A collection of important data on
lactoferrin (LF), which could potentially play some role in POIS.
Lactoferrin is one of the components of the immune system of the body; it has antimicrobial activity (bacteriocide, fungicide) and is part of the innate defense, mainly at mucoses. It is constantly produced and released into saliva, tears, as well as seminal and vaginal fluid.https://en.wikipedia.org/wiki/LactoferrinSeven out of fourteen differentially expressed proteins (prolactin-inducible proteins, lactoferrin, prostatic acid phosphatase, myeloperoxidase; zinc-alpha-2-glycoprotein, lactotransferrin, cystatin C) fell in a functional protein-protein network, centered on AR.
Five proteins (semenogelin 1, semenogelin 2, prolactin-inducible protein, prostatic acid phosphatase, lactotransferrin) increased after testosterone replacement therapy (TRT).https://www.mdpi.com/2075-1729/13/9/1854The seminal plasma is made of secretions from the testis, the epididymis, and the male accessory glands, which are dependent on the presence of androgenic stimuli.
In our study, lactoferrin and prostatic acid phosphatase (PAP) were absent in hypogonadic patients.
Lactoferrin has antibacterial, antioxidative, and an immune-modulating role in seminal plasma. Lactoferrin is also involved in maintaining normal sperm structure and motility and in modulating the composition and quality of the semen during sperm maturation and migration through the male genital tract. Male hypogonadism induces a significant reduction in lactoferrin, which might correspond to a reduction in binding activity, which is involved in the defenses against microbacteria and oxidative stress, both mechanisms linked with infertility.https://academic.oup.com/jcem/article/99/8/2813/2537991Having in mind innate Oxidative Stress (OS) prevention mechanisms, it should be expected that spermatozoa can be protected from OS by the endogenous antioxidants present in the seminal plasma including the enzymes catalase and SOD as well as non-enzymatic compounds – vitamins C and E and carotenoids. Spermatozoa also contain the antioxidants lactoferrin and coenzyme Q10.
For example, supplementation with antioxidants can be considered as a precaution from oxidative stress. Based on their mechanism of action they can be divided into two types: (1) preventive antioxidants which prevent the formation of ROS – metal chelators or binding proteins (lactoferrin and transferrin); (2) scavenging antioxidants which remove ROS that is already present - vitamins C and E. Another example is application of approved drug metformin, quercetin, lycopene, various flavonoids and many others.https://www.researchgate.net/profile/Ekaterina-Pavlova-2/publication/372703662_Spermatozoa_under_Oxidative_Stress_Risk_or_Benefit/links/64ff30e825ee6b7564e11e2d/Spermatozoa-under-Oxidative-Stress-Risk-or-Benefit.pdfLactoferrin is a natural cationic iron-binding glycoprotein of the transferrin family found in bovine milk and other exocrine secretions, including lacrimal fluid, saliva, and bile. Lactoferrin has been investigated for its numerous powerful influences, including anticancer, anti-inflammatory, anti-oxidant, anti-osteoporotic, antifungal, antibacterial, antiviral, immunomodulatory, hepatoprotective, and other beneficial health effects. Lactoferrin demonstrated several nutraceutical and pharmaceutical potentials and have a significant impact on improving the health of humans and animals. Lactoferrin plays a critical role in keeping the normal physiological homeostasis associated with the development of pathological disorders.
Lactoferrin is a key constituent of innate immune function that leads to the activation of the adaptive immune system. It is constantly produced and released into the exocrine secretion, including tears, saliva, vaginal, and seminal fluid.
Siqueiros-Cendón et al. suggested that lactoferrin significantly upregulated the adaptive and innate immune responses in neurodegenerative and inflammatory conditions by increasing lactoferrin secretion. Lactoferrin possesses anti-inflammatory and pro-inflammatory potential and can up- and downregulate endogenous inflammatory responses.
Again, another clinical study showed that lactoferrin prevented sepsis via the neutralization of microbial antigens, thus effectively downregulating the pro-inflammatory effects.
Lactoferrin is categorized as a small family protein and acts as an "alarmin" released by immune cells during pathological conditions and plays a vital role in immunomodulation to control pathological and clinical situations. Lactoferrin can develop the conditional interaction between dendritic cells and neutrophils, activating innate and adaptive immune responses.
Therefore, lactoferrin controls the release of NETs in autoimmune and other inflammatory conditions.
Thus, a lack of lactoferrin exacerbated the inflammatory response and encouraged macrophage chemotaxis to the site of inflammation.
Chelation of iron is the most important biological function of lactoferrin, which is essential for antimicrobial effects. It is also involved in antioxidant defense. Inflamed tissues and cells release and produce an abundant amount of ROS, which has antimicrobial activities and causes tissue necrosis and apoptosis. Furthermore, injured tissue discharges ferrous and ferric iron that contributes to the Haber-Weiss reaction and releases unique free radicals. The iron-scavenging potential of lactoferrin strongly contributes to mitigating oxidative stress.
Raychaudhuri et al. examined the interaction of quercetin with lactoferrin. This combination demonstrated a more substantial impact of the lactoferrin on the activity of antioxidant enzymes (SOD, catalase, and malondialdehyde).https://link.springer.com/article/10.1007/s12011-023-03658-4Aim: To investigate the biological effects of exogenous lactoferrin (LF) on phenotypic profile and invasiveness of human prostate cancer (PC) cells in vitro.
Results: Exogenous LF reduced expression of steroid hormone receptors (ERalpha and PR) and Ki-67 in both PC cell lines. The expression of E-cadherin increased significantly in LF-treated DU-145 cells.http://dspace.nbuv.gov.ua/handle/123456789/145599The lactoferrin concentration significantly correlated with the sperm concentration (in dogs).https://www.jstage.jst.go.jp/article/jvms/65/6/65_6_679/_article/-char/ja/Lactoferrin is a glycoprotein, characterized by a strong iron-binding capacity and implicated in a spectrum of physiopathological events related to oxidant and inflammatory processes, which was reported to cure intestinal disorders in various conditions. Our present study revealed the protective effects of LF on dietary DON-induced male reproductive malfunctions. Oral administration of LF restored the spermatogenesis disorder in mice fed a DON (mycotoxin) inclusion diet, a fact confirmed by an examination of the intact testicular spermatogenic epithelium and the larger amount of epididymis sperms, and eliminated the oxidative stress and breakages in adhesion junction caused by DON treatment.
Taken together, the present results revealed that LF preserved the spermatogenesis and integral aspects of the blood–testis barrier (BTB) that were impaired by DON exposure, which was obtained by reduced oxidative stress. Additionally, LF improved the integrity of N-cadherin established adhesion junction between Sertoli cells and spermatid cells, and reversed the signaling pathways, including cell adhesion and apical junction, inflammatory response, and TNF-alpha signaling via NF-kB and TGF-beta signaling.https://www.mdpi.com/2076-3921/12/1/152Pieces of evidence have shown that LF benefits gut health including gut immune enhancement, fortification of the intestinal barrier, and risk reduction of colon cancers. LF is partially digested and found to be able to modulate microbiota as a prebiotic agent which may contribute to its beneficial functions in gut health.
Fig. 2. Function and applications of lactoferrin!
LF binds and neutralize endotoxins such as LPS, which reduces the level of stimulation of the immune system. This process prevents excessive stimulation of intestinal tissues by LPS and reduces LPS invasion of the bloodstream.
Indeed, LF can inhibit LPS-induced activation of inflammatory cells by reducing expression of strong pro-inflammatory factors such as tumor necrosis factor-alpha (TNF-a), interleukin (IL)-1, and IL-6. LF also increases the secretion of IL-12 by antigen-presenting cells (APCs) in the face of pathogenic agents and stimulates the expression of the anti-inflammatory cytokine IL-10.
Specifically, LF works with granulocytes, lymphocytes, macrophages, and natural killer (NK) cells to enhance their functions such as migration, proliferation, maturation, cytokine production, and cytotoxicity.
In addition, LF is able to adjust the balance of T-helper (Th)1 and Th2 cell subsets, thereby limiting the excessive inflammatory response.https://www.sciencedirect.com/science/article/pii/S1756464623003419Neutrophils are innate immune cells that kill invading pathogens by phagocytosis, releasing cytotoxic enzymes and proteases or forming neutrophil extracellular traps (NETs). NETs are highly decondensed chromatin decorated with cytotoxic enzymes and proteases like neutrophil elastase, calprotectin, MMP9, cathepsin G and LF released into extracellular space to kill microbial pathogens.
Both endogenous (LF as a component of NETs) and exogenous (intravenous administration) LF suppressed the release and formation of NETs. Though endogenous LF can inhibit NETs formation; it lacks the ability to inhibit excess NETs formed during disease conditions. The administration of exogenous LF can be a good prospect to prevent NETosis in pathological conditions.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10629726/
