Exosomes in Food: Health Benefits and Clinical Relevance in Diseases.

Exosomes are membrane-bound organelles generally secreted by eukaryotic cells that contain mRNAs, microRNAs, and/or proteins. However, recent studies have reported the isolation of these particles from foods such as lemon, ginger, and milk. Owing to their absorption by intestinal cells and further travel via the bloodstream, exosomes can reach distant organs and affect overall health in both infants and adults. The potential role of food-derived exosomes (FDEs) in alleviating diseases, as well as in modulating the gut microbiota has been shown, but the underlying mechanism is still unknown. Moreover, exosomes may provide biocompatible vehicles for the delivery of anti-cancer drugs, such as doxorubicin. Thus, exosomes may allow medical nutritionists and clinicians to develop safe and targeted therapies for the treatment of various pathologies. The present review introduces FDEs and their contents, highlights their role in disease and infant/adult health, and explores their potential use as therapeutic agents.

[1]  Hong Jiang,et al.  Delivery of therapeutic agents by nanoparticles made of grapefruit-derived lipids , 2013, Nature Communications.

[2]  D. Merlin,et al.  Oral administration of ginger-derived nanolipids loaded with siRNA as a novel approach for efficient siRNA drug delivery to treat ulcerative colitis. , 2017, Nanomedicine.

[3]  T. Nakanishi,et al.  Apple-Derived Nanoparticles Modulate Expression of Organic-Anion-Transporting Polypeptide (OATP) 2B1 in Caco-2 Cells. , 2018, Molecular pharmaceutics.

[4]  M. Warda,et al.  Dromedary milk exosomes as mammary transcriptome nano-vehicle: Their isolation, vesicular and phospholipidomic characterizations , 2016 .

[5]  J. Suttles,et al.  Broccoli-Derived Nanoparticle Inhibits Mouse Colitis by Activating Dendritic Cell AMP-Activated Protein Kinase. , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[6]  B. Melnik,et al.  Exosomes of pasteurized milk: potential pathogens of Western diseases , 2019, Journal of Translational Medicine.

[7]  Riitta Lahesmaa,et al.  Exosomes with Immune Modulatory Features Are Present in Human Breast Milk1 , 2007, The Journal of Immunology.

[8]  M. L. Nielsen,et al.  The SOCS2 Ubiquitin Ligase Complex Regulates Growth Hormone Receptor Levels , 2011, PloS one.

[9]  J. Adamec,et al.  A diet defined by its content of bovine milk exosomes and their RNA cargos has moderate effects on gene expression, amino acid profiles and grip strength in skeletal muscle in C57BL/6 mice. , 2018, The Journal of nutritional biochemistry.

[10]  L. Fowke,et al.  The morphology of multivesicular bodies in soybean protoplasts and their role in endocytosis , 1987, Protoplasma.

[11]  S. Raimondo,et al.  Citrus limon-derived nanovesicles inhibit cancer cell proliferation and suppress CML xenograft growth by inducing TRAIL-mediated cell death , 2015 .

[12]  R. Hückelhoven,et al.  Do Plant Cells Secrete Exosomes Derived from Multivesicular Bodies? , 2007, Plant signaling & behavior.

[13]  Xiaodi Qiu,et al.  miR-1307 promotes the proliferation of prostate cancer by targeting FOXO3A. , 2017, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[14]  Rosalind J Wright,et al.  Detection of long non-coding RNAs in human breastmilk extracellular vesicles: Implications for early child development , 2016, Epigenetics.

[15]  Jiujiu Yu,et al.  Exosome-like Nanoparticles from Ginger Rhizomes Inhibited NLRP3 Inflammasome Activation. , 2019, Molecular pharmaceutics.

[16]  Peixuan Guo,et al.  Arrowtail RNA for Ligand Display on Ginger Exosome-like Nanovesicles to Systemic Deliver siRNA for Cancer Suppression , 2018, Scientific Reports.

[17]  Sascha Keller,et al.  Exosomes: from biogenesis and secretion to biological function. , 2006, Immunology letters.

[18]  R. Welti,et al.  Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[19]  S. Gabrielsson,et al.  Differences in exosome populations in human breast milk in relation to allergic sensitization and lifestyle , 2014, Allergy.

[20]  G. Blackburn,et al.  Review of Infant Feeding: Key Features of Breast Milk and Infant Formula , 2016, Nutrients.

[21]  Mohsen Poursadeghiyan,et al.  Diet and cancer prevention: Dietary compounds, dietary MicroRNAs, and dietary exosomes , 2018, Journal of cellular biochemistry.

[22]  C. Boyd,et al.  Breast milk and gene delivery: is lysinuric protein intolerance an exemplar? , 2010, Molecular genetics and metabolism.

[23]  V. Vlassov,et al.  Purified horse milk exosomes contain an unpredictable small number of major proteins , 2017, Biochimie open.

[24]  A. Dávalos,et al.  Breast milk microRNAs harsh journey towards potential effects in infant development and maturation. Lipid encapsulation can help , 2018, Pharmacological research.

[25]  Elmar L. Gool,et al.  Recent developments in the nomenclature, presence, isolation, detection and clinical impact of extracellular vesicles , 2016, Journal of thrombosis and haemostasis : JTH.

[26]  J. Lippolis,et al.  Bovine milk exosome proteome. , 2012, Journal of proteomics.

[27]  W. B. van den Berg,et al.  Commercial Cow Milk Contains Physically Stable Extracellular Vesicles Expressing Immunoregulatory TGF-β , 2015, PloS one.

[28]  J. Zempleni,et al.  MicroRNAs are absorbed in biologically meaningful amounts from nutritionally relevant doses of cow milk and affect gene expression in peripheral blood mononuclear cells, HEK-293 kidney cell cultures, and mouse livers. , 2014, The Journal of nutrition.

[29]  Ming Li,et al.  Exosomal microRNAs in giant panda (Ailuropoda melanoleuca) breast milk: potential maternal regulators for the development of newborn cubs , 2017, Scientific Reports.

[30]  Xiong Guo,et al.  Dietary exosome-miR-23b may be a novel therapeutic measure for preventing Kashin-Beck disease , 2018, Experimental and therapeutic medicine.

[31]  S. Srinivasan,et al.  Edible ginger-derived nanoparticles: A novel therapeutic approach for the prevention and treatment of inflammatory bowel disease and colitis-associated cancer. , 2016, Biomaterials.

[32]  A. Benmoussa,et al.  Commercial Dairy Cow Milk microRNAs Resist Digestion under Simulated Gastrointestinal Tract Conditions. , 2016, The Journal of nutrition.

[33]  Huan Wang,et al.  Edible Ginger-derived Nano-lipids Loaded with Doxorubicin as a Novel Drug-delivery Approach for Colon Cancer Therapy. , 2016, Molecular therapy : the journal of the American Society of Gene Therapy.

[34]  S. Onteru,et al.  Curcumin Encapsulated in Milk Exosomes Resists Human Digestion and Possesses Enhanced Intestinal Permeability in Vitro , 2017, Applied Biochemistry and Biotechnology.

[35]  Denis Gris,et al.  Fatty acid–induced NLRP3-ASC inflammasome activation interferes with insulin signaling , 2011, Nature Immunology.

[36]  S. Raimondo,et al.  Label-free quantitative proteomic profiling of colon cancer cells identifies acetyl-CoA carboxylase alpha as antitumor target of Citrus limon-derived nanovesicles. , 2018, Journal of proteomics.

[37]  J. Milner,et al.  Bioactive Food Components that Enhance γδ T Cell Function May Play a Role in Cancer Prevention , 2008 .

[38]  S. Onteru,et al.  Small Interfering RNA in Milk Exosomes Is Resistant to Digestion and Crosses the Intestinal Barrier In Vitro. , 2017, Journal of agricultural and food chemistry.

[39]  J. Aldag,et al.  Comparison of Milk Output Between Mothers of Preterm and Term Infants: The First 6 Weeks After Birth , 2005, Journal of human lactation : official journal of International Lactation Consultant Association.

[40]  J. Zempleni,et al.  Milk exosomes are bioavailable and distinct microRNA cargos have unique tissue distribution patterns , 2018, Scientific Reports.

[41]  F. V. D. van den Hoogen,et al.  Milk‐Derived Nanoparticle Fraction Promotes the Formation of Small Osteoclasts But Reduces Bone Resorption , 2017, Journal of cellular physiology.

[42]  Bo Li,et al.  Breast milk-derived exosomes promote intestinal epithelial cell growth. , 2017, Journal of pediatric surgery.

[43]  J. McCarthy,et al.  Whey protein-derived exosomes increase protein synthesis and hypertrophy in C2-C12 myotubes. , 2017, Journal of dairy science.

[44]  C. McKinnon,et al.  The tumor suppressor RhoBTB1 controls Golgi integrity and breast cancer cell invasion through METTL7B , 2017, BMC Cancer.

[45]  S. Mandal CURCUMIN, A PROMISING ANTI-CANCER THERAPEUTIC: IT’S BIOACTIVITY AND DEVELOPMENT OF DRUG DELIVERY VEHICLES , 2017 .

[46]  Juw Won Park,et al.  Plant-Derived Exosomal MicroRNAs Shape the Gut Microbiota. , 2018, Cell host & microbe.

[47]  M. Heneka,et al.  NLRP3 is activated in Alzheimer´s disease and contributes to pathology in APP/PS1 mice , 2012, Nature.

[48]  D. Merlin,et al.  Plant derived edible nanoparticles as a new therapeutic approach against diseases , 2016, Tissue barriers.

[49]  A. Ahmadi,et al.  Transdermal delivery of bovine milk vesicles in patients with multiple sclerosis: A novel strategy to induce MOG-specific tolerance. , 2015, Medical hypotheses.

[50]  F. Aqil,et al.  Bovine milk-derived exosomes for drug delivery. , 2016, Cancer letters.

[51]  Subbarao Bondada,et al.  Milk-derived exosomes for oral delivery of paclitaxel. , 2017, Nanomedicine : nanotechnology, biology, and medicine.

[52]  Xiwei Wu,et al.  Cross-kingdom inhibition of breast cancer growth by plant miR159 , 2016, Cell Research.

[53]  J. Zempleni,et al.  Biological Activities of Extracellular Vesicles and Their Cargos from Bovine and Human Milk in Humans and Implications for Infants. , 2017, The Journal of nutrition.

[54]  C. McClain,et al.  Ginger-derived nanoparticles protect against alcohol-induced liver damage , 2015, Journal of extracellular vesicles.

[55]  Bo Li,et al.  Bovine milk-derived exosomes enhance goblet cell activity and prevent the development of experimental necrotizing enterocolitis , 2019, PloS one.

[56]  Kumaran Sundaram,et al.  Blood exosomes regulate the tissue distribution of grapefruit-derived nanovector via CD36 and IGFR1 pathways , 2018, Theranostics.

[57]  J. Garssen,et al.  Comprehensive Proteomic Analysis of Human Milk-derived Extracellular Vesicles Unveils a Novel Functional Proteome Distinct from Other Milk Components* , 2016, Molecular & Cellular Proteomics.

[58]  S. Fernando,et al.  Dietary Bovine Milk Exosomes Elicit Changes in Bacterial Communities in C57BL/6 Mice. , 2019, American journal of physiology. Gastrointestinal and liver physiology.

[59]  J. Milner Molecular targets for bioactive food components. , 2004, The Journal of nutrition.

[60]  Min Li,et al.  Isolation of Exosome-Like Nanoparticles and Analysis of MicroRNAs Derived from Coconut Water Based on Small RNA High-Throughput Sequencing. , 2018, Journal of agricultural and food chemistry.

[61]  R. Wu,et al.  Comparative proteomic analysis of milk-derived exosomes in human and bovine colostrum and mature milk samples by iTRAQ-coupled LC-MS/MS. , 2017, Food research international.

[62]  W. Xu,et al.  Exosomal MicroRNAs in Milk from Mothers Delivering Preterm Infants Survive in Vitro Digestion and Are Taken Up by Human Intestinal Cells , 2018, Molecular nutrition & food research.

[63]  W. B. van den Berg,et al.  Oral administration of bovine milk derived extracellular vesicles attenuates arthritis in two mouse models. , 2015, Molecular nutrition & food research.

[64]  J. Lötvall,et al.  Human saliva, plasma and breast milk exosomes contain RNA: uptake by macrophages , 2011, Journal of Translational Medicine.

[65]  J. Zempleni,et al.  Depletion of Dietary Bovine Milk Exosomes Impairs Sensorimotor Gating and Spatial Learning in C57BL/6 Mice , 2017 .

[66]  N. Kosaka,et al.  Bovine milk exosomes contain microRNA and mRNA and are taken up by human macrophages. , 2015, Journal of dairy science.

[67]  S. Taneja,et al.  Optimal breastfeeding practices and infant and child mortality: a systematic review and meta‐analysis , 2015, Acta paediatrica.

[68]  R. Salehi,et al.  Leucine-rich Repeat-containing G-protein Coupled Receptor 5 Gene Overexpression of the Rat Small Intestinal Progenitor Cells in Response to Orally Administered Grape Exosome-like Nanovesicles , 2018, Advanced biomedical research.

[69]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[70]  H. Matsuura,et al.  Intake of garlic and its bioactive components. , 2001, The Journal of nutrition.

[71]  G. Shu,et al.  Exploration of microRNAs in porcine milk exosomes , 2014, BMC Genomics.

[72]  Y. Teng,et al.  Grapefruit-derived Nanovectors Delivering Therapeutic miR17 Through an Intranasal Route Inhibit Brain Tumor Progression. , 2016, Molecular therapy : the journal of the American Society of Gene Therapy.

[73]  Xi Chen,et al.  Immune modulatory function of abundant immune-related microRNAs in microvesicles from bovine colostrum , 2013, Protein & Cell.

[74]  Hong Jiang,et al.  Interspecies communication between plant and mouse gut host cells through edible plant derived exosome-like nanoparticles. , 2014, Molecular nutrition & food research.

[75]  M. Q. Kemp,et al.  Survival and Diversity of Human Homologous Dietary MicroRNAs in Conventionally Cooked Top Sirloin and Dried Bovine Tissue Extracts , 2015, PloS one.

[76]  A. Agrawal,et al.  Exosomal formulation of anthocyanidins against multiple cancer types. , 2017, Cancer letters.

[77]  K. Nicholas,et al.  Differential temporal expression of milk miRNA during the lactation cycle of the marsupial tammar wallaby (Macropus eugenii) , 2014, BMC Genomics.

[78]  Hong Jiang,et al.  Targeted drug delivery to intestinal macrophages by bioactive nanovesicles released from grapefruit. , 2014, Molecular therapy : the journal of the American Society of Gene Therapy.

[79]  M. El-Magd,et al.  Therapeutic Effect of Camel Milk and Its Exosomes on MCF7 Cells In Vitro and In Vivo , 2018, Integrative cancer therapies.

[80]  J. Zempleni,et al.  Human vascular endothelial cells transport foreign exosomes from cow's milk by endocytosis. , 2016, American journal of physiology. Cell physiology.

[81]  L. Parker,et al.  Exosomal delivery of berry anthocyanidins for the management of ovarian cancer. , 2017, Food & function.

[82]  N. Aoki,et al.  Isolation of bovine milk-derived microvesicles carrying mRNAs and microRNAs. , 2010, Biochemical and biophysical research communications.

[83]  Lei Chen,et al.  Lactation-Related MicroRNA Expression Profiles of Porcine Breast Milk Exosomes , 2012, PloS one.

[84]  Chun-Hung Lai,et al.  miRNA arm selection and isomiR distribution in gastric cancer , 2012, BMC Genomics.

[85]  W. B. van den Berg,et al.  Milk extracellular vesicles accelerate osteoblastogenesis but impair bone matrix formation. , 2016, The Journal of nutritional biochemistry.

[86]  Xiaolian Gao,et al.  Immune-related MicroRNAs are Abundant in Breast Milk Exosomes , 2011, International journal of biological sciences.