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Abstract

Human β-defensins (hBDs) are cationic peptides with an amphipathic spatial shape and a high cysteine content. The members of this peptide family have been found in the human body with various functions, including the human reproductive system. Of among β-defensins in the human body, β-defensin 1, β-defensin 2, and β-defensin 126 are known in the human reproductive system. Human β-defensin 1 interacts with chemokine receptor 6 (CCR6) in the male reproductive system to prevent bacterial infections. This peptide has a positive function in antitumor immunity by recruiting dendritic cells and memory T cells in prostate cancer. It is necessary for fertilization via facilitating capacitation and acrosome reaction in the female reproductive system. Human β-defensin 2 is another peptide with antibacterial action which can minimize infection in different parts of the female reproductive system such as the vagina by interacting with CCR6. Human β-defensin 2 could play a role in preventing cervical cancer via interactions with dendritic cells. Human β-defensin 126 is required for sperm motility and protecting the sperm against immune system factors. This study attempted to review the updated knowledge about the roles of β-defensin 1, β-defensin 2, and β-defensin 126 in both the male and female reproductive systems.

Keywords

β-defensin human reproduction sperm fertility oocyte cancer infections

Introduction

Antimicrobial peptides (AMPs), include a wide range of biomolecules, are divided into numerous groups depending on their fundamental structures and topologies (Beisswenger & Bals, 2005; Gordon et al., 2005; Toke, 2005; Zare-Zardini et al., 2016, 2017). Defensins are a type of essential AMPs in mammals that are cationic and amphipathic peptides filled with β-sheets. These peptides are composed of six cysteine residues which create distinct networks of disulfide bridges that maintain the structure of the peptides (Mallow et al., 1996; Selsted et al., 1993; Selsted & Ouellette, 2005). Based on evidence obtained from the disulfide topology, there are three groups of α, β, and θ defensins in mammals (Ganz, 2003; Lehrer, 2004; Selsted & Ouellette, 2005; Zasloff, 2002) which α and β-defensins are two major protein family (Tang et al., 1999). α-defensin is part of the arginine-rich neutrophilic proteins with 29–35 amino acids found in azurophilic granules and their phagocytic vacuoles (Zimmermann et al., 1995). So far, six types of α-defensin, including human neutrophil peptide (HNP)-1, HNP-2, HNP-3, HNP-4, human alpha defensin (HD)-5, and HD-6, have been discovered in humans (Escribese et al., 2011; Mallow et al., 1996; Selsted & Harwig, 1989; Skalicky et al., 1994). As chemical mediators, α-defensins directly support the innate immune system by promoting leukocytes (monocytes, dendritic cells, and T cells) and indirectly by collaborating with other mediators to suppress infection(Ayabe et al., 2000). α-defensin may be related to female fertility and ovulation because of the presence of HNP1–3 in follicular fluid (Das et al., 2008).

β-defensins are considered a family of peptides with an antimicrobial activity that can destroy bacteria (Gram-negative and Gram-positive), viruses, and fungi (Pazgier et al., 2006). The tracheal AMP, identified in the bovine airway in 1991, was the first β-defensin to be discovered (Diamond et al., 1991). Depending on their function, human β-defensins (hBDs) can be found in different body parts, especially in the reproductive system with different roles, as seen in Table 1 and Figure 1.

Table 1.

The Roles of Human β-Defensins in the Human Reproductive System

β-defensin type	Role in the reproductive system		Detection technique	References
hBD-1	Reproductive tract infections	Male	Western blot	(Diao et al., 2014)
		Female	qRT-PCR	(Zhao et al., 1996)
			Northern blots	(Aguilar-Jiménez et al., 2011)
			qRT-PCR	(Aguilar-Jiménez et al., 2011)
	Reproductive cancers	Male	qRT-PCR	(Bose et al., 2009)
	Reproductive cancers	Female	—	—
	Role in human infertility	Sperm	qRT-PCR	(Bose et al., 2009)
	Role in human infertility	Oocyte	ELISA	(Zupin et al., 2019)
hBD-2	Reproductive tract infections	Male	—	—
		Female	PCR	(Harder, Bartels, et al., 1997)
			ELISA	(Boldenow et al., 2015)
			ELISA	(Fan et al., 2008)
			qRT-PCR	(Pivarcsi et al., 2005)
			qRT-PCR	(Midorikawa et al., 2003)
			Chemotaxis assay	(Yang et al., 2000)
			ELISA	(Soto et al., 2007)
			Liquid bacterial killing assay (for testing antibacterial activity)	(Dorschner et al., 2003)
			qRT-PCR	(Bals et al., 1998)
			hybridization
			Western blot
			Antimicrobial assays
			IHC	(King, Paltoo, et al., 2007)
			qRT-PCR	(Zhao et al., 1996)
	Reproductive cancers	Male	—	—
		Female	qRT-PCR	(Chong et al., 2006)
			qRT-PCR	(Kreuter et al., 2009)
			Immunohistochemistry	(Meyer-Hoffert et al., 2008)
			Immunostaining	(Hubert et al., 2007)
	Role in human infertility	Sperm	—	—
	Role in human infertility	Oocyte	—	—
hBD-26	Sperm quality, maturation, and infertility	Male	Immunocytochemistry	(Boroujeni et al., 2019)
			qRT-PCR	(Tollner et al., 2014)
			Western Blot	(Yudin et al., 2005)
			qRT-PCR	(Duan et al., 2015)
			Western Blot	(Duan et al., 2015)
			Western Blot	(Aram et al., 2020)

Note. hBD = human β-defensins; qRT-PCR = Quantitative Real -Time Polymerase Chain Reaction; ELISA = Enzyme-linked immunosorbent assay; IHC = Immunohistochemistry.

Figure 1.

Roles of hBD-1 in the Human Reproductive System

In the male reproductive system, the expression of hBDs in the prostate, testes, and sperm has been reported to have protective activity against infections and regulatory activity on other sperm functions (Zupin et al., 2019). In the female’s reproductive system, hBDs have been seen in the vagina, cervix, endometrium, fallopian tubes, and pregnant uterus, with expression in the amniotic sac, decidua, chorion, and placental trophoblasts. The expression of hBDs, which is variable during the menstrual cycle, is vital throughout pregnancy to keep the uterus and fetus healthy (Horne et al., 2008; King, Kelly, et al., 2007).

θ-defensin is found exclusively in rhesus macaque leukocytes (Tang et al., 1999) but in humans, θ-defensin genes have a premature stop codon, which hinders successful translation of the required precursors; as a result, these peptides are absent from human leukocytes (Lehrer et al., 2012).

Although several hBDs are known in humans (Pazgier et al., 2006) and many studies have been conducted on the role of hBD, increasing the knowledge gathered about the role of hBDs in human reproduction gathered over the past several years has not been adequately reviewed. This document has focused on hBDs with distinct roles in the human reproductive system. Based on the literature review, we found that human β-defensin 1 (hBD-1), human β-defensin 2 (hBD-2), and human β-defensin 126 (hBD-26) are involved in the male and female reproductive systems.

Structure of Human β-Defensin

hBD is a cationic peptide with an amphipathic spatial shape and many cysteine residues (Khayamabed et al., 2020). Three disulfide bridges in hBDs are located between residues 1-5, 2-4, and 3-6, resulting in peptides with one α-helix, a triple-stranded β-sheet structure, and a cationic charged β-hairpin loop. This can be found in almost all members of this family, such as hBD-1, hBD-2, and other isoforms (de Smet & Contreras, 2005; Pujianto et al., 2020).

The first member of the hBD family, hBD-1, was discovered in 1995 by separating it from the hemofiltration of dialysis patients (Bensch et al., 1995). This peptide contains 36 amino acids (Pazgier et al., 2006), which are released by different kinds of epithelia throughout the body that are directly exposed to the microbial flora or environment, such as the lung, mammary gland, salivary gland, kidney, pancreas, and prostate (Bensch et al., 1995; Diao et al., 2014). Some studies show that hBD-1 is present in the male reproductive system in seminal plasma and sperm (Com et al., 2003) and in women in placental tissue and follicular fluid in addition to the epithelium of the female reproductive system (Horne et al., 2008; King, Kelly, et al., 2007).

hBD-2 is the second member of this family, which was first identified in 1997 by deriving from psoriatic skin lesions (Harder, Bartels, et al., 1997), and contains 41 amino acids (Pazgier et al., 2006). hBD-2 is a transcriptionally regulated inducible peptide generated inside the skin and respiratory system (Harder, Siebert, et al., 1997). It is induced because of infection (Boldenow et al., 2015). Sipilla, in 2006 and 2009, reported that the hBD-2 gene is expressed in the epididymis (Pujianto et al., 2020) and studies have also demonstrated that hBD-2 concentrations in lavage fluid are higher in women with bacterial vaginal infections than in healthy women (Fan et al., 2008; Pivarcsi et al., 2005).

hBD-26 is a binding peptide, especially in the epithelial cell layer of the testis and epididymis, which contains 91 amino acids (Pazgier et al., 2006). hBD-26, a cysteine-rich glycoprotein, covers the entire surface of sperm and is secreted by primary epididymal cells. As sperm pass through the corpus/caudal area of the epididymis, hBD-26 is secreted from the epithelium and covers the entire surface of the sperm (Tollner et al., 2012; Yamaguchi et al., 2002). Results show it is present in ejaculated sperm, which is needed for transmission through the female reproductive system (Tollner et al., 2008).

Method

The following keywords and phrases were used in conjunction with one another to conduct a thorough search of the scientific literature in PubMed, Scopus, and Google Scholar up until April 2022: Defensin, human defensin, human beta defensin, human defensin structure, human beta defensin structure, beta defensins and infertility, pregnancy, and the reproductive system, beta defensin and sperm, epididymis, testis, prostate, vaginal microbiota, male microbiota, viral infections, and beta-defensin and prostate cancer, among other terms. Finally, to fully analyze the newest discoveries and the comprehension of hBDs in the human reproductive system, the review studies were removed and pertinent data and findings from original research were incorporated. Studies related to other animal species other than humans were also excluded.

Roles in the Human Reproduction System

Function in Infections of the Reproductive Tract

Male Reproductive System

According to the World Health Organization (Cao et al., 2011), the presence of 1 × 10⁶ leukocytes per milliliter in human ejaculated sperm is defined as leukocytospermia, which affects between 5% and 10% of the male population and indicates an infection of the male reproductive system, which might be one of the causes of infertility (Cumming & Carrell, 2009; Korrovits et al., 2008). The question then becomes, how does the body get rid of these infections? In the human body, chemicals with antimicrobial characteristics in the innate immune system stop uncontrolled bacterial growth and preserve the microbiota balance (Berscheid et al., 2017). Members of the β-defensin family are compounds classified as AMPs due to their capacity to disrupt bacterial cytoplasmic membranes (Selsted & Ouellette, 2005). The most notable member of this family is hBD-1, which is consistently expressed by epithelial cells in contrast to other defensins (Berscheid et al., 2017). In individuals with leukocytospermia, recombinant hBD-1 therapy has been demonstrated to restore bactericidal action (Diao et al., 2014).

In normal and leukocytospermic individuals, the quantity of semen leukocytes, which is related to the severity of the bacterial infection, is negatively linked to the expression of hBD-1 in sperm. To prove the previous relationship, two bacterial species of Escherichia coli and Staphylococcus aureus were used to incubate sperm for 1 hr. Normal sperm has significant antibacterial activity against both types of bacteria, as determined by counting the bacterium’s colony-forming units (CFU) following overnight culture. Remarkably, hBD-1 was first detected in bacteria that lacked hBD-1 after incubation with sperm. This phenomenon represents the hBD-1 transfer of sperm to the bacteria, explaining its antibacterial properties (Diao et al., 2014).

The antibacterial activity of hBD-1 is most likely due to its affinity for chemokine receptor 6 (CCR6) in sperm since the use of antibodies against CCR6 reduces the antibacterial activity of sperm. In support of this idea, it has been observed that if the sperm of leukocytospermic patients are incubated with recombinant hBD-1, the amount of bacterial infection is reduced. It has been observed that people with leukocytospermia exhibit poor resistance to infection as a result of deficiencies in the expression of the CCR6 and hBD-1 genes (Diao et al., 2014).

Regarding the stated content, it is suggested that research to design a clinical test based on hBD-1 protein can help in the diagnosis of male genital tract infections. Furthermore it is suggested that research on compounds containing hBD-1 as a recombinant drug for the treatment of male genital tract infections can be a step forward in the treatment of patients.

Female Reproductive System

To understand the role of β-defensin in the female vaginal tract, a study conducted by Pivarcsi Andor in 2005 examined the expression of the hBD-2 gene in the vaginal epithelial cell line (PK E6/E7 cells) before exposure and 3, 6, 12, and 24 hr after exposure to microbial substances such as gram-negative, gram-positive, and fungal pathogens. Lipopolysaccharide, a Gram-negative cell wall molecule, and peptidoglycan, a Gram-positive cell wall molecule, were reported to have a very significant stimulatory impact on hBD-2 mRNA expression in PK E6/E7 cells. The study also revealed that heat-killed C. albicans had a powerful effect on the stimulation of hBD-2. According to the research, bacterial metabolites are more effective than fungal compounds in inducing AMPs in vaginal epithelial cells (Pivarcsi et al., 2005). According to studies, hBD-2 is highly efficient in eliminating gram-negative bacteria (E. coli and Pseudomonas aeruginosa) and yeasts (Candida albicans), as well as having bacteriostatic effects on gram-positive bacteria like Staphylococcus or Streptococcus sp (Harder, Bartels, et al., 1997; Lee et al., 2004; Midorikawa et al., 2003). hBD-2, produced by cells during innate host defense, can also function as a signal for adaptive immune response initiation, mobilization, and amplification. By interacting with CCR6, hBD-2 can be a chemoattractant for immature dendritic cells (iDCs) and CD45RO memory T cells (Oppenheim et al., 2003; Yang et al., 2000, 2002).

Amniotic fluid is another part of the female reproductive system with antimicrobial properties in which hBD-2 can be found, although its source is unknown, and its concentration does not change with age. The presence of hBD-2 in chorioamnionitis, also known as microbial invasion of the amniotic cavity (MIAC), suggests that this AMP is involved in the host response to microorganisms found in the amniotic hole (Soto et al., 2007). hBD-2 in amniotic fluid and several other antimicrobial proteins can kill germs. For example, hBD-2, with the help of IL-37, kills 100% of group B streptococci (GBS), while each alone has the lowest lethality against GBS (Dorschner et al., 2003). It has also been revealed that in the presence of other antimicrobial molecules such as lysozyme and lactoferrin, hBD-2 has synergistic effects with them and increases the bactericidal power of the female reproductive system (Bals et al., 1998).

hBD-1 is present in the female reproductive system, the placental cord, which may be a significant barrier to various infections (King, Paltoo, et al., 2007; Zhao et al., 1996). For example, in positive HIV mothers, it has been seen that the expression of hBD-1 in the placenta is higher than in negative HIV mothers, but the role of HIV-1 in the induction of hBD-1 in the placenta has not been explored. It has been hypothesized that single nucleotide polymorphisms (SNPs) in the hBD-1 gene are linked to the likelihood of HIV-1 infection (Aguilar-Jiménez et al., 2011).

As a result, both hBD-2 and hBD-1 appear to play a role in antibacterial activities in the uterus, with hBD-2 playing a more significant function. AMPs like hBD-2 should be considered a possible source to fight against in light of our findings in individuals with vaginal infections. In addition, hBD-2 production stimulation in the vagina can be a therapy alternative.

Function in Reproductive Cancers

Male Reproductive System

The hBD-1 gene is situated in a region on chromosome 8 that is thought to house several tumor suppressor genes. A Global transcriptome study of human tumor tissues led to the discovery that hBD-1 is initially linked to prostate cancer because the loss of chromosome 8p was widely observed in prostate cancer patients. Through the CCR6 chemokine receptor, hBD-1 collaborates with adaptive immunity by acting as a chemotactic agent to draw in iDC and memory T-cells (Donald et al., 2003; Yang et al., 1999). The dendritic cells (DC) is the most potent antigen-presenting cell that can amplify naive T cells and trigger tumor immune responses (Thomas-Kaskel et al., 2007). However, tumors have devised strategies to avoid detection and elimination by the immune system, including disrupting or decreasing the amount of functioning DC. hBD-1 also directly causes cytotoxicity in mammalian cells to combat cancer cells. Given its cytotoxic action against cancer cells and its capacity to attract DC to tumors, hBD-1 may be implicated in tumor suppression via an antitumor response involving the immune system. hBD-1 kills cancer cells by causing necrosis via increasing membrane permeability (Bose et al., 2009). As a result, there could be a decrease in defensin-mediated tumor cytotoxicity or a deficiency of host immune system identification due to the altered epithelium’s lack of production of this protein (Donald et al., 2003).

The hBD-1 promoter has a growth-control gene called PAX2, whose expression is typically suppressed during terminal differentiation in most tissues (Bose et al., 2009; Eccles et al., 2002). The PAX2 recognition region, which includes seven nucleotides out of the 11 cores of the hBD-1 promoter sequence, is positioned upstream of the hBD-1’s TATA box and the transcription start site at the location of the reported pair recognition sequences from-170 to 159 (Bose et al., 2009). In prostate cancer, hBD-1 gene transcription is inhibited by the PAX2 oncogene, which is independent of p53, as PAX2 binds to the hBD-1 promoter and inhibits transcriptional activity. When the expression of hBD-1 is suppressed, it means that there is no agent that destroys the cancer cell, and as a result, the integrity of the tumor cell membrane is preserved and not destroyed, which stopping PAX2 can stop this process (Bose et al., 2009).

By inhibiting PAX2 and hBD-1 by siRNA at the same time, cells kept their intact membranes and did not die necrotically. In antitumor immunity, necrotic cells are DCs activators (Bose et al., 2009). Consequently, by suppressing hBD-1, PAX2 may be able to attenuate this vital mechanism for the diagnosis and death of cancer cells. It has previously been described as hBD-1 being able to recruit DC. The capacity of hBD-1 to attract DC and memory T cells in prostate cancer cells implies that the protein may play a role in antitumor immunity (Bose et al., 2009).

According to immunohistochemistry research, 82% of human prostate tumors have lost the cancer-specific hBD-1 protein. Therefore, hBD-1 is now recognized as a marker for the detection of prostate cancer. By utilizing it, novel therapeutic approaches, such as the administration of recombinant hBD-1, can be employed to cure cancer (Donald et al., 2003).

Female Reproductive System

The human papillomavirus (HPV) belongs to the Papillomaviridae family of viruses (Belnap et al., 1996). At least 40 HPV genotypes are thought to prevail in the female reproductive epithelium (Rositch et al., 2013). Concurrent HPV infection is believed to be responsible for 90% of all cervical cancers detected yearly (Kitchener et al., 2013; Tommasino, 2014). Because of their position and involvement in antigen presentation, epithelial dendritic cells are thought to be critical for initiating the adaptive immune response to HPV infection (Chong et al., 2006). So, the role of β-defensin in operating DC and its antimicrobial activity could be significant in preventing cervical cancer in the first step.

Studies have been reported that hBD-2 levels are elevated in HPV patients, indicating that HPV can cause hBD-2 to be secreted. The expression of the hBD-2 protein was elevated in genital condyloma acuminata, which is corroborated by a study on vulvovaginal lesions brought on by HPV. In addition, it has been discovered that hBD-2 can draw DC from women with cervical cancer. hBD-2 can attract DC in organotypic cultures of HPV-transformed keratinocytes maintained in vitro or transplanted in vivo, indicating that these molecules might help restore several immune functions that have been demonstrated to be disrupted during cervical carcinogenesis (Chong et al., 2006; Hubert et al., 2007; Kreuter et al., 2009; Meyer-Hoffert et al., 2008). Consequently, papillomaviruses control the activity of hBD-2. Concerning papillomavirus-induced epithelial lesions, this novel study implies that hBD-2 may support both innate and adaptive immune responses. Therefore, research on hBD-2 as a supportive treatment in strengthening HPV treatment for future studies can be worthy of attention.

Role in Human Infertility

Sperm

As previously mentioned, hBD-1 affects sperm motility by binding to CCR6 present in sperm. The sperm absorbs hBD-1 via attaching to the CCR6 receptor as it travels through the epididymis, where the epithelium releases it. When hBD-1 binds to this receptor, a heterotrimeric G protein is triggered. This heterotrimeric G protein then activates a series of additional signaling events, which in turn trigger pathways involving intracellular second messengers like cAMP and PKA and result in the movement of the sperm tail (Caballero-Campo et al., 2014). Considering the high expression of hBD-1 in the epididymal epithelium and the presence of CCR6 in sperm, it is possible that CCR6 acts as a receptor for secreted hBD-1 during sperm passage from the epididymis. The reduction of the positive correlation between the expression of hBD-1 and CCR6 in asthenospermic patients and the improvement of sperm function after incubation with recombinant hBD-1 are some of the reasons that lends credence to this idea. This indicates that hBD-1 interaction with sperm is CCR6-dependent and that decreased hBD-1 levels in the defective sperm may be partially attributed to decreased CCR6 expression in sperm (Diao et al., 2014).

Like in the epididymis, those reactions must also occur in the uterus for egg fertilization. hBD-1 secreted from uterine epithelium binds to CCR6 and induces Ca²⁺ influx that is dependent on CatSper, thereby increasing sperm motility. When the sperm reaches the vicinity of the fertilization site, progesterone secreted from the cumulus-oocyte complex binds to CCR6/CatSper. This action leads to a stronger influx of Ca²⁺ into the sperm, resulting in hyperactivity and acrosome reaction which is required for fertilization (Caballero-Campo et al., 2014).

Another role of hBD-1 is in sperm fertility. In mammals, including humans, sperm must undergo many changes before they gain their fertilizing ability. The two most significant changes are capitation and the acrosome reaction (Brucker & Lipford, 1995). Fresh sperm need biochemical and metabolic changes, including lowering cholesterol levels in the sperm membrane and hyperpolarization, to achieve fertilization through a process called “capacitation.” However, when sperm attaches to the zona pellucida, it enhances calcium entrance into the sperm, making the “acrosome reaction” process easier (Khayamabed et al., 2020).

Capacitation is a post-ejaculatory change in the physiological function of sperm that occurs in the female reproductive system. In addition to the modifications in sperm membrane structure which is required for the acrosome reaction, the intracellular calcium concentration increases slowly during capacitation with Ca^{2 +}-ATPase control which is controlled by hBD-1 (Brucker & Lipford, 1995; Diao et al., 2014). The acrosome reaction is required for sperm transmission in the female reproductive system. It must occur before the sperm penetrates the egg layers and fertilizes the egg (Agarwal et al., 2016). When sperm comes into contact with the zona pellucida under physiological circumstances, it attaches to it, and the acrosome reaction starts (Hsu et al., 1999). Sometimes the two previous events occur prematurely before the sperm is transferred to the female reproductive system. These sperms lose fertility with the premature release of acrosomal enzymes (Agarwal et al., 2016). To prevent these events, hBD-1 appears on the surface of sperm passing through the epididymis, stopping premature capacitation and premature acrosomal reaction by avoiding the removal of cholesterol from the sperm membrane or preventing hyperpolarization (Khayamabed et al., 2020).

The level of hBD-1 was also shown to be lower in people with sperm motility issues than in those with normal sperm in a research we did to examine the expression of the hBD-1 and hBD-2 genes in the semen samples of infertile couples. Our findings indicated that hBD-1 deficiency may result in sperm losing their motility (perhaps due to lack of capacitation) and being unable to fertilize (Firouzabadi et al., n.d.).

Sperm should be protected against the immune by passing through the female genital tract (Boroujeni et al., 2019; Tollner et al., 2014). In humans, hBD-26 protects sperm, preventing them from being recognized by immunocompetent cells in a new in vivo model system and when challenged with anti-sperm antibodies in vitro. Because of its sialic acid moieties, hBD-26 has a significant negative charge, and this sialic acid appears to be the source of hBD-26’s immunological protective activity. It has been postulated that sialic acid residues cover sperm antigens in some way and so help to immune protection of exposed antigens (Yudin et al., 2005). Sperm preservation in the epididymal tail, sperm mobility in cervical mucus, sperm capacitation, attachment to the oviduct epithelium, and eventually the development of a spermatozoa reservoir in the oviduct are all processes in which hBD-26 is engaged. hBD-26, which appears to be crucial in aiding binding to the zona pellucida, is released from the sperm surface during capacitation (Boroujeni et al., 2019). Also, hBD-26 plays an essential role in sperm motility (Solanki et al., 2023). The ability of sperm cells not coated with hBD-26 to reach the egg is demonstrated to be diminished, which results in reduced motility and lower fertility (Tollner et al., 2014). In support of the aforementioned connection, R. Aram’s 2020 research on humans discovered that exposing immature sperm to H9C2 cells transfected with hBD-26 led to a 15% increase in motility (Aram et al., 2020).

Oocyte

In women, hBD-1 also appears to affect oocyte quality and female fertility. The presence of hBD-1 in the follicular fluid may be linked to the inflammatory response required for efficient folliculogenesis, the initiation of ovulation, and the tissue remodeling that follows (Abramov et al., 1996). In a study conducted by Louisa Zupin in 2019, the hBD-1 rate in follicular fluid was significantly higher in women with good oocyte fertility (≥75%) than in women with poor oocyte fertility (<75%). These findings imply that hBD-1 may have a fertilization-promoting impact, although this work did not explore the link between hBD-1 concentration and pregnancy success (Zupin et al., 2019).

hBD-1 can improve the quality of oocytes and eliminate their destructive microbial agents. Animal studies have clarified that oocyte quality is impaired due to changes in the follicular environment due to pathogens and significantly impacts fertility. hBD-1 association in response to inflammatory cytokines may also be associated with infertility (Bedaiwy et al., 2007; Sarapik et al., 2012; Semple & Dorin, 2012; Sheldon et al., 2014).

Hence, given their involvement in sperm motility and its capacitation which is necessary for sperm maturation and their role in oocyte maturation and quality, the findings of this article indicate that hBDs are essential for successful fertilization. Based on our findings, the issues with the synthesis or release of hBD from the male or female reproductive system may be to responsible for infertility in couples with idiopathic infertility. So, evaluation of hBDs can be utilized as a diagnostic test for infertility. Recombinant hBDs medications may also be a good choice for treating infertility.

Statistical Information and Sequence Analysis

Based on the literature review, there are more than 1,036 reported defensins. Among these peptides, 100 β-defensins were identified based on a database search in various mammals (please refer to the supplementary data for more information). Among these peptides, 31 peptides were identified from a human. Table 2 summarizes the features of those 31 kinds of peptides. CLC software was used to do bioinformatics analysis on the collected peptides (amino acid composition analysis, alignment, structure prediction, and so on). The average length of all identified β-defensins is 46.12 amino acids. The average net charge is +4.91. The positive net amount of β-defensins increases their antimicrobial activities. These peptides protect the male and female reproductive systems against pathogens such as gram-positive and gram-negative bacteria, viruses, and fungal strains. Cys (13.07%), Gly (10.18%), and Arg (9.98%) are the most common amino acids in all peptides. These three amino acids are found in the most significant number of β-defensins. Met (1.24%), Trp (1.97%), and His (1.83%) are the amino acids with the most negligible value. Cysteine has the highest frequency of all the reported peptides (please refer to the supplementary data for more information).

Table 2.

Information of All Reported Human β-Defensins

Name	Source	Sequence
hBD-1	Human	DHYNCVSSGGQCLYSACPIFTKIQGTCYRGKAKCCK
hBD-2	Human	GIGDPVTCLKSGAICHPVFCPRRYKQIGTCGLPGTKCCKKP
hBD-3	Human	GIINTLQKYYCRVRGGRCAVLSCLPKEQIGKCSTRGRKCCRRKK
hBD-4	Human	EFELDRICGYGTARCKKCRSQYRIGRCPNTYACCLRKWDESLLNRTKP
hBD-5	Human	GLDFSQPFPSGEFAVCESCKLGRGKCKECLENKPDGNCRLNFLCCRQRI
hBD-6	Human	FFDEKCNKLKGTCNNCGKNELIALCQKSLKCCRTIQPCGSIID
hBD-7	Human	AIHRALISKRMEGHCEAECLTFVKIGGCRAELAPFCCKNR
hBD-8	Human	KFKEICERPNGSCDFCLETIHVGRCLNSQPCCLPL
hBD-9	Human	RGDLGPVEGHCLNLSGVCRDVCKVVDQIGACRRRMKCCRTWWILMPIPTPLIM
hBD-10	Human	ERCEKVRGICKTFCDDVEYDYYCIKWRSQCCV
hBD-11	Human	RECRIGNGQCNQCHENIRIAYCIRPGTHCCLQQ
hBD-12	Human	TEKISTARSEGHHITFSRWKSCTAIGGRCNQCDDSFRISYCARPTTHCCVTECDPTDPNNWIPKDSVGTQEWYPKDSRH
hBD-13	Human	RECQLVRGACKPECNSWEYVYYYCNVNPCCAVWE
hBD-14	Human	TLVNADRCTKRYGRCRDCLESKQIDICSLPGKICCTEKLYEEDDMF
hBD-15	Human	RRCYYGTGRCKSCKEIERKKEKCGEKHICCVPKEKD
hBD-16	Human	NPCELYQGMCRNACREYEIQYLTCPNDQKCCLKLSVK
hBD-17	Human	KSCWIIKGHCRKNCKPGEQVKKPCKNGDYCCIPSNTDS
hBD-18	Human	YSGEKKCWNRSGHCKQCKDGAVKDTCKNLRACCIPSNEDHRRVPATSPTPLSDSTPGIIDDILTVRFTTDYFEVSSKKDMVEESEAGRGTETSLPNVHHSS
hBD-19	Human	KRHILRCMGNSGICASCKKNQPYLYCRNCQSCCLQSYMRISISGKEENTDWSYEKQWPRLP
hBD-20	Human	VECWMDGHCLLCKDGDSIIRCRNRKRCCVPSRYLTIQPVTIHGILGWTTPQMSTTAPKMKTNITNR
hBD-21	Human	VMKCWGKSGRCTTCKESVYYILCKTEAKCCVDPKYVPVKPKLTDTNTSLESTSAV
hBD-22	Human	ETCWNFRGSCRDECLKNERVYVFCVSGKLCCLKPKDQ
hBD-23	Human	GTQRCWNLYGKCYRCSKKRVYVYCINNKMCCVKPKYQPKERWWPF
hBD-24	Human	KRCWKGQGACQTYCTRQETYMRLCPDASLCCLSYALK
hBD-25	Human	SFEPQKCWKNNVGHCRRCLDTRYILLCRNKLSCCISIISHEYTRRPAFPVIHLEDITLDYSDVDSFTGSPVSMLNDLITFDTTKFGETMTPETNTPETTMPPSEATTPETTMPPSETATSETMPPPSQTALTHN
hBD-26	Human	NWYVKKCLNDVGICKKCKPEMHVKNGWAMCGKQRDCCVPADRRANYPVFCVQTKTTRISTVTATTATTTLMMTTASMSSMAPTPVSPTG
hBD-27	Human	EQLKKCWNNYVQGHCKICRVNVPEALCENGRYCCLNIKELEACKKITKPPRPKPATLALTLQDYVTIIENFPSLKTQST
hBD-28	Human	LKKCFNKVTGYCKKCKVGRYEIGCLSGKLCCANDEEEKKHVSFKKPHQHSGEKLSVLQDYIILPTITIFTV
hBD-29	Human	EFIGLRRCLMGLGRCDHCNVDKEIQKCKMKKCCVGPKVVKLIKNYLQYGTPNVLNEDVQEMLKPAKNSSAVIQRKHILSVLPQIKSTSFFANTNFVIIPNATPMNSATISTMTPGQITYTATSTKSNTKESRDSATASPPPAPPPPNIL
hBD-30	Human	GVIPGQKQCIALKGVCRDKLCSTLDDTIGICNEGKKCCRRWWILEPYPTPVPKGKSP
hBD-31	Human	FISNDECPSEYYHCLKCNADHAIRYCADFSICCKLKIIEIDGQKKW

Note. hBD = human β-defensins.

Bridge structures have been shown in β-defensins due to the presence of Cys. Disulfide bridges maintain the structural stability of these peptides. The BOMAN index assesses a protein’s ability to interact with other proteins. This factor is determined by the amount of all amino acid solubility ratios in a peptide or protein sequence (Soltaninejad et al., 2021; Zare-Zardini et al., 2021). All reported human β-defensin has a higher BOMAN index than 2.468 (Lira et al., 2013). This situation leads to better interaction of the peptide with other proteins and cell receptors, especially in male and female reproductive systems. This interaction can alter gene expression, protein penetration, enzyme activity, and so on. This interaction is essential due to the enhancement of the peptide’s ability to bind to active enzymes in the health of male and female reproductive systems (Johansson-Åkhe et al., 2019; Stanfield & Wilson, 1995). The phylogenetic tree showed that the β-defensin sequence is conserved throughout evolution, and no significant changes in the amino acid sequence have occurred. Humans and other mammalian β-defensins are found in a typical branch of the phylogenetic tree with the closest evolutionary relationship. We separately compared the human β-defensins (Figure 2). All 31 peptides are 39.12 residues long on average. The average net charge of these peptides is 4.00. Similar to other reported β-defensins, Cys (15.38%), Gly (14.52%), and Arg (10.25%) have more frequency in all sequences. The lowest frequency of amino acids belongs to Met (0.54%), Asp (1.7%), and Glu (1.7%) (Table 3). The phylogenetic tree also revealed that the human β-defensin sequence has remained relatively unchanged throughout evolution (Figure 3).

Figure 2.

Sequence Alignment of All Reported Human β-Defensins

Table 3.

The Sequence Information of Reported Human β-Defensins

Amino acid	%	Average length	Average net charge
I	3.41	39.12	4
V	0.85
L	5.44
F	2.56
C	15.38
M	0.54
A	5.12
W	1.7
G	14.52
P	2.56
T	5.98
S	5.98
Y	4.27
Q	1.7
N	4.27
E	3.41
D	1.7
H	5.12
K	5.12
R	10.25

Figure 3.

Phylogenetic Tree of All Reported Human β-Defensins

Conclusion

AMPs known as hBDs have differential effects on the male and female reproductive systems. Due to their antibacterial functions, these peptides could contribute to preventing infections associated with the male/female reproductive systems. The use of hBDs may have benefits as a diagnostic/prognostic indicator of cancers related tothe human reproductive tract as well as human fertility because of their involvement in sperm maturation and oocyte quality, but because different hBDs are still in the research phase, their limitations and strength are not clear. Also, the utilization of recombinant hBDs may consider a practical option in male and female infertility treatment, although, in this study, the effect of other factors on the performance of hBDs was not investigated, more extensive research is needed for greater certainty.

Supplemental Material

sj-docx-1-jmh-10.1177_15579883231182673 – Supplemental material for Roles of Different β-Defensins in the Human Reproductive System: A Review Study

Supplemental material, sj-docx-1-jmh-10.1177_15579883231182673 for Roles of Different β-Defensins in the Human Reproductive System: A Review Study by Farzaneh Fesahat, Amir Masoud Firouzabadi, Hadi Zare-Zardini and Maryam Imani in American Journal of Men's Health

Footnotes

Authors’ Note

F.F. and A.M.F. are the co-first authors.

Data Availability

Data sharing is not applicable as no new data were generated or analyzed during this study.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research project officially approved with the National Id code 11299 of Shahid Sadoughi University of Medical Sciences, Yazd. The authors did not receive financial support for this research.

Ethical Approval

The Shahid Sadoughi University of Medical Sciences approved this study with approval number: IR.SSU.SPH.REC.1400.152.

ORCID iDs

Farzaneh Fesahat

Amir Masoud Firouzabadi

Supplemental Material

Supplemental material for this article is available online.

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