free condition reduced the levels of IL-1β by BV-2 cells in response to LPS stimulation. These results warrant further studies of the use of SFM for producing EVs derived from canine MSCs.

scholarly journals Extracellular Vesicles: An Emerging Mechanism Governing the Secretion and Biological Roles of Tenascin-C

2021 ◽  
Vol 12 ◽  
Author(s):  
Lucas Albacete-Albacete ◽  
Miguel Sánchez-Álvarez ◽  
Miguel Angel del Pozo
Keyword(s):  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Cell Communication ◽  
Cell Types ◽  
Target Cells ◽  
Tenascin C ◽  
Signalling Molecules ◽  
Inflammatory Processes ◽  
Bona Fide ◽  
Cellular Components

ECM composition and architecture are tightly regulated for tissue homeostasis. Different disorders have been associated to alterations in the levels of proteins such as collagens, fibronectin (FN) or tenascin-C (TnC). TnC emerges as a key regulator of multiple inflammatory processes, both during physiological tissue repair as well as pathological conditions ranging from tumor progression to cardiovascular disease. Importantly, our current understanding as to how TnC and other non-collagen ECM components are secreted has remained elusive. Extracellular vesicles (EVs) are small membrane-bound particles released to the extracellular space by most cell types, playing a key role in cell-cell communication. A broad range of cellular components can be transported by EVs (e.g. nucleic acids, lipids, signalling molecules and proteins). These cargoes can be transferred to target cells, potentially modulating their function. Recently, several extracellular matrix (ECM) proteins have been characterized as bona fide EV cargoes, exosomal secretion being particularly critical for TnC. EV-dependent ECM secretion might underpin diseases where ECM integrity is altered, establishing novel concepts in the field such as ECM nucleation over long distances, and highlighting novel opportunities for diagnostics and therapeutic intervention. Here, we review recent findings and standing questions on the molecular mechanisms governing EV–dependent ECM secretion and its potential relevance for disease, with a focus on TnC.

The Molecular Mechanisms Through Which Placental Mesenchymal Stem Cell‐Derived Extracellular Vesicles Promote Myelin Regeneration

2022 ◽  
pp. 2101099
Author(s):  
Kaitlin C. Clark ◽  
David Wang ◽  
Priyadarsini Kumar ◽  
Sirjan Mor ◽  
Edwin Kulubya ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Extracellular Vesicles ◽  
Molecular Mechanisms

Dissecting interactions between EB1, microtubules and APC in cortical clusters at the plasma membrane

2002 ◽  
Vol 115 (8) ◽  
pp. 1583-1590 ◽  
Author(s):  
Angela I. M. Barth ◽  
Kathleen A. Siemers ◽  
W. James Nelson
Keyword(s):  
Amino Acids ◽  
Cluster Formation ◽  
Adenomatous Polyposis ◽  
Polyposis Coli ◽  
Binding Domains ◽  
C Terminus ◽  
Endogenous Proteins ◽  
Apc Protein ◽  
Necessary And Sufficient ◽  
Armadillo Repeats

End-binding protein (EB) 1 binds to the C-terminus of adenomatous polyposis coli (APC) protein and to the plus ends of microtubules (MT) and has been implicated in the regulation of APC accumulation in cortical clusters at the tip of extending membranes. We investigated which APC domains are involved in cluster localization and whether binding to EB1 or MTs is essential for APC cluster localization. Armadillo repeats of APC that lack EB1- and MT-binding domains are necessary and sufficient for APC localization in cortical clusters; an APC fragment lacking the armadillo repeats, but containing MT-and EB1-binding domains, does not localize to the cortical clusters but instead co-aligns with MTs throughout the cell. Significantly, analysis of endogenous proteins reveals that EB1 does not accumulate in the APC clusters. However, overexpressed EB1 does accumulate in APC clusters; the APC-binding domain in EB1 is located in the C-terminal region of EB1 between amino acids 134 and 268. Overexpressed APC- or MT-binding domains of EB1 localize to APC cortical clusters and MT, respectively, without affecting APC cluster formation itself. These results show that localization of APC in cortical clusters is different from that of EB1 at MT plus ends and appears to be independent of EB1.

scholarly journals The Anti-Inflammatory and Antioxidant Properties of n-3 PUFAs: Their Role in Cardiovascular Protection

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 306 ◽  
Author(s):  
Francesca Oppedisano ◽  
Roberta Macrì ◽  
Micaela Gliozzi ◽  
Vincenzo Musolino ◽  
Cristina Carresi ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Vascular Reactivity ◽  
Molecular Mechanisms ◽  
Antioxidant Properties ◽  
Cardiac Cells ◽  
Membrane Phospholipids ◽  
Mitochondrial Functions ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Polyunsaturated fatty acids (n-3 PUFAs) are long-chain polyunsaturated fatty acids with 18, 20 or 22 carbon atoms, which have been found able to counteract cardiovascular diseases. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in particular, have been found to produce both vaso- and cardio-protective response via modulation of membrane phospholipids thereby improving cardiac mitochondrial functions and energy production. However, antioxidant properties of n-3 PUFAs, along with their anti-inflammatory effect in both blood vessels and cardiac cells, seem to exert beneficial effects in cardiovascular impairment. In fact, dietary supplementation with n-3 PUFAs has been demonstrated to reduce oxidative stress-related mitochondrial dysfunction and endothelial cell apoptosis, an effect occurring via an increased activity of endogenous antioxidant enzymes. On the other hand, n-3 PUFAs have been shown to counteract the release of pro-inflammatory cytokines in both vascular tissues and in the myocardium, thereby restoring vascular reactivity and myocardial performance. Here we summarize the molecular mechanisms underlying the anti-oxidant and anti-inflammatory effect of n-3 PUFAs in vascular and cardiac tissues and their implication in the prevention and treatment of cardiovascular disease.

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