The trend in parenthood at an older age is increasing for both men and women in developed countries, raising concerns about the reproductive ability and the consequences for the offspring’s health. While reproductive activity in women stops with menopause, a complete cessation of the reproductive potential does not occur in men. Although several studies have been published on the effects of aging on semen parameters and spermatozoa DNA integrity, literature on impact of aging on the testis, particularly cellular and molecular alterations, has been, so far, limited and controversial. This work discusses the current knowledge on testicular aging in humans and other mammals, covering topics from tissue ultrastructure, to cellular and molecular alterations. Aging affects male reproductive function at multiple levels, from sperm production and quality, to the morphology and histology of the male reproductive system. The morphological and functional changes that occur in the testes result in variations in the levels of many hormones, changes in molecules involved in mitochondrial function, receptors and signaling proteins. Despite knowing that these age-related alterations occur, their real impact on male fertility and reproductive health are still far from being fully understood, highlighting that research in the field is crucial.

Bisphenol A (BPA), a well-known endocrine disruptor present in epoxy resins and polycarbonate plastics, negatively disturbs the male reproductive system affecting male fertility. In vivo studies showed that BPA exposure has deleterious effects on spermatogenesis by disturbing the hypothalamic–pituitary–gonadal axis and inducing oxidative stress in testis. This compound seems to disrupt hormone signalling even at low concentrations, modifying the levels of inhibin B, oestradiol, and testosterone. The adverse effects on seminal parameters are mainly supported by studies based on urinary BPA concentration, showing a negative association between BPA levels and sperm concentration, motility, and sperm DNA damage. Recent studies explored potential approaches to treat or prevent BPA-induced testicular toxicity and male infertility. Since the effect of BPA on testicular cells and spermatozoa is associated with an increased production of reactive oxygen species, most of the pharmacological approaches are based on the use of natural or synthetic antioxidants. In this review, we briefly describe the effects of BPA on male reproductive health and discuss the use of antioxidants to prevent or revert the BPA-induced toxicity and infertility in men.

Amyloid precursor protein (APP) is widely recognized for playing a central role in Alzheimer's disease pathogenesis. Although APP is expressed in several tissues outside the human central nervous system, the functions of APP and its family members in other tissues are still poorly understood. APP is involved in several biological functions which might be potentially important for male fertility, such as cell adhesion, cell motility, signaling, and apoptosis. Furthermore, APP superfamily members are known to be associated with fertility. Knowledge on the protein networks of APP in human testis and spermatozoa will shed light on the function of APP in the male reproductive system. We performed a Yeast Two-Hybrid screen and a database search to study the interaction network of APP in human testis and sperm. To gain insights into the role of APP superfamily members in fertility, the study was extended to APP-like protein 2 (APLP2). We analyzed several topological properties of the APP interaction network and the biological and physiological properties of the proteins in the APP interaction network were also specified by gene ontologyand pathways analyses. We classified significant features related to the human male reproduction for the APP interacting proteins and identified modules of proteins with similar functional roles which may show cooperative behavior for male fertility. The present work provides the first report on the APP interactome in human testis. Our approach allowed the identification of novel interactions and recognition of key APP interacting proteins for male reproduction, particularly in sperm-oocyte interaction.

The major post-translational modification in eukaryotes is protein phosphorylation which mediates responses to signals in a myriad of cellular processes. Not surprisingly, many steps in spermatogenesis involve the concerted action of the protein (de)phosphorylation key players, kinases and phosphatases. Phosphoprotein phosphatase 1 catalytic subunit (PPP1C), an evolutionarily conserved Ser/Thr-protein phosphatase, catalyzes the majority of eukaryotic protein dephosphorylation reactions. Three genes, PPP1CA, PPP1CB and PPP1CC, encode four PPP1C isoforms, PPP1CA, PPP1CB, PPP1CC1, and PPP1CC2. After transcription, PPP1CC undergoes tissue-specific splicing, originating a ubiquitously expressed isoform, PPP1CC1 and a testis-enriched and sperm-specific isoform, PPP1CC2 which is essential for completion of spermatogenesis. Highly similar PPP1C isoforms – PPP1CA and PPP1CB – are capable of compensating the loss of Ppp1cc in every tissue except in testis. PPP1C cellular functions depend on the complexes it forms with PPP1C Interacting Proteins (PIPs), which together with the different catalytic subunits, account for PPP1C specificity. This review will focus on the role of the major serine/threonine phosphatase – PPP1C and its holoenzymes in spermatogenesis. Furthermore, current challenges on the protein phosphatases field as targets to male contraception will be addressed.

Prostate cancer (PCa) incidence and mortality have decreased in recent years. Nonetheless, it remains one of the most prevalent cancers in men, being a disquieting cause of men’s death worldwide. Changes in many cell signaling pathways have a predominant role in the onset, development, and progression of the disease. These include prominent pathways involved in the growth, apoptosis, and angiogenesis of the normal prostate gland, such as androgen and estrogen signaling, and other growth factor signaling pathways. Understanding the foundations of PCa is leading to the discovery of key molecules that could be used to improve patient management. The ideal scenario would be to have a panel of molecules, preferably detectable in body fluids, that are specific and sensitive biomarkers for PCa. In the early stages, androgen deprivation is the gold standard therapy. However, as the cancer progresses, it eventually becomes independent of androgens, and hormonal therapy fails. For this reason, androgen-independent PCa is still a major therapeutic challenge. By disrupting specific protein interactions or manipulating the expression of some key molecules, it might be possible to regulate tumor growth and metastasis formation, avoiding the systemic side effects of current therapies. Clinical trials are already underway to assess the efficacy of molecules specially designed to target key proteins or protein interactions. In this review, we address that recent progress made towards understanding PCa development and the molecular pathways underlying this pathology. We also discuss relevant molecular markers for the management of PCa and new therapeutic challenges. 这篇综述系统地阐述了前列腺癌的发生、 发展、 相关分子信号通路以及分子标志物用于前列腺癌的临床诊断和前列腺癌诊治所面临的挑战。 许多分子信号通路通过影响细胞生长、 凋亡、 血管生成等病理生理过程而参与了前列腺癌的起始、 发生和发展。这些研究基础有助于寻找前列腺癌的肿瘤标志物和改进前列腺癌的治疗。 虽然去势治疗是早期前列腺癌治疗的金标准, 但是晚期的激素抵抗型前列腺癌(CRPC)的治疗仍面临着巨大的挑战。所幸的是, 目前研究发现可以通过切断特异的蛋白-蛋白相互作用或者通过调节某些影响肿瘤生长和转移的关键分子来治疗前列腺癌, 能减少传统治疗所带来的副作用; 相关临床研究已开始实施。这些研究进展给前列腺癌的诊治带来了新的曙光。