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Alteration of microglial metabolism and inflammatory profile contributes to neurotoxicity in a hiPSC-derived microglia model of frontotemporal dementia 3.

Frontotemporal dementia (FTD) is a common cause of early-onset dementia, with no current treatment options. FTD linked to chromosome 3 (FTD3) is a rare sub-form of the disease, caused by a point mutation in the Charged Multivesicular Body Protein 2B (CHMP2B). This mutation causes neuronal phenotypes, such as mitochondrial deficiencies, accompanied by metabolic changes and interrupted endosomal-lysosomal fusion. However, the contribution of glial cells to FTD3 pathogenesis has, until recently, been largely unexplored. Glial cells play an important role in most neurodegenerative disorders as dri

Characterization of the Quasi-Enveloped Hepatitis E Virus Particles Released by the Cellular Exosomal Pathway.

Our previous studies demonstrated that membrane-associated hepatitis E virus (HEV) particles-now considered "quasi-enveloped particles"-are present in the multivesicular body with intraluminal vesicles (exosomes) in infected cells and that the release of HEV virions is related to the exosomal pathway. In this study, we characterized exosomes purified from the culture supernatants of HEV-infected PLC/PRF/5 cells. Purified CD63-, CD9-, or CD81-positive exosomes derived from the culture supernatants of HEV-infected cells that had been cultivated in serum-free medium were found to contain HEV RNA

Disrupting the TRIB3-SQSTM1 interaction reduces liver fibrosis by restoring autophagy and suppressing exosome-mediated HSC activation.

Impaired macroautophagy/autophagy is involved in the pathogenesis of hepatic fibrosis. However, how aberrant autophagy promotes fibrosis is far from understood. Here, we aimed to define a previously unrevealed pro-fibrotic mechanism for the stress protein TRIB3 (tribbles pseudokinase 3)-mediated autophagy dysfunction. Human fibrotic liver tissues were obtained from patients with cirrhosis who underwent an open surgical repair process. The functional implications of TRIB3 were evaluated in mouse models of hepatic fibrosis induced by bile duct ligation (BDL) or thioacetamide (TAA) injection. Hum

Abnormal podocyte TRPML1 channel activity and exosome release in mice with podocyte-specific Asah1 gene deletion.

Podocytopathy and associated nephrotic syndrome (NS) have been reported in a knockout mouse strain (Asah1fl/fl/PodoCre) with a podocyte-specific deletion of α subunit (the main catalytic subunit) of acid ceramidase (Ac). However, the pathogenesis of podocytopathy of these mice remains unknown. The present study tested whether exosome release from podocytes is enhanced due to Asah1 gene knockout, which may serve as a pathogenic mechanism switching on podocytopathy and associated NS in Asah1fl/fl/PodoCre mice. We first demonstrated the remarkable elevation of urinary exosome excretion in Asah1fl

Presenilin deficiency or lysosomal inhibition enhances Wnt signaling through relocalization of GSK3 to the late-endosomal compartment.

Sustained canonical Wnt signaling requires the inhibition of glycogen synthase kinase 3 (GSK3) activity by sequestration of GSK3 inside multivesicular endosomes (MVEs). Here, we show that Wnt signaling is increased by the lysosomal inhibitor chloroquine, which causes accumulation of MVEs. A similar MVE expansion and increased Wnt responsiveness was found in cells deficient in presenilin, a protein associated with Alzheimer's disease. The Wnt-enhancing effects were entirely dependent on the functional endosomal sorting complex required for transport (ESCRT), which is needed for the formation of

Differences in plasma proteomes for active tuberculosis, latent tuberculosis and non-tuberculosis mycobacterial lung disease patients with and without ESAT-6/CFP10 stimulation.

BACKGROUND: Tuberculosis (TB) is one of the world's most problematic infectious diseases. The pathogen Mycobacterium tuberculosis (Mtb) is contained by the immune system in people with latent TB infection (LTBI). No overt disease symptoms occur. The environmental and internal triggers leading to reactivation of TB are not well understood. Non-tuberculosis Mycobacteria (NTM) can also cause TB-like lung disease. Comparative analysis of blood plasma proteomes from subjects afflicted by these pathologies in an endemic setting may yield new differentiating biomarkers and insights into inflammatory

Morphological and ultrastructural changes in the placenta of the diabetic pregnant Egyptian women.

Diabetes mellitus (DM) is a chronic metabolic disease in which the body fails to produce enough insulin or increased tissue resistance to insulin. The diabetes may have profound effects on placental development and function. This study was designed to detect the placental changes in pregnancy associated with DM comparing these changes with normal placenta. The study was carried out on sixty full-term placentae; divided into three equal groups; control group (group I): placentae of normal pregnancy, uncontrolled diabetes (group II): placentae from pregnant women whose blood glucose is poorly co

RPS6KA3/RSK2-mediated phosphorylation of DRAM2 promotes lysosomal targeting and autophagic flux in melanoma.

Macroautophagy/autophagy is a critical process for maintaining cellular homeostasis and has emerging implications in cancer biology. DRAM2 (DNA damage regulated autophagy modulator 2), a transmembrane protein enriched at lysosomal membranes, has been implicated in autophagy regulation; however, the upstream mechanisms governing its trafficking and function remain unclear. In this study, we identified RPS6KA3/RSK2, a stress-responsive kinase downstream of the MAPK pathway, as a novel upstream kinase of DRAM2. RPS6KA3/RSK2 interacted with and phosphorylated DRAM2 at Ser263 within its cytosolic t

Proteomics of human duodenum in pre-diabetes and type 2 diabetes reveals potential novel therapeutic targets for aetiology and therapeutics.

BACKGROUND: Remission from pre-diabetes and type 2 diabetes (T2D) is frequently observed immediately after a duodenal/jejunal bypass. This demonstrates the reversibility of T2D and involvement of the proximal small intestine in T2D pathology. This study investigates the role of the duodenum in the pathophysiology of T2D, in line with the hypothesis, that exclusion of duodenum/jejunum in T2D (for example, in RYGB surgery) prevents release of unidentified factors that impair insulin sensitivity, leading to T2D remission. The study aimed at identifying novel protein therapeutic targets in human d

Podocyte-specific silencing of acid sphingomyelinase gene to abrogate hyperhomocysteinemia-induced NLRP3 inflammasome activation and glomerular inflammation.

Acid sphingomyelinase (ASM) has been reported to increase tissue ceramide and thereby mediate hyperhomocysteinemia (hHcy)-induced glomerular nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation, inflammation, and sclerosis. In the present study, we tested whether somatic podocyte-specific silencing of Smpd1 gene (mouse ASM gene code) attenuates hHcy-induced NLRP3 inflammasome activation and associated extracellular vesicle (EV) release in podocytes and thereby suppresses glomerular inflammatory response and injury. In vivo, somatic p

The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy.

Primary dysfunction of autophagy due to Mendelian defects affecting core components of the autophagy machinery or closely related proteins have recently emerged as an important cause of genetic disease. This novel group of human disorders may present throughout life and comprises severe early-onset neurodevelopmental and more common adult-onset neurodegenerative disorders. Early-onset (or congenital) disorders of autophagy often share a recognizable "clinical signature," including variable combinations of neurological, neuromuscular and multisystem manifestations. Structural CNS abnormalities,

WNT2B impairs endosomal trafficking via WASHC5 to inhibit autophagy: a novel non-secretory WNT pathway.

WNT2B is canonically characterized as a secreted WNT-family ligand, which is transported to the extracellular space via the endoplasmic reticulum (ER)-Golgi pathway and binds to cell surface FZDs (frizzled class receptors) to trigger downstream signaling cascades. Here, we identify a previously unrecognized non-secretory intracellular function of WNT2B in impairing endosomal trafficking to inhibit macroautophagy/autophagy, as well as a non-canonical LC3B-II-dependent autophagic secretion mechanism for WNT2B. Specifically, the non-secretory intracellular pool of WNT2B via its conserved middle d

Plasma neuronal exosomes serve as biomarkers of cognitive impairment in HIV infection and Alzheimer's disease.

Fluid biomarkers for cognitive impairment have the advantage of being relatively noninvasive and capable of monitoring neuronal and other br … found in all biofluids; they are divided into exosomes (30-150 nm) originating from late endosomes/multivesicular bodies and microvesicles (150-1000 nm) produced through budding of the plasma membrane. Both types of vesicles are implicated in the pathogenesis of neurodegenerative diseases and may provide biomarkers (Bellingham et al., Front Physiol 3: 124, 2012). In t …

Exosomes: A new option for osteoporosis treatment.

Osteoporosis is a systemic bone disease characterized by reduced bone mass and destruction of bone microarchitecture, leading to increased bone fragility and susceptibility to fracture. However, the pathogenesis and molecular mechanisms of this disease remain unclear. Extracellular vesicles, structures originating from the plasma membrane and ranging from 30 nm to 5 µm in diameter, play an important role in intercellular communication in the bone microenvironment. Exosomes are extracellular vesicles that deliver cargo molecules, including endogenous proteins, lipids and nucleic acids. These ca

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… Late intranuclear bodies containing multiple ILVs are known as multivesicular bodies (MVBs). … Molecular mechanism of multivesicular body biogenesis by ESCRT complexes. Nature . 2010 ; 464 : 864 – 9 . 20305637 10.1038/nature08849 PMC2851844 [15] Katzmann DJ Babst M Emr SD . …

An expanding horizon of complex injectable products: development and regulatory considerations.

There has been a constant evolution in the pharmaceutical market concerning the new technologies imbibed in delivering drug substances for various indications. This is either market-driven or technology-driven to improve the overall therapeutic efficacy and patients' quality of life. The pharmaceutical industry has experienced rapid growth in the area of complex injectable products because of their effectiveness in the unmet market. These novel parenteral products, viz, the nanoparticles, liposomes, microspheres, suspensions, and emulsions, have proven their worth as "Safe and Effective" produ

The Power of Extracellular Vesicles in Myeloproliferative Neoplasms: "Crafting" a Microenvironment That Matters.

Myeloproliferative Neoplasms (MPN) are acquired clonal disorders of the hematopoietic stem cells and include Essential Thrombocythemia, Polycythemia Vera and Myelofibrosis. MPN are characterized by mutations in three driver genes (JAK2, CALR and MPL) and by a state of chronic inflammation. Notably, MPN patients experience increased risk of thrombosis, disease progression, second neoplasia and evolution to acute leukemia. Extracellular vesicles (EVs) are a heterogeneous population of microparticles with a role in cell-cell communication. The EV-mediated cross-talk occurs via the trafficking of

Совпадение в полном тексте источника
… Exosomes originate from the endosomal system with a progressive accumulation of intraluminal vesicles within large multivesicular bodies. … The generation of multivesicular bodies is driven by Endosomal Sorting Complex Required for Transport (ESCRT)-dependent and -independent pathways [ 59 ]. …

Exosomes as a Novel Approach to Reverse Osteoporosis: A Review of the Literature.

Osteoporosis is a chronic disease requiring long-term, sometimes lifelong, management. With the aging population, the prevalence of osteoporosis is increasing, and with it so is the risk of hip fracture and subsequent poor quality of life and higher mortality. Current therapies for osteoporosis have various significant side effects limiting patient compliance and use. Recent evidence has demonstrated the significant role of exosomes in osteoporosis both in vivo and in vitro. In this review, we summarize the pathogenesis of senile osteoporosis, highlight the properties and advantages of exosome

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… Exosomes, as intraluminal endosomal vesicles, are released by exocytosis when multivesicular bodies (MVBs) fuse with the plasma membrane ( Figure 3 ) ( Heijnen et al., 1999 ). … Exosomes are vesicles of endocytic origin formed by the inward budding of the multivesicular body (MVB) membrane. …

Latest advances in extracellular vesicles: from bench to bedside.

Extracellular vesicles (EVs) are small membraned vesicles and approximately 50-150 nm in diameter. Almost all of the type of cells releases the EVs and circulates in the body fluids. EVs contain multiple functional components, such as mRNAs, microRNAs (miRNAs), DNAs, and proteins, which can be transferred to the recipient cells, resulting in phenotypic changes. Recently, EV research has focused on their potential as a drug delivery vehicle and in targeted therapy against specific molecules. Moreover, some surface proteins are specific to particular diseases, and therefore, EVs also have promis

Совпадение в полном тексте источника
… Exosomes are initially formed by a process of inward budding in early endosomes to form multivesicular bodies (MVBs) and released into the extracellular microenvironment to transfer their components [ 3 , 4 ]. … References [1] Denzer K , Kleijmeer M , Heijnen H , et al Exosome: from internal vesicle of the multivesicular body to intercellular signaling device . J Cell Sci . 2000 ; 19 : 3365 – 3374 . 10.1242/jcs.113.19.3365 10984428 [2] Raposo G , Stoorvogel W. …

Tumour-Derived Extracellular Vesicles (EVs): A Dangerous "Message in A Bottle" for Bone.

Several studies have shown the importance of Extracellular Vesicles (EVs) in the intercellular communication between tumour and resident cells. Through EVs, tumour cells can trigger cell-signalling molecules and shuttle exogenous information to target cells, thus promoting spread of the disease. In fact, many processes are fuelled by EVs, such as tumour invasion and dormancy, drug-resistance, immune-surveillance escape, extravasation, extracellular matrix remodelling and metastasis. A key element is certainly the molecular profile of the shed cargo. Understanding the biochemical basis of EVs w

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… Ubiquitin-Dependent Sorting into the Multivesicular Body Pathway Requires the Function of a Conserved Endosomal Protein Sorting Complex, ESCRT-I Cell 2001 106 145 155 10.1016/S0092-8674(01)00434-2 11511343 24. Cappariello A. Ponzetti M. Rucci N. … Rab11 Promotes Docking and Fusion of Multivesicular Bodies in a Calcium-Dependent Manner Traffic 2005 6 131 143 10.1111/j.1600-0854.2004.00257.x 15634213 107. Bobrie A. Krumeich S. Reyal F. Recchi C. Moita L.F. Seabra M.C. Ostrowski M. Théry C. …

Effect of PLA2G6 and SMPD1 Variants on the Lipid Metabolism in the Cerebrospinal Fluid of Patients with Parkinson's Disease: A Non-targeted Lipidomics Study.

IntroductionSleep patterns are more frequently interrupted in patients with Parkinson's disease (PD), and it is still unclear whether genetic factors are involved in PD-related sleep disorders. In this study, we hypothesize that PD-associated genetic risk affects lipid metabolism, which in turn contributes to different types of sleep disorders.MethodsWe used a non-targeted lipidomics to explore the lipid composition of cerebrospinal fluid (CSF) exosomes derived from patients with PD carrying phospholipase A2 Group VI (PLA2G6) and sphingomyelin phosphodiesterase 1 (SMPD1) mutations.ResultsPLA2G

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… Some studies have shown that ceramide synthesis is involved in the formation of extracellular vesicles in the lumen of multivesicular bodies independent of the ESCRT biogenesis pathway, and that the vesicles are released in the form of exosomes after the fusion of multivesicular bodies with the plasma … The tapered structure of ceramides induces a spontaneous negative curvature of the endosomal membrane, favoring the formation of endosomes inside multivesicular bodies. …