What you have to know about Human Milk Oligosaccharides

Human Milk Oligosaccharides (HMOs), the third most important solid components of BM (the first and the second being lactose and lipids respectively), are a highly variable family of unconjugated glycans related to many pathophysiological short- and long-term effects on infants and, as recently demonstrated, even on the mother. Among their functions are promotion and modulation of gut microbiota, effects on intestinal mucosa and its development, protection against intestinal or extra-intestinal infections, modulation of several immune responses and even extra-intestinal effects, such as brain development, as described in literature. Regarding HMOs composition, it appears that maternal genetic factors play the major role in conferring its high and peculiar inter- and intra-individual variability to BM. HMOs greatly depend on four maternal phenotypes, defined depending on the expression of two specific genes and maternal blood group. The α-1-2-fucosyltransferase (FUT2) gene, expressed in more than 70% of Caucasian women, is codified by the Se gene and allows classification of secretor (Se+) and non-secretor (Se-) mothers. In addition, the α-1-3-4-fucosyltransferase (FUT3) gene indicates positivity or negativity for the Lewis Group (Le+ or Le-). Even other environmental and maternal factors, represented by age, diet, health status, medication and drugs appear to play a role in HMOs composi­tion

Once we were bacteria… mitochondria to infinity and beyond

Mitochondria, cytoplasmic organelles originated from endosymbiotic bacteria, can be metaphorically described using “Janus bifrons” image, due to their involvement in life, providing cellular energy and resulting essential even for stem cells, but playing a key role also in cell death. Mitochondria own a maternally inherited genome and are the site of aerobic respiration; they can produce proteins, nucleotides, lipids, steroids and heme and result involved in iron homeostasis. Moreover, mitochondria can generate free radicals, break down waste products and represent the primary source of cellular heat. The size and shape of mitochondria depend on the intracellular metabolic status, from tubular presentation to a blob form in case of irreversible damage. Each mitochondrion carries different sets of DNA; when one set accumulates mutations, it can be replaced by another. It has been widely demonstrated that mitochondrial disorders are involved in many pathologies, including autism, multiple endocrinopathies, diabetes, Alzheimer’s disease, ataxia, Barth’s syndrome, myopathy, and even aging and cancer. Human population is characterized by different mitochondrial DNA haplogroups reflecting the mutations accumulated and useful to characterize genetic diversity. The mitochondrial role also results relevant in pregnancy, providing information about maternal-fetal dyad in physiological and in pathological conditions. Recent evidence suggests that an intriguing bidirectional inter-talk exists between microbiota and mitochondria, influencing cellular homeostasis and metabolism. A recently demonstrated mitochondrial property is the possibility to be transferred from a donor cell to a recipient cell, through a system of tunneling nanotubes. Recently, a promising integrated approach involving omics sophisticate technologies has been applied in mitochondrial pathophysiology. This is still at an early stage, and further studies will clarify such complex genotype-phenotype relationships. In conclusion, mitochondria are not simple energetic organelles but represent dynamic structures communicating with the cell nucleus and even with other cells, influencing metabolism and their targets’ functions. More detailed knowledge of their involvement in disease, even though a combined omics approach, could represent a chance for new therapies

Oct-4 is highly expressed in stem/progenitor cells and in primordial follicles of the fetal human ovary

Oct-4 (Octamer-binding transcription factor 4) is a member of the POU (Pit-Oct-Unc) family. During development, Oct-4 is expressed in embryonic stem cells and in germ cell precursors. In this study, we investigated the expression of Oct-4 in the ovaries of human fetuses during gestation. The ovaries of 14 human fetuses and newborns, ranging in gestational age from 12 up to 38 weeks of gestation, were formalin-fixed, routinely processed and paraffin-embedded. Paraffin sections were immunostained with an anti-Oct-4 commercial antibody. Oct-4 expression was demonstrated in all the ovaries analyzed. Immunoreactivity for Oct-4 was detected in multiple stem/progenitor cells, including oogonia. Moreover, Oct-4 was expressed in oocytes, in primordial follicles. In ovarian stem/progenitor cells, Oct-4 was expressed in the nucleus, whereas in oocytes reactivity for Oct-4 was restricted to the cytoplasm. In the initial stages of gestation, the majority of Oct-4-positive precursor cells were detected in the external cortex. These preliminary data indicate Oct-4 as a major player in germ cell differentiation in the human ovary and as a useful marker for ovarian stem/progenitor cells. Given the ability of Oct-4 for the detection of ovarian stem/progenitor cells, further studies are needed in order to verify its ability to detect stem cells in adult ovaries

ISL-1: a new potential marker of stem/progenitor cells in the developing human uterus

The human uterus is a highly dynamic organ with peculiar plasticity and marked reproductive ability, due to the presence of a vast number of multiple stem/progenitor cell types, including endometrial, stromal and vascular progenitor cells. Conflicting results have been published regarding which uterine population might represent the real stem/progenitor cell fraction in terms of in vivo stem cell activity. Human endometrial side population (ESP) cells were shown to differentiate into multiple endometrial lineages in the stem cell niche provided by whole endometrial cells, suggesting that ESP cells might represent the most important stem/progenitor cells responsible of the cyclical regeneration of the endometrium throughout a woman’s reproductive life. This study was aimed at analyzing the localization, composition, and occurrence of stem cell niches in the human fetal uterus at different stages of development. To this end, the whole uterus was obtained at autopsy by 12 human fetuses and newborns, ranging in gestational age from 12 up to 39 weeks of gestation. Tissue paraffin sections were immunostained with antibodies against insulin gene enhancer protein (ISL-1), a transcription factor previously utilized as a marker of stem/progenitor cells in the pancreas, heart and nervous system. Reactivity for ISL-1 was detected in both epithelial and stromal uterine precursors, at all gestational ages, allowing the detection of uterine progenitor cells. The loss of reactivity for ISL-1 in some stromal cell precursors was interpreted as a sign of differentiation. These preliminary data indicate ISL-1 as a useful marker for the detection of stem/progenitor cells in the human fetal endometrium. Further studies are needed to verify the utility of ISL-1 as a marker of stem/progenitor cells in the adult endometrium

Human Breast Milk-Acquired Cytomegalovirus Infection: Certainties, Doubts And Perspectives

Breast Milk (BM) is the best source of nutrition for newborns, especially if premature. In fact, its beneficial impact on short- and long-term neonatal outcome has was deeply described. Unfortunately, BM could not be always so safe, especially due to the possible presence of maternal viruses that can shed and transferred to the breastfed neonate. Among these, Cytomegalovirus (CMV) can potentially lead to a serious and acute illness, mostly in case of low gestational age. Some studies also report the association of CMV-acquired infection to an increased risk of structural and functional brain modifications and neurological impairment. Due to these reasons, a strategy to remove CMV from BM with a minimal or absent impact on its beneficial components, would be desirable. Up to now, pasteurization, freezing, ultraviolet- C or microwave irradiation are the available techniques; they show different levels of efficacy and variable effects on BM composition, even if many studies are still needed to fully clarify these implications. In this review, we provide an update of the current evidence about these topics. We focus on the factors promoting CMV shedding through BM; moreover, the possible occurrence of a severe disease in preterm neonates is also described. Finally we investigate the potential effects showed on BM properties by the strategies that prevent or reduce viral transmission, therefore influencing newborns' healthy, and the new techniques which could show a relevant role in the next future, such as metabolomics

Breast Milk and COVID-19: From Conventional Data to “Omics” Technologies to Investigate Changes Occurring in SARS-CoV-2 Positive Mothers

In this context of COVID-19 pandemic, great interest has been aroused by the potential maternal transmission of SARS-CoV-2 by transplacental route, during delivery, and, subsequently, through breastfeeding. Some open questions still remain, especially regarding the possibility of finding viable SARS-CoV-2 in breast milk (BM), although this is not considered a worrying route of transmission. However, in BM, it was pointed out the presence of antibodies against SARS-CoV-2 and other bioactive components that could protect the infant from infection. The aim of our narrative review is to report and discuss the available literature on the detection of anti-SARS-CoV-2 antibodies in BM of COVID-19 positive mothers, and we discussed the unique existing study investigating BM of SARS-CoV-2 positive mothers through metabolomics, and the evidence regarding microbiomics BM variation in COVID-19. Moreover, we tried to correlate metabolomics and microbiomics findings in BM of positive mothers with potential effects on breastfed infants metabolism and health. To our knowledge, this is the first review summarizing the current knowledge on SARS-CoV-2 effects on BM, resuming both “conventional data” (antibodies) and “omics technologies” (metabolomics and microbiomics)

The dark side of ibuprofen in the treatment of patent ductus arteriosus: could paracetamol be the solution?

Patent Ductus Arteriosus (PDA) persistence is associated, in prematures, to several complications. The optimal PDA management is still under debate, especially regarding the best therapeutic approach and the time to treat. The available drugs are not exempt from contraindications and side effects; ibuprofen itself, although representing the first-choice therapy, can show nephrotoxicity and other complications. Paracetamol seems a valid alternative to classic Non Steroidal Anti-inflammatory Drugs, whith a lower toxicity. Areas covered: Through an analysis of the published literature on ibuprofen and paracetamol effects in preterm neonates, this review compares the available treatments for PDA, analyzing the mechanisms underlining ibuprofen-associated nephrotoxicity and the eventual paracetamol-induced hepatic damage, also providing an update of what has been yet demonstrated and a clear description of the still open issues. Expert Opinion: Paracetamol is an acceptable alternative in case of contraindication to ibuprofen; its toxicity, in this setting, is very low. Lower doses may be effective, with even fewer risks. In the future, paracetamol could represent an efficacious first-line therapy, although its safety, optimal dosage and global impact have to be fully clarified through long-term trials, also in the perspective of an individualized and person-based therapy taking into account the extraordinary individual variability

Omics in human colostrum and mature milk: Looking to old data with new eyes

Human Milk (HM) is the best source for newborn nutrition until at least six months; it exerts anti-inflammatory and anti-infective functions, promotes immune system formation and supports organ development. Breastfeeding could also protect from obesity, diabetes and cardiovascular disease. Furthermore, human colostrum (HC) presents a peculiar role in newborn support as a protective effect against allergic and chronic diseases, in addition to long-term metabolic benefits. In this review, we discuss the recent literature regarding â\u80\u9comicsâ\u80\u9d technologies and growth factors (GF) in HC and the effects of pasteurization on its composition. Our aim was to provide new evidence in terms of transcriptomics, proteomics, metabolomics, and microbiomics, also in relation to maternal metabolic diseases and/or fetal anomalies and to underline the functions of GF. Since HC results are so precious, particularly for the vulnerable pre-terms category, we also discuss the importance of HM pasteurization to ensure donated HC even to neonates whose mothers are unable to provide. To the best of our knowledge, this is the first review analyzing in detail the molecular pattern, microbiota, bioactive factors, and dynamic profile of HC, finding clinical correlations of such mediators with their possible in vivo effects and with the consequent impact on neonatal outcomes

Paracetamol in patent Ductus Arteriosus treatment: efficacious and safe?

In preterm infants, failure or delay in spontaneous closure of Ductus Arteriosus (DA), resulting in the condition of Patent Ductus Arteriosus (PDA), represents a significant issue. A prolonged situation of PDA can be associated with several short- and long-term complications. Despite years of researches and clinical experience on PDA management, unresolved questions about the treatment and heterogeneity of clinical practices in different centers still remain, in particular regarding timing and modality of intervention. Nowadays, the most reasonable strategy seems to be reserving the treatment only to hemodynamically significant PDA. The first-line therapy is medical, and ibuprofen, related to several side effects especially in terms of nephrotoxicity, is the drug of choice. Administration of oral or intravenous paracetamol (acetaminophen) recently gained attention, appearing effective as traditional nonsteroidal anti-inflammatory drugs (NSAIDs) in PDA closure, with lower toxicity. The results of the studies analyzed in this review mostly support paracetamol efficacy in ductal closure, with inconstant low and transient elevation of liver enzymes as reported side effect. However, more studies are needed to confirm if this therapy shows a real safety profile and to evaluate its long-term outcomes, before considering paracetamol as first-choice drug in PDA treatment

Regenerating the womb: The good, bad and ugly potential of the endometrial stem cells

The human endometrium is a very dynamic tissue undergoing an extraordinary growth during pregnancy and, in a cyclic manner, during the reproductive life of each woman. Endometrial stem cells (ESCs), undifferentiated auto-renewable cells able to generate daughter cells showing a higher level of differentiation, play a fundamental role in endometrial regeneration and repair. Therefore, they have a great therapeutic potential in many diseases and research fields. However, recent data suggest that an irregular function of ESCs can contribute to the pathogenesis of endometriosis and other disorders. In addition, ESCs have also been found in human leiomyomas and malignant tumours, and could be involved in their development. In this review we analyze the enormous regenerative potential of endometrium, which is, unfortunately, not exempted from its negative effects. This coexists with the good one as two faces of the same coin and constitutes the risk behind the fundamental protective and regenerative mechanisms to defend reproduction, and therefore the miracle of life itself