Testosterone and cardiovascular disease

Cardiovascular disease [CVD] is a leading cause of mortality accounting for a global incidence of over 31%. Atherosclerosis is the primary pathophysiology underpinning most types of CVD. Historically, modifiable and non-modifiable risk factors were suggested to precipitate CVD. Recently, epidemiological studies have identified emerging risk factors including hypotestosteronaemia, which have been associated with CVD. Previously considered in the realms of reproductive biology, testosterone is now believed to play a critical role in the cardiovascular system in health and disease. The actions of testosterone as they relate to the cardiac vasculature and its implication in cardiovascular pathology is reviewed.peer-reviewe

The role of testosterone in colorectal carcinoma : pathomechanisms and open questions

Colorectal cancer (CRC) is the fourth commonest type of malignancy after breast, lung and prostate in the USA and accounts for approximately 49,190 deaths annually in USA alone. The 5-year survival rate of CRC has increased over the past decades, in part, due to greater awareness and the widespread implementation of national screening programmes. Recently, a number of studies reported that males have a higher risk of developing CRC due to the action of testosterone. Testosterone is an androgen that is responsible for the development of male secondary sex characteristics and for spermatogenesis. Studies on rats with mutated Apc tumour-suppressor gene subjected to either ovariectomy or orchidectomy exhibit different risks of CRC. Female rats subjected to ovariectomy are at higher risk of CRC, whereas orchidectomised male rats exhibit a lower risk of developing CRC. Sex hormones, in particular estrogen and testosterone, play a significant role in the development of CRC since the anti-neoplastic effect of estrogen lost during ovariectomy increases the risk of females developing CRC. Male mice exposed to testosterone after orchidectomy were also at greater risk than those who were orchidectomised but administered placebo only. Moreover, the recently established role of membrane androgen receptors in regression of CRC via non-genomic androgen-dependent action sets these receptors apart from intracellular androgen receptors (iARs) which themselves promote CRC development. In addition, testosterone-albumin conjugates are selective to membrane androgen receptors (mARs) and lead to apoptosis via caspase-3 activation. Akt kinases promote invasion of colon cancer cells when phosphorylated. These kinases are dephosphorylated upon activation of mARs, thereby reducing colon cancer cell motility and invasiveness. Testosterone similarly plays important roles in human CRC. Long cytosine-adenine-guanine (CAG) repeats in the gene for the androgen receptors have been associated with a poor 5-year survival compared to shorter CAG repeats. Very recently, the measurement of serum unbound testosterone has been suggested as a novel biomarker along with carcinoembryonic antigen in CRC. In conclusion, testosterone may promote the development of CRC via a number of pathways, which may place males at greater risk. Testosterone holds promise as a potential biomarker in CRC risk prediction; however, further studies are required to better define its role in colorectal neoplasia.peer-reviewe

The role of TLR2, TLR4, and TLR9 in the pathogenesis of atherosclerosis

Toll-like receptors (TLRs) are key players in the pathogenesis of inflammatory conditions including coronary arterial disease (CAD). They are expressed by a variety of immune cells where they recognize pathogen-associated molecular patterns (PAMPs). TLRs recruit adaptor molecules, including myeloid differentiation primary response protein (MYD88) and TIRF-related adaptor protein (TRAM), to mediate activation of MAPKs and NF-kappa B pathways. They are associated with the development of CAD through various mechanisms. TLR4 is expressed in lipid-rich and atherosclerotic plaques. In TLR2−/− and TLR4−/− mice, atherosclerosis-associated inflammation was diminished. Moreover, TLR2 and TLR4 may induce expression of Wnt5a in advanced staged atheromatous plaque leading to activation of the inflammatory processes. TLR9 is activated by CpG motifs in nucleic acids and have been implicated in macrophage activation and the uptake of oxLDL from the circulation. Furthermore, TLR9 also stimulates interferon-α (INF-α) secretion and increases cytotoxic activity of CD4+ T-cells towards coronary artery tunica media smooth muscle cells. This review outlines the pathophysiological role of TLR2, TLR4, and TLR9 in atherosclerosis, focusing on evidence from animal models of the disease.peer-reviewe

The microbial hypothesis : contributions of adenovirus infection and metabolic endotoxaemia to the pathogenesis of obesity

The global obesity epidemic, dubbed “globesity” by the World Health Organisation, is a pressing public health issue. The aetiology of obesity is multifactorial incorporating both genetic and environmental factors. Recently, epidemiological studies have observed an association between microbes and obesity. Obesity-promoting microbiome and resultant gut barrier disintegration have been implicated as key factors facilitating metabolic endotoxaemia. This is an influx of bacterial endotoxins into the systemic circulation, believed to underpin obesity pathogenesis. Adipocyte dysfunction and subsequent adipokine secretion characterised by low grade inflammation, were conventionally attributed to persistent hyperlipidaemia. They were thought of as pivotal in perpetuating obesity. It is now debated whether infection and endotoxaemia are also implicated in initiating and perpetuating low grade inflammation. The fact that obesity has a prevalence of over 600 million and serves as a risk factor for chronic diseases including cardiovascular disease and type 2 diabetes mellitus is testament to the importance of exploring the role of microbes in obesity pathobiology. It is on this basis that Massachusetts General Hospital is sponsoring the Faecal Microbiota Transplant for Obesity and Metabolism clinical trial, to study the impact of microbiome composition on weight. The association of microbes with obesity, namely, adenovirus infection and metabolic endotoxaemia, is reviewed.peer-reviewe

Potential role of caffeine in the treatment of Parkinson’s disease

Parkinson's disease [PD] is the second most common neurodegenerative disorder after Alzheimer's disease, affecting 1% of the population over the age of 55. The underlying neuropathology seen in PD is characterised by progressive loss of dopaminergic neurons in the substantia nigra pars compacta with the presence of Lewy bodies. The Lewy bodies are composed of aggregates of α-synuclein. The motor manifestations of PD include a resting tremor, bradykinesia, and muscle rigidity. Currently there is no cure for PD and motor symptoms are treated with a number of drugs including levodopa [L-dopa]. These drugs do not delay progression of the disease and often provide only temporary relief. Their use is often accompanied by severe adverse effects. Emerging evidence from both in vivo and in vitro studies suggests that caffeine may reduce parkinsonian motor symptoms by antagonising the adenosine A2A receptor, which is predominately expressed in the basal ganglia. It is hypothesised that caffeine may increase the excitatory activity in local areas by inhibiting the astrocytic inflammatory processes but evidence remains inconclusive. In addition, the co-administration of caffeine with currently available PD drugs helps to reduce drug tolerance, suggesting that caffeine may be used as an adjuvant in treating PD. In conclusion, caffeine may have a wide range of therapeutic effects which are yet to be explored, and therefore warrants further investigation in randomized clinical trials.peer-reviewe

Faith and Forensic: A Case Study

A multidisciplinary forensic approach is applied to the study of ancient human skeletal remains of an historical figure venerated as a Saint by the Catholic Church, Fortunato of Serracapriola (South of Italy). Despite the forensic multidisciplinary approach is recommended for the study of ancient human skeletal remains, to the best of our knowledge, it is rare that this approach can be used on historical figure venerated as a Saint by Catholic Church. A radiological investigation was carried out for preliminary information: sex, stature, age and/or pathological signs. Subsequently radiocarbon analysis for dating of skeletal remains was performed. Finally the biological profile (STRs and mtDNA) and statistical analysis of genetic data were done to confirm the sex and to establish the provenience. Although we were not able to matching our data, it was very important to collect as much as possible information from the sample, it was the only way to confirm the correspondence of the scientific data with Saint's life. This case highlights the complexity of study of remains that were skeletonized. Therefore a multidisciplinary investigation as well as paying careful attention in the collection and correct interpretation of findings is important. We found a strong scientific concordance between our findings and the époque of the saint's existence, sex, and ethnicity. Archaeological remains can provide concrete cases, making it possible to develop, refine or validate medico-legal techniques

Nandrolone decanoate interferes with testosterone biosynthesis altering blood-testis barrier components

The aim of this study was to investigate whether nandrolone decanoate (ND) use affects testosterone production and testicular morphology in a model of trained and sedentary mice. A group of mice underwent endurance training while another set led a sedentary lifestyle and were freely mobile within cages. All experimental groups were treated with either ND or peanut oil at different doses for 6 weeks. Testosterone serum levels were measured via liquid chromatography-mass spectrometry. Western blot analysis and quantitative real-time PCR were utilized to determine gene and protein expression levels of the primary enzymes implicated in testosterone biosynthesis and gene expression levels of the blood-testis barrier (BTB) components. Immunohistochemistry and immunofluorescence were conducted for testicular morphological evaluation. The study demonstrated that moderate to high doses of ND induced a diminished serum testosterone level and altered the expression level of the key steroidogenic enzymes involved in testosterone biosynthesis. At the morphological level, ND induced degradation of the BTB by targeting the tight junction protein-1 (TJP1). ND stimulation deregulated metalloproteinase-9, metalloproteinase-2 (MMP-2) and the tissue inhibitor of MMP-2. Moreover, ND administration resulted in a mislocalization of mucin-1. In conclusion, ND abuse induces a decline in testosterone production that is unable to regulate the internalization and redistribution of TJP1 and may induce the deregulation of other BTB constituents via the inhibition of MMP-2. ND may well be considered as both a potential inducer of male infertility and a potential risk factor to a low endogenous bioavailable testosterone