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Oxidative stress and disruption of blood‒testis barrier permeability are considered key factors in the pathogenesis of testicular inflammation, degeneration, and functional impairment, which play crucial roles in male infertility. Antimicrobial peptides (AMPs) are internationally recognized as some of the most promising alternatives to antibiotics. However, the molecular mechanisms by which AMPs regulate oxidative stress and the blood‒testis barrier in the testis are still poorly understood. In this study, we orally administered 0.5 mg/kg antimicrobial peptide MPX (MPX) to mice for 20 and 40 days and evaluated its effects on Lipopolysaccharide LPS-induced testicular oxidative stress and blood‒testis barrier repair, and elucidateed the pharmacokinetics of MPX in mice. The experiment was divided into six groups, control, LPS, MPX, MPX + LPS, Polymyxin and Polymyxin + LPS, respectively. The results showed that oral administration of MPX effectively increased testicular Glutathione (GSH), Total superoxide dismutase (T-SOD), and Catalase (CAT) levels and reduced Nitric oxide (NO) and Malondialdehyde (MDA) levels in the testes and Lactate dehydrogenase (LDH) levels in serum; these findings were consistent with the oxidative stress parameters in the liver. MPX significantly upregulated the expression of Kelch-like ECH-associated protein 1 (Keap1), Nuclear factor erythroid 2-related factor 2 (Nrf2), and Glutamate cysteine ligase, modifier (GLCM) in the testes while downregulating the expression of Glutamate cysteine ligase, catalytic (GCLC) and Inducible nitric oxide synthase (iNOS), thus exerting a regulatory effect on oxidative stress. MPX also effectively increased sperm count and motility and counteracted the LPS-induced blood‒testis barrier damage, and its molecular mechanism involved upregulating the expression of Slug, which subsequently promoted high expression of Claudin, Occludin, Zonula occludens-1 (ZO-1), N-cadherin, and E-cadherin in the testes. After intragastric administration of FITC-MPX for 30 min, FITC-MPX was mainly distributed in the stomach and thoracic cavity, then showed multi-tissue distribution after 30 min. The fluorescence signal could be detected in the testis 1 h later, which confirmed that MPX had testicular targeting. Moreover, both intraperitoneal and intravenous injection of FITC-MPX also confirmed its testicular targeting ability. In conclusion, this study systematically evaluated the long-term effects of the orally administered antimicrobial peptide MPX on oxidative stress and the blood‒testis barrier in the male reproductive system. This study laid the foundation for the antimicrobial peptide MPX to be used in the treatment of male testicular inflammatory diseases.

Background: Manganese (Mn) is a trace element essential for multiple physiological and biological processes. The testis plays a key role in male reproduction by producing sperm and synthesizing male hormones. This study investigates how Mn deficiency affects testicular development, spermatogenesis, and the blood–testis barrier (BTB), and evaluates associated variations in oxidative stress to explore potential mechanisms. Methods: A Mn-deficient diet was used to induce Mn deficiency in mice, with MnCl2 administered via intraperitoneal injection. Mn levels in testicular tissue were measured by atomic absorption spectrometry. Testis and sperm morphology were assessed by H.E. and sperm staining. BTB markers were analyzed using immunofluorescence, Western blot, and qPCR. Oxidative stress was evaluated biochemically. Nrf2 pathway changes were detected by qPCR and Western blot. Results: The results indicated that Mn deficiency dramatically decreased the testicular index, caused abnormal testicular tissue structure, and significantly decreased Johnsen’s score. At the same time, sperm density and motility were significantly reduced, and the sperm deformity rate was significantly increased. In addition, the BTB function was impaired, as indicated by the significantly down-regulated expression of tight junction proteins including Occludin, ZO-1, JAM-A, and Claudin-11. As the oxidative stress levels increased, the mRNA and protein expression levels of molecules (including Nrf2 and HO-1) related to the Nrf2 signaling pathway were significantly down-regulated, while its inhibitor Keap1 exhibited significantly up-regulated expression. Notably, after supplementing MnCl2, all the above abnormal indicators were significantly improved. Conclusions: Mn deficiency can lead to testicular tissue damage, decreased sperm quality, and BTB dysfunction, and the potential mechanism is probably closely associated with the increase in the oxidative stress level mediated by the Nrf2 pathway.

The blood-testis barrier (BTB) is composed of tight junctions (TJ) between adjacent Sertoli cells (SCs) and is crucial for sperm growth and development. Aging-induced TJ impairment is closely related to testicular dysfunction. Curcumin, a natural compound, has been widely demonstrated to have a wide range of pharmacological activities, but its regulatory effects on tight junction damage in the testis remain unclear. We here explored the effect of curcumin on TJ function and its underlying molecular mechanism by using D-galactose (D-gal)-induced mouse testis and mouse testicular SCs (TM4) aging models in vitro . In this study, D-gal increased the expression of aging-related proteins p16 and p21, whereas significantly decreased the expression of TJ proteins (ZO-1, Claudin-4, Claudin-7, and Occludin). In addition, curcumin restored the adverse effects of D-gal in the SCs. Autophagy is a degradation system for maintaining cell renewal and homeostasis. D-gal significantly decreased the autophagy level, whereas curcumin restored the effect of D-gal. Using chloroquine (CQ), an inhibitor of autophagy, and rapamycin (RAPA), an activator of autophagy, it was demonstrated that autophagy plays a key role in curcumin amelioration of TJ injury in testicular SCs. Further studies unveiled that autophagy activation was mediated through the AMPK/mTOR pathway. In conclusion, curcumin ameliorates aging-induced TJ damage through AMPK/mTOR signaling pathway-regulated autophagy. This study thus clearly identifies a novel action mechanism of curcumin in the treatment of age-related male reproductive disorders.

Flaviviruses including Dengue virus (DENV), Yellow fever virus (YFV), West Nile virus (WNV), and Japanese encephalitis virus (JEV) are global health problems that caused several serious diseases such as fever, hemorrhagic fever, and encephalitis in the past century. Recently, Zika virus (ZIKV) which spreads from Asia to American and causes millions of infections emerges as a new dangerous member of the genus of . Unlike other well-known flaviviruses, ZIKV can be transmitted sexually and infect testes in murine models. Its impacts on sperm functions, and the exact susceptible cells, however, are not entirely clear. To investigate these issues, we infected interferon α/β and γ receptors deficient AG6 mice with ZIKV and examined the outcomes of infection using an assortment of physiological, histopathological, immunological, and virological techniques. We found that infected mice displayed signs of reproductive system disorder, altered androgen levels in serum, and high viral load in semen and testes. Additionally, histopathological examinations revealed marked atrophy of seminiferous tubules and significant reduction in lumen size. Notably, these were accompanied by positive staining of ZIKV antigens on sertoli cells, detection of viral particles and vacuole changes within cytoplasm of sertoli cells. The susceptibility of sertoli cells to ZIKV was further validated study using cell lines. Importantly, the disruption of tight junctions within testis and altered sperm morphology were also observed in ZIKV infected mice. It is well-known that tight junctions formed by adjacent sertoli cells are major component of blood testis barrier, which plays important roles in maintenance of microenvironment for spermagenesis in testis. Taken together, these results demonstrate that sertoli cells are susceptible to ZIKV infection, which results in the disruption of tight junctions in testis and causes abnormal spermatogenesis in mice. These results also imply that long-term impact of ZIKV infection on human male reproductive system requires close monitoring.

In order to clarify injure mechanism of busulfan to spermatogenic function, we treated mice with busulfan, the testicular and epididymal weights and sperm concentration significantly decreased and the sperm malformation rate increased over time. Moreover, testicular interstitial cell infiltration, a smaller seminiferous tubule, and disorganized and shed spermatogenic cells were also observed by immunohistochemical, immunofluorescence detection after the busulfan treatment. Furthermore, the enzyme-linked absorbance assays showed serum interleukin (IL)-6, IL-1β, and tumor necrosis factor-apha levels (inflammatory factors) were significantly upregulated; blood-testis barrier (BTB)-related protein levels (e.g., N-Cadherin, occludin, and connexin 43) and vimentine gradually decreased. So we infer busulfan treatment induced orchitis, further disrupted the BTB and disrupted the spermatogenic microenvironment, then decreased vimentine and gradually damaged the cytoskeleton, which cause spermatogenic cells losing their supporting from sertoli cells, androgen regulation was also affected, which was detrimental to spermatogenesis. The study result will improve the efficiency and safety in spermatogonial stem cell transplant recipients.

To facilitate temperature adjustments, the testicles are located outside the body cavity. In most mammals, the temperature of the testes is lower than the body temperature to ensure the normal progression of spermatogenesis. Rising temperatures affect spermatogenesis and eventually lead to a decline in male fertility or even infertility. However, the testes are composed of different cell types, including spermatogonial stem cells (SSCs), spermatocytes, spermatozoa, Leydig cells, and Sertoli cells, which have different cellular responses to heat stress. Recent studies have shown that using different drugs can relieve heat stress-induced reproductive damage by regulating different signaling pathways. Here, we review the mechanisms by which heat stress damages different cells in testes and possible treatments.

Perfluorohexane sulfonic acid (PFHxS) is extensively used in waterproof coatings and fire‐fighting foams, and several studies have found it to be a potential health hazard, but there is still unknown about its effects on spermatogenesis. Our results showed that PFHxS‐treated mice have significant reproductive toxicity, including a decrease in sperm count and motility, and the levels of sex hormones (P < 0.05). Concurrently, structural abnormalities are observed in sperm, affecting ≈60–75% of those in the PFHxS‐treated group. Additionally, it is found that the structure of the blood‐testis barrier (BTB) is damaged after PFHxS treatment, leading to higher expression levels of inflammatory cytokines in the microenvironment for spermatogenesis. Moreover, the expression of proteins associated with mitochondrial biogenesis, including PTEN‐induced kinase 1 (PINK1) and NADPH oxidase 4 (NOX4), is dysregulated in the testes after PFHxS treatment. Based on metabolome data, the differential metabolite 3‐hydroxybutanoic acid is identified in the PFHxS‐treated group, which can regulate the histone Kac levels, especially H3K4ac and H3K9ac. In summary, the results of this study suggest that in the testes of PFHxS‐treated mice, inflammatory factors disrupt the mitochondrial function and metabolic profiles and hinder the progress of gene transcription through histone Kac, ultimately causing sperm dysfunction. Exposure to PFHxS disrupts the immune‐isolated microenvironment and mitochondrial function homeostasis during spermatogenesis. Subsequently, it up‐regulates the metabolite β‐hydroxybutyrate which is involved in the post‐translational modification of proteins, and resulting in a decrease in histone acetylation level. Ultimately, this interference affects the transcriptional activity of genes, leading to abnormal sperm function.

A local autocrine axis exists in the testes that regulates spermatogenesis. In this Review, Cheng and Mruk review findings from the past decade that support the presence and reveal the importance of this axis, which is an emerging target for male contraceptive development. Spermiation—the release of mature spermatozoa from Sertoli cells into the seminiferous tubule lumen—occurs by the disruption of an anchoring device known as the apical ectoplasmic specialization (apical ES). At the same time, the blood–testis barrier (BTB) undergoes extensive restructuring to facilitate the transit of preleptotene spermatocytes. While these two cellular events take place at opposite ends of the Sertoli cell epithelium, the events are in fact tightly coordinated, as any disruption in either process will lead to infertility. A local regulatory axis exists between the apical ES and the BTB in which biologically active laminin fragments produced at the apical ES by the action of matrix metalloproteinase 2 can regulate BTB restructuring directly or indirectly via the hemidesmosome. Equally important, polarity proteins play a crucial part in coordinating cellular events within this apical ES–BTB–hemidesmosome axis. Additionally, testosterone and cytokines work in concert to facilitate BTB restructuring, which enables the transit of spermatocytes while maintaining immunological barrier function. Herein, we will discuss this important autocrine-based cellular axis that parallels the hormonal-based hypothalamic–pituitary–testicular axis that regulates spermatogenesis. This local regulatory axis is the emerging target for male contraception. Key Points The apical ectoplasmic specialization–BTB (blood–testis barrier)–hemidesmosome axis, a novel functional axis in the testis, coordinates events occurring at opposite ends of the seminiferous epithelium during spermatogenesis To maintain immunological barrier function at the BTB during the transit of spermatocytes, 'new' tight junction fibrils are assembled below migrating spermatocytes before 'old' tight junction fibrils are disassembled Protein endocytosis, recycling, transcytosis and endosome-mediated or ubiquitin-mediated protein degradation play a critical part in the homeostasis of this apical ectoplasmic specialization–BTB–hemidesmosome functional axis Polarity proteins are important regulators of endocytic vesicle-mediated protein trafficking events in the seminiferous epithelium during spermatogenesis

Heparan sulfate (HS), an abundant component of the apical cell surface and basement membrane, belongs to the glycosaminoglycan family of carbohydrates covalently linked to proteins called heparan sulfate proteoglycans. After endocytosis, HS is degraded in the lysosome by several enzymes, including heparan-alpha-glucosaminide N-acetyltransferase (HGSNAT), and in its absence causes Mucopolysaccharidosis III type C (Sanfilippo type C). Since endocytosis occurs in epithelial cells of the testis and epididymis, we examined the morphological effects of Hgsnat inactivation in these organs. In the testis, Hgsnat knockout ( Hgsnat-Geo ) mice revealed statistically significant decrease in tubule and epithelial profile area of seminiferous tubules. Electron microscopy (EM) analysis revealed cross-sectional tubule profiles with normal and moderately to severely altered appearances. Abnormalities in Sertoli cells and blood-testis barrier and the absence of germ cells in some tubules were noted along with altered morphology of sperm, sperm motility parameters and a reduction in fertilization rates in vitro . Along with quantitatively increased epithelial and tubular profile areas in the epididymis, EM demonstrated significant accumulations of electrolucent lysosomes in the caput-cauda regions that were reactive for cathepsin D and prosaposin antibodies. Lysosomes with similar storage materials were also found in basal, clear and myoid cells. In the mid/basal region of the epithelium of caput-cauda regions of KO mice, large vacuolated cells, unreactive for cytokeratin 5, a basal cell marker, were identified morphologically as epididymal mononuclear phagocytes (eMPs). The cytoplasm of the eMPs was occupied by a gigantic lysosome suggesting an active role of these cells in removing debris from the epithelium. Some eMPs were found in proximity to T-lymphocytes, a feature of dendritic cells. Taken together, our results reveal that upon Hgsnat inactivation, morphological alterations occur to the testis affecting sperm morphology and motility parameters and abnormal lysosomes in epididymal epithelial cells, indicative of a lysosomal storage disease.