More than Nutrition: Therapeutic Potential of Breast Milk-Derived Exosomes in Cancer

Human breast milk (HBM) is an irreplaceable source of nutrition for early infant growth and development. Breast-fed children are known to have a low prevalence and reduced risk of various diseases, such as necrotizing enterocolitis, gastroenteritis, acute lymphocytic leukemia, and acute myeloid leukemia. In recent years, HBM has been found to contain a microbiome, extracellular vesicles or exosomes, and microRNAs, as well as nutritional components and non-nutritional proteins, including immunoregulatory proteins, hormones, and growth factors. Especially, the milk-derived exosomes exert various physiological and therapeutic function in cell proliferation, inflammation, immunomodulation, and cancer, which are mainly attributed to their cargo molecules such as proteins and microRNAs. The exosomal miRNAs are protected from enzymatic digestion and acidic conditions, and play a critical role in immune regulation and cancer. In addition, the milk-derived exosomes are developed as drug carriers for delivering small molecules and siRNA to tumor sites. In this review, we examined the various components of HBM and their therapeutic potential, in particular of exosomes and microRNAs, towards cancer.

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Nano-HPLC-HRMS Analysis to Evaluate Leptin Level in Milk Samples: A Pilot Study

Applied Sciences ◽

10.3390/app10176135 ◽

2020 ◽

Vol 10 (17) ◽

pp. 6135

Author(s):

Federica Dal Bello ◽

Enrica Mecarelli ◽

Daniela Gastaldi ◽

Francesco Savino ◽

Claudio Medana

Keyword(s):

Pilot Study ◽

Breast Milk ◽

Infant Formula ◽

Analytical Method ◽

Critical Role ◽

Bovine Milk ◽

Human Breast Milk ◽

Human Breast ◽

Milk Samples ◽

Limit Of Quantitation

Leptin is a 16 kDa lipophilic protein hormone secreted by adipocytes and its most significant function is to inform the brain with negative feedback that regulates food intake. Recently the protein found in human breast milk was related to breast feeding and onset of obesity, and the evidence of a low probability to develop pediatric obesity in children fed with breast milk was also confirmed. Since leptin could have a critical role, its quantitation both in human breast, bovine milk and in infant formula products is interesting. For this reason, we developed an analytical method based on immunoaffinity purification followed by an analysis with nano-High Pressure Liquid Chromatography coupled with High Resolution Mass Spectrometry analyzer (nano-HPLC-HRMS) to identify and quantify leptin in milk samples and performed a pilot study using samples of human breast milk, bovine milk and infant formulas. With an obtained lower limit of quantitation (LLOQ) of 100 ng mL−1 we quantified leptin in human breast milk finding an average of 6.70 ng mL−1. Our results show that leptin was under LLOQ both in bovine milk and in infant formula products. In conclusion, the developed analytical method here described was suitable to quantify leptin in milk samples with a good sensitivity and selectivity, and without the use of radioactive reagents.

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Human Immunodeficiency Virus-Specific CD8+ T Cells in Human Breast Milk

Journal of Virology ◽

10.1128/jvi.76.15.7365-7373.2002 ◽

2002 ◽

Vol 76 (15) ◽

pp. 7365-7373 ◽

Cited By ~ 43

Author(s):

Steffanie Sabbaj ◽

Bradley H. Edwards ◽

Mrinal K. Ghosh ◽

Katherine Semrau ◽

Sanford Cheelo ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Breast Milk ◽

Critical Role ◽

The United States ◽

Transmission Risk ◽

Target Cells ◽

Human Breast Milk ◽

Chromium Release Assay ◽

Immunodeficiency Virus

ABSTRACT Breast-feeding infants of human immunodeficiency virus (HIV)-infected women ingest large amounts of HIV, but most escape infection. While the factors affecting transmission risk are poorly understood, HIV-specific cytotoxic T-lymphocyte (CTL) responses play a critical role in controlling HIV levels in blood. We therefore investigated the ability of breast milk cells (BMC) from HIV-infected women from the United States and Zambia to respond to HIV-1 peptides in a gamma interferon enzyme-linked immunospot assay. All (n = 11) HIV-infected women had responses to pools of Gag peptide (range, 105 to 1,400 spot-forming cells/million; mean = 718), 8 of 11 reacted to Pol, 7 reacted to Nef, and 2 of 5 reacted to Env. Conversely, of four HIV-negative women, none responded to any of the tested HIV peptide pools. Depletion and tetramer staining studies demonstrated that CD8+ T cells mediated these responses, and a chromium-release assay showed that these BMC were capable of lysing target cells in an HIV-specific manner. These data demonstrate the presence of HIV-specific major histocompatibility complex class I-restricted CD8+ CTLs in breast milk. Their presence suggests a role in limiting transmission and provides a rationale for vaccine strategies to enhance these responses.

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Nicotinamide Promotes Apoptosis In Chronic Lymphocytic Leukemia through Activation of the p53/Mir-34a/SIRT1 Tumor Suppressor Network

Blood ◽

10.1182/blood.v116.21.4627.4627 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4627-4627

Author(s):

Valentina Audrito ◽

Tiziana Vaisitti ◽

Sara Serra ◽

Davide Rossi ◽

Daniela Gottardi ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

B Lymphocytes ◽

Conflicts Of Interest ◽

Therapeutic Potential ◽

Critical Role ◽

Disease Model ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Intrinsic Resistance

Abstract Abstract 4627 Nicotinamide (Nam), is the main precursor of nicotinamide adenine dinucleotide (NAD+). It regulates intracellular levels of NAD+ and consequently activities of four classes of NAD+-consuming enzymes, including NADases, mono-ADP-ribosyl transferases (ARTs), poly-ADP-ribose polymerases (PARPs) and sirtuins. Pharmacological doses of Nam inhibit the physiological activation and proliferation of mouse B lymphocytes, suggesting that this agent might affect also human B cell homeostasis. We approaches this issue by comparing the effects of Nam on normal vs. leukemic B lymphocytes. Chronic lymphocytic leukemia (CLL) was selected as disease model, for testing in vitro the therapeutic potential of Nam, due its intrinsic resistance to apoptosis, mediated by an imbalance in the mechanisms regulating cell death, mainly regulated through the activities of NAD+-dependent enzymes. This study shows that pharmacological doses of Nam (5-10 mM) significantly inhibit proliferation and induce apoptosis of CLL cells. At earlier time points, Nam markedly reduces phosphorylation of multiple intracellular substrates, including ERK1/2. Normal B lymphocytes, used as control, were significantly less sensitive to the action of Nam. We hypothesized that these effects could be explained at least in part as a consequence of the inhibitory effects of Nam on NAD+-consuming enzymes. Attention was focused on SIRT1, a deacetylase that plays a critical role in cancer and that acts as a longevity factor. The results demonstrate that Nam exposure inhibits the activity, and also the expression of SIRT1. This effect is apparent only in leukemic cells, where SIRT1 protein levels are significantly higher than in normal B lymphocytes, obtained from spleen or tonsils, markedly less sensitive to Nam effects. The functional block of SIRT1 induced by Nam is followed by activation of p53, transcription of miR-34a and translational repression of SIRT1 mRNA (p53/miR-34a/SIRT1 functional loop). The endpoint is the activation of apoptosis. The same loop is the target of conventional DNA-damaging drugs, such as etoposide. Thus, addition of Nam to conventional DNA-damaging chemotherapeutics agents, leads to an inhibition of SIRT1 through two independent and synergic pathways, resulting in additive effects on apoptosis. In conclusion this work suggests that Nam represents a potentially useful non-chemotherapeutic agent, characterized by a known and established safety profile, to be associated to conventional cytotoxic drugs in the treatment of selected forms of CLL. Disclosures: No relevant conflicts of interest to declare.

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Bioactive Factors in Human Breast Milk Attenuate Intestinal Inflammation during Early Life

Nutrients ◽

10.3390/nu12020581 ◽

2020 ◽

Vol 12 (2) ◽

pp. 581 ◽

Cited By ~ 4

Author(s):

Julie D. Thai ◽

Katherine E. Gregory

Keyword(s):

Breast Milk ◽

Preterm Infants ◽

Early Life ◽

Protective Factor ◽

Intestinal Inflammation ◽

Critical Role ◽

High Morbidity ◽

Human Breast Milk ◽

Bioactive Components ◽

Human Breast

Human breast milk is well known as the ideal source of nutrition during early life, ensuring optimal growth during infancy and early childhood. Breast milk is also the source of many unique and dynamic bioactive components that play a key role in the development of the immune system. These bioactive components include essential microbes, human milk oligosaccharides (HMOs), immunoglobulins, lactoferrin and dietary polyunsaturated fatty acids. These factors all interact with intestinal commensal bacteria and/or immune cells, playing a critical role in establishment of the intestinal microbiome and ultimately influencing intestinal inflammation and gut health during early life. Exposure to breast milk has been associated with a decreased incidence and severity of necrotizing enterocolitis (NEC), a devastating disease characterized by overwhelming intestinal inflammation and high morbidity among preterm infants. For this reason, breast milk is considered a protective factor against NEC and aberrant intestinal inflammation common in preterm infants. In this review, we will describe the key microbial, immunological, and metabolic components of breast milk that have been shown to play a role in the mechanisms of intestinal inflammation and/or NEC prevention.

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The Therapeutic Potential of Breast Milk-Derived Extracellular Vesicles

Nutrients ◽

10.3390/nu12030745 ◽

2020 ◽

Vol 12 (3) ◽

pp. 745 ◽

Cited By ~ 6

Author(s):

Jeffrey D. Galley ◽

Gail E. Besner

Keyword(s):

Breast Milk ◽

Extracellular Vesicles ◽

Therapeutic Potential ◽

Gastrointestinal Disease ◽

The Body ◽

Parent Cell ◽

Therapeutic Effects ◽

Human Breast Milk ◽

Therapeutic Benefits ◽

Health And Disease

In the past few decades, interest in the therapeutic benefits of exosomes and extracellular vesicles (EVs) has grown exponentially. Exosomes/EVs are small particles which are produced and exocytosed by cells throughout the body. They are loaded with active regulatory and stimulatory molecules from the parent cell including miRNAs and enzymes, making them prime targets in therapeutics and diagnostics. Breast milk, known for years to have beneficial health effects, contains a population of EVs which may mediate its therapeutic effects. This review offers an update on the therapeutic potential of exosomes/EVs in disease, with a focus on EVs present in human breast milk and their remedial effect in the gastrointestinal disease necrotizing enterocolitis. Additionally, the relationship between EV miRNAs, health, and disease will be examined, along with the potential for EVs and their miRNAs to be engineered for targeted treatments.

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Association of sCD14 in human breast milk with child atopic dermatitis: Results of the Ulm Birth Cohort Study and the Ulm SPATZ Health Study

10.1055/s-0037-1605765 ◽

2017 ◽

Author(s):

CA Logan ◽

J Weiss ◽

W Koenig ◽

V Walter ◽

H Brenner ◽

...

Keyword(s):

Atopic Dermatitis ◽

Cohort Study ◽

Breast Milk ◽

Birth Cohort ◽

Health Study ◽

Birth Cohort Study ◽

Human Breast Milk ◽

Human Breast

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Molecular Properties of Egg Allergen in Human Breast Milk and Its Physiological Function

Nippon Shokuhin Kagaku Kogaku Kaishi ◽

10.3136/nskkk.61.450 ◽

2014 ◽

Vol 61 (9) ◽

pp. 450-454

Author(s):

Hiroshi Narita

Keyword(s):

Breast Milk ◽

Physiological Function ◽

Molecular Properties ◽

Human Breast Milk ◽

Human Breast

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The Potential of Milk-derived Exosomes for Drug Delivery

Current Drug Delivery ◽

10.2174/1567201817666200817112503 ◽

2020 ◽

Vol 17 ◽

Author(s):

Shuyuan Li ◽

Yue Tang ◽

Yushun Dou

Keyword(s):

Drug Delivery ◽

Oral Delivery ◽

Therapeutic Potential ◽

Current Knowledge ◽

Biological Fluids ◽

Drug Loading ◽

Drug Carriers ◽

Current Application ◽

Therapeutic Benefits ◽

Loading Methods

Background: Exosomes, one of the extracellular vesicles, are widely present in all biological fluids and play an important role in intercellular communication. Because of its hydrophobic lipid bilayer and aqueous hydrophilic core structure, it is considered a possible alternative to liposome drug delivery systems. Not only do they protect the cargo like liposomes during delivery, they are less toxic and better tolerated. However, due to the lack of sources and methods for obtaining enough exosomes, the therapeutic application of exosomes as drug carriers is limited. Methods: A literature search was performed using the ScienceDirect and PubMed electronic databases to obtain information from published literature on milk exosomes related to drug delivery. Results: Here, we briefly reviewed the current knowledge of exosomes, expounded the advantages of milk-derived exosomes over other delivery vectors, including a higher yield, the oral delivery characteristic and additional therapeutic benefits. The purification and drug loading methods of milk exosomes, and the current application of milk exosomes were also introduced. Conclusion: The emergence of milk-derived exosomes is expected to break through the limitations of exosomes as therapeutic carriers of drugs. We hope to raise awareness of the therapeutic potential of milk-derived exosomes as a new drug delivery system.

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Across The “Sweetiest” Properties Of Human Breast Milk: Focus On Oligosaccharides

Current Pediatric Reviews ◽

10.2174/1573396316666200429114217 ◽

2020 ◽

Vol 16 ◽

Cited By ~ 1

Author(s):

Flaminia Bardanzellu ◽

Alessandra Reali ◽

Maria Antonietta Marcialis ◽

Vassilios Fanos

Keyword(s):

Breast Milk ◽

Active Role ◽

Individual Variability ◽

Human Breast Milk ◽

Formula Milk ◽

Target Organs ◽

Lactating Mothers ◽

Neonatal Nutrition ◽

Genetic And Environmental Factors ◽

Systemic Infections

Introduction: Breast Milk (BM), containing nutrients and bioactive components, represents the best source for neonatal nutrition and determines short- and long- term benefits. Human milk oligosaccharides (HMOs) play an active role in these pathophysiological mechanisms. In fact; they influence the shaping of breastfed infant’s gut microbiota, promote intestinal development, confer protection against intestinal or systemic infections modulating immune system; moreover, HMOs determine extra-intestinal effects on several target organs, i.e reducing necrotizing enterocolitis rate or improving brain development. Aims: In this review, we analyze the great inter- and intra-individual variability of BM HMOs, investigating maternal, genetic and environmental factors modulating their composition. Moreover, we provide an update regarding HMOs’ unique properties, underlining their complex interaction with intestinal microbiota and host-derived metabolites. The possible HMOs’ influence on extra-intestinal bacterial communities, potentially influencing newborns’ and even lactating mothers’ health, have been hypothesized. Finally, recognized HMOs’ crucial role, we underline the promising opportunities showed by their addition in formula milk, useful to create dairy products more similar to maternal milk itself.

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