Current Pharmaceutical Design - Volume 23, Issue 30, 2017

Parenthood at an older age is becoming a trend among men, especially in the most developed societies. Aging has a significant impact on male fertility. Older men exhibit notable disturbances in the reproductive axis, with steroidogenesis being impacted much more than spermatogenesis. The endocrine changes, together with morphological and functional alternations of the aging testis, result in decreased testosterone production. Nonetheless, studies are needed to scrutinize the impact of age per se versus age-induced dysfunction of the reproductive axis. Furthermore, the multiple effects of aging on the acquisition of sperm motility, on sperm morphology and concentration indicate that the quality of spermatozoa declines over time, but few works have shed light on the molecular mechanisms that hamper sperm function in old men. In fact, this question is far from being completely answered and this is a subject of controversy. Hence, we will present an up-to-date review and discuss the molecular mechanisms involved in the alteration of the reproductive function in aging men. We will focus on the functioning of the reproductive axis and what are the major effects of aging in spermatogenesis. We will also discuss how aging affects sperm quality and possible causes underlying sperm dysfunction with special emphasis in oxidative stress.

Oxidative stress (OS), an imbalance between reactive oxygen species (ROS) and antioxidant scavengers, is considered an important underlying mechanism associated with ageing, age-related chronic diseases and reproductive decline in males. However, OS is an important regulator of numerous molecular pathways essential for homeostasis within cells, tissues and systems. A fine balance between factors promoting OS and those that scavenge ROS is critically important. In the male reproductive tract and ejaculate, ROS are critical molecular players in essential reproductive processes, including spermatogenesis, epididymal transport, spermatozoa maturation and post-ejaculation processes such as motility, capacitation and the acrosome reaction. Increasing evidence suggests there is an overlap between age-related OS and male reproductive tract dysfunction correlating with reduced fertility potential due to semen quality decline, endocrine changes and sexual dysfunction. With increasing life expectancy in many regions of the world, together with an increasing paternal age and associated risk of for infertility, pregnancy complications and reduced health potential in the offspring, it is becoming increasingly important to fully understand the mechanism linked with these associations. This review considers the role of ROS and OS in fertility regulation, the ageing process, the role for OS in age-related reproductive decline, the approach to assessment in male infertility and the current use of antioxidants as a therapeutic option. Although evidence suggests exogenous antioxidant supplementation is useful in male infertility, caution to excessive or unnecessary use of these approaches is required to avoid the paradox of antioxidants inhibiting essential and beneficial ROS activities in male reproductive biology.

The aging phenomenon is intrinsically responsible for diseases and lifestyle-associated conditions afflicting the aging male. In particular, male infertility seems to result from deleterious lifestyle choices. However, the aging effect at the individual gene/protein level is poorly discussed and valuable information is certainly missing. We have thus used an omics approach to identify differentially expressed proteins and genes from spermatozoa and seminal plasma samples across several conditions affecting adult male fertility. Our search resulted in 400 differentially expressed proteins in seminal plasma and 409 differentially expressed proteins in spermatozoa as well as, almost 6,000 differentially expressed spermatozoa mRNAs. We have functionally analyzed these proteins and genes to understand and discuss how biological processes and signaling pathways associated with aging might affect male fertility. Sperm and seminal fluid proteins from infertile males display significant alterations in i) processes previously implicated in the aging phenomena, such as mitochondrial dysfunction, DNA instability, oxidative stress, protein misfolding and intracellular mistrafficking, and ii) processes specifically involved in reproductive phenomena, such as sperm-egg recognition/acrosome reaction, embryo and morula development, blastocyst implantation and DNA methylation involved in embryo development. These proteins display a widespread distribution and seem to be significantly influenced by deleteriously lifestyle choices. Conventional assays to assess male fertility are inadequate to comprehensively reveal the broad-spectrum of alterations at the transcriptional and translational levels afflicting the infertile aging male. In turn, proteomics and transcriptomics are suitable options for addressing these key issues that may explain many poorly understood fertility-associated phenomena resulting from the aging process.

Advances in medicine and progressive improvements in the health of the general population in developed countries have led to considerable increases in life expectancy over recent years. Metabolic syndrome (MetS) affects approximately 25% of the adult population and its prevalence is increasing all over the world. Central obesity plays an important role in emergence of MetS. Some studies have suggested that there may be link between low Total Testosterone levels and emergence of MetS. The objective of this review is to analyze the complex network of interactions between MetS and low testosterone levels in elderly men, considering etiologic, diagnostic, and therapeutic aspects. Recent evidence confirms that central obesity is the independent MetS component correlated to Total Testosterone Levels. Experimental studies suggest a two way road between Low Testosterone Levels and abdominal obesity. Besides that, Testosterone Replacement Therapy should be restricted to men with biochemical and clinical features of late onset hypogonadism.

Andropause or male menopause is defined as androgen decline and onset of hypogonadism in the aging male. Testosterone deficiency in adult male is associated with diabetes mellitus, coronary artery disease, and heart failure. Type 2 diabetic male patients aged above 30 years showed low testosterone levels which is common in diabetic men and had symptoms of hypogonadism. Male sexual dysfunction among diabetic patients can include disorders of libido, ejaculatory problems, and erectile dysfunctions are common among people with diabetes, particularly in older men who had diabetes for years. Older diabetics tend to have both impaired insulin release as well as insulin resistance. There is growing evidence indicating the pathophysiological connections among the mechanisms of oxidative damage by disruption of the oxidative balance, increased levels of enzymatic glycation products in testicular region and glucose transporters, obesity and proinflammatory cytokines in male infertile patients with diabetes. Epidemiological studies suggest that many clinical findings in diabetics are linked to low testosterone levels. This article reviews pathophysiological mechanisms, observational studies, and clinical implications of testosterone therapy in type 2 diabetes mellitus.

Sarcopenia is defined as the loss of muscle mass associated with a loss of muscle function, e.g., walking speed. A number of consensus definitions exist for sarcopenia with cut-off points being ethnically specific. A rapid screen test (SARC-F) is available and does not require different ethnic cut-off points. Sarcopenia leads to the development of frailty, disability and mortality. The prevalence of sarcopenia varies from 1-29% in community- dwelling and 14 to 33% in long-term care populations. Hormones play a role in the development of muscle mass and in the regulation of muscle strength. Testosterone appears to be the central hormone involved in the development of sarcopenia; it increases both muscle mass and activates satellite cells leading to increased muscle function. Growth hormone deficiency leads to the loss of muscle mass but not muscle strength. Lack of insulin or insulin resistance leads to accelerated development of sarcopenia. Vitamin D deficiency plays a role in the loss of muscle strength. A variety of other hormones appear to play minor roles in age-related alterations in muscle mass and function. At present, the treatment of sarcopenia is resistance exercise, leucine enriched essential amino acids or hydroxymethylbutyrate and vitamin D replacement.

Hepatitis C is a current pandemic liver disease caused by the hepatitis C virus (HCV) with high morbidity and mortality. Recently, the direct-acting antiviral agents (DAAs) targeting HCV NS3/4A, NS5A and NS5B have become the most effective therapies against HCV infection in the clinical treatment. Among them, the second-generation of NS3/4A inhibitors have emerged as the mainstay of the DAA therapies, which are derived from the peptide substrate of NS3/4A protease and modified with various tailor-made amino acids in order to achieve high sustained virologic response (SVR) against HCV. This review summarizes sixteen examples of the second-generation of HCV NS3/4A inhibitors, mainly focusing on the clinical application, structure development, structure-activity relationship (SAR) and their synthesis.

Malaria, an infectious disease caused by Plasmodium spp, is one of the world's most dangerous diseases, accounting for more than half a million deaths yearly. The long years of co-habitation between the parasite and its hosts (human and mosquito), is a testimony to the parasite's ability to escape the immune system and develop drug resistance mechanisms. Currently, an important search area for improved pharmacotherapy are molecular chaperones of the heat shock protein family, abundant in Plasmodium falciparum and contributing to its continuous survival and development. Thus far, small molecule inhibitor studies on P. falciparum Hsp70s and Hsp90s have indicated that they are promising antimalarial targets. However, not much attention has been given to Hsp40s as potential antimalarial drug targets. Hsp40s are known to function as chaperones by preventing protein aggregation, and as co-chaperones, by regulating the chaperone activities of Hsp70s to ensure proper protein folding. There are only a limited number of reviews on Hsp40s as drug targets, and the few reviews on plasmodial Hsp40s tend to focus largely on the intra-erythrocytic stage of the parasite life cycle. Therefore, this review will summarize what is known about Hsp40s throughout the malaria parasite life cycle, and critically evaluate their potential to serve as new avenues for antimalarial drug discovery.