Buffalo colostrum peptide mitigates Parkinson's disease pathophysiology through Cullin-3 inhibition.

Colostrum/Milk is a chief repertoire of antioxidant peptides. Nuclear factor-erythroid 2 related factor 2 (Nrf2) is a viable target for Parkinson's Disease (PD), as this pathway deduced to be impaired in PD. Cullin-3 is one of the crucial E3 ligase responsible for its regulation. The present study screened peptide libraries of buffalo colostrum & milk peptides for Cullin-3 inhibition, thus ensuing activation of Nrf2 to alleviate the molecular etiopathology in PD using the C. elegans as a model. The structure was modelled, binding sites analyzed and peptide-interactions analyzed by docking. Among the 55 sequences (≤1 kDa), the peptide SFVSEVPEL having the highest dock score (-16.919) was synthesized and evaluated for its effects on oxidative stress markers, antioxidant enzymes, neurochemical marker and Nrf2/Skn-1 levels. The lead peptide alleviated the oxidative pathophysiology and behavioural deficits associated with PD in C. elegans.

Revealing the diversity of endogenous peptides and parent proteins in human colostrum and mature milk through peptidomics analysis.

Endogenous peptides and their parent proteins are important nutritional components with diverse biological functions. The objective of this study was to analyze and compare endogenous peptides and parent proteins found in human colostrum (HC) and human mature milk (HM) using a 4D label-free technique. In total, 5162 and 940 endogenous peptides derived from 258 parent proteins were identified in human milk by database (DB) search and de novo, respectively. Among these peptides, 2446 differentially expressed endogenous peptides with various bioactivities were identified. The Gene Ontology analysis unveiled the cellular components, biological processes, and molecular functions associated with these parent proteins. Metabolic pathway analysis suggested that neutrophil extracellular trap formation had the greatest significance with 24 parent proteins. These findings will offer a fresh perspective on the development of infant formula powder, highlighting the potential for incorporating these changes to enhance its nutritional composition and benefits.

Novel Multitarget ACE Inhibitory Peptides from Bovine Colostrum Immunoglobulin G: Cellular Transport, Efficacy in Regulating Endothelial Dysfunction, and Network Pharmacology Studies.

In this study, we used traditional laboratory methods, bioinformatics, and cellular models to screen novel ACE inhibitory (ACEI) peptides with strong ACEI activity, moderate absorption rates, and multiple targets from bovine colostrum immunoglobulin G (IgG). The purified fraction of the compound proteinase hydrolysate of IgG showed good ACEI activity. After nano-UPLC-MS/MS identification and in silico analysis, eight peptides were synthesized and verified. Among them, SFYPDY, TSFYPDY, FSWF, WYQQVPGSGL, and GVHTFP were identified as ACEI peptides, as they exhibited strong ACEI activity (with IC50 values of 104.7, 80.0, 121.2, 39.8, and 86.3 µM, respectively). They displayed good stability in an in vitro simulated gastrointestinal digestion assay. In a Caco-2 monolayer model, SFYPDY, FSWF, and WYQQVPGSGL exhibited better absorption rates and lower IC50 values than the other peptides and were thereby identified as novel ACEI peptides. Subsequently, in a H2O2-induced endothelial dysfunction (ED) model based on HUVECs, SFYPDY, FSWF, and WYQQVPGSGL regulated ED by reducing apoptosis and ROS accumulation while upregulating NOS3 mRNA expression. Network pharmacology analysis and RT-qPCR confirmed that they regulated multiple targets. Overall, our results suggest that SFYPDY, FSWF, and WYQQVPGSGL can serve as novel multitarget ACEI peptides.

Effect of bovine colostrum liposomes on the bioavailability of immunoglobulin G and their immunoregulatory function in immunosuppressed BALB/c mice.

Bovine colostrum (BC) has high nutritional value; however, the low bioavailability of immune active substances in BC may affect their immunoregulatory function. Our previous studies indicated that encapsulating bovine colostrum with liposomes could enable the sustained release of immunoglobulin G in vitro; however, the effect of bovine colostrum liposomes (BCLs) on the bioavailability of immunoglobulins in vivo is still unknown. In addition, the immunoregulatory function of BCLs on immunosuppressed mice is still unclear. Therefore, our current study aimed to explore the effect of BCLs on the bioavailability of immunoglobulins, and further explore their immunoregulatory effect on immunosuppressed BALB/c mice. Through metabolic cage experiments, it was shown that BCLs decreased the urine and fecal concentrations of IgG and exhibited a higher bioavailability of IgG in mice than BC (about 2-fold). In addition, by establishing an immunosuppressed animal model, it was found that BCLs could increase the body weight, spleen weight, and thymus weight in immunosuppressed BALB/c mice, which further restored the serum levels of interleukin-4 (IL-4), interleukin-10 (IL-10), tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). Through histology analysis, it was suggested that BCLs restored the structure of jejunal epithelial cells, which was accompanied by an improvement in intestinal cytokine levels (IL-4, IL-10, TNF-α, and IFN-γ). Finally, BCLs increased serum and intestine concentrations of immunoglobulin G (IgG) and immunoglobulin A (IgA) in immunosuppressed BALB/c mice, which further indicated that BCLs had a sustained-release effect for immunoglobulin G in vivo. Our current research will provide a basis for understanding the role of BCLs on the bioavailability of IgG and their immunoregulatory effect on immunosuppressed mice, which might further provide some reference for the application of BCLs.

Polarization of Melatonin-Modulated Colostrum Macrophages in the Presence of Breast Tumor Cell Lines.

Human colostrum and milk contain diverse cells and soluble components that have the potential to act against tumors. In breast cancer, macrophages play a significant role in immune infiltration and contribute to the progression and spread of tumors. However, studies suggest that these cells can be reprogrammed to act as an antitumor immune response. This study aimed to evaluate the levels of melatonin and its receptors, MT1 (melatonin receptor 1) and MT2 (melatonin receptor 2), in colostrum and assess the differentiation and polarization of the colostrum macrophages modulated by melatonin in the presence of breast tumor cells. Colostrum samples were collected from 116 mothers and tested for their melatonin and receptor levels. The colostrum cells were treated with or without melatonin and then cultured for 24 h in the presence or absence of breast tumor cells. The results showed that melatonin treatment increased the expression of MT1 and MT2 in the colostrum cells. Furthermore, melatonin treatment increased the percentage of M1 macrophages and decreased the percentage of M2 macrophages. When the colostrum macrophages were cocultured with breast tumor cells, melatonin reduced the percentage of both macrophage phenotypes and the cytokines tumor necrosis factor-alpha (TNF-α) and interleukin 8 (IL-8). These data suggest that melatonin can regulate the inflammatory process via M1 macrophages in the tumor microenvironment and, simultaneously, the progression of M2 macrophages that favor tumorigenesis.

The Effects of 12 Weeks Colostrum Milk Supplementation on the Expression Levels of Pro-Inflammatory Mediators and Metabolic Changes among Older Adults: Findings from the Biomarkers and Untargeted Metabolomic Analysis.

Senescence is a normal biological process that is accompanied with a series of deteriorations in physiological function. This study aimed to investigate the effects of bovine colostrum milk supplementation on metabolic changes and the expression of various biomarkers on inflammation, antioxidant and oxidative damage, nutrient metabolism, and genomic stability among older adults. Older adults (50-69 years old) who participated in the 12-week randomized, double-blinded, placebo-controlled trial were instructed to consume the IgCo bovine colostrum-enriched skim milk or regular skim milk (placebo) twice daily. Following 12 weeks of intervention, participants in the intervention group had lower expression levels in pro-inflammatory mediators (CRP, IL-6, and TNF-α), with significant (p < 0.05) interaction effects of the group and time observed. However, no significant interaction effect was observed in the vitamin D, telomerase, 8-OHdG, MDA, and SOD activities. UPLC-MS-based untargeted metabolomics analysis revealed that 22 metabolites were upregulated and 11 were downregulated in the intervention group compared to the placebo group. Glycerophospholipid metabolism, along with cysteine and methionine metabolism were identified as the potential metabolic pathways that are associated with bovine colostrum milk consumption. In conclusion, consuming bovine colostrum milk may induce metabolic changes and reduce the expression of various pro-inflammatory mediators, thus improving the immune function in older adults.

Endocrine changes during the peripartal period related to colostrogenesis in mammalian species.

This review discusses endocrine and functional changes during the transition from late gestation to lactation that are related to the production of colostrum in different mammalian species. Species covered in this article include ungulate species (cattle, sheep, goats, pigs, horses), rodents (rat, mouse), rabbits, and carnivores (cats, dogs), as well as humans. An immediate availability of high quality colostrum for the newborn after birth is crucial in species where a transfer of immunoglobulins (Ig) does not or only partially occur via the placenta during pregnancy. Declining activity of gestagens, in most species progesterone (P4), is crucial at the end of pregnancy to allow for the characteristic endocrine changes to initiate parturition and lactation, but the endocrine regulation of colostrogenesis is negligible. Both, the functional pathways and the timing of gestagen withdrawal differ considerably among mammalian species. In species with a sustaining corpus luteum throughout the entire pregnancy (cattle, goat, pig, cat, dog, rabbit, mouse, and rat), a prostaglandin F2α (PGF2α)-induced luteolysis shortly before parturition is assumed to be the key event to initiate parturition as well as lactogenesis. In species where the gestagen production is taken over by the placenta during the course of gestation (e.g., sheep, horse, and human), the reduction of gestagen activity is more complex, as PGF2α does not affect placental gestagen production. In sheep the steroid hormone synthesis is directed away from P4 towards estradiol-17ß (E2) to achieve a low gestagen activity at high E2 concentrations. In humans the uterus becomes insensitive to P4, as parturition occurs despite still high P4 concentrations. However, lactogenesis is not completed as long as P4 concentration is high. Early colostrum and thus Ig intake for immune protection is not needed for the human newborn which allows a delayed onset of copious milk secretion for days until the placenta expulsion causes the P4 drop. Like humans, horses do not need low gestagen concentrations for successful parturition. However, newborn foals need immediate immune protection through Ig intake with colostrum. This requires the start of lactogenesis before parturition which is not fully clarified. The knowledge of the endocrine changes and related pathways to control the key events integrating the processes of colostrogenesis, parturition, and start of lactation are incomplete in many species.

This manuscript reviews and compares hormonal and functional changes occurring in the conceptus (embryo and its extra-embryonic membranes) and their effects on the mammary gland during development from pregnancy to colostrum formation and milk production in multiple mammalian species. Declining activity of gestagens at the end of pregnancy is crucial to allow for both parturition and onset of milk production in most mammals. Strategies to achieve this state of low gestagen activity are different among species. In species where the corpus luteum is sustained throughout the entire pregnancy, luteolysis is the key event to initiate parturition and onset of milk secretion (cattle, goat, pig, cat, dog, rat, mouse, rabbit). However, in species where the placenta takes over gestagen production during the course of pregnancy, the achievement of a state of low gestagen activity is more complex. It ranges from redirection of the hormone production pathway away from gestagens in sheep, to decreasing sensitivity of the uterus towards gestagens in humans. In the horse, there is evidence pointing towards redirection of the hormone production as well as a decrease in sensitivity towards gestagens, but the exact mechanisms are still not clarified.

Fermented Bamboo Fiber Improves Productive Performance by Regulating Gut Microbiota and Inhibiting Chronic Inflammation of Sows and Piglets during Late Gestation and Lactation.

Sows exhibit metabolic syndrome and significant changes in intestinal microbiota during late gestation and lactation, affecting sow performance and piglet health. Dietary fiber (DF) is widely applied to improve sow performance by modulating gut microbiota and their by-products. Here, 60 sows were randomly allocated to groups, including CON (8% wheat bran), FBF-1 (1% fermented bamboo fiber), FBF-2 (2.5% fermented bamboo fiber), and FBF-3 (4% fermented bamboo fiber) from day 80 of gestation (G80d) to the end of lactation (L21d). Compared with CON, the FBF-3 diet decreased lactation backfat loss, increased average daily feed intake (ADFI) during lactation, and the weight gain of piglets, while supplementation of FBF increased fecal water content and reduced the rate of constipation in sows. Further, the yield and quality of milk of sows in FBF groups were improved. The FBF-3 diet significantly reduced markers of intestinal permeability (diamine oxidase and endotoxin) and systemic inflammation (interleukin-6 [IL-6] and tumor necrosis factor alpha) in sow serum during lactation, while it increased the anti-inflammatory marker (IL-10). Similarly, the piglets in the FBF-2 and FBF-3 groups had lower levels of IL-6 and higher levels of IgG, IgM, and insulin-like growth factor in serum. In addition, sows fed the 4% FBF diet had higher levels of acetate, propionate, butyrate, and total short-chain fatty acids (SCFAs) in feces than CON, and total SCFAs were promoted in piglets from the FBF-3 group. Spearman correlation analysis showed that immunity, inflammation, and intestinal microbiota are closely related to sow performance, which can affect piglet growth. The potential mechanism could be that FBF promoted the enrichment of beneficial genera such as Lachnospira, Lachnospiracea_XPB1014_Group, and Roseburia and the production of SCFAs in the sow's intestine, and reduced the relative abundance of harmful bacteria such as Fusobacterium, Sutterellaceae, and Sutterella. Meanwhile, the intake of FBF by sows affected the gut microbial composition of their offspring piglets, significantly increasing the relative abundance of beneficial bacteria Alistipes and Lachnoclostridium and decreasing the relative abundance of pathogenic bacteria Trueperella among colonic microorganisms. IMPORTANCE Dietary fiber is widely applied in the nutrition of sows due to its potential value in improving performance and intestinal health. Fermented bamboo fiber, rich in dietary fiber, has not been fully evaluated to be used in sow diets. Sows mobilize body reserves during gestation and lactation due to nutrients being prioritized for lactation purposes while feeding piglets, which generally leads to metabolism and immunity undergoing drastic changes. The main manifestations are increased inflammation and intestinal permeability and disturbed intestinal flora, which ultimately reduces the ADFI and milk quality, thus affecting the growth of piglets. The study described here is the first attempt to provide FBF for sows in late gestation and lactation can reverse this process. The 4% FBF was initially explored to have the most significantly beneficial effect. It provides a potentially effective method for dietary modification to control the gut microbiota and its metabolites to improve sow and piglet health. Moreover, the sow-piglet model offers a reference for investigating the impact of dietary fiber on the intestinal health of human mothers and infants.

Milk/colostrum exosomes: A nanoplatform advancing delivery of cancer therapeutics.

Chemotherapeutics continue to play a central role in the treatment of a wide variety of cancers. Conventional chemotherapy involving bolus intravenous doses results in severe side effects - in some cases life threatening - delayed toxicity and compromised quality-of-life. Attempts to deliver small drug molecules using liposomes, polymeric nanoparticles, micelles, lipid nanoparticles, etc. have produced limited nanoformulations for clinical use, presumably due to a lack of biocompatibility of the material, costs, toxicity, scalability, and/or lack of effective administration. Naturally occurring small extracellular vesicles, or exosomes, may offer a solution and a viable system for delivering cancer therapeutics. Combined with their inherent trafficking ability and versatility of cargo capacity, exosomes can be engineered to specifically target cancerous cells, thereby minimizing off-target effects, and increasing the efficacy of cancer therapeutics. Exosomal formulations have mitigated the toxic effects of several drugs in murine cancer models. In this article, we review studies related to exosomal delivery of both small molecules and biologics, including siRNA to inhibit specific gene expression, in the pursuit of effective cancer therapeutics. We focus primarily on bovine milk and colostrum exosomes as the cancer therapeutic delivery vehicles based on their high abundance, cost effectiveness, scalability, high drug loading, functionalization of exosomes for targeted delivery, and lack of toxicity. While bovine milk exosomes may provide a new platform for drug delivery, extensive comparison to other nanoformulations and evaluation of long-term toxicity will be required to fully realize its potential.

Bovine colostrum promoted ileal health in newborn lambs at 24 h after birth: insight from intestinal morphology and innate immunity.

The contribution of colostrum to passive immunity transfer and intestinal protection in newborn ruminants is well known; however, it is currently unclear how colostrum intake affects intestinal innate immunity. We investigated the effects of bovine colostrum intake on ileal morphology, expression of genes involved in intestinal innate immunity, and serum concentrations of inflammatory cytokines in newborn lambs. Twenty-seven newborn male Hu lambs were used, of which 18 were bottle-fed either bovine colostrum (C24h; n = 9) or bovine mature milk (M24h; n = 9) within the first 2 h after birth at an intake of approximately 8% of BW; the remaining nine lambs did not receive any feeding (N24h). Blood and ileal tissue samples were collected after the lambs were slaughtered at 24 h after birth. Ileal villus height and villus height-to-crypt depth ratio were significantly higher in C24h than those in N24h and M24h lambs (P < 0.01). Messenger RNA (mRNA) abundance of toll-like receptor (TLR)-2, TLR3, TLR4, TLR6, TLR7, TLR8 and tumour necrosis factor alpha in the ileum was lower in C24h than that in N24h lambs (P < 0.05). Moreover, C24h lambs had a lower TLR3 mRNA abundance (P < 0.01) and a trend of lower TLR6 (P = 0.06) and interleukin 1 beta (P = 0.08) expression compared with those in M24h lambs. We also observed strong positive correlations of tumour necrosis factor alpha expression with that of TLR2 (r = 0.71; P < 0.001), TLR4 (r = 0.88; P < 0.001) and TLR8 (r = 0.83; P < 0.001). Interestingly, the expression of barrier-related molecules, including mucin-13, lysozyme, claudin (CLDN)-1, CLDN2, CLDN4, CLDN7, CLDN12, occludin, zonula occluden-1 and junctional adhesion molecule-1, was consistently lower in C24h lambs than that in N24h and M24h lambs (P < 0.05). These results indicated that the beneficial roles of colostrum intake on intestinal protection in newborn lambs were associated with low TLR expression, which was reflected by improved intestinal development and reduced inflammatory response. Further studies using fluorescence in situ hybridisation and immunohistochemical methods are needed to further explore the mechanisms underlying the lower expression of intestinal barrier-related molecules due to colostrum feeding.

The impact on colostrum oxidative stress, cytokines, and immune cells composition after SARS-CoV-2 infection during pregnancy.

Background: Limited data are available regarding the differences between immunological, biochemical, and cellular contents of human colostrum following maternal infection during pregnancy with coronavirus 2 disease (COVID-19). Objective: To investigate whether maternal COVID-19 infection may affect immunological, biochemical, and cellular contents of human colostrum. Methods: Using a case-control study design, we collected colostrum from 14 lactating women with a previous diagnosis of COVID-19 during pregnancy and 12 without a clear diagnosis during September 2020 to May 2021. Colostrum samples were analysed for some enzymes and non-enzymatic oxidative stress markers (SOD, CAT, GPx, MDA, GSH, GSSG, H2O2, MPO) and for IL-1ß, IL-6, tumour necrosis factor (TNF)-α, protein induced by interferon gamma (IP)-10, IL-8, IFN-λ1, IL12p70, IFN-α2, IFN-λ2/3, granulocyte macrophage colony stimulating factor (GM-CSF), IFN-ß, IL-10 and IFN-γ, along with IgA and IgG for the SARS-CoV-2 S protein. We perform immunophenotyping to assess the frequency of different cell types in the colostrum. Results: Colostrum from the COVID-19 symptomatic group in pregnancy contained reduced levels of H2O2, IFN-α2, and GM-CSF. This group had higher levels of GSH, and both NK cell subtypes CD3-CD56brightCD16-CD27+IFN-γ+ and CD3-CD56dimCD16+CD27- were also increased. Conclusion: The present results reinforce the protective role of colostrum even in the case of mild SARS-Cov-2 infection, in addition to demonstrating how adaptive the composition of colostrum is after infections. It also supports the recommendation to encourage lactating women to continue breastfeeding after COVID-19 illness.

Proteomics analysis reveals digestion-resistant proteins from colostrum are associated with inflammatory and cytotoxic responses in intestinal epithelial cells.

BACKGROUND: Although human-milk feeding reduces the risk of necrotizing enterocolitis (NEC) in preterm infants compared with formula feeding, the exact risk-reduction mechanism remains unknown. As NEC occurs at the distal small intestine in which digestion has occurred, we applied proteomics to examine the extent to which colostrum proteins survive simulated infant in vitro-digestion and, thus, have potential to exert biological function. METHODS: Ten preterm colostrum samples were left undigested or in vitro-digested, and lipopolysaccharide (LPS)-binding protein, soluble cluster of differentiation 14, and tumor necrosis factor (TNF) receptors I and II were measured using enzyme-linked immunosorbent assay in all undigested and in vitro-digested samples. Fully differentiated Caco-2 cells were exposed to digested colostrum samples before stimulation with LPS or TNF or no stimulation. Inflammation (interleukin-8) and cytotoxicity (lactate dehydrogenase) were measured. Proteomic analyses of undigested and in vitro-digested samples were done using mass spectrometry. RESULTS: We found that most proteins in colostrum are significantly, if not completely, degraded after in vitro-digestion. We found select individual and combination digestion-resistant proteins that were positively correlated with LPS- and TNF-induced inflammation. CONCLUSION: These results indicate the importance of considering the extent to which specific dietary compounds survive digestion to reach their site of claimed action (distal intestine) and that some digestion-resistant proteins may be contributing toward "low-grade" inflammation that is necessary to promote intestinal growth and maturation during early infancy. This work provides the most detailed understanding of human-milk protein degradation with simulated infant in vitro-digestion to date.

A Neuroprotective Bovine Colostrum Attenuates Apoptosis in Dexamethasone-Treated MC3T3-E1 Osteoblastic Cells.

Glucocorticoid-induced osteoporosis (GIO) is one of the most common secondary forms of osteoporosis. GIO is partially due to the apoptosis of osteoblasts and osteocytes. In addition, high doses of dexamethasone (DEX), a synthetic glucocorticoid receptor agonist, induces neurodegeneration by initiating inflammatory processes leading to neural apoptosis. Here, a neuroprotective bovine colostrum against glucocorticoid-induced neuronal damage was investigated for its anti-apoptotic activity in glucocorticoid-treated MC3T3-E1 osteoblastic cells. A model of apoptotic osteoblastic cells was developed by exposing MC3T3-E1 cells to DEX (0-700 µM). Colostrum co-treated with DEX was executed at 0.1-5.0 mg/mL. Cell viability was measured for all treatment schedules. Caspase-3 activation was assessed to determine both osteoblast apoptosis under DEX exposure and its potential prevention by colostrum co-treatment. Glutathione reduced (GSH) was measured to determine whether DEX-mediated oxidative stress-driven apoptosis is alleviated by colostrum co-treatment. Western blot was performed to determine the levels of p-ERK1/2, Bcl-XL, Bax, and Hsp70 proteins upon DEX or DEX plus colostrum exposure. Colostrum prevented the decrease in cell viability and the increase in caspase-3 activation and oxidative stress caused by DEX exposure. Cells, upon colostrum co-treated with DEX, exhibited higher levels of p-ERK1/2 and lower levels of Bcl-XL, Bax, and Hsp70. Our data support the notion that colostrum may be able to reduce DEX-induced apoptosis possibly via the activation of the ERK pathway and modulation of the Hsp70 system. We provided preliminary evidence on how bovine colostrum, as a complex and multi-component dairy product, in addition to its neuroprotective action, may affect osteoblastic cell survival undergoing apoptosis.

Therapeutic potential of camel milk exosomes against HepaRG cells with potent apoptotic, anti-inflammatory, and anti-angiogenesis effects for colostrum exosomes.

This study aimed to evaluate and compare the therapeutic effect of camel milk exosomes derived from colostrum, early, mid, and late lactation periods on liver cancer HepaRG cells. These exosomes showed cytotoxicity on HepaRG while being safer on normal human liver THLE-2 cells. Among the four different isolated exosome groups, exosomes isolated from colostrum exhibited the highest apoptotic potential on HepaRG as indicated by highest DNA damage and upregulated expression of Bax and caspase3 expression, but with lowest Bcl2 expression. HepaRG-treated with colostrum-derived exosomes also exhibited the lowest expression of inflammation-related genes (TNFα, NFkB, TGFß1, and Cox2) and the angiogenesis-related gene VEGF. Colostrum-derived exosomes had significantly higher expression of lactoferrin and kappa casein than other milk-derived exosomes. These results indicate that colostrum-derived exosomes have a more potent anti-cancer effect on HepaRG cells than exosomes derived from the early, mid, and lat lactation periods. This effect could be mediated through induction of apoptosis and inhibition of inflammation and angiogenesis. Therefore, these exosomes could be used as safe adjuvants/carriers to deliver chemotherapeutics and to potentiate their anticancer effect on liver cancer cells.

Milk Proteins-Their Biological Activities and Use in Cosmetics and Dermatology.

Milk and colostrum have high biological potential, and due to their natural origin and non-toxicity, they have many uses in cosmetics and dermatology. Research is ongoing on their potential application in other fields of medicine, but there are still few results; most of the published ones are included in this review. These natural products are especially rich in proteins, such as casein, ß-lactoglobulin, α-lactalbumin, lactoferrin, immunoglobulins, lactoperoxidase, lysozyme, and growth factors, and possess various antibacterial, antifungal, antiviral, anticancer, antioxidant, immunomodulatory properties, etc. This review describes the physico-chemical properties of milk and colostrum proteins and the natural functions they perform in the body and compares their composition between animal species (cows, goats, and sheep). The milk- and colostrum-based products can be used in dietary supplementation and for performing immunomodulatory functions; they can enhance the effects of certain drugs and can have a lethal effect on pathogenic microorganisms. Milk products are widely used in the treatment of dermatological diseases for promoting the healing of chronic wounds, hastening tissue regeneration, and the treatment of acne vulgaris or plaque psoriasis. They are also increasingly regarded as active ingredients that can improve the condition of the skin by reducing the number of acne lesions and blackheads, regulating sebum secretion, ameliorating inflammatory changes as well as bestowing a range of moisturizing, protective, toning, smoothing, anti-irritation, whitening, soothing, and antiaging effects.

Exosomal circRNAs contribute to intestinal development via the VEGF signalling pathway in human term and preterm colostrum.

Human breast milk (HBM) provides essential nutrients for newborn growth and development, and contains a variety of biologically active ingredients that can affect gastrointestinal tract and immune system development in breastfed infants. HBM also contains mRNAs, microRNAs and lncRNAs, most of which are encapsulated in milk-derived exosomes and exhibit various important infant development related biological functions. While previous studies have shown that exosomal circRNAs are involved in the intestinal epithelial cells' proliferation and repair. However, the effect of HBM exosomal circRNAs on intestinal development is not clear. In this study, we identified 6756 circRNAs both in preterm colostrum (PC) and term colostrum (TC), of which 66 were upregulated, and 42 were downregulated (|fold change>2|, p < 0.05) in PC. Pathway analysis showed that the VEGF signalling pathway was involved, and network analysis revealed that the differentially expressed circRNAs bound various miRNAs. Further analyses showed that has_circRNA_405708 and has_circRNA_104707 were involved in the VEGF signalling pathway, and that they all bound various mirRNAs. Exosomes found in preterm colostrum (PC) and term colostrum (TC) promoted VEGF protein expression and induced the proliferation and migration of small intestinal epithelial cells (FHCs). Exosomal circRNAs found in human colostrum (HC) binding to related miRNAs may regulate VEGF signalling, and intestinal development.

Lactancia materna y COVID-19 / Breastfeeding and COVID-19

Resumen La pandemia de enfermedad por coronavirus 2019 (COVID-19) ha afectado a todas las dimensiones de la atención en salud, entre ellas el aseguramiento de la lactancia materna exclusiva y su promoción. El riesgo de contagio y las consecuencias de la pandemia han provocado preocupación entre las futuras madres o las que se ya encuentran lactando debido al riesgo de una posible transmisión del virus a través de la leche materna. Aunque aún no se ha detectado el coronavirus 2 del síndrome respiratorio agudo grave (SARS-CoV-2) activo en la leche materna. El miedo al contagio ha favorecido las políticas de aislamiento madre-hijo. Hasta el momento no existe evidencia de transmisión vertical y el riesgo de transmisión horizontal en el lactante es similar al de la población general. En lactantes con COVID-19 la lactancia materna incluso puede cambiar favorablemente el curso clínico de la enfermedad.

Abstract The COVID-19 pandemic has affected the health attention in all dimensions, one of them, the exclusive breastfeeding assurance and her promotion. The high risk of contagion and the pandemic consequences have raised a number of concerns in future mothers or those who are breastfeeding because of the risk of a possible transmission of the virus through breast milk. Although SARS-CoV2 has no evidence of being active on breast milk, the fear of contagion has favored mother-child isolation policies. At this point, there are no evidence of vertical transmission and the risk of horizontal transmission in the infant is similar to the general population. Breastfeeding in newborn with COVID-19, can even favorably change the clinical course of the disease.

Colostrogenesis: Role and Mechanism of the Bovine Fc Receptor of the Neonate (FcRn).

Colostrogenesis is a separate and unique phase of mammary epithelial cell activity occurring in the weeks before parturition and rather abruptly ending after birth in the bovine. It has been the focus of research to define what controls this process and how it produces high concentrations of specific biologically active components important for the neonate. In this review we consider colostrum composition and focus upon components that appear in first milked colostrum in concentrations exceeding that in blood serum. The Fc Receptor of the Neonate (FcRn) is recognized as the major immunoglobulin G (IgG) and albumin binding protein that accounts for the proteins' long half-lives. We integrate the action of the pinocytotic (fluid phase) uptake of extracellular components and merge them with FcRn in sorting endosomes. We define and explore the means of binding, sorting, and the transcytotic delivery of IgG1 while recycling IgG2 and albumin. We consider the means of releasing the ligands from the receptor within the endosome and describe a new secretion mechanism of cargo release into colostrum without the appearance of FcRn itself in colostrum. We integrate the insulin-like growth factor family, some of which are highly concentrated bioactive components of colostrum, with the mechanisms related to FcRn endosome action. In addition to secretion, we highlight the recent findings of a role of the FcRn in phagocytosis and antigen presentation and relate its significant and abrupt change in cellular location after parturition to a role in the prevention and resistance to mastitis infections.

Supplemental effects of dietary lysophospholipids in lactation diets on sow performance, milk composition, gut health, and gut-associated microbiome of offspring.

Dietary lysophospholipids (LPL) would influence milk composition of sows, thus positively affect intestinal health of offspring. The objective of this study was to determine effects of dietary LPL fed to lactating sows on performance, milk characteristics, gut health, and gut-associated microbiome of offspring. Sixty pregnant sows were allotted to 2 treatments in a randomized complete block design with parity and BW as blocks on day 110 of gestation. Treatments were CON (no added LPL) and LPL (0.05% LPL; Lipidol-Ultra, Pathway Intermediates, Shrewsbury, UK). Sows were fed 2 kg/d from day 110 of gestation until farrowing and ad libitum after farrowing. Diets were formulated to meet NRC requirement for lactating sows. Colostrum and milk samples from 12 sows per treatment were collected to measure nutrients and immunoglobulins on days 1 and 18 of lactation, respectively. Twelve piglets per treatment (1 piglet per litter) were euthanized on day 18 to collect tissues to measure tumor necrosis factor-α, interleukin-8 (IL-8), malondialdehyde, protein carbonyl, IgA, histomorphology, crypt cell proliferation rate, and microbiota in the jejunum and colon. Data were analyzed using the MIXED procedure of SAS, and the mortality was analyzed using the GLIMMIX procedure of SAS. There was no difference in sow BW, parity, and litter size between treatments on day 0 of lactation. Sows fed LPL had increased (P < 0.05) litter BW gain (53.9 vs. 59.4 kg) and decreased piglet mortality (13.9% vs. 10.6%) on day 18 of lactation. Sows fed LPL had increased (P < 0.05) omega-6:omega-3 (22.1 vs. 23.7) and unsaturated:saturated (1.4 vs. 1.6) fatty acids ratios with increased oleic acid (29.1% vs. 31.4%) and tended to have increased (P = 0.092) IgG (1.14 vs. 1.94 g/L) and linoleic acid (17.7% vs. 18.7%) in the milk on day 18 of lactation. Piglets from sows fed LPL had increased (P < 0.05) IL-8 (184 vs. 245 pg/mg) and crypt cell proliferation rate (39.4% vs. 40.9%) and tended to have increased (P = 0.095) Firmicutes:Bacteroidetes ratio (1.0 vs. 3.5) in the jejunum. In conclusion, sows fed with LPL had milk with increased IgG, oleic acids, and linoleic acids without changes in BW and backfat during lactation. These changes could contribute to improved survivability and intestinal health of piglets by increasing IL-8 concentration, enhancing balance among gut-associated microbiome, and increasing enterocyte proliferation in the jejunum.

Marked variability in bioactivity between commercially available bovine colostrum for human use; implications for clinical trials.

BACKGROUND: Colostrum, the milk produced during first few days after birth, is rich in immunoglobulins, antimicrobial peptides & growth factors. Multiple clinical trials using bovine colostrum are ongoing but with no assessment of test product bioactivity. OBJECTIVES: To examine variability of bioactivity between 20 commercial colostrum products, contribution of TGFß and EGFR in mediating effects, heat sensitivity of bioactivity and changes in bioactivity of colostrum milkings in the days following calving. DESIGN: In vitro bioactivity used AGS, RIE-1 and Caco-2 cell proliferation (Alamar blue) and migration (wounded monolayers) assays. Changes in colostrum bioactivity determined following addition of TGFß-neutralising antibody, EGFR blocker (Typhostin) and after heating (40-60°C, 60 min). In vivo bioassay assessed ability of colostrum gavage (2ml, 7mg/ml) to reduce gastric damage (NSAID + restraint) in rats. Milkings from 6 cows, days 0-3 post calving were assessed for bioactivity and growth factor concentrations. RESULT: Six-fold differences in pro-proliferative and migratory activity were seen comparing commercial products. Comparison of most- and least-active samples from in vitro studies showed two- to three-fold differences in ability to reduce gastric injury (86% reduction using most-active vs 48% using least-active, p<0.01). Tyrphostin reduced pro-migratory and proliferative activity by 23% and 55%. TGFß neutralisation reduced migratory activity by 83% but did not affect proliferation Heating colostrum powder to 50°C did not affect immunoactivity of haptoglobin, EGF, TGFß, IgG, IGF-1 or betacellulin but decreased bioactivity by >40%. Milking studies showed high bioactivity during first and second milkings on day 0 but 77% reduction by day 3. Changes in total protein, haptoglobin, EGF, TGFß, IgG and IGF-1 paralleled falls in bioactivity. CONCLUSION: Commercial colostrum products possess widely different bioactivity. Variation in heat exposure and/or proportion of day 0 colostrum content may contribute to this. Assessment of colostrum bioactivity has advantages to growth factor quantitation for quality control.