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Pediatric infections account for approximately one-third of all deaths in children under 5 years globally. Lactoferrin (LF) supplementation has the potential to reduce infection-related morbidity due to its antimicrobial, anti-inflammatory, and immunoregulatory properties. We conducted a systematic review and meta-analysis of oral LF supplementation randomized controlled trials in population under 18 years old. The primary outcomes were infection-associated outcomes: late onset sepsis (LOS), diarrhea, and upper respiratory infections (URIs). We also analyzed mortality among LOS studies. Of 1594 citations identified, 25 studies met eligibility criteria, including 10 studies of LOS, 14 of diarrhea, and 8 of URI. LF supplementation was associated with fewer patients with culture-proven or probable neonatal LOS compared to placebo (odds ratio (OR): 0.60; 95% confidence interval (CI): 0.42-0.86), with fewer patients with diarrhea compared to placebo in children (OR: 0.56; 95% CI: 0.41-0.75), and no significant fewer patients with URI (OR: 0.61; 95% CI: 0.27-1.40). Before LF can be used as a public health intervention, it is necessary to refine some aspects of the design of future trials. Ideally these trials should be conducted in countries with the highest burden of infections, where the potential benefit is expected to have the largest impact. © 2025 The Author(s). Permission for reuse (free in most cases) can be obtained from copyright.com.

BACKGROUND: The network meta-analysis (NMA) investigated the efficacy of six food supplements, namely glutamine, arginine, lactoferrin, prebiotics, synbiotics, and probiotics, in preventing necrotizing enterocolitis in premature infants. METHODS: MEDLINE, Embase, and Cochrane Library were searched. Randomized controlled trials comparing different food supplements for premature infants were included. RESULTS: Probiotics (OR, 0.47; 95% CrI, 0.33-0.63), arginine (OR, 0.38; 95% CrI, 0.14-0.98), glutamine (OR, 0.30; 95% CrI, 0.079-0.90), and synbiotics (OR, 0.13; 95% CrI, 0.037-0.37). were associated with a decreased incidence of NEC. Only probiotics (OR, 0.81; 95% CrI, 0.69-0.95) and lactoferrin (OR, 0.74; 95% CrI, 0.54-0.92) achieved lower risk of sepsis. Probiotics (OR, 0.58; 95% CrI, 0.40-0.79), prebiotics (OR, 0.23; 95% CrI, 0.043-0.86), and synbiotics (OR, 0.15; 95% CrI, 0.035-0.50) were associated with lower odds of mortality. Probiotics (MD, -2.3; 95% CrI: -3.7- -0.63) appeared to have earlier age of attainment of full feeding. CONCLUSIONS: Based on this NMA, probiotics and synbiotics had the potential to be the top two preferable food supplements.

Erratum in JAMA Pediatr. 2024 Jan 1;178(1):99. doi: 10.1001/jamapediatrics.2023.5514. Comment in JAMA Pediatr. 2023 Nov 1;177(11):1129-1131. doi: 10.1001/jamapediatrics.2023.3856. J Obstet Gynecol Neonatal Nurs. 2024 Mar;53(2):101-105. doi: 10.1016/j.jogn.2024.01.006. IMPORTANCE: Modulation of intestinal microbiome by administering probiotics, prebiotics, or both may prevent morbidity and mortality in premature infants. OBJECTIVE: To assess the comparative effectiveness of alternative prophylactic strategies through a network meta-analysis (NMA) of randomized clinical trials. DATA SOURCES: MEDLINE, EMBASE, Science Citation Index Expanded, CINAHL, Scopus, Cochrane CENTRAL, and Google Scholar from inception until May 10, 2023. STUDY SELECTION: Eligible trials tested probiotics, prebiotics, lactoferrin, and combination products for prevention of morbidity or mortality in preterm infants. DATA EXTRACTION AND SYNTHESIS: A frequentist random-effects model was used for the NMA, and the certainty of evidence and inferences regarding relative effectiveness were assessed using the GRADE approach. MAIN OUTCOMES AND MEASURES: All-cause mortality, severe necrotizing enterocolitis, culture-proven sepsis, feeding intolerance, time to reach full enteral feeding, and duration of hospitalization. RESULTS: A total of 106 trials involving 25 840 preterm infants were included. Only multiple-strain probiotics were associated with reduced all-cause mortality compared with placebo (risk ratio [RR], 0.69; 95% CI, 0.56 to 0.86; risk difference [RD], -1.7%; 95% CI, -2.4% to -0.8%). Multiple-strain probiotics alone (vs placebo: RR, 0.38; 95% CI, 0.30 to 0.50; RD, -3.7%; 95% CI, -4.1% to -2.9%) or in combination with oligosaccharides (vs placebo: RR, 0.13; 95% CI, 0.05 to 0.37; RD, -5.1%; 95% CI, -5.6% to -3.7%) were among the most effective interventions reducing severe necrotizing enterocolitis. Single-strain probiotics in combination with lactoferrin (vs placebo RR, 0.33; 95% CI, 0.14 to 0.78; RD, -10.7%; 95% CI, -13.7% to -3.5%) were the most effective intervention for reducing sepsis. Multiple-strain probiotics alone (RR, 0.61; 95% CI, 0.46 to 0.80; RD, -10.0%; 95% CI, -13.9% to -5.1

Lactoferrin (Lf) is a glycoprotein present in human and bovine milk with antimicrobial and immune-modulating properties. This review aimed to examine the evidence for the effect of Lf supplementation on inflammation, immune function, and respiratory tract infections (RTIs) in humans. Online databases were searched up to December 2020 to identify relevant, English-language articles that examined the effect of Lf supplementation in human subjects of all ages, on either inflammation, immune cell populations or activity, or the incidence, duration, or severity of respiratory illness or RTIs. Twenty-five studies (n = 20 studies in adults) were included, of which 8 of 13 studies (61%) in adults reported a decrease in at least 1 systemic inflammatory biomarker. Immune function improved in 6 of 8 studies (75%) in adults, with changes in immune cell populations in 2 of 6 studies (33%), and changes in immune cell activity in 2 of 5 studies (40%). RTI outcomes were reduced in 6 of 10 studies (60%) (n = 5 in adults, n = 5 in children), with decreased incidence in 3 of 9 studies (33%), and either decreased frequency (2/4, 50%) or duration (3/6, 50%) in 50% of studies. In adults, Lf reduced IL-6 [mean difference (MD): -24.9 pg/mL; 95% CI: -41.64, -8.08 pg/mL], but not C-reactive protein (CRP) [standardized mean difference: -0.09; 95% CI: -0.82, 0.65], or NK cell cytotoxicity [MD: 4.84%; 95% CI: -3.93, 13.60%]. RTI incidence was reduced in infants and children (OR: 0.78; 95% CI: 0.61, 0.98) but not in adults (OR: 1.00; 95% CI: 0.76, 1.32). Clinical studies on Lf supplementation are limited, although findings show 200 mg Lf/d reduces systemic inflammation, while formulas containing 35-833 mg Lf/d may reduce RTI incidence in infants and children, suggesting improved immune function. Future research is required to determine optimal supplementation strategies and populations most likely to benefit from Lf supplementation. This trial was registered at PROSPERO (https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021232186) as CRD42021232186. © The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.

INTRODUCTION: The aim of this systematic review was to report the role of lactoferrin supplementation for the prevention of preterm birth (PTB) in women at risk. EVIDENCE ACQUISITION: PubMed and Embase databases were searched. Inclusion criteria were studies exploring maternal and perinatal outcomes in women at high-risk for preterm birth receiving compared to those not receiving lactoferrin during pregnancy. The primary outcome was preterm PTB<37 weeks; the secondary outcomes were gestational age at birth, PTB<34 and 28 weeks, preterm premature rupture of the membranes (PPROM), chorioamnionitis and admission to Neonatal Intensive Care Unit. Random effect meta-analyses were used to analyze the data. EVIDENCE SYNTHESIS: Six studies (333 pregnancies) were included. Overall, women taking lactoferrin had a lower risk of PTB<37 weeks of gestation with an OR of 0.43 (95% CI: 0.2-0.9). Likewise, gestational age at delivery was higher in women-taking compared to those not-taking lactoferrin (MD=0.46 weeks, SD=0.17, P=0.006). The other included studies explored the role of lactoferrin in affecting the inflammatory profile in the amniotic fluid of women undergoing invasive test, without reporting its actual role in preventing PTB. CONCLUSIONS: Prophylactic administration of lactoferrin can reduce the risk of PTB in women at risk. Further large and adequately powered randomized trial are needed in order to elucidate the actual role of lactoferrin in reducing the risk of preterm birth and in affecting perinatal outcomes in women at risk.

Ferrous sulfate is a commonly used iron supplement for the correction of iron-deficiency anemia but with frequent gastrointestinal side effects. Milk-derived iron-binding glycoprotein lactoferrin possesses well gastrointestinal tolerance and fewer side effects caused by the intake of high-dose iron. However, the underlying mechanism of the iron-enhancing effect of lactoferrin remains unclear. In addition, the comparative efficacies between lactoferrin and ferrous sulfate are also remained to be determined. We conducted a systematic review and meta-analysis on published intervention studies to investigate how lactoferrin modulate iron metabolism and evaluate the comparative effects between lactoferrin and ferrous sulfate supplementation on iron absorption, iron storage, erythropoiesis and inflammation. Lactoferrin supplementation had better effects on serum iron (WMD: 41.44 ug/dL; p < 0.00001), ferritin (WMD: 13.60 ng/mL; p = 0.003) and hemoglobin concentration (11.80 g/dL; p < 0.00001), but a reducing effect on fractional iron absorption (WMD: −2.08%; p = 0.02) and IL-6 levels (WMD: −45.59 pg/mL; p < 0.00001) compared with ferrous sulfate. In conclusion, this study supports lactoferrin as a superior supplement to ferrous sulfate regarding the improvement in serum iron parameters and hemoglobin levels. Considering the weak influence of lactoferrin on iron absorption, the anti-inflammation effect of lactoferrin may be the potential mechanism to explain its efficacy on iron status and erythropoiesis.

BACKGROUND: Lactoferrin (Lf) is one of the key immunomodulatory substances found naturally in various body fluids, such as saliva, tears, and breast milk, and forms a vital part of the innate defense against invading pathogens. Various studies have demonstrated antibacterial, antifungal, and antiviral properties of Lf and its protective role against respiratory tract infections (RTIs). The present meta-analysis aims to elucidate the association of Lf administration in reducing the risk of RTIs by systematically reviewing the data from randomized controlled trials (RCTs). METHODS: We systematically searched PubMed, Cochrane Library, Medline & CINAHL, Turning Research into Practice (TRIP), ProQuest Theses & Dissertations Databases, and China National Knowledge Infrastructure (CNKI) from inception till March 15, 2021. The primary outcome measure was a reduction in respiratory illness; decrease in frequency, symptoms, and duration. Random-effects model was used to estimate the odds ratio (OR) and 95% confidence interval (CI). We used Cochrane's RoB-2 to appraise the risk of bias of included RCTs. RESULTS: A total of nine RCTs were eligible for this review, of which six were included in the meta-analysis. Overall, two studies demonstrated a high risk of bias. The meta-analysis revealed a significantly reduced odds of developing respiratory infections with the use of Lf relative to the control (pooled odds ratio = 0.57; 95% confidence interval 0.44 to 0.74, n = 1,194), with sufficient evidence against the hypothesis of 'no significant difference' at the current sample size. CONCLUSIONS: The administration of Lf shows promising efficacy in reducing the risk of RTIs. Current evidence also favours Lf fortification of infant formula. Lf may also have a beneficial role in managing symptoms and recovery of patients suffering from RTIs and may have potential for use as an adjunct in COVID-19, however this warrants further evidence from a large well-designed RCT.

Feeding preterm infants with mother's own milk is associated with a reduction in postnatal complications and an improved neurocognitive outcome. Therefore, the bioactive factor composition of human milk has been used as a tool for the development of nutritional supplements with a potential prophylactic or therapeutic effect. The aim of this systematic review was to provide an overview on bioactive factors which have been studied as supplement to enteral nutrition in randomized controlled trials, and to provide an overview of ongoing trials. MEDLINE, EMBASE, CENTRAL, and clinical trial registers were searched. Studies on the antimicrobial protein lactoferrin were excluded as these were summarized very recently in three separate systematic reviews. Studies on vitamins D, K and iron were also excluded as they are already incorporated in most international guidelines. We identified 17 different bioactive factors, which were investigated in 26 studies. Despite the encouraging potential effects of several bioactive factors, more high-quality studies with a sufficient number of preterm infants are required before a certain factor may be implemented into clinical practice. Three large trials (n > 500) that investigate the effects of either enteral insulin or vitamin A are currently ongoing and could provide more definite answers on these specific supplements.

In this commentary, we summarize the current evidence from randomized controlled trials on enteral lactoferrin supplementation in preterm neonates. Our recently completed systematic review includes 12 randomized controlled trials performed all over the world. Our meta-analysis suggests clinical benefit in decreasing late-onset sepsis, late-onset fungal sepsis, length of stay in the hospital and urinary tract infections. There were no adverse effects. There was no statistically significant decrease in necrotizing enterocolitis, mortality or neurodevelopmental impairment in lactoferrin supplemented preterm infants. There was significant statistical heterogeneity in the effects of lactoferrin on late-onset sepsis between larger and smaller studies, which may reflect either small study biases, differences in the effectiveness, dose or duration of supplemental lactoferrin products, or differences in underlying population risk, or any or all of these.

BACKGROUND: Lactoferrin, a normal component of human colostrum and milk, can enhance host defenses and may be effective for prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates. OBJECTIVES: To assess the safety and effectiveness of lactoferrin supplementation to enteral feeds for prevention of sepsis and NEC in preterm neonates. Secondarily, we assessed the effects of lactoferrin supplementation to enteral feeds on the duration of positive-pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to update our search. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 9), MEDLINE via PubMed (1966 to 20 January 2020), PREMEDLINE (1996 to 20 January 2020), Embase (1980 to 20 January 2020), and CINAHL (1982 to 20 January 2020). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA: In our search, we included randomized controlled trials (RCTs) evaluating enteral lactoferrin supplementation at any dose or duration to prevent sepsis or NEC in preterm neonates. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal and the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Meta-analysis of data from twelve randomized controlled trials showed that lactoferrin supplementation to enteral feeds decreased late-onset sepsis (typical RR 0.82, 95% CI 0.74 to 0.91; typical RD -0.04, 95% CI, -0.06, -0.02; NNTB 25, 95% CI 17 to 50; 12 studies, 5425 participants, low-certainty evidence) and decreased length of hospital stay (MD -2.38, 95% CI, -4.67, -0.09; 3 studies, 1079 participants, low-certainty evidence). Sensitivity analysis including only good methodological certainty studies suggested a decrease in late-onset sepsis with enteral lactoferrin supplementation (typical RR 0.87, 95% CI, 0.78, 0.97; typical RD -

BACKGROUND AND OBJECTIVE: Lactoferrin is an iron-binding glycoprotein existing in mammalian milk. It has immunomodulatory, antioxidant, and anti-inflammatory properties, and it can also regulate metabolism. The present study investigated the effect of lactoferrin in obese children and adolescents with metabolic dysfunction-associated steatotic liver disease. METHODS: This randomized controlled trial was performed on 73 obese children and adolescents with metabolic dysfunction-associated steatotic liver disease. The patients were randomized into two groups: group I, who received lactoferrin 100 mg once daily for 3 months, and group II, who did not receive lactoferrin or placebo as the control group. Both groups were on a hypocaloric diet. Measurements of weight, body mass index, alanine aminotransferase, aspartate aminotransferase, fasting blood glucose, fasting insulin, homeostatic model assessment method of insulin resistance, lipid profile, homocysteine, malondialdehyde, interleukin-6, and interleukin-10 were assessed at baseline and after 3 months of treatment. RESULTS: Seventy patients completed the study. After 3 months of treatment, the lactoferrin group had a significantly lower weight, body mass index (28.7 ± 1.48 vs 30.2 ± 1.45, p < 0.001), alanine aminotransferase (47.7 ± 4.4 vs 56.4 ± 4.3, p < 0.001), homeostatic model assessment method of insulin resistance (2.86 ± 0.43 vs 3.08 ± 0.4, p = 0.03), aspartate aminotransferase, fasting blood glucose, total cholesterol, triglycerides, homocysteine, malondialdehyde, and interleukin-6 compared with the control group and the pre-treatment levels. CONCLUSIONS: Lactoferrin may help in weight reduction, improve insulin resistance and lipid profile, and decrease oxidative stress and inflammation in obese children and adolescents with metabolic dysfunction-associated steatotic liver disease. CLINICAL TRIAL REGISTRATION: The clinical trial was registered at Pan African Clinical Trial Registry with ID: PACTR202302847529384,T https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=24309 . © 2026. The Author(s).

OBJECTIVES: Two infant formulas with unique combinations of 1,3-dioleoyl-2-palmitoyl-sn-glycerol sn2 palmitate, galactooligosaccharide, polydextrose, fructooligosaccharide, β-carotene, lutein, α-lactalbumin, osteopontin, and lactoferrin were evaluated for non-inferiority compared to a commercially available formula. METHODS: In a randomized, controlled, parallel-arm, double-blind, multicenter, non-inferiority study, eligible infants were enrolled to receive an experimental (BBN-001 [Part 1; N = 129], BBN-102 [Part 2; N = 117]) formula or commercial formula (Brand; N = 143) for 120 days (Clinical Trials.gov NCT03331276). Infants were considered eligible if they were healthy, term (≥ 37 and ≤ 42 weeks of gestation), singleton newborns, with a birth weight of at least 2,500 g, and no more than 14 postnatal days-of-age. Anthropometric growth, formula intake, gastrointestinal tolerance, and adverse events were measured throughout the study, and fecal soap fatty acids were measured at the end. The primary endpoint was weight gain at the end of the trial, with treatment groups to be considered non-inferior if their weight gain was > -3 g/d compared to the control group. RESULTS: Both experimental formulas were non-inferior to the Brand formula according to anthropometric outcomes. Formula intake, total adverse events, and stool frequency and consistency were similar to Brand formulas. Some measures of gassiness and fussiness improved in the experimental formulas (P < 0.05). Fecal calcium increased and fecal palmitic acid soaps decreased in both experimental formulas (all P ≤ 0.045), and total soap fatty acids were decreased in the BBN-102 group compared to the Brand group (P = 0.020). CONCLUSIONS: The experimental formulas were well tolerated and deemed non-inferior to those of a Brand formula. The experimental formulas improved some measures of gastrointestinal tolerance compared to standard commercially available infant formulas. TRIAL REGISTRATION: ClinicalTrials.gov NCT03331276. Copyright: © 2025 Fleming et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and r

OBJECTIVES: The aim of this follow-up was to investigate how reduced iron concentration and added bovine lactoferrin in infant formula affect neurodevelopment, iron status, and growth at 12 months of age. METHODS: Swedish healthy term formula-fed infants (n = 180) were randomly assigned to receive, from 6 weeks to 6 months of age, a low-iron formula (2 mg/L) fortified with bovine lactoferrin (1.0 g/L) (Lf+, n = 72), the same formula without lactoferrin fortification (Lf-, n = 72) or a control standard formula with 8 mg/L and no lactoferrin (CF, n = 36). Breast-fed infants were recruited as a reference (n = 72). At 12 months of age, Bayley Scales of Infant and Toddler Development-III (BSID-III), iron status, and anthropometrics were assessed. RESULTS: There were no intervention effects on BSID-III. Explored outcomes were unaffected by lactoferrin and the two low-iron groups (Lf+ and Lf-) were combined. The low-iron group had lower hepcidin (37.8 vs. 49.4 ng/mL, p = 0.027), compared to the CF group. Furthermore, they had iron status indicators more similar to the breast-fed reference group. The prevalence of iron deficiency (ID) and iron deficiency anemia (IDA) was low with no significant differences among groups. Weight and length were unaffected by intervention, however head circumference was minimally higher in infants fed low-iron formula compared to CF with mean difference (95% confidence interval) of 0.3 (0.0-0.6) standard-deviation-scores, p = 0.03. CONCLUSIONS: Infant formula iron concentration at 2 mg/L was adequate in this population of infants with low risk of ID. Adding bovine lactoferrin did not affect the explored long-term clinical outcomes. © 2025 The Author(s). Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

BACKGROUND: Accumulation of dental plaque can lead to gingival problems. A fluoride toothpaste containing naturally occurring enzymes and proteins has been shown to improve gingival health and reduce supragingival plaque in European populations. The objective of the current study was to evaluate the ability of this toothpaste to improve gingival condition and reduce supragingival plaque in an alternative study population. METHODS: This was a double-blind (participant, examiner, investigator, statistician), randomised, parallel group, efficacy study conducted at a Chinese university dental hospital. Participants (age 18-70) with a mean Gingival Index (GI) ≥ 1.0 and mean Modified Quigley and Hein Plaque Index (MQHPI) ≥ 1.5 were randomised at baseline using sex stratification to twice-daily brushing with either test toothpaste (n=127) or control fluoride toothpaste (n=124) for 26 weeks. Assessments of GI (primary outcome) and MQHPI were conducted at baseline and after 4, 13 and 26 weeks of product use. Results were analysed using ANCOVA model for between product comparison (α= 0.05). RESULTS: One hundred and six participants using test toothpaste and 92 using control toothpaste completed the study. The test toothpaste showed significantly greater improvements in gingival health than the control toothpaste. The estimated differences in GI between groups were -0.18 (95% CI: -0.23 to -0.12) at week 4, -0.16 (95% CI: -0.20 to -0.11) at week 13, and -0.53 (95% CI: -0.60 to -0.46) at week 26 (all p < 0.0001). Similarly, reductions in supragingival plaque were greater in the test group, with differences in MQHPI of -0.29 (95% CI: -0.38 to -0.21) at week 4, -0.35 (95% CI: -0.45 to -0.25) at week 13, and -0.96 (95% CI: -1.06 to -0.85) at week 26 (all p < 0.0001). CONCLUSIONS: The study demonstrated that a toothpaste containing naturally occurring enzymes and proteins significantly improved gingival health and reduced supragingival plaque compared to a control toothpaste, after 4, 13, and 26 weeks of use. CLINICAL TRIAL REGISTRATION: NCT06932211 (retrospectively registered on April 17, 2025). © 2025. The Author(s).

Background/Objectives: Late-onset neonatal sepsis (LOS) remains a leading cause of morbidity and mortality in very low birth weight (VLBW) infants (<1500 g and/or gestational age <32 weeks), with limited preventive strategies. We evaluated whether early enteral bovine lactoferrin (bLf), given its antimicrobial, immunomodulatory, and antioxidant properties, reduces LOS and improves immunologic, antioxidant, and hematologic markers in these infants. Methods: In this randomized, double-blind, placebo-controlled trial, 103 VLBW infants received bLf (150 mg/kg/day; n = 50) or the placebo (n = 53) within 72 h of birth for four weeks or until discharge. Outcomes included culture-confirmed LOS, mortality, and major morbidities. Risk ratios (RRs) were calculated, adjusting for gestational age, human milk intake, and ventilatory support when ≥25 events occurred. Pre/post changes in cytokines, total antioxidant capacity (TAC), and hemoglobin (Hb) were analyzed for interaction effects (time x intervention). Results: bLf reduced LOS (adjusted RR 0.54; 95% CI 0.31-0.93; p = 0.028), without differences in other morbidities or mortality. bLf preserved MCP-1 levels, declining in the placebo group (interaction p = 0.022). Among LOS infants receiving bLf, IL-6 remained stable and MCP-1 increased, while both declined in other groups (interaction p = 0.007 for IL-6; p = 0.052 for MCP-1). Although TAC showed a non-significant interaction, the placebo group declined (p = 0.002), while bLf remained stable (p = 0.400) in the post hoc analysis. In non-transfused infants, bLf increased Hb by 0.9 g/dL vs. controls (p = 0.028). Conclusions: Early bLf supplementation safely reduces LOS in VLBW infants and may support immunologic, antioxidant, and hematologic stability.

PURPOSE: This study aimed to examine the acute effects of continuous and interval cycling on salivary secretory immunoglobulin A (SIgA) and anti-microbial peptides. METHODS: In a randomized crossover trial, 12 healthy young untrained men (22 ± 1 years) performed two exercise patterns: continuous exercise (CE) for 20-min cycling load equivalent to 70% maximal oxygen uptake (V·O2max) and interval exercise (IE) for 20-min cycling exercise, with five sets of 2 min at 50% V·O2max and five sets of 2 min at 90% V·O2max. Saliva samples were collected at baseline and post-0 min and post-30 min after exercise. We evaluated salivary SIgA as well as salivary lysozyme, lactoferrin, human β-defensin-2, and LL-37 as the anti-microbial peptides at each time point. RESULTS: In the CE trial, the salivary SIgA secretion rate decreased immediately after exercise (p = 0.0002). However, in the IE trial, the salivary SIgA secretion rate did not change. In addition, the percentage change in salivary SIgA secretion rate immediately after exercise decreased in the CE as compared to the IE (CE: -37.6 ± 19.7% vs IE: 3.6 ± 33.6%, p = 0.0014). However, salivary lysozyme, lactoferrin, human β-defensin-2, and LL-37 secretion rates did not change from baseline to after exercise in both trials. CONCLUSION: These results suggest that salivary SIgA secretion may differ between acute CE and IE, whereas secretory responses to salivary anti-microbial peptides may not differ. © 2025. The Author(s).

Background: Sepsis remains a significant cause of morbidity and mortality in preterm and low birth weight (LBW) neonates, especially in low- and middle-income countries (LMICs). Lactoferrin, a glycoprotein present in breast milk with antimicrobial activity, is a low-cost, readily available, and promising intervention currently under investigation. The available literature presents conflicting results on the impact of lactoferrin on the risk of late-onset sepsis (LOS). This study evaluated the effectiveness of two doses of bovine lactoferrin (bLF) supplementation in preventing LOS and necrotizing enterocolitis (NEC) in preterm and LBW neonates in Pakistan. Methods: A three-arm, double-blind, placebo-controlled, randomized clinical trial in the neonatal intensive care unit of Aga Khan University was conducted from July 2019 to August 2020. Preterm (28 to 36 + 5 weeks gestational age) and low birth weight (≥1000 g to <2500 g) neonates who established enteral feeding by 72 h were eligible. The exclusion criteria included sepsis before randomization, maternal history of chorioamnionitis or group B streptococcus colonization, and congenital anomalies. Enrolled neonates were randomly assigned in a 1:1:1 ratio using a computer-generated random allocation sequence to receive placebo (D-glucose), 150 mg bLF, or 300 mg bLF mixed with breast milk once daily for 28 days. The study staff, parents, and outcome assessors were blinded to the allocation. The primary outcome was late-onset sepsis from the trial entry to 28 days. The secondary outcome was NEC from the trial entry to 28 days. Neonates were followed weekly for 28 ± 2 days, and episodes of LOS and NEC were recorded. Results: Of 305 neonates enrolled, 102, 102, and 101, respectively, were randomized to receive a placebo (arm A), 150 mg bLF (arm B), and 300 mg bLF (arm C), respectively. Outcome data of 291 participants (99 in arm A, 95 in arm B, and 97 in arm C) were available for inclusion in the intention-to-treat analysis. The frequency of culture-proven sepsis was 8/102 (7.8%) in arm A compared to 1/102 (0.98%) (p = 0.020) in arm B and 5/101 (4.9%) in arm C (p = 0.390). We did not find any difference in episodes of

BACKGROUND: Prevention of a very prevalent problem such as urinary tract infections (UTIs), is of utmost importance, particularly during pregnancy, in order to limit the irrational use of antibiotics. Lactoferrin (Lf) has proven in vivo and in vitro antibacterial actions, especially against Escherichia coli, which is the main causative organism of UTIs. The study question is, "Does the administration of Lf to pregnant women with a history of RUTIs reduce the incidence of new episodes of UTIs during pregnancy?". METHODS: This was a randomized controlled study over 6 months that started from February 2024 to August 2024, conducted at the antenatal clinic of El-Shatby University Hospital, Alexandria, Egypt. The study included 220 pregnant women (14-24 weeks' gestation) who had experienced two or more UTI episodes in the previous six months. A negative urine culture right before enrollment was an inclusion criterion. Participants were randomly allocated into two groups; 110 women received a daily dose of 200 mg of lactoferrin, and 110 women as controls. Women were followed up by urine cultures and sensitivity monthly, and they were asked to report any symptoms of UTIs present. The outcomes were the number of episodes of asymptomatic bacteriuria (ASB), acute cystitis, or pyelonephritis in both groups. RESULTS: A total of 874 urine samples were collected from women in both groups (438 from the Lf group and 436 from the control group), and their results were analyzed. Over the follow-up period we diagnosed 164 episodes of ASB (33 episodes in the lactoferrin group versus 131 episodes in the control group) and 46 episodes of acute cystitis (4 episodes in the lactoferrin group versus 42 episodes in the control group) were diagnosed. These results were statistically significant (P < 0.00001). No episodes of pyelonephritis were observed in our study cohort. Escherichia coli (E. coli) was the most prevalent isolated organism, accounting for 27% of the ASB episodes in the lactoferrin group and 51% of the ASB episodes in the control group. Similarly, E. coli was isolated in 25% of acute cystitis episodes in the Lf group and 45.2% in the control group. In the exposed group, Lf

BACKGROUND: It is plausible that one of the key biological pathways through which kangaroo mother care (KMC) improves health outcomes in low birth weight (LBW) infants is by enhancing human milk intake and quality. This hypothesis needs to be tested. OBJECTIVES: This study aims to estimate the effect of promotion and support of KMC in LBW infants compared with control during the neonatal period on human milk intake and human milk components. METHODS: We randomly assigned 550 LBW infants (1500-2250 g) to the intervention arm with promotion of and support for continuous skin-to-skin contact and exclusive breastfeeding through home visits or to no such intervention (control) during the neonatal period. All infants received routine home-based postnatal care visits. We estimated human milk intake by the infant over a 14-d period using the deuterium dilution technique and measured the concentration of carbohydrate, protein and amino acids, fat, lactoferrin, and secretory immunoglobulin A (sIgA) in human milk of a subsample of 250 mothers. RESULTS: The mean infant human milk intake was 331 ± 144 g/d or 142 ± 57 g/kg/d in the control arm and 368 ± 135 g/d or 154 ± 50 g/kg/d in the intervention arm participants, yielding a mean difference of 37 [95% confidence interval (CI): 12, 63] g/d or 12 (95% CI: 2, 22) g/kg/d. The mean concentration of carbohydrate in human milk in the intervention arm was 51.2 ± 6.1 g/L against 50 ± 6.8 g/L in the control arm. The corresponding values for protein were 15.0 ± 2.9 g/L and 16.3 ± 4.6 g/L, respectively. We did not find any substantial differences in the concentration of amino acids, fat, lactoferrin, or sIgA between the study arms. CONCLUSIONS: Our findings show that KMC is associated with a substantially higher human milk intake in LBW infants during the neonatal period. There was no evidence of any effect of KMC on the concentration of several human milk components. This trial was registered at Clinical Trials Registry-India as CTRI/2017/04/008430.

Environmental enteric dysfunction (EED) is a subacute syndrome characterized by increased intestinal inflammation and permeability that affects children in low-income countries. It is associated with growth and neurodevelopmental deficits, and there is currently no known treatment for EED. VS001 (AmiLyfe Bioscience, LLC, Norwood, MA) is a medical food (beverage) containing free amino acids that has been shown to decrease enteric inflammation and improve gut permeability in murine models. We conducted a double-blind, placebo-controlled pilot study to assess the acceptability and tolerability of VS001 in Bangladeshi children aged 1-2 years (n = 10 per arm). We also examined the effects on EED biomarkers (lactulose-mannitol (LM) ratio, fecal lactoferrin, alpha-antitrypsin, myeloperoxidase, and neopterin). Participants received 8 oz. of VS001 or an identical vehicle without amino acids daily for 14 days. Tolerability and acceptability were measured using parental surveys and daily in-home adverse event monitoring. Subjects took an average of 118 minutes to complete the dose each day. Caregivers found the product convenient and easy to administer and either agreed or strongly agreed that they would give this product to their child again. None reported that the intervention negatively affected their child's appetite. There were three mild adverse events deemed possibly related to the intervention, with two occurring in the active arm and one in the control arm. Children in the active arm exhibited a nonsignificant decrease in LM ratios (a marker of intestinal permeability) after treatment compared with the control arm (0.19-0.08 versus 0.19-0.17; P = 0.16). VS001 was acceptable to parents and reasonably well tolerated. Given the decrease in permeability observed in the active arm, a larger trial is warranted.

Antimicrobial resistance (AMR) poses a significant global health threat; a major group of AMR organisms are the ESKAPE pathogens. Among these, Gram-negative ESKAPE organisms are particularly concerning due to their extensive contribution to morbidity and mortality. These bacteria are highly adaptable to stressful environments and rapidly develop resistance to antibiotics, often within a few years. Consequently, there is an imperative need to identify novel pathways and molecules for their inhibition. Lactoferrin (LF) is a key innate immune protein recognized for its antimicrobial, immunomodulatory, iron-sequestering, and bacterial membrane-disrupting activities. This study explores the potential of LF and its functional fragments to combat multidrug-resistant (MDR) Gram-negative bacteria. We have evaluated the minimum inhibitory concentrations (MICs) of these molecules against both susceptible control strains and clinical isolates of Gram-negative ESKAPE pathogens. Using checkerboard assays, we assessed the synergy between LF and conventional antimicrobial agent, colistin against clinical isolates. The results demonstrate that Lactoferricin (LFcin) is the most potent biomolecule against ESKAPE pathogens, with an MIC of 125 µg/ml. Importantly, LF showed enhanced antibacterial activity specifically against MDR clinical isolates. Moreover, synergy testing revealed that LF significantly boosts the effectiveness of the antibiotic colistin against these clinical strains, resulting in a 2- to 83-fold improvement in activity depending on the strain. © 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

BACKGROUND: The incidence of drug-resistant candidiasis has increased in recent decades, leading to significant treatment challenges and high morbidity and mortality rates. The development of new therapeutic options is crucial, but it is a complex and time-consuming process; an interesting strategy to face this problem is to combine existing antifungal drugs with synergistic agents to enhance treatment efficacy, reduce dosage and prevent resistance development. METHODS: We analyzed the activity of lactoferrin against 80 isolates of 14 Candida species, including Candida auris according to both EUCAST and CLSI guidelines. Moreover, interaction between fluconazole and lactoferrin was assessed by checkerboard method against a selection of 38 isolates of eight Candida species, and by time-kill curves against six isolates of two Candida species, including fluconazole susceptible and resistant isolates. RESULTS: Synergistic and additive effects were demonstrated, with effective inhibition of Candida growth. Furthermore, combination therapy significantly reduced fluconazole minimum inhibitory concentrations (MICs) and showed synergistic effect against fluconazole-resistant isolates. CONCLUSIONS: Lactoferrin has significant potential value in the treatment of candidiasis and further exploration of its potential clinical applications is of great importance. The ability of lactoferrin to enhance the efficacy of existing antifungal drugs while potentially reducing the development of antifungal resistance makes it an intriguing candidate for future research and development efforts. © 2025. The Author(s).

This study systematically evaluated the in vitro antibacterial activity, synergistic effects, and outer membrane permeabilizer-mediated enhancement of enzybiotics (AB469, lysozyme, Ply187) and antimicrobial peptides (nisin, S16) against Helicobacter pylori. To our knowledge, this is the first report demonstrating in vitro synergistic anti-Helicobacter pylori activity between engineered enzybiotics and antimicrobial peptides. Results demonstrated that AB469 exhibited the strongest antibacterial activity with a minimum inhibitory concentration (MIC) of 0.1 μM (3.9 μg/mL), significantly outperforming lysozyme (1.3 μM/19.5 μg/mL), Ply187 (1.4 μM/25 μg/mL), S16 (3.3 μM/8 μg/mL), and nisin (3.6 μM/12.5 μg/mL). Synergistic assays revealed that the combination of AB469 and lysozyme achieved the most potent synergy (FIC index = 0.249), reducing their MICs by 8-fold each. Similarly, S16 and lysozyme showed synergistic effects (FIC = 0.249), with MICs reduced by 8-fold. In contrast, nisin combined with AB469 or lysozyme displayed indifferent effects (FIC = 2.0). Additionally, outer membrane permeabilizers (EDTA-2Na, lactoferrin, and citric acid) significantly enhanced the antibacterial activity of AB469 and lysozyme. For example, EDTA-2Na, lactoferrin, and citric acid reduced AB469's MIC by 16-fold, 8-fold, and 16-fold, respectively. This study highlights a dual-targeting strategy combining peptidoglycan degradation and outer membrane disruption, providing critical insights for combating drug-resistant H. pylori. © The Author(s) 2025. Published by Oxford University Press on behalf of FEMS. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site-for further information please contact [email protected].

Current treatment strategies for Pseudomonas aeruginosa pulmonary infections are limited by severe side effects and the emergence of multidrug resistance. This study evaluated the therapeutic potential of nisin and lactoferrin, two antimicrobial peptides with distinct modes of action, against P. aeruginosa lung infections. In vitro, the combination exhibited potent synergistic antibacterial activity with significant suppression of biofilm formation and pyocyanin production. Morphological analysis by field-emission scanning electron microscopy revealed extensive structural disruption of bacterial cells exposed to the nisin/lactoferrin combination. In a rat model of pulmonary P. aeruginosa infection, co-administration of nisin and lactoferrin prevented weight loss, preserved lung architecture, and achieved 100% survival compared with untreated animals. Treatment significantly reduced bacterial burden in the lungs and trachea, restored cytokine balance, enhanced antioxidant defenses, and lowered oxidative stress. These findings highlight the nisin/lactoferrin combination as a safe and effective peptide-based therapeutic approach for multidrug-resistant P. aeruginosa lung infections. © 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature. Synergistic Neuroprotective Effects of Ergothioneine and Lactoferrin in APP/PS1 Transgenic Mice and Mouse N2a Cells. Li H(1), Wang X(2), Li R(3), Chen L(1), Cheng G(2)(4)(5)(6), Xiong J(4)(7). Author information: (1)West China School of Nursing, West China Second University Hospital, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China. (2)Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Maternal & Child Nutrition Center, West China Second University Hospital, Sichuan University, Chengdu 610041, China. (3)Department of Nutrition and Food Safety, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China. (4)Food Safety Monitoring and Ris

2. J Agric Food Chem. 2025 Apr 30;73(17):10186-10200. doi: 10.1021/acs.jafc.4c10263. Epub 2025 Apr 17. Synergistic Neuroprotective Effects of Ergothioneine and Lactoferrin in APP/PS1 Transgenic Mice and Mouse N2a Cells. Li H(1), Wang X(2), Li R(3), Chen L(1), Cheng G(2)(4)(5)(6), Xiong J(4)(7).

Cancer treatment is among today's most active and challenging research fields. In recent years, significant progress has been made in developing new cancer therapies, including nutraceuticals and natural compounds with anticancer properties. Lactoferrin, a glycoprotein present in mammals, is of significant interest due to its pleiotropic behavior, demonstrating a broad spectrum of biological activities such as antimicrobial, antioxidant, anti-inflammatory, immunomodulatory, and anticancer effects. In this review, we examine the current knowledge of Lf's role in cancer. In addition, it exhibits a synergistic effect along with conventional drugs, potentially enhancing their efficacy and, at the same time, reducing the side effects associated with most traditional therapies. However, it is essential to consider the precise molecular mechanism by which Lf exerts its antitumor activity. Searching interactions with several molecules can provide insight into this mechanism. Additionally, finding lactoferrin receptors can improve the strategies for the specific release of the conjugates. For all these reasons, Lactoferrin becomes a potential therapeutic agent that should be examined in depth. © 2025. The Author(s), under exclusive licence to Springer Nature B.V.

BACKGROUND: Parkinson's disease (PD) is a chronic neurodegenerative disorder primarily characterized by oxidative stress and dopaminergic neuron damage. While levodopa remains the cornerstone of PD treatment, its efficacy is limited by poor bioavailability and neuroprotective effects. Curcumin, a potent antioxidant derived from turmeric, demonstrates neuroprotective promise but also suffers from low bioavailability, hindering its therapeutic application. The combined therapeutic use of levodopa and curcumin offers a potential synergistic approach, though its neuroprotection potential through brain-targeted delivery remains underexplored. PURPOSE: To develop a lactoferrin-modified organic-inorganic hybrid mesoporous silica nanoparticle system (Lf-lip@LC-MSNs) for co-delivering levodopa and curcumin, aiming to enhance neuroprotective efficacy and achieve brain-targeted delivery in PD. METHODS: Lf-lip@LC-MSNs were engineered to encapsulate levodopa within a curcumin-loaded lipid bilayer, modified with lactoferrin for optimized brain-targeted delivery. In vitro studies were conducted on rotenone-damaged neuronal models to evaluate oxidative stress, mitochondrial dysfunction, α-synuclein aggregation, and neuronal survival. In vivo experiments on MPTP-induced PD mouse models evaluated biodistribution, therapeutic efficacy, and safety in healthy mice, focusing on motor function recovery. RESULTS: The combination of levodopa and curcumin significantly reduced oxidative stress and α-synuclein accumulation, enhancing neuronal survival compared to monotherapies. Lf-lip@LC-MSNs further amplified these effects, achieving superior brain-targeted delivery and improved motor function restoration with minimal systemic toxicity. CONCLUSIONS: The combination of curcumin and levodopa provided synergistic neuroprotection in PD models. By employing a targeted delivery system, the Lf-lip@LC-MSNs not only facilitated efficient brain targeting but also potentiated therapeutic outcomes, providing a compelling strategy for treating PD and paving the way for advancements in managing other neurodegenerative diseases.

INTRODUCTION: The human-derived amnion-chorion membrane (ACM) has endogenous antimicrobial properties, which are important for preventing the colonization and survival of oral bacteria on exposed membranes. This project aimed to decipher the underlying mechanism by identifying the components of ACM that confer antibacterial properties. In addition, the antimicrobial efficacy of these identified components on oral bacteria was assessed. METHODS: Four antimicrobial proteins, histone H2A/H2B, cathelicidin LL-37, lactoferrin, and lysozyme, were identified via mass spectrometry in ACM. These proteins were then assessed for their efficacy in killing Streptococcus gordonii Challis. Log-phased bacterial cells were cultured with the commercially available proteins that were identified in ACM, either individually or in combination, at different concentrations. After incubation for 8 or 24 hours, the bacteria were stained with a live/dead viability kit and analyzed via confocal microscopy. RESULTS: The combination of these proteins effectively killed S. gordonii in a dose-dependent fashion after 8 or 24 hours of incubation. When each protein was tested individually, it killed S. gordonii at a much lower efficacy relative to the combinations. The synergistic effects of the antimicrobial protein combinations were also observed in both the viable cell count recovery and minimum inhibitory concentration assays. DISCUSSION: By shedding light on the mechanisms in the ACM's antimicrobial property, this study may raise more awareness of the potential benefit of utilization of a membrane with endogenous antimicrobial properties in regeneration surgeries.

Aim: Currently, we have limited armamentarium of antifungal agents against Mucorales. There is an urgent need to discover novel antifungal agents that are effective, safe and affordable. Materials & methods: In this study, the anti-Mucorale action of native lactoferrin (LF) and its functional fragments CLF, RR6 and LFcin against three common Mucorale species are reported. The synergistic action of LF with antifungal agents like amphotericin B, isavuconazole and posaconazole was analyzed using checkerboard technique. Results: All the three mucor species showed inhibition when treated with fragments. The checkerboard assay confirmed that native LF showed the best synergistic action against Mucorales in combination with Amphotericin B. Conclusion: These results highlight the potential therapeutic value of native LF against Mucorales. Plain Language Summary: Black fungus, or ‘mucormycosis’, is a dangerous fungal infection. Normally, it affects people with a weakened immune system. It is only treatable when diagnosed early. It spreads by breathing the fungus in, eating contaminated food or direct contact with an infected wound. There are not many medicines that can treat this type of fungus, so it is important to find new ones. In this study, we tested a natural protein called lactoferrin and some of its building blocks, called peptides, to see if they could stop the fungus from growing. Lactoferrin and its peptides could stop the fungus from growing, especially when used with a medicine called amphotericin B. This means that lactoferrin could potentially be a helpful treatment for this fungal infection.

Novel amphiphilic nanoconjugates of hyaluronic acid (HA), 50 kDa (HA50) and 100 kDa (HA100), and the lipopeptide biosurfactant surfactin (SF) were developed for potential anticancer applications. Physicochemical characterization indicated the formation of an ester conjugate (HA: SF molar ratio 1: 40) with the HA50-SF derivative exhibiting higher degree of substitution, hydrolytic stability, and surface activity. Self-assembly resulted in nanomicelles with smaller size and greater negative charge relative to SF micelles. Biological data demonstrated distinct anticancer activity of HA50-SF which displayed greater synergistic cytotoxicity and selectivity for MDA-MB 231 and MCF-7 breast cancer cells alongside greater modulation of apoptosis-related biomarkers leading to apoptosis. As bioactive vector for chemotherapeutic agents, the selected HA50-SF nanoconjugate efficiently (70 %) entrapped berberine (BER) producing a sustained release BER-HA50-SF synergistic anticancer nanoformulation. Lactoferrin (Lf) coating for dual HA/Lf targeting endowed Lf/BER-HA50-SF with significantly greater selectivity for both cell lines. A murine Ehrlich breast cancer model provided evidence for the efficacy and safety of Lf/BER-HA50-SF via tumoral, histological, immunohistochemical, molecular and systemic toxicity assessments. Thus, HA-SF nanoconjugates integrating the HA and SF properties and biofunctionalties present a novel biopolymer-biosurfactant platform of benefit to oncology nanomedicine and possibly other applications.