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Background: The gene FOXO3, encoding the transcription factor forkhead box O-3 (FoxO3), is one of only two for which genetic polymorphisms have exhibited consistent associations with longevity in diverse human populations. Objective: Here, we review the multitude of actions of FoxO3 that are relevant to health, and thus healthy ageing and longevity. Methods: The study involved a literature search for articles retrieved from PubMed using FoxO3 as keyword. Results: We review the molecular genetics of FOXO3 in longevity, then current knowledge of FoxO3 function relevant to ageing and lifespan. We describe how FoxOs are involved in energy metabolism, oxidative stress, proteostasis, apoptosis, cell cycle regulation, metabolic processes, immunity, inflammation and stem cell maintenance. The single FoxO in Hydra confers immortality to this fresh water polyp, but as more complex organisms evolved, this role has been usurped by the need for FoxO to control a broader range of specialized pathways across a wide spectrum of tissues assisted by the advent of as many as 4 FoxO subtypes in mammals. The major themes of FoxO3 are similar, but not identical, to other FoxOs and include regulation of cellular homeostasis, particularly of stem cells, and of inflammation, which is a common theme of age-related diseases. Other functions concern metabolism, cell cycle arrest, apoptosis, destruction of potentially damaging reactive oxygen species and proteostasis. Conclusions: The mechanism by which longevity-associated alleles of FOXO3 reduce age-related mortality is currently of great clinical interest. The prospect of optimizing FoxO3 activity in humans to increase lifespan and reduce age-related diseases represents an exciting avenue of clinical investigation. Research strategies directed at developing therapeutic agents that target FoxO3, its gene and proteins in the pathway(s) FoxO3 regulates should be encouraged and supported.

Abstract-The kidney has long been invoked in the etiology of essential hypertension. This could involve alterations in expression of specific genes and microRNAs (miRNAs). The aim of the present study was to identify, at the transcriptome-wide level, mRNAs and miRNAs that were differentially expressed between kidneys of 15 untreated hypertensive and 7 normotensive white male subjects of white European ancestry. By microarray technology we found 14 genes and 11 miRNAs that were differentially expressed in the medulla. We then selected and confirmed by real-time quantitative PCR expression differences for NR4A1, NR4A2, NR4A3, PER1, and SIK1 mRNAs and for the miRNAs hsa-miR-638 and hsa-let-7c. Luciferase reporter gene experiments in human kidney (HEK293) cells confirmed the predicted binding of hsa-let-7c to the 3Ј untranslated region of NR4A2 mRNA. In the renal cortex we found differential expression of 46 genes and 13 miRNAs. We then confirmed expression differences for AIFM1, AMBP, APOE, CD36, EFNB1, NDUFAF1, PRDX5, REN, RENBP, SLC13A1, STX4,. Functional experiments in HEK293 cells demonstrated that hsa-miR-663 can bind to the REN and APOE 3Ј untranslated regions and can regulate REN and APOE mRNA levels, whereas hsa-miR-181a regulated REN and AIFM1 mRNA. Our data demonstrated for the first time that miRNAs can regulate renin expression. The observed downregulation of 2 miRNAs in hypertension could explain the elevation in intrarenal renin mRNA. Renin, CD36, and other mRNAs, as well as miRNAs and associated pathways identified in the present study, provide novel insights into hypertension etiology. (Hypertension. 2011;58:1093-1098.) • Online Data SupplementKey Words: microarrays Ⅲ microRNAs Ⅲ renin angiotensin system Ⅲ kidney Ⅲ hypertension S olving the molecular etiology of essential hypertension has been challenging. 1 Studies of selected blood pressure (BP) genes and large genome-wide association studies have identified only a handful of gene variants of small effect sizes. The interplay between genetic and environmental factors that contributes to the heterogeneity of hypertension has made the identification of causative alleles, genes, and transcripts difficult. 1 A further impediment has been the difficulty in obtaining suitable human tissue samples other than blood.Guyton and colleagues 2,3 theorized that hypertension is caused by a primary defect in the kidney. This idea has gained support from rare monogenic forms of hypertension, in which single mutations in genes responsible for renal sodium reabsorption 4 result in BP elevation. 3 MicroRNAs (miRNAs) are important for physiological and pathophysiological processes in various diseases. 5 These 18 to 30 nucleotides noncoding RNAs regulate the expression and translation of half of protein-coding mRNAs in humans by binding to target sites in the 3Ј untranslated region (UTR) to destabilize them or impede translation. 5 If miRNAs modulate mRNAs for BP genes, they could form the basis for novel antihypertensive therapies. 6,7 Knowledge of effects of miRNAs ...

Since the discovery of renin 80 years ago, there have been remarkable advances in our understanding of the renin-angiotensin system. The system as it is known today is summarized in Figure 1. Angiotensin III, the active component of the system, has several important physiological actions. The fi rst of these to be identifi ed was its pressor action, and for many years it was felt that the sole function of the renin-angiotensin system was regula tion of blood pressure. A new dimension was added in 1960 with the discovery that angiotensin II stimulates the secretion of aldosterone and is therefore in a position to exert important effects on salt and water balance. Several additional actions of angiotensin II were then discovered. It was fo und that the peptide can increase the secretion of catecholamines from the adrenal and facilitate adrenergic transmission. It also acts directly on the brain to increase blood pressure via sympathetic and parasympathetic path ways, to produce thirst, and to stimulate the secretion of vasopressin and ACTH. Through these actions, the renin-angiotensin system plays an im portant role in the regulation of blood pressure and of the volume and composition of the extracellular fl uid.Major advances have also been made in our understanding of other aspects of the renin-angiotensin system. It has become clear that the hep tapeptide metabolite of angiotensin II, [des-Aspl] angiotensin II ("angioIThe IUPAC-IUB Commission on Biochemical Nomenclature Recommenda tions (J. Dial Chem.2S0:321S) has suggested that the peptide hormones referred to in this review-angiotensin I, angiotensin II, ACTH, and growth hormone-be termed proangiotensin, angiotensin, corticotropin, and somatotropin, respectively.

To isolate a human glandular kallikrein gene, a human genomic library was screened with a probe made from a mouse kallikrein cDNA (pMK-1). Overlapping clones were obtained and nucleotide sequence determination showed that they together contained a human glandular preprokallikrein gene, hGK-1, of 5.2 kb. The gene encoded a unique preproprotein of 261 amino acids. The sequence of the mature 237-amino-acid protein had 66% homology with the sequence predicted for human kallikrein synthesized in the pancreas, kidney, and salivary gland. Moreover, it had even stronger homology (78%) with human prostate-specific antigen. The latter lacks an aspartic acid residue essential for kallikrein-specific cleavage, whereas the sequence of this new protein had all of the attributes needed to confer kallikrein-like specificity. Southern blotting indicated that the number of glandular kallikrein genes in man could be limited to three, a situation very different from mouse and rat, which each have a large multigene family. Furthermore, unlike kallikrein genes in the mouse, hGK-1 was not closely linked to other human kallikrein genes. In other respects the structure of the human kallikrein gene resembled that in mouse: coding sequences in the five exons were organized similarly, homology was higher with other members of the kallikrein gene family in the same species, and the three key amino acid residues required by serine proteases for their catalytic activity, together with the residue that confers kallikrein-specific cleavage, were conserved and located on different exons. Thus, if hGK-1 is expressed, its product represents a new, and possibly the only other enzyme with true kallikrein-like specificity in man.

Abstract-Essential hypertensives display enhanced signal transduction through pertussis toxin-sensitive G proteins. The T allele of a C825T variant in exon 10 of the G protein ␤3 subunit gene (GNB3) induces formation of a splice variant (G␤3-s) with enhanced activity. The T allele of GNB3 was shown recently to be associated with hypertension in unselected German patients (frequencyϭ0.31 versus 0.25 in control). To confirm and extend this finding in a different setting, we performed an association study in Australian white hypertensives. This involved an extensively examined cohort of 110 hypertensives, each of whom were the offspring of 2 hypertensive parents, and 189 normotensives whose parents were both normotensive beyond age 50 years. Genotyping was performed by polymerase chain reaction and digestion with BseDI, which either cut (C allele) or did not cut (T allele) the 268-bp polymerase chain reaction product. T allele frequency in the hypertensive group was 0.43 compared with 0.25 in the normotensive group ( 2 ϭ22; Pϭ0.00002; odds ratioϭ2.3; 95% CIϭ1.7 to 3.3). The T allele tracked with higher pretreatment blood pressure: diastolicϭ105Ϯ7, 109Ϯ16, and 128Ϯ28 mm Hg (meanϮSD) for CC, CT, and TT, respectively (Pϭ0.001 by 1-way ANOVA). Blood pressures were higher in female hypertensives with a T allele (Pϭ0.006 for systolic and 0.0003 for diastolic by ANOVA) than they were in male hypertensives. In conclusion, the present study of a group with strong family history supports a role for a genetically determined, physiologically active splice variant of the G protein ␤3 subunit gene in the causation of essential hypertension.

Male circumcision protects against cancer of the penis, the invasive form of which is a devastating disease confined almost exclusively to uncircumcised men. Major etiological factors are phimosis, balanitis, and high-risk types of human papillomavirus (HPV), which are more prevalent in the glans penis and coronal sulcus covered by the foreskin, as well as on the penile shaft, of uncircumcised men. Circumcised men clear HPV infections more quickly. Phimosis (a constricted foreskin opening impeding the passage of urine) is confined to uncircumcised men, in whom balanitis (affecting 10%) is more common than in circumcised men. Each is strongly associated with risk of penile cancer. These findings have led to calls for promotion of male circumcision, especially in infancy, to help reduce the global burden of penile cancer. Even more relevant globally is protection from cervical cancer, which is 10-times more common, being much higher in women with uncircumcised male partners. Male circumcision also provides indirect protection against various other infections in women, along with direct protection for men from a number of genital tract infections, including HIV. Given that adverse consequences of medical male circumcision, especially when performed in infancy, are rare, this simple prophylactic procedure should be promoted.

BackgroundMale circumcision (MC) status and genital infection risk are interlinked and MC is now part of HIV prevention programs worldwide. Current MC prevalence is not known for all countries globally. Our aim was to provide estimates for country-specific and global MC prevalence.MethodsMC prevalence data were obtained by searches in PubMed, Demographic and Health Surveys, AIDS Indicator Surveys, and Behavioural Surveillance Surveys. Male age was ≥15 years in most surveys. Where no data were available, the population proportion whose religious faith or culture requires MC was used. The total number of circumcised males in each country and territory was calculated using figures for total males from (i) 2015 US Central Intelligence Agency (CIA) data for sex ratio and total population in all 237 countries and territories globally and (ii) 2015 United Nations (UN) figures for males aged 15–64 years.ResultsThe estimated percentage of circumcised males in each country and territory varies considerably. Based on (i) and (ii) above, global MC prevalence was 38.7 % (95 % confidence interval [CI]: 33.4, 43.9) and 36.7 % (95 % CI: 31.4, 42.0). Approximately half of circumcisions were for religious and cultural reasons. For countries lacking data we assumed 99.9 % of Muslims and Jews were circumcised. If actual prevalence in religious groups was lower, then MC prevalence in those countries would be lower. On the other hand, we assumed a minimum prevalence of 0.1 % related to MC for medical reasons. This may be too low, thereby underestimating MC prevalence in some countries.ConclusionsThe present study provides the most accurate estimate to date of MC prevalence in each country and territory in the world. We estimate that 37–39 % of men globally are circumcised. Considering the health benefits of MC, these data may help guide efforts aimed at the use of voluntary, safe medical MC in disease prevention programs in various countries.Electronic supplementary materialThe online version of this article (doi:10.1186/s12963-016-0073-5) contains supplementary material, which is available to authorized users.