What is the effect of lactoferrin on oral and jawbone tissue repair? A systematic review.

Currently, there is growing interest in the potential use of lactoferrin (LTF), a member of the transferrin family, for the improvement of tissue healing. In this sense, a literature search was conducted to integrate data published on the effect of LTF on jawbone repair. PubMed/MEDLINE, Scopus, Embase, Web of Science, LILACS, and Cochrane databases were retrieved according to the PRISMA 2020 statement. Articles in English, Spanish, and Portuguese were recovered, with no year restriction. In vitro, in vivo, and clinical studies were selected. A total of 742 articles were retrieved, 11 of which met the inclusion criteria (5 in vitro and 5 in vivo studies, and one clinical trial). The included data demonstrated wide variations in study design and LTF therapy protocols. Cell proliferation and viability were the primary outcomes evaluated in the in vitro studies, all of which reported a potential effect of LTF on the repair process. Of three in vivo studies, one reported a reduction in the overall healing rate, whereas the other two showed that LTF inhibited bone resorption and increased bone formation. The clinical trial's findings showed that LTF is a potential promoter of wound repair in patients with medication-related osteonecrosis of the jaws. Overall, data from the studies support a potential effect of LTF therapy on the process of jawbone repair.

Preparation and characterization of brain-targeted polymeric nanocarriers (Frankincense-PMBN-lactoferrin) and in-vivo evaluation on an Alzheimer's disease-like rat model induced by scopolamine.

Experiments have demonstrated that frankincense may offer protection against scopolamine-induced Alzheimer's disease by mitigating cholinergic dysfunction and inhibiting inflammatory mediators. Nevertheless, its instability and limited water solubility lead to diminished medicinal efficacy. In this study, we utilized PMBN (poly [MPC-co-(BMA)-co-(MEONP)]) as a nanocarrier for targeted brain drug delivery of frankincense, employing lactoferrin as a ligand for precise targeting. Characterization of nanoparticle properties was conducted through FTIR and FESEM analysis, and the in-vitro drug release percentage from the nanoparticles was quantified. To induce Alzheimer's-like dementia in rats, scopolamine was intraperitoneally administered at a dose of 1 mg/kg/day for 14 days. Subsequently, behavioral assessments (Y-maze, passive avoidance test, tail suspension test) were performed, followed by evaluations of acetylcholinesterase (AChE), reduced glutathione (GSH), catalase (CAT), and brain histopathology at the conclusion of the treatment period. The results revealed that the nanoparticles had a size of 106.6 nm and a zeta potential of -3.8 mV. The maximum release of frankincense in the PBS environment from PMBN nanoparticles was 18.2 %, in accordance with the Peppas model. Behavioral tests indicated that targeted drug nanoparticles (F-PMBN-Lf) exhibited the capability to alleviate stress and depression while enhancing short-term memory in scopolamine-induced animals. Additionally, F-PMBN-Lf counteracted the scopolamine-induced elevation of AChE activity and GSH levels. However, it resulted in decreased activity of the antioxidant enzyme CAT compared to the scopolamine group. Histological analysis of brain tissue suggested that F-PMBN-Lf exerted a notable neuroprotective effect, preserving neuronal cells in contrast to the scopolamine-induced group. It appears that the polymer nanoparticles containing this plant extract have introduced a novel neuroprotective approach for the treatment of Alzheimer's disease.

Lactoferrin improves symptoms of dextran sulfate sodium-induced colitis in mice through modulation of cellular senescence.

The multifaceted effects of lactoferrin (LF) on the digestive and immune systems make it an attractive therapeutic option in inflammatory bowel diseases. In this study, we aimed to explore the anti-inflammatory effects of LF in colitis, particularly in relation to cellular senescence. We hypothesize that LF has the potential to modulate the senescence process. The effects of LF on senescence were tested in vitro using HCT116 and SW480 cell lines, and in vivo, the dextran sulfate sodium-induced mouse model of colitis. LF (500 mg/kg) alleviated symptoms of colitis in mice with a significant decrease in colon damage (P < .0001 vs. control) and microscopic (P < .05 vs. control) scores. Cellular senescence markers p16 and p21 were significantly upregulated in the mouse colon during inflammation (both P < .01 vs. control), and LF at 500 mg/kg decreased these markers (both P < .05 vs. dextran sulfate sodium-treated mice). In vitro, LF significantly affected the expression of p16 and p21 (P < .05-P < .0001 vs. control), senescence associated secretory phenotype (P < .01-P < .0001 vs. control), and telomere-specific proteins: telomeric repeat binding factor 1 and 2 (P < .05-P < .0001 vs. control) in a concentration-dependent manner. LF modulates the expression of cellular senescence markers and shows hallmarks of senolytic and pro-senescent activity, depending on dose. Further studies are needed to fully understand the anti-inflammatory effect of LF in the context of senescence and safe utilization in patients with inflammatory bowel diseases.

Early Neuroprotective Effects of Bovine Lactoferrin Associated with Hypothermia after Neonatal Brain Hypoxia-Ischemia in Rats.

Neonatal hypoxic-ischemic (HI) encephalopathy (HIE) in term newborns is a leading cause of mortality and chronic disability. Hypothermia (HT) is the only clinically available therapeutic intervention; however, its neuroprotective effects are limited. Lactoferrin (LF) is the major whey protein in milk presenting iron-binding, anti-inflammatory and anti-apoptotic properties and has been shown to protect very immature brains against HI damage. We hypothesized that combining early oral administration of LF with whole body hypothermia could enhance neuroprotection in a HIE rat model. Pregnant Wistar rats were fed an LF-supplemented diet (1 mg/kg) or a control diet from (P6). At P7, the male and female pups had the right common carotid artery occluded followed by hypoxia (8% O2 for 60') (HI). Immediately after hypoxia, hypothermia (target temperature of 32.5-33.5 °C) was performed (5 h duration) using Criticool®. The animals were divided according to diet, injury and thermal condition. At P8 (24 h after HI), the brain neurochemical profile was assessed using magnetic resonance spectroscopy (1H-MRS) and a hyperintense T2W signal was used to measure the brain lesions. The mRNA levels of the genes related to glutamatergic excitotoxicity, energy metabolism and inflammation were assessed in the right hippocampus. The cell markers and apoptosis expression were assessed using immunofluorescence in the right hippocampus. HI decreased the energy metabolites and increased lactate. The neuronal-astrocytic coupling impairments observed in the HI groups were reversed mainly by HT. LF had an important effect on astrocyte function, decreasing the levels of the genes related to glutamatergic excitotoxicity and restoring the mRNA levels of the genes related to metabolic support. When combined, LF and HT presented a synergistic effect and prevented lactate accumulation, decreased inflammation and reduced brain damage, pointing out the benefits of combining these therapies. Overall, we showed that through distinct mechanisms lactoferrin can enhance neuroprotection induced by HT following neonatal brain hypoxia-ischemia.

Probiotics, Prebiotics, Lactoferrin, and Combination Products for Prevention of Mortality and Morbidity in Preterm Infants: A Systematic Review and Network Meta-Analysis.

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%) or in combination with oligosaccharides (RR, 0.45; 95% CI, 0.29 to 0.67; RD, -14.1%; 95% CI, -18.3% to -8.5%) and single-strain probiotics (RR, 0.61; 95% CI, 0.51 to 0.72; RD, -10.0%; 95% CI, -12.6% to -7.2%) proved of best effectiveness in reduction of feeding intolerance vs placebo. Single-strain probiotics (MD, -1.94 days; 95% CI, -2.96 to -0.92) and multistrain probiotics (MD, -2.03 days; 95% CI, -3.04 to -1.02) proved the most effective in reducing the time to reach full enteral feeding compared with placebo. Only single-strain and multistrain probiotics were associated with greater effectiveness compared with placebo in reducing duration of hospitalization (MD, -3.31 days; 95% CI, -5.05 to -1.58; and MD, -2.20 days; 95% CI, -4.08 to -0.31, respectively). Conclusions and Relevance: In this systematic review and NMA, moderate- to high-certainty evidence demonstrated an association between multistrain probiotics and reduction in all-cause mortality; these interventions were also associated with the best effectiveness for other key outcomes. Combination products, including single- and multiple-strain probiotics combined with prebiotics or lactoferrin, were associated with the largest reduction in morbidity and mortality.

Lactoferrin as treatment for iron-deficiency anemia in children: a systematic review.

BACKGROUND: Anemia is a common nutritional problem in children, especially those under five. Lactoferrin (Lf) as a supplement in treating iron deficiency anemia (IDA) has been studied, but its results in children have not been reviewed. This review aims to evaluate the effect of lactoferrin on children with IDA. METHODS: PubMed, ProQuest, EBSCO and Ovid databases were searched using a variation of keywords: lactoferrin, anemia, and children. The literature selected must be clinical trial-based in design. The years of the studies published were limited to 2012 and 2022. RESULTS: Eleven studies were included in the final systematic review, consisting of 10 randomized controlled trials (RCTs) and 1 non-randomized trial. Serum ferritin (SF) and hemoglobin (Hb) were found to be increased in groups treated with Lf or a combination of Lf and elemental iron compared to iron only or placebo supplementation. Adverse events such as constipation, vomiting, anorexia, and abdominal pain were found; particularly, a significant decrease in constipation is seen in Lf-treated groups. CONCLUSIONS: This study supports Lf as a superior treatment for IDA in children regarding the improvement in hematological and iron indices and fewer adverse effects.

Lactoferrin: Antimicrobial impacts, genomic guardian, therapeutic uses and clinical significance for humans and animals.

Lactoferrin (LF) is a protein found in several bodily fluids, such as milk. This protein has a diverse range of functions and is evolutionarily conserved. Lactoferrin is a multifunction protein with distinct biological abilities affecting mammals' immune structures. Reports indicated that the daily uptake of LF from dairy products is unsatisfactory in detecting further health-promoting abilities. Research has shown that it protects against infection, mitigates cellular senescence, and improves nutritional quality. Additionally, LF is being studied as a potential treatment for various diseases and conditions, including gastrointestinal issues and infections. Studies have also demonstrated its effectiveness against various viruses and bacteria. In this article, we'll look closer at the structure of LF and its various biological activities, including its antimicrobial, anti-viral, anti-cancer, anti-osteoporotic, detoxifying, and immunomodulatory properties. More specifically, the protective effect of LF against oxidative DNA damage was also clarified through its ability to abolish DNA damaging issues without interfacing with host genetic material. Fortification with LF protects mitochondria dysfunction syndromes via sustaining redox status and biogenesis and suppressing apoptosis and autophagy singling. Additionally, we'll examine the potential benefits of lactoferrin and provide an overview of recent clinical trials conducted to examine its use in laboratory and living models.

Fecal lactoferrin early predicts long-term outcomes in ulcerative colitis: A post-hoc analysis of the UNIFI and PURSUIT trials.

BACKGROUND: Fecal lactoferrin (FL) is associated with disease activity and relapse in ulcerative colitis. However, whether FL could early predict long-term outcomes in ulcerative colitis is poorly understood. METHODS: This post-hoc analysis included participants who received biologics and had available data of FL concentration at week 4 from the UNIFI and PURSUIT trials (n = 1063). Therapeutic outcomes, including clinical remission, endoscopic improvement and remission, and histological improvement and remission, were evaluated at the end of maintenance therapy. The incidence of colectomy was observed from week 0 to maximum week 228 in the PURSUIT trial (n = 667). Multivariate logistic and Cox proportional-hazard regression were conducted to evaluate the associations between FL and therapeutic outcomes and colectomy, respectively. RESULTS: A high FL level at week 4 was associated with poor long-term clinical, endoscopic and histologic outcomes. FL >84.5 µg/mL predicted a low likelihood of clinical (OR [95% CI]: 0.43 [0.32, 0.57]; p < 0.001), endoscopic (OR [95% CI]: 0.40 [0.29, 0.56]; p < 0.001), and histological (OR [95% CI]: 0.27 [0.14, 0.53]; p < 0.001) remission. Moreover, week-4 FL could add prognostic value to fecal calprotectin and clinical and endoscopic scores for informing long-term therapeutic outcomes. For the risk of colectomy, patients with week-4 FL <20.1 and ≥20.1 µg/mL had an incidence rate of 1.10% and 6.39%, respectively. Patients with FL ≥20.1 µg/mL had a 995% higher risk of colectomy (HR [95% CI], 10.95 [1.45, 82.74]). CONCLUSION: FL could be a promising prognostic biomarker for long-term therapeutic outcomes and risk of colectomy in patient of ulcerative colitis.

Role of the protein kinase A signaling pathway and identification of mediators in the cardioprotective effects of enteral lactoferrin for ischemia-reperfusion injury in an isolated rat heart model.

OBJECTIVE: Lactoferrin is an iron-binding glycoprotein. Enteral lactoferrin attenuates myocardial ischemia-reperfusion (IR) injury, but the underlying mechanism remains unknown. The aim of this study was to investigate protein kinase A (PKA) signaling pathway activation and levels of serum glucagonlike peptide-1 (GLP-1), secreted by intestinal endocrine L cells, and adiponectin, secreted by adipose tissue, after enteral lactoferrin administration. METHODS: Hearts (N = 32) were excised from Wistar rats and perfused using a Langendorff system. To assess the role of the PKA pathway in the cardioprotective effects of lactoferrin, an inhibitor of PKA (H89) was applied before no-flow ischemia. Rats were randomly divided into four groups: control, lactoferrin (LF), control+H89, and LF+H89. The control and control+H89 groups were administered normal saline by gavage, and the LF and L +H89 groups were administered bovine lactoferrin (1000 mg/kg) by gavage 15 min before intraperitoneal pentobarbital injection. Muscle sampling was performed at the end of reperfusion. When rats were sacrificed, blood was sampled to measure hormone levels. The primary outcome was maximum left ventricular pressure derivative (LV dP/dt max) 15 min after reperfusion. RESULTS: LV dP/dt max at 10 and 15 min after reperfusion was significantly higher in the LF group than in the control group (P < 0.05), and the effect was diminished by H89. The PKA pathway was significantly activated in the LF group. Enteral lactoferrin increased serum GLP-1 but not serum adiponectin levels. CONCLUSIONS: Enteral lactoferrin induces cardioprotective effects against myocardial IR injury via the PKA signaling pathway and increases serum GLP-1 levels.

Lactoferrin for the postoperative management of term neonates after gastrointestinal surgery.

BACKGROUND: Neonates who have undergone gastrointestinal surgery are particularly susceptible to infectious complications in the postoperative period. This may be due in part to disruption of the integrity of the gut and its altered intestinal microflora. Lactoferrin is a whey protein found in milk and is an important innate mammalian defence mechanism. Lactoferrin has been reported to have antimicrobial and anti-inflammatory properties. It has also been reported to help establish a healthy gut microflora and aid in the intestinal immune system. Lactoferrin supplementation has been reported to decrease sepsis in preterm infants. There may be a role for lactoferrin to reduce the incidence of sepsis, thus reducing morbidity and mortality and improving enteral feeding in postoperative term neonates. OBJECTIVES: The primary objective of this review was to evaluate the efficacy of administering lactoferrin on the incidence of sepsis and mortality in term neonates after gastrointestinal surgery. The secondary objective was to assess the impact of administering lactoferrin on time to full enteral feeds, the intestinal microflora, duration of hospital stay, and mortality before discharge in the same population. SEARCH METHODS: The Cochrane Neonatal Information Specialist searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase Ovid, CINAHL, the WHO ICTRP and ClinicalTrials.gov trials registries. The date of the last search was February 2023. There were no restrictions to language, publication year or publication type. We checked references of potentially relevant studies and systematic reviews. SELECTION CRITERIA: We planned to include randomised controlled trials that studied infants born at 37 or more weeks of gestation who had one or more episodes of gastrointestinal surgery within 28 days of birth, and compared administration of lactoferrin with a placebo. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We planned to use the GRADE approach to assess the certainty of evidence for each outcome. MAIN RESULTS: We identified no published randomised controlled studies that assessed the efficacy of lactoferrin for the postoperative management of term neonates following gastrointestinal surgery. AUTHORS' CONCLUSIONS: There is currently no evidence available from randomised controlled trials to show whether lactoferrin is effective or ineffective for the postoperative management of term neonates after gastrointestinal surgery. There is a need for randomised controlled trials to be performed to assess the role of lactoferrin in this setting.

The Efficacy of Topical Lactoferrin on Wound Healing in an Experimental Animal Model of Nasal Septum Perforation.

The aim of the present experimental animal study was to investigate the efficacy of bovine lactoferrin (LF) on wound healing in an animal model of nasal septum perforation (NSP).Twenty-two, 8 to 10 weeks of age, male Sprague-Dawley rats were separated into two groups. Nasal septum perforation was created in each rat. The saline (control) and 0.05 mg LF (study) groups were delivered locally for 14 days. On the 14th day of the study, after the sacrifice, the cartilage nasal septa of the animals were excised. The degeneration and regeneration observed in the nasal septum epithelium and cartilage, the number of acute inflammatory cells, the number of eosinophils, the amount of new vessel formation, the amount of granulation, and the collagen density were examined microscopically. The microscopic parameters and macroscopic healing of NSPs were analyzed. The epithelium regeneration, the fibroblast number, the granulation tissue formation, the collagen density, and the macroscopic healing were significantly higher in the LF group (p < 0.05). Besides, the acute inflammatory cell count was lower in the LF group (p = 0.034). In conclusion, the topically delivered LF can improve wound healing in an experimental rat model of NSP.

Gastrointestinally absorbable lactoferrin-heparin conjugate with anti-angiogenic activity for treatment of brain tumor.

Glioblastoma multiforme (GBM) is a central nervous system disease with poor prognosis. Curative treatments for GBM involve chemotherapy, radiotherapy, and surgical pathways. Recently, antiangiogenic therapy through medications has been tried to slow tumor growth, but the drugs can induce side effects. To overcome these limitations, we developed a new orally absorbable form of heparin that can attenuate angiogenic activity by binding to growth factors around the tumor tissue. We conjugated lactoferrin (Lf) to heparin because Lf can be orally absorbed, and it interacts with the lactoferrin receptor (Lf-R) expressed on the intestine, blood-brain barrier (BBB), and glioma tumor masses. We successfully conjugated Lf and heparin by amide bond formation, as evidenced by advanced physicochemical properties such as pharmacokinetics and stability in acidic condition. This new material inhibited angiogenesis in vitro without toxicity. In addition, Lf-heparin administered orally to GBM orthotopic mice was absorbed in the small intestine and delivered specifically to the brain tumor by receptor transcytosis (Lf-R). Lf-heparin further attenuated angiogenesis progression in GBM orthotopic mice. Based on these results, Lf-heparin shows potential as a new oral medication for treatment of glioblastoma.

AGA Clinical Practice Guideline on the Role of Biomarkers for the Management of Ulcerative Colitis.

BACKGROUND & AIMS: Biomarkers are used frequently for noninvasive monitoring and treatment decision making in the management of patients with ulcerative colitis (UC). This American Gastroenterological Association (AGA) guideline is intended to support practitioners in decisions about the use of biomarkers for the management of UC. METHODS: A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation framework to prioritize clinical questions, identify patient-centered outcomes, and conduct an evidence synthesis on the clinical performance of serum C-reactive protein (CRP), fecal calprotectin, and fecal lactoferrin as biomarkers of disease activity in patients with established UC in symptomatic remission or with active symptoms. The guideline panel used the Evidence-to-Decision framework to develop recommendations for the use of biomarkers for monitoring and management of UC and provided implementation considerations for clinical practice. RESULTS: The guideline panel made 7 conditional recommendations. In patients with UC in symptomatic remission, the panel suggests the use of a biomarker- and symptom-based monitoring strategy over a symptom-based monitoring strategy. For patients in symptomatic remission, the panel suggests using fecal calprotectin <150 µg/g, normal fecal lactoferrin, and/or normal CRP to rule out active inflammation and avoid routine endoscopic assessment of disease. In patients with UC with moderate to severe symptoms, the panel suggests using fecal calprotectin >150 µg/g, elevated fecal lactoferrin, or elevated CRP to inform treatment decisions and avoid routine endoscopic assessment of disease. However, in patients in symptomatic remission but elevated biomarkers, and in patients with moderate to severe symptoms with normal biomarkers, the panel suggests endoscopic assessment of disease to inform treatment decisions. In patients with UC with mild symptoms, the panel suggests endoscopic assessment of disease activity to inform treatment decisions. The panel identified the use of a biomarker-based monitoring strategy over an endoscopy-based monitoring strategy as a knowledge gap. The panel also proposed key implementation considerations for optimal use of biomarkers, and identified areas for future research. CONCLUSIONS: In patients with UC, noninvasive biomarkers, including fecal calprotectin, fecal lactoferrin, and serum CRP can inform disease monitoring and management.

Comparison of the efficacy of intra-articular injections of hyaluronic acid and lactoferrin in mono-iodoacetate-induced temporomandibular joint osteoarthritis: A histomorphometric, immunohistochemistry, and micro-computed tomography analysis.

OBJECTIVES: This study aims to evaluate the efficacy of high-molecular-weight hyaluronic acid (HMWHA) and lactoferrin (LF) injections on temporomandibular joint (TMJ) cartilage and subchondral bone in mono-iodoacetate (MIA)-induced temporomandibular joint osteoarthritis model in rats. MATERIALS AND METHODS: In this in vivo study, a total of 24 rats were divided into three groups as follows: saline group (Group 1), HMWHA group (Group 2), and LF group (Group 3) including eight rats in each group. The intra-articular injections were administered once a week for three weeks after osteoarthritis was induced. All animals were euthanized 28 days after induction of osteoarthritis, and TMJs were harvested for histomorphometric, immunohistochemical, and micro-computed tomography (CT) analysis. RESULTS: There was no significant difference between the HMWHA and LF groups in terms of the histomorphometric and immunohistochemical analysis results (p>0.05). According to the micro-CT analysis, the LF group had the highest mean bone volume fraction (74.9±0.5) and trabecular thickness (0.122±0.002), while the saline group had the lowest mean values (55.0±0.3 and 0.071±0.002, respectively) (p<0.001). There was no significant difference between the HMWHA and LF groups according to the micro-CT analysis (p>0.05). Both groups had better healing effects than the saline group in all analyses. CONCLUSION: Lactoferrin has a healing effect at least as much as HMWHA in MIA-induced TMJ osteoarthritis. We suggest that LF may be evaluated in future clinical studies as a promising agent in the treatment of osteoarthritis.

Therapeutic uses and applications of bovine lactoferrin in aquatic animal medicine: an overview.

Aquaculture is an important food sector throughout the globe because of its importance in ensuring the availability of nutritious and safe food for human beings. In recent years, this sector has been challenged with several obstacles especially the emergence of infectious disease outbreaks. Various treatment and control aspects, including antibiotics, antiseptics, and other anti-microbial agents, have been used to treat farmed fish and shrimp against diseases. Nonetheless, these medications have been prohibited and banned in many countries because of the development of antimicrobial-resistant bacterial strains, the accumulation of residues in the flesh of farmed fish and shrimp, and their environmental threats to aquatic ecosystems. Therefore, scientists and researchers have concentrated their research on finding natural and safe products to control disease outbreaks. From these natural products, bovine lactoferrin can be utilized as a functional feed supplement. Bovine lactoferrin is a multi-functional glycoprotein applied in various industries, like food preservation, and numerous medications, due to its non-toxic and ecological features. Recent research has proposed multiple advantages and benefits of using bovine lactoferrin in aquaculture. Reports showed its potential ability to enhance growth, reduce mortalities, regulate iron metabolism, decrease disease outbreaks, stimulate the antioxidant defense system, and recuperate the overall health conditions of the treated fish and shrimp. Besides, bovine lactoferrin can be considered as a safe antibiotic alternative and a unique therapeutic agent to decrease the negative impacts of infectious diseases. These features can be attributed to its well-known antibacterial, anti-parasitic, anti-inflammatory, immunostimulatory, and antioxidant capabilities. This literature review will highlight the implications of bovine lactoferrin in aquaculture, particularly highlighting its therapeutic features and ability to promote immunological defensive pathways in fish. The information included in this article would be valuable for further research studies to improve aquaculture's sustainability and the functionality of aquafeeds.

Folic acid-modified lactoferrin nanoparticles coated with a laminarin layer loaded curcumin with dual-targeting for ulcerative colitis treatment.

Curcumin (CUR) is a promising natural compound in ulcerative colitis (UC) treatment, but limited by its low oral bioavailability and poor targeting ability. Therefore, given the targeting action of lactoferrin (LF) by binding to the LF receptors of intestinal epithelial cells (IECs) and of folic acid (FA) by binding to the FA receptors of macrophages, we developed an oral dual-targeting nanosystem. Laminarin (LA)-coated, FA-modified LF nanoparticles (NPs) were used to encapsulate CUR (LA/FA/CUR-NPs) with a food-grade, enzyme-sensitive, and dual-targeting capacity. For the generated NPs, LF improved the loading efficiency of CUR (95.08 %). The LA layer could improve the upper gastrointestinal tract stability of the NPs while improve drug release around colon lesion through ß-glucanase digestion. Based on the cellular uptake evaluation, FA/CUR-NPs were capable of specifically targeting colonic epithelial cells and macrophages through LF and FA ligands, respectively, to enhance the uptake efficiency. Moreover, based on the advantage of the dual-targeting strategy, oral administration of FA/CUR-NPs obviously reduced colitis symptoms by alleviating inflammation, accelerating colonic mucosal barrier repair and restoring the balance of the intestinal microbiota. This dual-targeted nanodesign corresponded to the multi-bioresponsibilities of CUR, thus offering a promising approach in UC treatment.

Role of lactoferrin in preventing preterm birth and pregnancy complications: a systematic review and meta-analysis.

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.

Effect of bovine lactoferrin on recurrent urinary tract infections: in vitro and in vivo evidences.

Uropathogenic Escherichia coli (UPEC) strains are the primary cause of urinary tract infections (UTIs). UPEC strains are able to invade, multiply and persisting in host cells. Therefore, UPEC strains are associated to recurrent UTIs requiring long-term antibiotic therapy. However, this therapy is suboptimal due to the increase of multidrug-resistant UPEC. The use of non-antibiotic treatments for managing UTIs is required. Among these, bovine lactoferrin (bLf), a multifunctional cationic glycoprotein, could be a promising tool because inhibits the entry into the host cells of several intracellular bacteria. Here, we demonstrate that 100 µg/ml bLf hinders the invasion of 2.0 ± 0.5 × 104 CFU/ml E. coli CFT073, prototype of UPEC, infecting 2.0 ± 0.5 × 105 cells/ml urinary bladder T24 epithelial cells. The highest protection (100%) is due to the bLf binding with host surface components even if an additional binding to bacterial surface components cannot be excluded. Of note, in the absence of bLf, UPEC survives and multiplies, while bLf significantly decreases bacterial intracellular survival. After these encouraging results, an observational survey on thirty-three patients affected by recurrent cystitis was performed. The treatment consisted in the oral administration of bLf alone or in combination with antibiotics and/or probiotics. After the observation period, a marked reduction of cystitis episodes was observed (p < 0.001) in all patients compared to the episodes occurred during the 6 months preceding the bLf-treatment. Twenty-nine patients did not report cystitis episodes (87.9%) whereas the remaining four (12.1%) experienced only one episode, indicating that bLf could be a worthwhile and safe treatment in counteracting recurrent cystitis.

Clinical research review: usefulness of bovine lactoferrin in child health.

Lactoferrin (LF) is abundant in human milk and plays an important role in the health of children. Bovine LF (bLF) has high homology with human LF and has been reported to have multiple biological functions. Several clinical studies have been conducted considering these properties, which reported the usefulness of bLF. This review was aimed to provide an overview of the clinical evidence in children. We searched clinical reports investigating the effects of bLF in children and identified 36 studies on the role of bLF in infections, iron metabolism, body growth, cerebral development, and fecal microbiome. Considering the accumulated evidence, bLF may contribute to the child health, particularly by suppressing or alleviating gastrointestinal and respiratory symptoms, and improving the iron status of children with anemia or those at high risk of anemia. The dose of bLF varies depending on the expected effect and target age, but may not necessarily have to be as high as human LF in human milk. Some of the beneficial effects of bLF have not been fully validated due to limited clinical evidence or being observed in the secondary analysis of some studies. Further clinical evidence would add significant value to the use of bLF in child health.

Modulation of TDM-induced granuloma pathology by human lactoferrin: a persistent effect in mice.

Lactoferrin (LTF), an iron binding protein, is known to exhibit immune modulatory effects on pulmonary pathology during insult-induced models of primary Mycobacterium tuberculosis (Mtb) infection. The effects of LTF correlate with modulation of the immune related development of the pathology, and altering of the histological nature of the physically compact and dense lung granuloma in mice. Specifically, a recombinant human version of LTF limits immediate progression of granulomatous severity following administration of the Mtb cell wall mycolic acid, trehalose 6,6'-dimycolate (TDM), in part through reduced pro-inflammatory responses known to control these events. This current study investigates a limited course of LTF to modulate not only initiation, but also maintenance and resolution of pathology post development of the granulomatous response in mice. Comparison is made to a fusion of LTF with the Fc domain of IgG2 (FcLTF), which is known to extend LTF half-life in circulation. TDM induced granulomas were examined at extended times post insult (day 7 and 14). Both LTF and the novel FcLTF exerted sustained effects on lung granuloma pathology. Reduction of pulmonary pro-inflammatory cytokines TNF-α and IL-1ß occurred, correlating with reduced pathology. Increase in IL-6, known to regulate granuloma maintenance, was also seen with the LTFs. The FcLTF demonstrated greater impact than the recombinant LTF, and was superior in limiting damage to pulmonary tissues while limiting residual inflammatory cytokine production.