Cytotoxic Lactalbumin-Oleic Acid Complexes in the Human Milk Diet of Preterm Infants

Abstract

Frozen storage is necessary to preserve expressed human milk for critically ill and very preterm infants. Milk pasteurization is essential for donor milk given to this special population. Due to these storage and processing conditions, subtle changes occur in milk nutrients. These changes may have clinical implications. Potentially, bioactive complexes of unknown significance could be found in human milk given to preterm infants. One such complex, a cytotoxic α-lactalbumin-oleic acid complex named “HAMLET,” (Human Alpha-Lactalbumin Made Lethal to Tumor cells) is a folding variant of alpha-lactalbumin that is bound to oleic acid. This complex, isolated from human milk casein, has specific toxicity to both carcinogenic cell lines and immature non-transformed cells. Both HAMLET and free oleic acid trigger similar apoptotic mechanisms in tissue and stimulate inflammation via the NF-κB and MAPK p38 signaling pathways. This protein-lipid complex could potentially trigger various inflammatory pathways with unknown consequences, especially in immature intestinal tissues. The very preterm population is dependent on human milk as a medicinal and broadly bioactive nutriment. Therefore, HAMLET’s possible presence and bioactive role in milk should be addressed in neonatal research. Through a pediatric lens, HAMLET’s discovery, formation and bioactive benefits will be reviewed.

Determination of vitamin D3 encapsulated in liprotide β-lactoglobulin crosslink oleic acid by HPLC and SEM

“…In HPLC 1-4 conditions, a mixture of eluents (acetonitrile: methanol) was used, referring to several previous studies, but with some variations in composition (Fatemeh et al, 2017). The determination of Vitamin D3 using a mobile phase as a mixture of butanol was based on previous studies, but with variations in eluent composition (Chetta et al, 2021;Fang et al, 2012). Specifications of the HPLC conditions used are listed in Table 2.…”

“…Studies have been carried out using protein (β-lactoglobulin) and casein have been used to deliver vitamin D3, docosahexaenoic acid, and genistein (Anjani, 2014). Research conducted by Chetta et al (2021) and Fang et al (2012) used α-Lactalbumin with oleic acid (0A) to form a complex compound that showed cytotoxic activity against tumor cells. Research conducted by Nadeem et al (2019) examined the function of the protein in α-lactalbumin using a 3-dimensional structure, which has several similarities to the β-lactoglobulin protein, especially in triple-stranded antiparallel β-sheets.…”

World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines update - III - Cow's milk allergens and mechanisms triggering immune activation

“…ALA linked to oleic acid has been shown to acquire bactericidal and cytotoxic anti-tumoral activities, 51 especially when thermally unfolded and stabilized by oleic acid. 52 This apoptotic complex has been termed Human Alpha-Lactalbumin Made Lethal to Tumor cells (HAMLET), and in bovines accordingly BAMLET. However, more recent studies have shown that the cytotoxic effect of these complexes depends on oleic acid rather than ALA. 38 As HAMLET is secreted into human breast milk, its occurrence in frozen human donor milk stored for critically ill and preterm babies should be critically investigated, given its potential capacity to trigger inflammation in the sensitive neonates.…”

“…However, more recent studies have shown that the cytotoxic effect of these complexes depends on oleic acid rather than ALA. 38 As HAMLET is secreted into human breast milk, its occurrence in frozen human donor milk stored for critically ill and preterm babies should be critically investigated, given its potential capacity to trigger inflammation in the sensitive neonates. 52 Linoleic acid has been shown to promote a Th2 environment 53 and complex formation of ALA, but also BLG with linoleic acid leads to aggregation, enhanced IgE-binding and degranulation capacity. 54 In contrast, processing modifications like glycation, phosphorylation and acetylation reduce the allergenicity of these complexes.…”

The Era of Precision Nutrition in the Field of Reproductive Health and Pregnancy

“…One of the challenging events facing mothers of preterm infants is related to nutritional care and measures that are crucial to ensure proper development and growth of their bodies. A paper published in this Special Issue by Chetta KE et al [ 9 ] investigated the natural formation, significance and potentially harmful effects of cytotoxic α-lactalbumin-oleic acid complex named “HAMLET,” (Human Alpha-Lactalbumin Made Lethal to Tumor cells) in the human milk diet of preterm birth offspring. These protein–lipid complexes have been observed to exhibit cytotoxic effects and induce inflammatory pathways in intestinal and immune cells of preterm infants.…”