GEFOLAT is a dietary supplement based on Lactoferrin.
Lactoferrin (LF) is a protein belonging to the glycoprotein group; although it is a constituent of cow and human milk, it is present throughout the body and is found in all secretions that moisten the mucous membranes (saliva, tears, bronchial and nasal secretions, bile, pancreatic fluids) and is an essential factor in the immune response, performs the task of transporting iron in the blood and has antimicrobial action.
It was discovered by Sorensen and Sorensen in cow’s milk in 1939, more abundant in colostrum than in transitional and maintenance milk, Lactoferrin is also typical of neutrophil granulocytes, immune cells with defense functions against bacterial and fungal infections (Candida albicans).
The antimicrobial properties of lactoferrin are mainly due to its ability to bind iron, an essential medium for reproduction and growth: in the presence of lactoferrin, iron is withdrawn from the metabolism of those bacterial species-such as Escherichia coli, Salmonella, Staphylococcus aureus – that depend on it to reproduce, grow, and adhere to the intestinal mucosa (bacteriostatic effect) it also has a direct antibacterial (bactericidal) action, due to its ability to injure the outermost layers of the cell membrane (LPS) of some GRAM-negative bacterial species.
Lactoferrin
The antiviral effect of lactoferrin is related to its ability to bind to plasma membrane glycosaminoglycans, preventing virus entry, blocking replication and nipping infection in the bud; this mechanism has appeared effective against Herpes Simplex, cytomegaloviruses, and HIV.
Lactoferrin also stimulates the growth of “good” intestinal flora and has direct antioxidant activity, participating in the control of cellular damage associated with aging In addition, several physiological roles have been attributed to lactoferrin, namely regulation of iron homeostasis, host defense against infection and inflammation, regulation of cell growth and differentiation, and protection against the development of cancer and metastasis.
Lactoferrin is a protein with multiple biological activities and therefore falls into several therapeutic areas:
In Immunology:
Neutrophils and Lactoferrin
Lactoferrin plays an important role in host defense upon its release from neutrophil and also enhances the activity of Natural Killer cells in immune defense and may limit virus entry into host cells during infection. As part of the host inflammatory response, leukocytes, including neutrophils, release lactoferrin from their granules, where it is normally stored.
Activated neutrophils also release chromatin fibers, known as neutrophil extracellular traps (NETs), which trap and kill, among others, bacteria. These NETs similarly modulate both acute and chronic inflammation. NETs are also found in various autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus.
In addition to being an integral part of body fluids, iron-free lactoferrin is stored in the cytoplasmic secondary granules of neutrophils.
During inflammation, lactoferrin is released and its concentration increases at the site of inflammation, playing an important role in the feedback mechanism of the inflammatory response.
Lactoferrin is also synthesized in the kidney by supporting the immune defense system by reducing free iron from the urine and thus making it available for metabolic functions.
Lactoferrin is known to modulate the immune system and inflammation due to the fact that it can interact with specific receptors present in epithelial and immune cells, as well as on the pathogen surface by binding to the lipopolysaccharide of gram-negative bacteria. Using two known signaling pathways, nuclear factor- kappa B (NF-kB) and MAP kinase, lactoferrin at the cellular level modulates the differentiation, maturation, activation, migration, proliferation, and functions of immune cells.
Lactoferrin enters intestinal microvilli through the help of certain receptors on the surface of intestinal mucosa. The lactoferrin molecule further increases the immune response due to IFN-Y, TNF- a, IL-6 and by activating NK cells, PMNs and CD3+.
Antibacterial Properties of Lactoferrin
Bacteria have evolved various ways to sequester iron. Shown in the figure is how bacteria acquire iron through receptor-mediated recognition of transferrin, hemopexin, hemoglobin or hemoglobin-aptoglobin complexes and also lactoferrin. In addition to binding it directly from the environment, bacterial siderophores can obtain iron by removing it from transferrin, lactoferrin or ferritin. These siderophore-iron complexes are then recognized by receptors on the bacterium. The host’s innate immune functions are supported by the circulating protein, siderocalin, also known as neutrophil gelatinase-associated lipocalin (NGAL), lipocalin2 or Lcn2 because it inhibits siderophore-mediated iron acquisition and release.
Several Gram-negative pathogens, including members of the genera Neisseria and Moraxella, have developed two-component systems capable of extracting iron from the host. N. meningitidis is a major cause of bacterial meningitis in children. While most pathogenic bacteria employ siderophores to chelate iron, Neisseria has developed a series of protein transporters that directly divert the sequestered iron into host transferrin, lactoferrin and hemoglobin. However, more than 90% of lactoferrin in human milk is in the form of apolactoferrin, which competes with siderophilic bacteria for ferric iron and disrupts the proliferation of these microbes and other pathogens. Similarly, lactoferrin supplements can play an important role in counteracting bacterial processes. Lactoferrin is consequently a significant element of host defense, and its levels may vary in health and during disease. It is therefore known to be a modulator of innate and adaptive immune responses.
Antiviral Properties of Lactoferrin
The antiviral effect of LF is to inhibit viral DNA and RNA replication. One of the mechanisms of action, confirmed in experimental models, is its protective effect on virus-free cells. Lactoferrin has also been observed to bind directly to molecules in the structures of viruses such as HSV, HIV, and HCV. Another mechanism of lactoferrin’s antiviral action is its ability to block cell surface receptors. Lactoferrin’s affinity for glycosaminoglycans causes initial blockade of virus binding sites upon infection. This prevents the use of surface molecules as specific receptors or coreceptors for different virus types and prevents viral fusion. This mechanism has been described in HBV, HPV, HSV and HIV, among others. It was also shown that the effect of apolactoferrin on some viruses was greater than that of ololactoferrin.
Lactoferrin clearly has immunological benefits as well as an important antibacterial and antiviral role. Because it is known to interfere with some of the receptors used by coronaviruses, it can usefully contribute to the prevention and treatment of infections by coronaviruses. Lactoferrin-HSPG (Heparan Sulfate Proteoglycans = proteoglycans highly expressed on the surface of pneumoglycans) binding prevents initial contact between virus and host cells and thus prevents subsequent infection. HSPGs themselves are not sufficient for SARS-CoV entry. However, in SARS-CoV infections, HSPGs play an important role in the process of cell entry. The anchor sites provided by HSPGs enable initial contact between the virus and host cells and the concentration of viral particles on the cell surface. SARS-CoV bound to HSPGs then rolls onto the cell membrane and scans for specific entry receptors, which leads to subsequent cellular entry.
In Hematology:
Sideropenic anemia is by far the most common and widespread hematological disease; it is characterized by deficiency of Iron, an essential element for life. Under normal conditions, about 4-5 g of Iron is present in our bodies, and the amount we lose is replenished with food, but if we experience a momentary deficiency, this is compensated for by mobilizing Fe in reserve: lactoferrin binds iron and regulates cellular and systemic iron homeostasis, restoring the physiological amount of iron in the blood and also preventing any harmful overload of this element in the tissues.
In Gynecology:
- During pregnancy about 40 percent of women experience anemia gravidarum: the amount of blood in the maternal body increases to support the growth of the unborn child, consequently the need for iron also increases.
Vulvovaginitis is an inflammation of the vulva and vagina marked mostly by burning, itching, discharge, and swelling of labia majora and labia minora. Lactoferrin is able to lyse the bacterial membrane, inhibiting its growth, with bactericidal and anti-inflammatory action.
Candidiasis is an infection by fungi of the genus Candida, whose replication depends on Iron. Lactoferrin removes iron from the surrounding environment.
- Cystitis is an inflammation of the bladder usually associated with infection Lactoferrin inhibits the formation of pathogenic biofilms.
Vulvodynia is a pathological condition that can affect the vulva characterized by pain, burning and discomfort. Lactoferrin is indicated as an adjunct in the treatment of vulvodynia because it has a potent infection-inhibiting effect, has bacteriostatic, bactericidal, antiviral, antifungal, and anti-inflammatory activities, and inhibits bacterial adhesion and internalization and biofilm formation.
In Endocrinology and Dietetics:
Lactoferrin plays an important role in regulating lipid metabolism; it inhibits lipogenesis (lipid synthesis) in the liver with weight reduction and amelioration of inflammation accompanying hepatic steatosis.
In Gastroenterology:
Lactoferrin blocks bacterial growth as it takes away the iron that bacteria need to reproduce and grow, and it prevents the proliferation and formation of pathogenic biofilms as it attacks and lyses the bacterial membrane.
Crohn’s disease is an inflammatory bowel disease in which chronic inflammation typically involves the lower part of the small intestine, the large intestine, or both, but can affect any part of the digestive tract. Lactoferrin reduces inflammation and intracellular survival of bacterial pathogens.
Diverticulitis is a disease of the digestive tract characterized by inflammation of one or more diverticula (extroversion of the mucosa). Lactoferrin increases bacterial defense at the expense of pathogenic bacteria.
In Phlebology:
Iron deposits in chronic venous insufficiency cause hyperpigmentation accompanied by a variety of symptoms such as heaviness of the legs, tingling, itching, burning, nocturnal pain and cramping, varicose veins, and ulceration. Lactoferrin is important in this setting because of its iron chelating action.
Lymphedema is edema due to poor circulation of lymph that accumulates in the tissues forming edema with high protein content (albumin). Lactoferrin plays an important role as iron deposits are found in the interstitial fluid: iron ions activate a peroxidation process that leads to gradual inflammation of the entire tissue.
In Dermatology and Aesthetics:
Lactoferrin is also useful in cutaneous hyperpigmentationsas a result of blood extravasation following trauma, cosmetic surgery, or taking drugs; hyperpigmentation is related to iron deposits, and in this situation the action of iron chelating lactoferrin is effective. Skin hyperpigmentation is also caused by UV rays, diet, pollution. Lactoferrin inhibits the degradation activity of collagen by metalloproteases, stimulates the proliferation of fibroblasts and keratinocytes, and increases the synthesis of extracellular matrix components (such as collagen and hyaluronic acid). Also being a potent antioxidant, it prevents skin aging by inhibiting the formation of free radicals.
Edematous fibrosclerotic panniculopathy or cellulite is a degenerative change in adipose tissue in which iron deposits are present. This, along with other factors, leads to the formation of typical skin irregularities such as orange peel skin. Lactoferrin inhibits lipogenesis (lipid synthesis).
There is scientific evidence demonstrating a correlation between insufficient iron and hair loss; in particular, low ferritin can cause disruption of the follicular cycle. Lactoferrin can optimize Iron deficiency and also reduces the amount of the hormone hepcidin responsible for variation in the normal and proper transport of Iron through cells.
Dentistry:
Lactoferrin is also used in the treatment of periodontal disease because of its bacteriostatic action against plaque-forming bacteria such as Streptococcus mitis, Streptococcus gordoni, Streptococcus salivarius, and Streptococcus mutans. The bacteriostatic properties of LF are confirmed by clinical trials. The frequent problem of halitosis (bad oral odor) caused by bacterial metabolism is found in about 50% of patients worldwide, and in 90% the etiology is related to microbial processes in the oral cavity. And accompanied by the presence of plaque and tartar, periodontal diseases such as periodontitis, and infections involving dentures, caries, and mouth ulcers. In randomized trials, in patients with halitosis, lactoferrin has been shown to be useful in inhibiting bad odor.
In Neurology:
In the brain, iron has essential functions in the processes of neurotransmitter biosynthesis, myelin formation, and energy metabolism. However, excess iron in the brain can cause neuronal damage and cell death because iron (Fe2+) increases oxidative stress through the generation of highly cytotoxic free radicals. Many neurodegenerative diseases including Alzheimer’s and Parkinson’s are characterized by iron accumulation in the brain, a promising target for treatment could be the use of iron chelators.
Reduced levels of salivary lactoferrin are specific for Alzheimer’s disease
Alzheimer’s disease (AD) is one of the most devastating neurodegenerative diseases and a major public health concern with more than 30 million people affected worldwide. The cause of the disease is still unknown, but the most accepted hypothesis states that the accumulation of amyloid-f (A£) in the brain could initially trigger the disease cascade. Scientific evidence suggests that bacterial and viral infections may be implicated in the pathogenesis of AD. In the cascade of events preceding AD, oral and gastrointestinal microorganisms may play a role, and several types of microbes have been shown to stimulate A£ aggregation and deposition. Thus, there may be an interaction between genetic and environmental risk factors, including toxins and/or bacterial, viral, and fungal pathogens in the sporadic late-onset form of AD that reflects its complex and multifactorial etiology.
The question of whether oral infections can be considered a risk factor for AD has generated considerable research in recent years. Antimicrobial proteins and peptides (APPs), also called” host defense agents,” are the primary effective molecules of innate immunity. A new role for APPs has been proposed in AD pathology. The emerging role of microbes and innate immune pathways in AD pathology also suggests that APPs may be considered for early therapeutic interventions in future clinical trials. Pathogens and markers of brain infections are involved in amyloid aggregation, strengthening the possible relationship between AD and brain infections.
Biomarkers that reflect the integrity of the innate immune system could therefore be useful for both accurate and early diagnosis as well as prognosis of the disease. One promising biomarker candidate is lactoferrin, previously detected in senile plaques, neurofibrillary tangles and microglia in AD brain.
Because LF is one of the major antimicrobial peptides in saliva, it also represents an important defensive element by inducing a broad spectrum of antimicrobial effects against bacteria, fungi, protozoa, viruses, and yeasts. The antimicrobial effects of LF are conferred by its highly positively charged N-terminal region. These functions are maintained by its hydrolysis products, a series of lactoferrin-derived peptides that, by retaining the N-terminal cationic region of the native protein, also retain many of the activities of lactoferrin and in some cases may be even more potent than the parent protein.
Salivary lactoferrin levels in patients with aMCI (mild cognitive disorder), AD and healthy controls.
(A) Lactoferrin levels decrease in aMCI and AD compared with the control group; (B) Correlation between salivary lactoferrin levels and cognitive decline in aMCI and AD groups. Lactoferrin levels appeared to be negatively correlated with disease severity (Kendall’s tau correlation analysis). Salivary lactoferrin correlated significantly with A8B42 (E) and total tau (tau is an intracellular protein, abundant in neurons and the central nervous system) (F) in cerebrospinal fluid (/a measure of AB42 and tau is supportive of diagnosis and monitoring of Alzheimer’s disease), based on Spearman’s correlation analysis.
Salivary lactoferrin classifies patients with aMCI and AD from healthy control subjects. The accuracy of detection is equal to or better than that obtained from other published studies on blood and cerebrospinal fluid. However, saliva is far more convenient and easier to obtain and costs less to acquire than blood and cerebrospinal fluid. In addition, the biomarker consists of a single protein, lactoferrin, unlike others based on a collection of proteins, lipids, or RNA arrays, making it more useful for screening in large-scale clinical trials and for future clinical use.
Further analysis is needed to evaluate how the salivary lactoferrin marker can help differentiate between AD and other neurodegenerative diseases, including dementia with Lewy bodies or frontotemporal dementia. The correlation of salivary lactoferrin levels with key CSF (cerebrospinal fluid) biomarkers and PET neuroimaging and potential confounding variables, including co-morbid disorders, physiological status or diet, will need to be investigated.
These new studies would be highly recommended, providing an indicative line of salivary lactoferrin’s ability to identify patients with aMCI/AD. In addition, it may also work to identify “apparently healthy” subjects suffering from advanced preclinical AD or aMCI, a large number of whom are currently underdiagnosed. Thus, it is believed that these results may represent a significant advance in the National Institute on Aging and Alzheimer’s Association consensus for biomarkers of preclinical AD.
Nutritional table
| INGREDIENT | Per daily dose (1 capsule) |
|---|---|
| Lactoferrin | 200 mg |
FORMAT
Jar of 60 capsules of 360 mg.
WEIGHT
21,6 g.
INGREDIENTS
Lactoferrin; Excipients: pregelatinized starch; Capsule: natural gelatin.
METHOD OF USE.
1 capsule daily.
WARNINGS
Keep out of reach of children under 3 years of age. Do not exceed the recommended daily dose. Dietary supplements should not be intended as a substitute for a varied and balanced diet and a healthy lifestyle.
Lactoferrin is a protein extracted from cow’s milk, so its use is not recommended in individuals with milk protein and lactose allergies.
Store in a cool, dry place
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