Is The Vesicle In Plant And Animal Cells
Int J Mol Sci. 2021 May; 22(10): 5366.
Extracellular Vesicles from Plants: Current Knowledge and Open up Questions
Ornella Urzì
oneDepartment of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.Due north.D), Department of Biology and Genetics, University of Palermo, 90133 Palermo, Italy; ti.apinu@izru.allenro
Stefania Raimondo
1Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), Department of Biology and Genetics, University of Palermo, 90133 Palermo, Italy; ti.apinu@izru.allenro
Riccardo Alessandro
oneDepartment of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D), Section of Biology and Genetics, University of Palermo, 90133 Palermo, Italy; ti.apinu@izru.allenro
twoInstitute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), 90146 Palermo, Italia
Marcello Iriti, Academic Editor
Received 2021 Apr 7; Accepted 2021 May xviii.
Abstruse
The scientific interest in the beneficial backdrop of natural substances has been recognized for decades, as well as the growing attention in extracellular vesicles (EVs) released by different organisms, in particular from animal cells. Nonetheless, there is increasing involvement in the isolation and biological and functional label of these lipoproteic structures in the plant kingdom. Like to beast vesicles, these plant-derived extracellular vesicles (PDEVs) exhibit a complex content of modest RNAs, proteins, lipids, and other metabolites. This sophisticated composition enables PDEVs to be therapeutically attractive. In this review, nosotros report and discuss current cognition on PDEVs in terms of isolation, characterization of their content, biological properties, and potential use equally drug delivery systems. In conclusion, we outline controversial problems on which the scientific customs shall focus the attention shortly.
Keywords: establish-derived extracellular vesicles, omics characterization, anti-tumor effects, anti-inflammatory effects, drug-delivery vehicles
ane. Extracellular Vesicles from Plants
In the final ii decades, at that place has been an exponential increase in the amount of enquiry aimed at studying the mechanisms of jail cell–cell communication mediated by extracellular vesicles (EVs). EVs are a family of lipoproteic structures, released by prokaryotic and eukaryotic cells, heterogeneous in terms of origin, size, and content. To date, the interest of the scientific community in the field has been focused on the purification of EVs from brute cells and biological fluids, as well as on their morphological and functional characterization. More recently, the role that these vesicles may have in cross-kingdom advice is attracting the attention of many research groups; in particular, growing studies are focusing on the comprehension of the interactions between vesicles isolated from plants, in this review defined as found-derived EVs (PDEVs), and mammalian cells. This involvement certainly stems from the natural origin of these structures and the potential applications that derive from them, specially in the field of human health. The first study related to the extracellular release of small vesicles in the plant kingdom was from 1967 [i], but it was just later, with the research of Regente [ii] on sunflower apoplastic fluid, that the number of studies on PDEVs increased. Starting from the investigations of Zhang et al. in 2013 [three], several studies have focused on EVs isolated from the juice of unlike fruits; recently, the attending is focused on the characterization of EV content.
In this section, we review the current methods used to isolate PDEVs from different institute matrices equally well as the studies aimed at identifying their RNAs, protein, and lipid content. Then, in the next paragraphs, we hash out the data focused on their biological properties and their potential use as drug delivery vehicles.
1.1. Isolation Techniques
Although the involvement in PDEVs has grown in recent years and many enquiry groups are exploring their backdrop, a standardized and unique isolation protocol withal does non exist.
The most mutual method of plant vesicle isolation is differential centrifugation followed by ultracentrifugation [iv,v,6,vii,8,nine,10,xi,12]. The starting material can be fruits [4,6,7,8,9,x], roots [v,13], stems [9,fourteen], leaves [ix,14,15,xvi], seeds [16], and saps [17]; these matrices can exist manually squeezed or using a mixer to obtain the juice. The juice is subjected to several differential centrifugation steps: low-speed centrifugation (most 500–3000× g for 10–xv min) to remove plant fibers and large particles; intermediate speed centrifugation (2000–10,000× g for xx–xl min) to remove large debris and subcellular organelles; and high-speed centrifugation (100,000–150,000× g for 1.v–2 h) to obtain PDEVs pellet.
In addition to these centrifugation steps, some protocols include filtration steps with 0.viii-, 0.45-, and 0.22-micron pore size filters. Notwithstanding, the type, quantity, and quality of PDEVs obtained past ultracentrifugation can be influenced past several parameters, such equally 1000-force, rotor type, rotor sedimentation angle, and solution viscosity. Furthermore, since ultracentrifugation too sediments other vesicles, proteins, and protein/RNA aggregates, a subsequent sucrose density gradient stride is used to dissever PDEVs from contaminants [v,ix,10,xi,12].
Other methods such as ultrafiltration or immune isolation that are routinely used for animal-derived EVs have not been widely used for plant-derived EVs. Sashin et al. used the Exo-spin™ Exosome Purification Kit, which combines precipitation with size exclusion chromatography, and successfully isolated EVs from Triticum aestivum [15]. Recently, Yang et al. proposed an alternative method to isolate EVs from the lemon. This method combines electrophoretic technique with a 300 kDa cut-off dialysis bag. They centrifuged lemon juice at 3000× g for ten min and 10,000× g for 20 min and filtered the supernatant through a 0.22 μm pore size filter. Then, the juice was placed in a 300 kDa dialysis bag placed in a gel holder cassette with a current of 300 mA [eighteen].
The yield of PDEVs obtained varies depending on the starting material. For example, Raimondo et al., starting from 240 mL of lemon juice, isolated about 600 µg of nanovesicles [four]. Some other group, however, obtained about 10 mg of EVs from 10 g of Dendropanax morbifera sap [17]. In addition to protein quantification, the recovery of EVs can be determined by other techniques, such as cytofluorimetry. For instance, Potestà et al. adamant that the number of EVs contained in 1 mg of Moringa olifera seed extracts is sixteen,921 ± 617 [19].
Despite being quite variable, the yield of plant-derived vesicles is college than those obtained from animal cells; this represents a very attractive point for their potential therapeutic apply. However, the lack of a standard isolation method notwithstanding represents a limitation to their utilise.
one.2. Content Label of PDEVs
Considering the circuitous and heterogeneous content of PDEVs, omics analysis plays a key role in the characterization and identification of their content. Several studies published to date take reported proteomic, lipidomic, metabolomic, and RNA seq analyses of vesicles isolated from diverse institute species, leading to the identification of proteins or lipids that could potentially serve as markers in the future, and in parallel to define specific molecular profiles of EVs from each species.
ane.2.one. Small RNAs in PDEVs
One of the most interesting findings regarding PDEVs content concerns the presence of small RNAs (sRNAs), in particular microRNAs (miRNAs); these complexes may stand for a new course of cross-kingdom modulators, by mediating fauna–plant interactions at the molecular level [20,21]. Xiao et al. observed the presence of miRNAs in 11 different plant species [22]; later on, they analyzed the expression distribution of miRNAs isolated from coconut, orange, and lycopersicon esculentum EVs, categorizing them into frequent miRNAs, moderately nowadays miRNAs, and rare miRNAs. Target prediction analyses using TargetScan showed that some of the near expressed miRNAs regulate the expression of mammalian genes associated with the inflammatory and tumor response [22]. miRNAs were likewise constitute in EVs from ginger [12]; specifically, some of these miRNAs target several genes from Lactobacillus rhamnosus, thereby modulating the limerick of the host microbiome [12].
In a study on vesicles isolated from Moringa oleifera, xix miRNAs belonging to xx conserved families of found miRNAs were identified, two of which, miR396a and miR396c, were more than abundant in vesicles than in seed aqueous extract. The presence of these miRNAs was then correlated with the reduction of viability of tumor cells treated with EVs [19]. Analysis of miRNAs was too performed in strawberry juice and the PDEVs, detecting but miR166g in both matrices [eight].
A contempo written report, through a comparison of sRNA profiles obtained from EVs isolated from Arabidopsis, revealed the presence of small RNAs of x–17 nucleotides, called "tiny RNAs", whose part is still unknown [23].
Finally, a preliminary study published in March 2021 demonstrated, through in silico target prediction analysis, that vesicles from soybean, ginger, hamimelon, grapefruit, tomato, and pear possess multiple miRNAs targeting dissimilar regions within SARS-CoV-2. If further studies confirm these analyses, PDEVs containing these miRNAs could represent an bonny therapeutic strategy to target altered factor expression related to pathologic conditions [24].
While for the fauna kingdom increasing studies are focused on identifying the machinery of sorting of sRNAs in EVs [25,26], in the plant kingdom this had non been studied until recently; a very recent article has for the outset fourth dimension highlighted how fifty-fifty the small RNAs present in PDEVs are the effect of a selective loading process operated by several RNA-binding proteins. In item, the authors identified in Arabidopsis thaliana EVs Argonaute ane (AGO1) and RNA helicases (RH11 and RH37) that selectively bind sRNAs enriched in EVs but not those not contained in the vesicles [27]. Given the importance of RNAs of PDEVs in modulating cistron expression in mammals, a topic that is discussed in the following paragraphs, the in-depth study of the mechanisms of RNA loading in vesicles will assume considerable relevance in the time to come particularly taking into account their possible therapeutic utilize.
i.2.2. Poly peptide Profile of PDEVs
EVs do not contain a random profile of proteins, merely rather the specific protein composition depends on their origin in terms of secretory pathways and matrices. As discussed above, the origin of PDEVs is still debated and depends on the isolation techniques and the found matrices; even so, some protein families have been identified in PDEVs from different species.
1 of the families widely institute in PDEVs is that of annexins. Annexin A1 and Annexin A2 are crucial in the biogenesis of mammalian EVs and for the formation of the multivesicular bodies [28,29]. In the plant kingdom, these proteins accept been identified in EVs isolated from different matrices such as juice and apoplastic fluid. They are found in PDEVs from the juice of four Citrus species [4,thirty] and in those from the apoplastic fluid of sunflower seeds [2]. In addition, they were found in PDEVs from the apoplastic fluids of Arabidopsis leaves (Arabidopsis thaliana); these EVs are as well enriched in proteins involved in biotic and abiotic stress responses [31].
Mass spectrometry approaches accept also allowed the identification of another family of proteins extensively described in EVs from animal cells, the Heat Shock Proteins (HSPs). HSP60 is found in PDEVs from sunflower, as well as HSP70, which has also been described in PDEVs from several citrus fruits [30] where HSP80 and HSP90 have been too found [4,32]. In a recent study of EVs isolated from tomato plant by size exclusion chromatography techniques, high levels of HSPs were found, together with lipoxygenase and ATPases [33]. Finally, proteins belonging to the Aquaporin family were found in PDEVs from citrus [4,30,34] and grape [iii]. Aquaporins were also reported in vesicles isolated from broccoli [35]; in this study, the authors demonstrated that the presence of these proteins is correlated with the stability of the EV plasma membrane and with the osmotic water permeability. Interestingly, in a recent study on EVs isolated from C. plantagineum and N. tabacum, the authors identified proteins involved in the cell wall remodeling such equally hydrolases, e.yard., 1,3-β-glucosidases, pectinesterases, polygalacturonases, β-galactosidases, and β-xylosidase/α-50-arabinofuranosidase 2-like [36].
1.2.3. Lipid and Metabolic Profile of PDEVs
The lipidomic assay of PDEVs has present raised involvement considering their role in the interaction with mammalian cells, too as many of the functional effects of these vesicles, can be attributed to this component. The major lipid species constitute in PDEVs are phosphatidic acid (PA), phosphatidylethanolamine (PE), and phosphatidylcholine (PC). Phospatidic acid was described in the vesicular fraction of sunflower apoplastic fluid [2]; information technology is enriched in grape-EVs compared to the whole juice [3] and in ginger-derived EVs [12]. In item, in the last report, the presence of PA was correlated to internalization of ginger EVs past specific intestinal leaner, Lactobacillus rhamnosus, while the presence of PC to the uptake by intestinal Ruminococcaceae [12].
Phospatidic acrid was recently reported in nanovesicles from Uvae-ursi folium, Craterostigma plantagineum, and Zingiberis rhizoma [36]. Phosphatidylcholine was described in grapefruit [32], together with PE that was also constitute in grape-EVs [3], and in nanovesicles from C. plantagineum [36]. In this last study, PE was detected in EVs from C. plantagineum and Zingiberis rhizoma [36].
Recently, accurate lipidomic analysis of Arabidopsis rosette leaf EVs and the whole leafage tissues immune the identification of 23 classes and 279 species of lipids in EVs. Interestingly, the EV-lipid profile showed enrichment in sphingolipids (effectually 46%) in particular of glycosylinositolphosphoceramides compared to the leaf tissue [37].
In improver to lipid species, increasing studies also include a metabolomic analysis of PDEVs that, in addition to the other EV-enclosed biomolecules, may explain their benign backdrop. In PDEVs from ginger, the phytochemical shogaol was identified [13], while broccoli-derived EVs contain sulforaphane, a chemical compound of the isothiocyanate group [38]. In a written report from 2014, the flavonoid naringenin was found in grapefruit-EV [32]. More recently, another grouping working on grapefruit-derived EVs performed an untargeted GC-MS assay to identify the metabolites of iii different matrices: juice, microvesicles, and nanovesicles. The results from this assay show that the samples differ in terms of composition; in particular, the juice is enriched in fructose, citric acid, glucose, sucrose, and myo-inositol. Sugars and their derivates were also found in microvesicles, together with quinic and oxalic acid, while the nanovesicles are enriched in organic acids, such as glycolic and citric acids, and amino acids [39]. Ascorbic acid was found in strawberry-derived EVs (416 nmoles/mg EVs) [8].
The schematic representation of the content of establish-derived EVs is shown in Figure 1.
Schematic representation of PDEVs content. Upper corner: Small-scale RNAs contained in PDEVs, which include miRNAs and tiny RNAs. Right corner: Proteins carried in PDEVs, including annexins, RNA-BPs, HSPs, ATPases, lipoxygenases, and aquaporins. Lower corner: Metabolites present in PDEVs, such as shogaol, sulforaphane, naringenin, organic acids, and amino acids. Left corner: Lipids plant in PDEVs include PA, PE, PC, and sphingolipids. Abbreviations: miRNAs, microRNAs; HSPs, rut stupor proteins; RNA-BPs, RNA binding proteins; PA, phosphatidic acid; PE, phosphatidylethanolamine; PC, phosphatidylcholine.
two. Biological Properties of PDEVs
Since their preliminary clarification in the 1960s [one], institute-derived extracellular vesicles (PDEVs) have aroused increasing involvement in the field of scientific research. As described in the previous paragraph, different studies highlighted that PDEVs contain functional biomolecules such every bit proteins, lipids, RNAs, and metabolites, which can mediate prison cell–jail cell advice. The physiological role of PDEVs appears to exist related mainly to establish immune response [21,31,36] and plant–microbe symbiosis [xl,41]. Nevertheless, PDEVs take been shown to interact with mammalian cells, showing remarkable biological properties responsible for a cross-kingdom interaction. In this section, nosotros discuss the studies on anti-tumor, anti-inflammatory, and immune-modulatory activities of PDEVs.
2.1. Anti-Tumor Properties
Several studies have emphasized the anti-cancer properties of EVs derived from dissimilar plants, thus enabling them to become potential therapeutic compounds in combination with current treatments in cancer management [4,5,14,17,xviii,19,39].
In 2015, Raimondo et al. isolated EVs from Citrus limon juice, with a size of l–70 nm, which were able to inhibit jail cell proliferation of three tumor cell lines: A549 (human being lung carcinoma), LAMA84 (human chronic myeloid leukemia), and SW480 (man colorectal adenocarcinoma). The arrest in cell proliferation was selective for tumor cells because the same treatment did not affect normal jail cell growth, and it was mediated past TRAIL (TNF-related apoptosis-inducing ligand) [4]. Further studies from the same grouping demonstrated that proteins belonging to the lipid metabolism pathway were differentially modulated past lemon EV treatment in colon colorectal adenocarcinoma jail cell line; amid those, Acetyl-CoA carboxylase 1 and phospholipase DDHD1 were downregulated [42]. In line with this evidence, a recent written report by the same research grouping showed that the in vivo administration of a food supplement containing lemon EV, isolated at industrial scale, reduces LDL cholesterol in good for you volunteers [21].
Similarly, some other group demonstrated that lemon-derived extracellular vesicles (LDEVs) can be internalized by man gastric cancer prison cell lines both in second cultures of AGD and BGC-823 cells and in a 3D culture of SGC-7901 spheroids. They found that LDEVs- treatment induced GADD45A expression in gastric cancer cells. GADD45A is a poly peptide involved in cell cycle control and DNA repair, and it is considered a tumor suppressor [43]. The treatment of gastric cancer cells with LDEVs suppressed jail cell growth and induced apoptosis by upregulating GADD45A gene and protein expression and inducing reactive oxygen species (ROS) production [xviii]. Interestingly, both EVs isolated from Citrus limon juice and LDEVs had in vivo anti-tumor activities [four,18]. Moreover, a recently published study analyzed the anti-cancer properties of micro- and nanovesicles (MVs and NVs) derived from four Citrus species: C. sinensis, C. limon, C. paradisi, and C. aurantium. Both MVs and NVs isolated from all Citrus fruits negatively influenced cell growth of A375 (human melanoma), A549, and MCF-7 (homo breast carcinoma) but not of HaCat (human being keratinocytes) cells [39]. In particular, MVs and NVs from C. paradisi were able to arrest the cell bicycle of melanoma cells at the G2/M stage by enhancing the gene expression of p21, a cell cycle inhibitor, and reducing Ciclyn B1 and Ciclyn B2 levels, which regulate G2/Thousand transition [44]; in addition, these EVs promoted apoptosis through activation of PARP-ane [39]. Information technology was found that plant EVs can exert their anti-cancer activity acting on cells that take part in the tumor microenvironment. For instance, EVs derived from Panax ginseng (called GDNPs) could induce M1-like polarization in macrophages through the activation of Cost-similar receptor (TLR)-4/myeloid differentiation antigen 88 (MyD88) signaling pathway. This polarization was accompanied by an increment in the production of ROS and the conditioned media of GDNPs-treated macrophages were able to induce apoptosis in B16F10 cells (mouse melanoma), by increasing caspase three/7 protein expression [five]. Co-ordinate to this prove, EVs derived from Dendropanax morbifera, both from leaves and stems, inhibited melanogenesis by reducing the expression of TYR, TRP-ane, and TRP-2 in B16BL6 cells (mouse melanoma). These effects were mediated past the suppression of MITF (melanogenesis-associated transcription factor) expression through the UV-dependent α-MSHMC1R pathway in melanoma cells; EVs from leaves were stronger in the TYR inhibition than EVs derived from stems [14]. Another inquiry group has isolated EVs from Dendropanax morbifera (DM), Pinus densiflora (PD), Thuja occidentalis (TO), and Chamaecyparis obtusa (CO) saps to examination their cytotoxicity on human being cancer and normal cells. They establish that DM-EVs had cytotoxic effects on breast and skin cancer cells (MDA-MB-231, MCF7, and A431) just not on normal MCF10A (breast cells) and HNF (skin cells) prison cell lines. PDEVs, instead, decreased prison cell viability of MCF7 and especially A431 cells; TO-EVs and CO-EVs did not show cytotoxic effects on any cell line. The author demonstrated that the co-handling with DM-EVs and PDEVs had a synergic effect confronting tumor prison cell growth and improved apoptosis, but the mechanisms underlying these results remain unexplained [17]. The same group developed a 3D microfluidic cancer metastasis model to deepen the role of DM-EVs on cancer-associated fibroblasts (CAFs). This model employed a 3D microfluidic device supported by the collagen gel in which human being umbilical vein endothelial cells (HUVECs) were seeded as a monolayer; HUVECs were differentiated into CAFs through the treatment with melanoma-derived exosomes, reproducing the tumor microenvironment [45]. DM-EVs acquired a decrease in the survival charge per unit of CAFs both when administered with repeated handling and with pre-and co-handling. Moreover, DM-EVs-treated CAFs showed a gene expression panel dissimilar from that of untreated cells. Amid the genes with different expressions, there were cell migration related-genes (TFG-β2, PDGFC, ILK, and AK) and extracellular matrix (ECM)-related genes (CD44, PLAU, COL3A1, COL4A6, ITGA11, and ITGA6) [46]. Recently, Potestà et al. studied the properties of microvesicles (MVs) isolated from Moringa oleifera seed aqueous extract (MOES) [19]; in previous work, the same authors demonstrated that MOES contains miRNAs which could be responsible for its anti-proliferative and pro-apoptotic effects on cancer cells, and not on healthy cells [sixteen]. In the recent report [19], researchers treated Jurkat and HeLa cells (respectively, human acute T prison cell leukemia and cervical adenocarcinoma cells) with MOES MVs for 72 h and observed cytotoxic and pro-apoptotic effects in both tumor prison cell lines, fifty-fifty if HeLa were more resistant than Jurkat cells. In improver, the same treatment did non touch on the prison cell growth of PBMCs isolated from healthy donors, therefore, the MOES MVs could selectively touch on tumor jail cell proliferation and apoptosis. The pro-apoptotic property of MOES MVs could be attributed to their miRNA content since when the authors treat tumor cells with the mol-sR pool, they observed a comparable result to that of MVs [nineteen].
two.2. Anti-Inflammatory Properties
Growing evidence has demonstrated that constitute-derived EVs can as well take anti-inflammatory properties [three,6,9,10,38,47,48]. Inflammation can exist the leading cause of many diseases including ulcerative colitis, obesity, diabetes, heart diseases, cancer, and non-alcoholic fatty liver diseases (NAFLD). Because the side effects of existing anti-inflammatory therapies, the development of new drugs from natural sources is gaining interest among the scientific community [49].
Unlike groups found that grape exosomes-like nanoparticles (GELNs) accept a protective consequence against dextran sulfate sodium (DSS)-induced colitis [three,10]. Ju et al. demonstrated that subsequently gavage administration, GELNs were accumulated in the intestinal stem cells (Lgr5-EGFP+) of Lgr5-EGFP-IRESCreERT2 mice, enhanced the proliferation of the intestinal epithelium cells, and increased the number of intestinal stalk cells by upregulating Sox2, Nanog, OCT4, KLF4, c-Myc, and EGFR factor expression. These results encouraged the authors to investigate the effects of GELNs in mice with DSS-induced colitis. GELNs decreased mortality and contrasted the reduction of the intestine length in DSS treated mice by inducing the gene expression of Lgr5 and BMI1, two markers of intestinal stem cells [fifty], and the nuclear translocation and activation of β-catenin in abdominal crypt cells [3].
In line with these findings, another group analyzed the biological function of different edible plant-derived exosomes-like nanoparticles (EPDENs) and plant that when murine macrophages (RAW264.seven) were treated with EPDENs isolated from ginger, the gene and protein expression of heme oxygenase 1 (HO-1) and interleukin 10 (IL-10) was upregulated; carrot EPDENs, instead, upregulated only IL-x levels [47]. HO-i and IL-10 expression in macrophages is essential to prevent colitis since they have an anti-inflammatory function [51,52,53,54]. The upregulation of HO-1 and IL-10 was explained by the nuclear translocation of NRF2 in RAW264.seven treated with ginger EPDENs; it is known that NRF2 can stimulate HO-1 and IL-ten activation [55]. This, accompanied past the power of these nanoparticles to achieve intestinal macrophages when orally administrated to mice, makes them possible candidates for colitis treatment [47]. Moreover, amidst ginger-derived nanoparticles (GDNPs), a subpopulation called GDNPs 2 has been identified; GDNPs two possesses benign properties towards acute colitis and could prevent chronic colitis and colitis-associated cancer (CAC). In item, it was found that GDNPs ii handling could reduce lipocalin-ii (Lcn-2) fecal levels in mice with DSS-induced colitis, suggesting an anti-inflammatory role of these nanoparticles; Lcn-two is considered a biomarker for intestinal inflammation [56]. GDNPs two reduced spleen weight and assorted the reduction of colon length decreasing pro-inflammatory cytokines, such equally tumor necrosis factor-α (TNF-α), interleukin six (IL-6), and interleukin one-β (IL-1β), and increasing anti-inflammatory cytokines, e.g., interleukin 10 (IL-x) and interleukin 22 (IL-22). Similar results were obtained in IL10 knockout (IL10−/−) mice, using a chronic colitis model, in which GDNPs 2 were able to prevent splenic enlargement and colon length reduction, by downregulating TNF-α and IL-1β cistron expression. Finally, the administration of GDNPs 2 to AOM/DSS mice treated with the carcinogen Azoxymethane and DSS (AOM/DSS group), which recapitulate CAC, decreased Lcn-2 levels, the number of tumors per mouse, and IL-6 and IL-1β expression compared with the AOM/DSS grouping [48].
Another source of EVs which has been demonstrated to take protective properties confronting colitis in mice is broccoli [38]. Broccoli-derived nanovesicles (BDNs) were able to contrast the increase of pro-inflammatory cytokines, such as TNF-α, IL-17A, and IFN-γ, in colonic tissues of two colitis models (DSS-induced and T cell transfer model of colitis). Among the targets of BDNs, in that location were dendritic cells (DCs), whose number was reduced in BDN-treated mice compared with the control group. DCs treated with BDNs presented a tolerogenic signature, since they had higher expression levels of TGF-β, interleukin 10 (IL-10), and Aldh1a2; moreover, BDNs inhibited the recruitment of monocytes into the inflamed colon by decreasing chemotactic chemokines (CCL2, CXCL1, and CCL20). In vitro experiments showed that the treatment of BMDCs with lipids, especially sulforaphane (SFN), derived from BDNs induced a tolerogenic phenotype past activating AMPK [38].
Cheng et al. investigated the furnishings of several plants (cilantro, aloe vera, grapefruit, garlic, turmeric, dandelion, lavender, cactus, and ginger) derived EVs on NLRP3 inflammasome activation, a biological process involved in the initiation and progression of autoinflammatory, neurodegenerative, and metabolic diseases. Only ELNs isolated from ginger showed, in unlike murine macrophage cells, the ability to prevent NLRP3 inflammasome activation by inhibiting IL-1β and interleukin 18 (IL-xviii) release and Casp1 p10 protein expression levels, markers of this biological procedure [57]. As well, ginger-derived ELNs suppressed the oligomerization of the apoptotic speck poly peptide containing a caspase recruitment domain; PDEV activeness seems to be attributed to their lipid content [9]. Recent evidence shows that blueberries-derived ELNs (B-ELNs) likewise have anti-inflammatory properties on human being endothelial cells (EA.hy926) [6]. Pre-treatment of EA.hy926 cells with B-ELNs was able to revert TNFα-induced jail cell death besides equally ROS production. It was found that B-ELNs downregulated the gene expression of IL-half dozen, interleukin 1 receptor-like 1 (IL1RL1), mitogen-activated protein kinase one (MAPK1), intercellular adhesion molecule i (ICAM1), price-like receptor 8 (TLR8), and TNF and upregulated the factor expression of heme oxygenase 1 (HMOX1) and nuclear respiratory cistron ane (NRF1). These anti-inflammatory and antioxidant effects could be attributed to their miRNA content, since B-ELNs contain miR-156e, miR-162, and miR-319d, which potentially target PTGIS, MAPK14, and PDE7A genes [6]. It was recently found that strawberry-derived EPDENs accept antioxidant properties likewise. Adipose-derived mesenchymal stem cells (ADMSCs) pre-treated with strawberry EPDENs and then stimulated with H2O2 showed reduced cell death and lower ROS levels than cells treated with HiiO2 alone, probably because EPDENs contain vitamin C [8].
Ginger ELNs besides possess biological effects on hepatocytes, every bit it was seen that they can prevent alcohol-induced injury. These vesicles were internalized by primary murine hepatocytes and led to nuclear translocation of Nrf2 through TLR4/TRIF pathway. Furthermore, upregulation of antioxidant and detoxifying genes, such every bit HO-1, NQO1, GCLM, and GCLC, was observed in the liver of ginger ELNs-treated mice accompanied by protection from booze-induced damage, as the vesicles reduced ROS, liver triglycerides, and liver weight compared to alcohol-simply mice [13]. Recently, was plant that orange juice-derived nanovesicles (ONVs) could meliorate obesity [7]. The handling with ONVs of a co-culture of CACO and HT29 cells used as a model of in vivo intestinal barrier (IBs), decreased triglycerides and promoted their release in clan with chylomicrons. These in vitro data were confirmed by in vivo experiments in which HFHSD (loftier-fatty, loftier-sucrose diet) mice were treated with ONVs. The vesicles accumulated primarily in the jejunum of mice and induced an increment in villus size. ONVs gavage decreased triglyceride levels in the jejunum, chylomicron release, and gene expression of ANGPTL4, a novel therapeutic target of colonic inflammation.
Lastly, a work published in 2018 showed that establish EVs may too play a office in peel regeneration in vitro. It was found that nanovesicles isolated from Triticum aestivum (wheat) increased cell proliferation and migration of 3 cell lines: human dermal fibroblasts (HDFs), HUVECs, and HaCaT. In addition, wheat nanovesicles showed pro-angiogenic furnishings, as they promoted tube germination in HUVECs and increased COL1A gene and protein expression in HDFs [15].
two.iii. PDEVs Modulate Mammalian Microbiota
The microbiota is the set up of symbiotic microorganisms that coexist with the human organism without damaging it; the nutrition tin modulate its composition while its alterations tin lead to the onset of diseases [58]. Some recent bear witness shows how PDEVs can interact with the microbiota and the result of this cross-talk may offer new opportunities for their use as potential therapeutic agents [xi,12,59]. Ginger-derived ELNs administration in mice led to a modification of gut microbiota, leading to the increase of Lactobacillaceae and Bacteroidales S24-seven and the decrease in Clostridiaceae with respect to the control group. Ginger ELNs were preferentially internalized past Lactobacillus rhamnosus (LGG) due to their phosphatidic acid (PA) lipids and promoted their growth by repressing LexA factor and poly peptide expression. The small RNAs contained in ginger ELNs had protective effects against DSS-induced colitis by reducing the levels of pro-inflammatory cytokines, such as IL-1β and TNF-α, and by promoting the expression of interleukin 22 (IL-22) through I3A, which activates the aryl hydrocarbon receptor pathway [12]. The physiological part of ELNs is to defend plants from infection; however, in 2019, Sundaram et al. showed that ELNs tin besides protect mammalian cells against pathogens. Specifically, they demonstrated that ginger-derived ELNs were selectively internalized past Porphyromonas gingivalis and inhibited its growth. Ginger ELNs increased membrane depolarization, a key gene in the regulation of viability and indicate transduction pathway in bacteria, through their lipids, specially PA (34:two). The 34:ii PA was able to collaborate with a membrane protein of Porphyromonas gingivalis, hemin-binding protein 35 (HBP35), which is essential for the growth and survival of this bacterium [sixty]. Lipids and miRNAs from ginger ELNs besides inhibited the expression of Porphyromonas gingivalis virulence-related genes, such as AraC, HagA, and OmpA, as well as bacterial attachment and invasion of gingival epithelial cells (TIGKs). These results were confirmed past in vivo experiments showing that administration of the ginger ELNs reduced P. gingivalis colonization in the oral cavity of mice and bone loss [11]. The aforementioned group investigated the furnishings of lemon ELNs in Clostridioides difficile (C. difficile) infection. The authors treated C unequal-infected mice with a probiotic mixture containing Lactobacillus rhamnosus GG (LGG) and Streptococcus thermophilus ST-21 (STH) (LS) pre-treated with LELNs (LELN-LS) and observed that colonic length was similar to that of uninfected mice and that bloodshed was reduced compared with LS treatment alone. Metabolomic analysis and HPLC showed that I3Ad and I3LA, two ligands of the AhR, were increased in the grouping that received LELN-LSs compared with the PBS and LS groups. Treatment with LELN-LS decreased the colony-forming unit of C difficile in the feces of mice compared with the PBS control group since the treatment induced an increase in intestinal lactic acid, which leads to a decrease in indole production by inhibiting the gene expression of tryptophanase tnaA, responsible for indole synthesis [59].
The main findings discussed in this section are summarized in Figure 2.
The biological properties of plant-derived EVs. PDEVs have shown anti-cancer activities both in vitro and in vivo (top left): they tin deed straight on tumor cells simply too on those of the tumor microenvironment, thus promoting M2 macrophage polarization into M1 macrophages and inhibiting cancer-associated fibroblasts (CAFs). PDEVs take inflammatory activities (lesser left) since they upregulate anti-inflammatory cytokines, such as IL-10 and IL-22, and downregulate pro-inflammatory cytokines, TNFα, IL-6, IL-1β, IL-17A, and IFN-γ. They tin alleviate colitis in vivo and induce NRF2 nuclear translocation in murine macrophages, leading to IL-x and HO-one expression. PDEVs participate in skin regeneration (bottom right) by promoting the proliferation and the tube formation of endothelial cells. They tin can heighten fibroblasts proliferation and upregulate COL1A1 expression. Finally, PDEVs interact also with mammalian microbiota (top correct) inducing the growth of Lactobacillus rhamnosus (L. rhamnosus) and inhibiting that one of Porphyromonas gingivalis (P. gingivalis). Moreover, L. rhamnosus and Streptococcus thermophilus (Southward. thermophilus) pre-treated with PDEVs can counteract Clostridioides difficile (C. unequal) infection.
iii. PDEVs equally Drug Delivery Vehicles
The research and evolution of new drugs is a primary need in the globe since, for many diseases, an constructive cure has not yet been found. The principal problems with conventional drug therapies are: (i) poor selectivity; and (2) difficulty in crossing biological barriers. Chemotherapy, for example, is still the chief therapy confronting cancer; however, its poor selectivity causes several side effects. On the other paw, the claret–brain barrier (BBB), which separates the blood from the extracellular fluid of the central nervous system (CNS), hinders drug delivery from the blood to the brain tissue. In recent years, new drug delivery systems are being explored to overcome these challenges. Extracellular vesicles possess several characteristics that make them suitable as drug delivery systems, such as the ability to cross biological barriers, the stability in the circulatory organization, and prophylactic; indeed, several studies investigated the possibility to employ them as new drug nanocarriers [61,62]. However, some limitations to the employ of EVs as drug commitment vehicles however exist equally the development of a scalable and reproducible EV isolation method and the immune response that its administration may trigger.
PDEVs represent a promising model for drug commitment, every bit they are natural products that possess several advantageous backdrop including safe, non-toxicity, low immunogenicity. Moreover, PDEVs can be produced on big calibration and several studies accept demonstrated that they are stable and resistant in the stomach- and abdominal-similar solutions [ten,13,32,48]; they accept been institute, after oral gavage, in abdominal stem cells, liver, colon, and dendritic cells as well as in the intestinal macrophages of mice [three,10,xiii,32,38,48]. Therefore, in recent years, some studies have focused on the employment of PDEVs or their derived lipids as drug delivery vehicles.
Particularly, in 2013, Wang et al. developed nanovectors using lipids derived from grapefruit EVs and named them grapefruit-derived nanovectors (GNVs) [63]. GNVs were successfully internalized past different cell types, including GL26 (mouse glioma cells), A549 (human lung carcinoma cells), SW620 (human colon carcinoma cells), CT26 (mouse colon carcinoma cells), and 4T1 (mouse breast tumor cells), without inducing cytotoxicity. The authors evaluated the bio-distribution of GNVs following three dissimilar routes of administration and observed that after tail-vein or intraperitoneal injections the GNVs were located in the liver, lung, kidney, and splenic tissue, while GNVs were found in the lung and brain afterwards intramuscular and intranasal administration. They take also shown that GNVs tin can carry specific therapeutic agents, such every bit DNA, proteins, and short interfering RNAs (siRNAs), and can be modified to specifically target tumor tissues. As a proof of concept, they demonstrated that GNVs carrying Pentoxifylline (PTX), an anti-cancer drug [64], and binding folic acid (FA), which was chosen because many tumors take a high expression of folate receptors [65], were able to target and decrease tumor growth in in vivo model [63].
The same group further demonstrated that ginger EVs conjugated to methotrexate (MTX), an immunosuppressive and anti-inflammatory drug [66], tin contrast DSS-induced colitis in mice. After oral administration, ginger EVs conjugated with MTX (GMTX) preferentially localized in macrophages of lamina propria and reduced trunk weight, colon length shortening, and colon tissue damages in treated mice with respect to the command groups (MTX alone and PBS groups). GMTX decreased cistron and protein expression of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, in intestinal macrophages and showed fewer undesirable furnishings than MTX alone [32]. They also developed a novel siRNA transport arrangement using nanocarriers fabricated of lipids derived from ginger EVs, called GDLVs. In one case they isolated lipids from ginger ELNs, they reassembled them into nanoparticles using a standard method based on the hydration of a lipid film. GDLVs did not induce cytotoxicity in either RAWs or CT26 cells and were safe in vivo following oral administration. The authors encapsulated siRNA-CD98 in GDLVs and demonstrated that this siRNA carried by nanoparticles inhibited CD98 expression both in vitro, in RAWs and CT26 cells, and in vivo, in the ileum and colon of mice compared to the control group [67]. Furthermore, in 2015 they generated GNVs coated with inflammatory chemokine receptor enriched membrane fraction of activated T cells, called IGNVs. IGNVs had a greater ability to drift through a monolayer of HUVECs than GNVs and to home in sites of inflammation in several in vivo inflammatory models (LPS induced skin inflammation, DSS induced colitis model, CT26 colon cancer, and 4T1 breast cancer models). Next, the authors loaded IGNVs with doxorubicin (IGNVs-DOX), a drug widely used in cancer handling [68], and observed that intravenous injection of IGNVs-DOX into tumor-bearing mice acquired college DOX accumulation in the tumors and lower in the liver than DOX-NPTM and GNVs-DOX. In add-on, handling with IGNVs-DOX inhibited tumor growth and increased survival of the mice compared with the control groups. Similarly, the injection of IGNVs loaded with curcumin (IGNVs-Cur), a known anti-inflammatory agent [68], increased the survival charge per unit of mice with DSS-induced colitis and decreased TNF-α, IL-6, and IL-1β levels in colonic tissue compared with gratis Cur and GNVs-Cur [69]. The intranasal administration of GNVs, on the other hand, was shown to be useful for brain delivery [70]. The authors demonstrated that GNVs coated with FA, carrying miR17 (FA-GNV/miR17), successfully transported miR17 to brain tumor of mice and had therapeutic effects since FA-GNV/miR17 prolonged survival of tumor-bearing mice compared with command groups (FA-GNV/miRNA scramble and PBS). FA-GNV/miR17 also increased the number of DX5+NK cells in the encephalon tumor, probably because miR17 inhibited MHCI expression in cancer cells, which promoted NK jail cell activation [lxx].
Another group has investigated the drug delivery potential of GNVs, using these vesicles as nanovectors to transport miR-18a, a tumor suppressor microRNA [71], to contrast liver metastasis. GNVs loaded with miR-18a (GNV-miR-18a) were injected in the tail vein of metastatic colon tumor-bearing mice and were internalized by Kupffer cells (KCs); GNV-miR-18a inhibited liver metastasis by inducing M1 macrophages and inhibiting M2 in mice liver. These effects were mediated by the IFNγ/IRF2 centrality, which activated interleukin 12 (IL-12); this cytokine was responsible for the induction of natural killer (NK) and natural killer T (NKT) cells that inhibited colon cancer liver metastasis [72]. Finally, ginger-derived exosomes such as nanovesicles (GDENs) coated with FA demonstrated to be able to target and deliver survivin siRNA to tumor sites in vivo. Survivin siRNA was chosen considering its gene silencing is constructive in the inhibition of tumor growth and metastasis [73]. FA-GDENs carrying survivin siRNA displayed practiced biocompatibility; they did non alter cell viability of somatic prison cell (HEK293), Raw 264.7, and cancer cell (KB); and following retro-orbital IV injection they inhibited tumor growth past reducing survivin expression in tumor tissue compared to the scramble group and GDENs without FA [74].
The main findings discussed in this section are summarized in Effigy 3.
Found-derived EVs and nanovectors made with their lipids stand for promising drug delivery systems. PDEVs can exist loaded with both drugs and oligonucleotides (summit): PDEVs conveying methotrexate (MTX) counteract ulcerative colitis in vivo; PDEVs conveying miR18 reduce liver metastasis in vivo; PDEVs conjugated with folic acid (FA), and loaded with survivin siRNA, inhibit tumor growth. Nanovectors derived from PDEVs lipids have also been shown to be useful equally drug delivery vehicles (bottom): they inhibit tumor growth when they carry Pentoxifylline (PTX) or miR17 and are conjugated to FA, as well as when they behave doxorubicin (DOX) and are conjugated with inflammatory chemokine receptor enriched membrane fraction (plasma membranes). Moreover, they are besides able to annul ulcerative colitis when they deliver CD98 siRNA or curcumin (Cur) and are conjugated with plasma membranes.
4. Conclusions, Open Questions, and Challenges
In the terminal 2 decades, meaning growth of studies on extracellular vesicles was observed; it is only in the terminal years that this increase has regarded PDEVs. The rising testify on their properties, related to their complex content, together with the possibility to utilise PDEVs every bit delivery systems of other therapeutic substances, makes the report of these structures very attractive. Moreover, their natural origin, as well as the possibility of isolating PDEVs from large volumes, represent major advantages for their employ in nutraceuticals. Although the industrial application of PDEVs seems to be easier and more than rapid than the use of those from the fauna kingdom, many efforts notwithstanding have to be fabricated. Similar to the need to create guidelines for those working with mammalian EVs [75], the aforementioned requirement arises for PDEVs; several points remain to be explained. Among these, ane of the questions to be clarified is their origin, especially apropos those isolated from the juice. Indeed, while some studies of vesicles isolated from apoplastic fluid, such as those from sunflower seeds [2,76], have investigated their extracellular nature, no data to appointment is available most the origin of those isolated from plant matrices later on squeezing.
The isolation methods, which are non compatible to date, may contribute to the heterogeneity of PDEVs, fifty-fifty when they are isolated from the same constitute matrix. Indeed, although the results of the studies discussed in the previous paragraphs are consistent with conferring similar biological properties to PDVEs, often the application of different isolation protocols, besides as the dimensional characteristics of the isolated vesicles, suggests diverse populations whose content could also differs.
Finally, although omics analyses related to their content are increasing, the absenteeism of specific markers still hampers the label of PDEVs.
Considering the industrial awarding of PDEVs, clinical studies should be carried out to validate their safe, stability, and efficacy in vivo. This will afterward crave an in-depth analysis of the regulatory framework; in fact, how does the use of PDEVs as nutraceuticals fit into the regulatory context? Since PDEVs are structures containing different plant compounds already described as botanicals, tin we allocate them as nutrient supplements or should we refer to them equally novel nutrient?
Answering all of these points certainly requires the effort of researchers in the field, only the resulting findings would support the rapid application of PDEVs in daily use.
Acknowledgments
Stefania Raimondo is supported past PON "Ricerca due east Innovazione" 2014–2020—Azione ane.two "Mobilità dei Ricercatori", AIM "Attraction and International Mobility". Ornella Urzì is a PhD Educatee in "Biomedicina, Neuroscienze e Diagnostica Avanzata", XXXV ciclo, University of Palermo.
Author Contributions
Conceptualization, Due south.R. and R.A.; writing—original draft preparation, O.U and S.R.; and writing—review and editing, S.R. and R.A. All authors have read and agreed to the published version of the manuscript.
Funding
This enquiry received no external funding.
Institutional Review Lath Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Argument
Non applicable.
Conflicts of Interest
The authors declare no conflict of involvement.
Footnotes
Publisher's Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
1. Halperin W., Jensen Westward.A. Ultrastructural changes during growth and embryogenesis in carrot prison cell cultures. J. Ultrastruct. Res. 1967;18:428–443. doi: x.1016/S0022-5320(67)80128-X. [PubMed] [CrossRef] [Google Scholar]
2. Regente M., Corti-Monzon G., Maldonado A.K., Pinedo 1000., Jorrin J., de la Culvert 50. Vesicular fractions of sunflower apoplastic fluids are associated with potential exosome marker proteins. FEBS Lett. 2009;583:3363–3366. doi: 10.1016/j.febslet.2009.09.041. [PubMed] [CrossRef] [Google Scholar]
3. Ju S., Mu J., Dokland T., Zhuang X., Wang Q., Jiang H., Xiang Ten., Deng Z.B., Wang B., Zhang L., et al. Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis. Mol. Ther. 2013;21:1345–1357. doi: 10.1038/mt.2013.64. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
four. Raimondo South., Naselli F., Fontana S., Monteleone F., Lo Dico A., Saieva 50., Zito Thousand., Flugy A., Manno M., Di Bella Thou.A., et al. Citrus limon-derived nanovesicles inhibit cancer cell proliferation and suppress CML xenograft growth past inducing TRAIL-mediated cell death. Oncotarget. 2015;vi:19514–19527. doi: x.18632/oncotarget.4004. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
5. Cao M., Yan H., Han Ten., Weng 50., Wei Q., Sun 10., Lu W., Ye J., Cai X., Hu C., et al. Ginseng-derived nanoparticles modify macrophage polarization to inhibit melanoma growth. J. Immunother. Cancer. 2019;seven:326. doi: 10.1186/s40425-019-0817-4. [PMC gratis commodity] [PubMed] [CrossRef] [Google Scholar]
vi. De Robertis Chiliad., Sarra A., D'Oria V., Mura F., Bordi F., Postorino P., Fratantonio D. Blueberry-Derived Exosome-Similar Nanoparticles Counter the Response to TNF-alpha-Induced Alter on Gene Expression in EA.hy926 Cells. Biomolecules. 2020;x:742. doi: 10.3390/biom10050742. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
7. Berger E., Colosetti P., Jalabert A., Meugnier East., Wiklander O.P.B., Jouhet J., Errazurig-Cerda E., Chanon Due south., Gupta D., Rautureau 1000.J.P., et al. Use of Nanovesicles from Orangish Juice to Reverse Diet-Induced Gut Modifications in Diet-Induced Obese Mice. Mol. Ther. Methods Clin. Dev. 2020;18:880–892. doi: ten.1016/j.omtm.2020.08.009. [PMC gratis article] [PubMed] [CrossRef] [Google Scholar]
viii. Perut F., Roncuzzi L., Avnet S., Massa A., Zini N., Sabbadini S., Giampieri F., Mezzetti B., Baldini N. Strawberry-Derived Exosome-Like Nanoparticles Prevent Oxidative Stress in Human Mesenchymal Stromal Cells. Biomolecules. 2021;11:87. doi: 10.3390/biom11010087. [PMC gratuitous article] [PubMed] [CrossRef] [Google Scholar]
9. Chen X., Zhou Y., Yu J. Exosome-similar Nanoparticles from Ginger Rhizomes Inhibited NLRP3 Inflammasome Activation. Mol. Pharm. 2019;sixteen:2690–2699. doi: 10.1021/acs.molpharmaceut.9b00246. [PubMed] [CrossRef] [Google Scholar]
10. Rahimi Ghiasi Grand., Rahimi Due east., Amirkhani Z., Salehi R. Leucine-rich Repeat-containing G-protein Coupled Receptor 5 Cistron Overexpression of the Rat Small Abdominal Progenitor Cells in Response to Orally Administered Grape Exosome-like Nanovesicles. Adv. Biomed. Res. 2018;seven:125. doi: 10.4103/abr.abr_114_18. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
eleven. Sundaram K., Miller D.P., Kumar A., Teng Y., Sayed Yard., Mu J., Lei C., Sriwastva G.K., Zhang L., Yan J., et al. Plant-Derived Exosomal Nanoparticles Inhibit Pathogenicity of Porphyromonas gingivalis. iScience. 2019;21:308–327. doi: x.1016/j.isci.2019.10.032. [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]
12. Teng Y., Ren Y., Sayed M., Hu X., Lei C., Kumar A., Hutchins E., Mu J., Deng Z., Luo C., et al. Constitute-Derived Exosomal MicroRNAs Shape the Gut Microbiota. Prison cell Host Microbe. 2018;24:637–652.e638. doi: 10.1016/j.chom.2018.10.001. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
thirteen. Zhuang X., Deng Z.B., Mu J., Zhang L., Yan J., Miller D., Feng West., McClain C.J., Zhang H.G. Ginger-derived nanoparticles protect against alcohol-induced liver damage. J. Extracell Vesicles. 2015;four:28713. doi: 10.3402/jev.v4.28713. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
fourteen. Lee R., Ko H.J., Kim G., Sohn Y., Min South.Y., Kim J.A., Na D., Yeon J.H. Anti-melanogenic effects of extracellular vesicles derived from plant leaves and stems in mouse melanoma cells and human healthy skin. J. Extracell. Vesicles. 2020;nine:1703480. doi: 10.1080/20013078.2019.1703480. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
15. Sahin F., Kocak P., Gunes One thousand.Y., Ozkan I., Yildirim Due east., Kala E.Y. In Vitro Wound Healing Action of Wheat-Derived Nanovesicles. Appl. Biochem. Biotechnol. 2019;188:381–394. doi: ten.1007/s12010-018-2913-1. [PubMed] [CrossRef] [Google Scholar]
xvi. Potesta M., Minutolo A., Gismondi A., Canuti 50., Kenzo M., Roglia V., Macchi F., Grelli Due south., Canini A., Colizzi V., et al. Cytotoxic and apoptotic furnishings of unlike extracts of Moringa oleifera Lam on lymphoid and monocytoid cells. Exp. Ther. Med. 2019;18:v–17. doi: 10.3892/etm.2019.7544. [PMC gratuitous article] [PubMed] [CrossRef] [Google Scholar]
17. Kim K., Yoo H.J., Jung J.H., Lee R., Hyun J.K., Park J.H., Na D., Yeon J.H. Cytotoxic Furnishings of Plant Sap-Derived Extracellular Vesicles on Various Tumor Prison cell Types. J. Funct. Biomater. 2020;11:22. doi: ten.3390/jfb11020022. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
18. Yang M., Liu X., Luo Q., Xu L., Chen F. An efficient method to isolate lemon derived extracellular vesicles for gastric cancer therapy. J. Nanobiotechnol. 2020;xviii:100. doi: ten.1186/s12951-020-00656-9. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
nineteen. Potesta M., Roglia V., Fanelli Yard., Pietrobono Eastward., Gismondi A., Vumbaca S., Nguedia Tsangueu R.Yard., Canini A., Colizzi V., Grelli S., et al. Upshot of microvesicles from Moringa oleifera containing miRNA on proliferation and apoptosis in tumor prison cell lines. Cell Expiry Discov. 2020;6:43. doi: 10.1038/s41420-020-0271-vi. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
20. Rosenbloom R.A., Chaudhary J., Castro-Eschenbach D. Traditional botanical medicine: An introduction. Am. J. Ther. 2011;xviii:158–161. doi: 10.1097/MJT.0b013e31820e80df. [PubMed] [CrossRef] [Google Scholar]
21. Raimondo Due south., Nikolic D., Conigliaro A., Giavaresi G., Lo Sasso B., Giglio R.V., Chianetta R., Manno K., Raccosta Due south., Corleone V., et al. Preliminary Results of CitraVes Effects on Depression Density Lipoprotein Cholesterol and Waist Circumference in Good for you Subjects afterward 12 Weeks: A Pilot Open-Characterization Study. Metabolites. 2021;11:276. doi: 10.3390/metabo11050276. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
22. Xiao J., Feng S., Wang 10., Long K., Luo Y., Wang Y., Ma J., Tang Q., Jin L., Li X., et al. Identification of exosome-like nanoparticle-derived microRNAs from 11 edible fruits and vegetables. PeerJ. 2018;6:e5186. doi: 10.7717/peerj.5186. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
23. Baldrich P., Rutter B.D., Karimi H.Z., Podicheti R., Meyers B.C., Innes R.Due west. Establish Extracellular Vesicles Incorporate Diverse Small RNA Species and Are Enriched in 10- to 17-Nucleotide "Tiny" RNAs. Found Prison cell. 2019;31:315–324. doi: 10.1105/tpc.eighteen.00872. [PMC complimentary article] [PubMed] [CrossRef] [Google Scholar]
24. Kalarikkal South.P., Sundaram One thousand.M. Edible institute-derived exosomal microRNAs: Exploiting a cantankerous-kingdom regulatory machinery for targeting SARS-CoV-two. Toxicol. Appl. Pharmacol. 2021;414:115425. doi: 10.1016/j.taap.2021.115425. [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]
25. Temoche-Diaz M.M., Shurtleff M.J., Nottingham R.Thou., Yao J., Fadadu R.P., Lambowitz A.Thousand., Schekman R. Distinct mechanisms of microRNA sorting into cancer cell-derived extracellular vesicle subtypes. Elife. 2019;8:e47544. doi: x.7554/eLife.47544. [PMC gratuitous article] [PubMed] [CrossRef] [Google Scholar]
26. Santangelo L., Giurato G., Cicchini C., Montaldo C., Mancone C., Tarallo R., Battistelli C., Alonzi T., Weisz A., Tripodi Thou. The RNA-Binding Protein SYNCRIP Is a Component of the Hepatocyte Exosomal Machinery Controlling MicroRNA Sorting. Jail cell Rep. 2016;17:799–808. doi: 10.1016/j.celrep.2016.09.031. [PubMed] [CrossRef] [Google Scholar]
27. He B., Cai Q., Qiao 50., Huang C.Y., Wang South., Miao W., Ha T., Wang Y., Jin H. RNA-binding proteins contribute to small RNA loading in plant extracellular vesicles. Nat. Plants. 2021;seven:342–352. doi: 10.1038/s41477-021-00863-8. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
28. Mayran Due north., Parton R.G., Gruenberg J. Annexin II regulates multivesicular endosome biogenesis in the degradation pathway of brute cells. EMBO J. 2003;22:3242–3253. doi: 10.1093/emboj/cdg321. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
29. White I.J., Bailey L.Thou., Aghakhani M.R., Moss S.E., Futter C.E. EGF stimulates annexin ane-dependent inward vesiculation in a multivesicular endosome subpopulation. EMBO J. 2006;25:1–12. doi: 10.1038/sj.emboj.7600759. [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]
30. Pocsfalvi G., Turiak L., Ambrosone A., Del Gaudio P., Puska G., Fiume I., Silvestre T., Vekey K. Protein biocargo of citrus fruit-derived vesicles reveals heterogeneous send and extracellular vesicle populations. J. Constitute Physiol. 2018;229:111–121. doi: 10.1016/j.jplph.2018.07.006. [PubMed] [CrossRef] [Google Scholar]
31. Rutter B.D., Innes R.Westward. Extracellular Vesicles Isolated from the Leaf Apoplast Carry Stress-Response Proteins. Constitute Physiol. 2017;173:728–741. doi: 10.1104/pp.16.01253. [PMC complimentary commodity] [PubMed] [CrossRef] [Google Scholar]
32. Wang B., Zhuang X., Deng Z.B., Jiang H., Mu J., Wang Q., Xiang X., Guo H., Zhang Fifty., Dryden G., et al. Targeted drug commitment to intestinal macrophages by bioactive nanovesicles released from grapefruit. Mol. Ther. 2014;22:522–534. doi: 10.1038/mt.2013.190. [PMC gratis article] [PubMed] [CrossRef] [Google Scholar]
33. Bokka R., Ramos A.P., Fiume I., Manno M., Raccosta Southward., Turiak L., Sugar Southward., Adamo G., Csizmadia T., Pocsfalvi G. Biomanufacturing of Tomato-Derived Nanovesicles. Foods. 2020;9:1852. doi: ten.3390/foods9121852. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
34. Stanly C., Moubarak M., Fiume I., Turiak L., Pocsfalvi G. Membrane Transporters in Citrus clementina Fruit Juice-Derived Nanovesicles. Int. J. Mol. Sci. 2019;twenty:6205. doi: 10.3390/ijms20246205. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
35. Martinez-Ballesta M.D.C., Garcia-Gomez P., Yepes-Molina L., Guarnizo A.L., Teruel J.A., Carvajal Thousand. Plasma membrane aquaporins mediates vesicle stability in broccoli. PLoS 1. 2018;13:e0192422. doi: 10.1371/journal.pone.0192422. [PMC gratis article] [PubMed] [CrossRef] [Google Scholar]
36. Woith E., Guerriero G., Hausman J.F., Renaut J., Leclercq C.C., Weise C., Legay S., Weng A., Melzig M.F. Constitute Extracellular Vesicles and Nanovesicles: Focus on Secondary Metabolites, Proteins and Lipids with Perspectives on Their Potential and Sources. Int. J. Mol. Sci. 2021;22:3719. doi: 10.3390/ijms22073719. [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]
37. Liu Due north.J., Wang N., Bao J.J., Zhu H.X., Wang L.J., Chen X.Y. Lipidomic Analysis Reveals the Importance of GIPCs in Arabidopsis Leaf Extracellular Vesicles. Mol. Plant. 2020;13:1523–1532. doi: 10.1016/j.molp.2020.07.016. [PubMed] [CrossRef] [Google Scholar]
38. Deng Z., Rong Y., Teng Y., Mu J., Zhuang X., Tseng One thousand., Samykutty A., Zhang Fifty., Yan J., Miller D., et al. Broccoli-Derived Nanoparticle Inhibits Mouse Colitis by Activating Dendritic Cell AMP-Activated Poly peptide Kinase. Mol. Ther. 2017;25:1641–1654. doi: 10.1016/j.ymthe.2017.01.025. [PMC gratuitous article] [PubMed] [CrossRef] [Google Scholar]
39. Stanly C., Alfieri One thousand., Ambrosone A., Leone A., Fiume I., Pocsfalvi G. Grapefruit-Derived Micro and Nanovesicles Prove Distinct Metabolome Profiles and Anticancer Activities in the A375 Human Melanoma Prison cell Line. Cells. 2020;ix:2722. doi: 10.3390/cells9122722. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
40. Ivanov South., Austin J., 2nd, Berg R.H., Harrison 1000.J. All-encompassing membrane systems at the host-arbuscular mycorrhizal mucus interface. Nat. Plants. 2019;v:194–203. doi: 10.1038/s41477-019-0364-5. [PubMed] [CrossRef] [Google Scholar]
41. Roth R., Hillmer S., Funaya C., Chiapello M., Schumacher K., Lo Presti Fifty., Kahmann R., Paszkowski U. Arbuscular jail cell invasion coincides with extracellular vesicles and membrane tubules. Nat. Plants. 2019;5:204–211. doi: 10.1038/s41477-019-0365-4. [PubMed] [CrossRef] [Google Scholar]
42. Raimondo S., Saieva L., Cristaldi M., Monteleone F., Fontana South., Alessandro R. Label-free quantitative proteomic profiling of colon cancer cells identifies acetyl-CoA carboxylase blastoff every bit antitumor target of Citrus limon-derived nanovesicles. J. Proteom. 2018;173:1–11. doi: x.1016/j.jprot.2017.11.017. [PubMed] [CrossRef] [Google Scholar]
43. Tamura R.E., de Vasconcellos J.F., Sarkar D., Libermann T.A., Fisher P.B., Zerbini L.F. GADD45 proteins: Primal players in tumorigenesis. Curr. Mol. Med. 2012;12:634–651. doi: 10.2174/156652412800619978. [PMC costless article] [PubMed] [CrossRef] [Google Scholar]
44. King R.W., Jackson P.G., Kirschner Thou.W. Mitosis in transition. Cell. 1994;79:563–571. doi: x.1016/0092-8674(94)90542-eight. [PubMed] [CrossRef] [Google Scholar]
45. Yeon J.H., Jeong H.East., Seo H., Cho S., Kim G., Na D., Chung S., Park J., Choi N., Kang J.Y. Cancer-derived exosomes trigger endothelial to mesenchymal transition followed by the consecration of cancer-associated fibroblasts. Acta Biomater. 2018;76:146–153. doi: x.1016/j.actbio.2018.07.001. [PubMed] [CrossRef] [Google Scholar]
46. Kim Thousand., Jung J.H., Yoo H.J., Hyun J.M., Park J.H., Na D., Yeon J.H. Anti-Metastatic Furnishings of Institute Sap-Derived Extracellular Vesicles in a 3D Microfluidic Cancer Metastasis Model. J. Funct. Biomater. 2020;eleven:49. doi: 10.3390/jfb11030049. [PMC gratuitous article] [PubMed] [CrossRef] [Google Scholar]
47. Mu J., Zhuang X., Wang Q., Jiang H., Deng Z.B., Wang B., Zhang Fifty., Kakar S., Jun Y., Miller D., et al. Interspecies advice between plant and mouse gut host cells through edible institute derived exosome-like nanoparticles. Mol. Nutr. Nutrient Res. 2014;58:1561–1573. doi: ten.1002/mnfr.201300729. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
48. Zhang Chiliad., Viennois E., Prasad M., Zhang Y., Wang 50., Zhang Z., Han Grand.K., Xiao B., Xu C., Srinivasan S., et al. Edible ginger-derived nanoparticles: A novel therapeutic arroyo for the prevention and handling of inflammatory bowel disease and colitis-associated cancer. Biomaterials. 2016;101:321–340. doi: 10.1016/j.biomaterials.2016.06.018. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
49. Arulselvan P., Fard Thousand.T., Tan W.S., Gothai S., Fakurazi S., Norhaizan 1000.East., Kumar S.Southward. Role of Antioxidants and Natural Products in Inflammation. Oxidative Med. Cell. Longev. 2016;2016:5276130. doi: 10.1155/2016/5276130. [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]
50. Yan Chiliad.S., Chia 50.A., Li X., Ootani A., Su J., Lee J.Y., Su North., Luo Y., Heilshorn S.C., Amieva K.R., et al. The intestinal stalk cell markers Bmi1 and Lgr5 identify ii functionally distinct populations. Proc. Natl. Acad. Sci. USA. 2012;109:466–471. doi: 10.1073/pnas.1118857109. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
51. Sebastian V.P., Salazar Thousand.A., Coronado-Arrazola I., Schultz B.M., Vallejos O.P., Berkowitz L., Alvarez-Lobos One thousand.K., Riedel C.A., Kalergis A.Chiliad., Bueno S.M. Heme Oxygenase-1 every bit a Modulator of Intestinal Inflammation Development and Progression. Forepart. Immunol. 2018;ix:1956. doi: 10.3389/fimmu.2018.01956. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
52. Takagi T., Naito Y., Mizushima K., Hirai Y., Harusato A., Okayama T., Katada K., Kamada K., Uchiyama K., Handa O., et al. Heme oxygenase-i prevents murine abdominal inflammation. J. Clin. Biochem. Nutr. 2018;63:169–174. doi: 10.3164/jcbn.17-133. [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]
53. Li B., Gurung P., Malireddi R.K., Vogel P., Kanneganti T.D., Geiger T.L. IL-10 engages macrophages to shift Th17 cytokine dependency and pathogenicity during T-cell-mediated colitis. Nat. Commun. 2015;6:6131. doi: ten.1038/ncomms7131. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
54. Ahn J., Son Southward., Oliveira S.C., Hairdresser G.N. STING-Dependent Signaling Underlies IL-10 Controlled Inflammatory Colitis. Jail cell Rep. 2017;21:3873–3884. doi: 10.1016/j.celrep.2017.11.101. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
55. Saha South., Buttari B., Panieri E., Profumo E., Saso 50. An Overview of Nrf2 Signaling Pathway and Its Role in Inflammation. Molecules. 2020;25:5474. doi: x.3390/molecules25225474. [PMC gratuitous commodity] [PubMed] [CrossRef] [Google Scholar]
56. Moschen A.R., Adolph T.Eastward., Gerner R.R., Wieser 5., Tilg H. Lipocalin-2: A Master Mediator of Abdominal and Metabolic Inflammation. Trends Endocrinol. Metab. 2017;28:388–397. doi: 10.1016/j.tem.2017.01.003. [PubMed] [CrossRef] [Google Scholar]
57. Malik A., Kanneganti T.D. Inflammasome activation and assembly at a glance. J. Cell Sci. 2017;130:3955–3963. doi: 10.1242/jcs.207365. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
58. Sonnenburg East.D., Smits Southward.A., Tikhonov Chiliad., Higginbottom S.K., Wingreen N.S., Sonnenburg J.L. Nutrition-induced extinctions in the gut microbiota compound over generations. Nature. 2016;529:212–215. doi: x.1038/nature16504. [PMC gratis article] [PubMed] [CrossRef] [Google Scholar]
59. Lei C., Mu J., Teng Y., He L., Xu F., Zhang X., Sundaram K., Kumar A., Sriwastva Chiliad.K., Lawrenz M.B., et al. Lemon Exosome-like Nanoparticles-Manipulated Probiotics Protect Mice from C. diff Infection. iScience. 2020;23:101571. doi: 10.1016/j.isci.2020.101571. [PMC complimentary commodity] [PubMed] [CrossRef] [Google Scholar]
60. Shibata Y., Okano S., Shiroza T., Tahara T., Nakazawa K., Kataoka S., Ishida I., Kobayashi T., Yoshie H., Abiko Y. Characterization of human-type monoclonal antibodies against reduced form of hemin binding protein 35 from Porphyromonas gingivalis. J. Periodontal. Res. 2011;46:673–681. doi: 10.1111/j.1600-0765.2011.01389.10. [PubMed] [CrossRef] [Google Scholar]
61. Alvarez-Erviti L., Seow Y., Yin H., Betts C., Lakhal S., Wood Grand.J. Commitment of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 2011;29:341–345. doi: x.1038/nbt.1807. [PubMed] [CrossRef] [Google Scholar]
62. Guo M., Wu F., Hu G., Chen L., Xu J., Xu P., Wang Ten., Li Y., Liu S., Zhang S., et al. Autologous tumor cell-derived microparticle-based targeted chemotherapy in lung cancer patients with cancerous pleural effusion. Sci. Transl. Med. 2019;11:eaat5690. doi: 10.1126/scitranslmed.aat5690. [PubMed] [CrossRef] [Google Scholar]
63. Wang Q., Zhuang X., Mu J., Deng Z.B., Jiang H., Zhang L., Xiang X., Wang B., Yan J., Miller D., et al. Delivery of therapeutic agents past nanoparticles made of grapefruit-derived lipids. Nat. Commun. 2013;four:1867. doi: 10.1038/ncomms2886. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
64. Golunski G., Woziwodzka A., Piosik J. Potential Use of Pentoxifylline in Cancer Therapy. Curr. Pharm. Biotechnol. 2018;xix:206–216. doi: 10.2174/1389201019666180528084641. [PubMed] [CrossRef] [Google Scholar]
65. Didion C.A., Henne W.A. A Bibliometric analysis of folate receptor inquiry. BMC Cancer. 2020;20:1109. doi: 10.1186/s12885-020-07607-five. [PMC complimentary article] [PubMed] [CrossRef] [Google Scholar]
66. Hannoodee Yard., Mittal M. Methotrexate. StatPearls; Treasure Isle, FL, USA: 2020. [Google Scholar]
67. Zhang M., Wang X., Han M.K., Collins J.F., Merlin D. Oral administration of ginger-derived nanolipids loaded with siRNA every bit a novel arroyo for efficient siRNA drug delivery to treat ulcerative colitis. Nanomedicine. 2017;12:1927–1943. doi: 10.2217/nnm-2017-0196. [PMC complimentary commodity] [PubMed] [CrossRef] [Google Scholar]
68. Anders C.Thou., Adamo B., Karginova O., Bargain A.M., Rawal S., Darr D., Schorzman A., Santos C., Bash R., Kafri T., et al. Pharmacokinetics and efficacy of PEGylated liposomal doxorubicin in an intracranial model of breast cancer. PLoS ONE. 2013;8:e61359. doi: 10.1371/journal.pone.0061359. [PMC costless article] [PubMed] [CrossRef] [Google Scholar]
69. Wang Q., Ren Y., Mu J., Egilmez N.One thousand., Zhuang X., Deng Z., Zhang L., Yan J., Miller D., Zhang H.G. Grapefruit-Derived Nanovectors Utilise an Activated Leukocyte Trafficking Pathway to Deliver Therapeutic Agents to Inflammatory Tumor Sites. Cancer Res. 2015;75:2520–2529. doi: 10.1158/0008-5472.Tin-14-3095. [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]
70. Zhuang X., Teng Y., Samykutty A., Mu J., Deng Z., Zhang L., Cao P., Rong Y., Yan J., Miller D., et al. Grapefruit-derived Nanovectors Delivering Therapeutic miR17 Through an Intranasal Road Inhibit Encephalon Tumor Progression. Mol. Ther. J. Am. Soc. Gene Ther. 2016;24:96–105. doi: 10.1038/mt.2015.188. [PMC costless article] [PubMed] [CrossRef] [Google Scholar]
71. Liu Thousand., Liu Y., Yang Z., Wang J., Li D., Zhang 10. Tumor suppressor microRNA-18a regulates tumor proliferation and invasion by targeting TBPL1 in colorectal cancer cells. Mol. Med. Rep. 2015;12:7643–7648. doi: 10.3892/mmr.2015.4335. [PubMed] [CrossRef] [Google Scholar]
72. Teng Y., Mu J., Hu X., Samykutty A., Zhuang X., Deng Z., Zhang L., Cao P., Yan J., Miller D., et al. Grapefruit-derived nanovectors deliver miR-18a for handling of liver metastasis of colon cancer by consecration of M1 macrophages. Oncotarget. 2016;vii:25683–25697. doi: x.18632/oncotarget.8361. [PMC costless article] [PubMed] [CrossRef] [Google Scholar]
73. Garg H., Suri P., Gupta J.C., Talwar G.P., Dubey S. Survivin: A unique target for tumor therapy. Cancer Prison cell Int. 2016;sixteen:49. doi: 10.1186/s12935-016-0326-1. [PMC gratuitous article] [PubMed] [CrossRef] [Google Scholar]
74. Li Z., Wang H., Yin H., Bennett C., Zhang H.G., Guo P. Arrowtail RNA for Ligand Display on Ginger Exosome-like Nanovesicles to Systemic Deliver siRNA for Cancer Suppression. Sci. Rep. 2018;8:14644. doi: x.1038/s41598-018-32953-vii. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
75. Thery C., Witwer One thousand.W., Aikawa Eastward., Alcaraz M.J., Anderson J.D., Andriantsitohaina R., Antoniou A., Arab T., Archer F., Atkin-Smith Grand.G., et al. Minimal data for studies of extracellular vesicles 2018 (MISEV2018): A position argument of the International Social club for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles. 2018;7:1535750. doi: x.1080/20013078.2018.1535750. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
76. Regente One thousand., Pinedo Yard., Elizalde M., de la Canal 50. Apoplastic exosome-like vesicles: A new way of poly peptide secretion in plants? Constitute Betoken. Behav. 2012;seven:544–546. doi: 10.4161/psb.19675. [PMC free commodity] [PubMed] [CrossRef] [Google Scholar]
Manufactures from International Journal of Molecular Sciences are provided here courtesy of Multidisciplinary Digital Publishing Found (MDPI)
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160738/
Posted by: browncritheing.blogspot.com
0 Response to "Is The Vesicle In Plant And Animal Cells"
Post a Comment