Systematic review of antitumour efficacy and mechanism of metformin activity in prostate cancer models

Metformin, the first line pharmacotherapy for type 2 diabetes has demonstrated favourable effects in prostate cancer (PCa) across a range of studies evaluating PCa patient outcomes amongst metformin users. However, a lack of rigorously conducted prospective studies has stalled clinical use in this setting. Despite multiple studies evaluating the mechanisms underpinning antitumour effects of metformin in PCa, to date, no reviews have compared these findings. This systematic review and meta-analysis consolidates the mechanisms accounting for the antitumour effect of metformin in PCa and evaluates the antitumour efficacy of metformin in preclinical PCa studies. Data were obtained through Medline and EMBASE, extracted by two independent assessors. Risk of bias was assessed using the TOXR tool. Meta-analysis compared in vivo reductions of PCa tumour volume with metformin. In total, 447 articles were identified with 80 duplicates, and 261 articles excluded based on eligibility criteria. The remaining 106 articles were assessed and 71 excluded, with 35 articles included for systematic review, and eight included for meta-analysis. The mechanisms of action of metformin regarding tumour growth, viability, migration, invasion, cell metabolism, and activation of signalling cascades are individually discussed. The mechanisms by which metformin inhibits PCa cell growth are multimodal. Metformin regulates expression of multiple proteins/genes to inhibit cellular proliferation, cell cycle progression, and cellular invasion and migration. Published in vivo studies also conclusively demonstrate that metformin inhibits PCa growth. This highlights the potential of metformin to be repurposed as an anticancer agent, warranting further investigation of metformin in the setting of PCa

Carbon and nitrogen isotopic ratios of urine and faeces as novel nutritional biomarkers of meat and fish intake

Purpose Meat and fish consumption are associated with changes in the risk of chronic diseases. Intake is mainly assessed using self-reporting, as no true quantitative nutritional biomarker is available. The measurement of plasma fatty acids, often used as an alternative, is expensive and time-consuming. As meat and fish differ in their stable isotope ratios, δ13C and δ15N have been proposed as biomarkers. However, they have never been investigated in controlled human dietary intervention studies. Objective In a short-term feeding study, we investigated the suitability of δ13C and δ15N in blood, urine and faeces as biomarkers of meat and fish intake. Methods The dietary intervention study (n = 14) followed a randomised cross-over design with three eight-day dietary periods (meat, fish and half-meat–half-fish). In addition, 4 participants completed a vegetarian control period. At the end of each period, 24-h urine, fasting venous blood and faeces were collected and their δ13C and δ15N analysed. Results There was a significant difference between diets in isotope ratios in faeces and urine samples, but not in blood samples (Kruskal–Wallis test, p < 0.0001). In pairwise comparisons, δ13C and δ15N were significantly higher in urine and faecal samples following a fish diet when compared with all other diets, and significantly lower following a vegetarian diet. There was no significant difference in isotope ratio between meat and half-meat–half-fish diets for blood, urine or faecal samples. Conclusions The results of this study show that urinary and faecal δ13C and δ15N are suitable candidate biomarkers for short-term meat and fish intake

Subclinical Thyroid Disorders and Cognitive Performance Among Adolescents in the United States

Background: Thyroid hormone plays a crucial role in the growth and function of the central nervous system. The purpose of the study was to examine the relationships between the status of subclinical thyroid conditions and cognition among adolescents in the United States. Methods: Study sample included 1,327 adolescents 13 to 16 years old who participated in the Third National Health and Nutrition Examination Survey (NHANES III). Serum thyroxine (T4) and thyroid stimulating hormone (TSH) were measured and subclinical hypothyroidism, subclinical hyperthyroidism, and euthyroid groups were defined. Cognitive performance was assessed using the subscales of the Wide Range Achievement Test-Revised (WRAT-R) and the Wechsler Intelligence Scale for Children-Revised (WISC-R). The age-corrected scaled scores for arithmetic, reading, block design, and digit span were derived from the cognitive assessments. Results: Subclinical hypothyroidism was found in 1.7% and subclinical hyperthyroidism was found in 2.3% of the adolescents. Cognitive assessment scores on average tended to be lower in adolescents with subclinical hyperthyroidism and higher in those with subclinical hypothyroidism than the score for the euthyroid group. Adolescents with subclinical hypothyroidism had significantly better scores in block design and reading than the euthyroid subjects even after adjustment for a number of variables including sex, age, and family income level. Conclusion: Subclinical hypothyroidism was associated with better performance in some areas of cognitive functions while subclinical hyperthyroidism could be a potential risk factor

The reactive species interactome: evolutionary emergence, biological significance, and opportunities for redox metabolomics and personalized medicine

SIGNIFICANCE: Oxidative stress is thought to account for aberrant redox homeostasis and contribute to aging and disease. However, more often than not administration of antioxidants is ineffective, suggesting our current understanding of the underlying regulatory processes is incomplete. Recent Advances. Similar to reactive oxygen and nitrogen species (ROS, RNS), reactive sulfur species (RSS) are now emerging as important signaling molecules, targeting regulatory cysteine redox switches in proteins, affecting gene regulation, ion transport, intermediary metabolism and mitochondrial function. To rationalize the complexity of chemical interactions of reactive species with themselves and their targets and help define their role in systemic metabolic control, we here introduce a novel integrative concept coined the reactive species interactome (RSI). The RSI is a primeval multi-level redox-regulatory system whose architecture, together with the physicochemical characteristics of its constituents, allows efficient sensing and rapid adaptation to environmental changes and various other stresses to enhance fitness and resilience at the local and whole-organism level. CRITICAL ISSUES: To better characterise the RSI-related processes that determine fluxes through specific pathways and enable integration, it is necessary to disentangle the chemical biology and activity of reactive species (including precursors and reaction products), their targets, communication systems and effects on cellular, organ and whole-organism bioenergetics using systems-level/network analyses. FUTURE DIRECTIONS: Understanding the mechanisms through which the RSI operates will enable a better appreciation of the possibilities to modulate the entire biological system; moreover, unveiling molecular signatures that characterize specific environmental challenges or other stresses will provide new prevention/intervention opportunities for personalized medicine

Prevalence of adult ADHD in an all-female prison unit.

There is increasing evidence suggesting a link between ADHD and criminality, including a strong association between ADHD symptoms and the likelihood of being on probation or in prison. Most studies investigating the prevalence of ADHD in prison populations have focused on adult male offenders. In the current study, 69 female prisoners were screened for both childhood and adult ADHD symptoms using the Barkley Adult ADHD Rating Scale-IV. The results indicate that 41 % of the prisoners met the diagnostic criteria for ADHD in childhood and continued to meet criteria for ADHD as adults. More importantly, young female prisoners (aged 18-25) were significantly more likely to report symptoms of ADHD than older prisoners. Prisoners who reported symptoms of ADHD also reported high levels of impairment associated with these symptoms. A better understanding of the prevalence of ADHD in female prison units can highlight specific areas for intervention during rehabilitation, as well as the management of serious incidents within prison

Bafilomycin A1 activates respiration of neuronal cells via uncoupling associated with flickering depolarization of mitochondria

Bafilomycin A1 (Baf) induces an elevation of cytosolic Ca2+ and acidification in neuronal cells via inhibition of the V-ATPase. Also, Baf uncouples mitochondria in differentiated PC12 (dPC12), dSH-SY5Y cells and cerebellar granule neurons, and markedly elevates their respiration. This respiratory response in dPC12 is accompanied by morphological changes in the mitochondria and decreases the mitochondrial pH, Ca2+ and ΔΨm. The response to Baf is regulated by cytosolic Ca2+ fluxes from the endoplasmic reticulum. Inhibition of permeability transition pore opening increases the depolarizing effect of Baf on the ΔΨm. Baf induces stochastic flickering of the ΔΨm with a period of 20 ± 10 s. Under conditions of suppressed ATP production by glycolysis, oxidative phosphorylation impaired by Baf does not provide cells with sufficient ATP levels. Cells treated with Baf become more susceptible to excitation with KCl. Such mitochondrial uncoupling may play a role in a number of (patho)physiological conditions induced by Baf

Oyster Reefs as Natural Breakwaters Mitigate Shoreline Loss and Facilitate Fisheries

Shorelines at the interface of marine, estuarine and terrestrial biomes are among the most degraded and threatened habitats in the coastal zone because of their sensitivity to sea level rise, storms and increased human utilization. Previous efforts to protect shorelines have largely involved constructing bulkheads and seawalls which can detrimentally affect nearshore habitats. Recently, efforts have shifted towards “living shoreline” approaches that include biogenic breakwater reefs. Our study experimentally tested the efficacy of breakwater reefs constructed of oyster shell for protecting eroding coastal shorelines and their effect on nearshore fish and shellfish communities. Along two different stretches of eroding shoreline, we created replicated pairs of subtidal breakwater reefs and established unaltered reference areas as controls. At both sites we measured shoreline and bathymetric change and quantified oyster recruitment, fish and mobile macro-invertebrate abundances. Breakwater reef treatments mitigated shoreline retreat by more than 40% at one site, but overall vegetation retreat and erosion rates were high across all treatments and at both sites. Oyster settlement and subsequent survival were observed at both sites, with mean adult densities reaching more than eighty oysters m−2 at one site. We found the corridor between intertidal marsh and oyster reef breakwaters supported higher abundances and different communities of fishes than control plots without oyster reef habitat. Among the fishes and mobile invertebrates that appeared to be strongly enhanced were several economically-important species. Blue crabs (Callinectes sapidus) were the most clearly enhanced (+297%) by the presence of breakwater reefs, while red drum (Sciaenops ocellatus) (+108%), spotted seatrout (Cynoscion nebulosus) (+88%) and flounder (Paralichthys sp.) (+79%) also benefited. Although the vertical relief of the breakwater reefs was reduced over the course of our study and this compromised the shoreline protection capacity, the observed habitat value demonstrates ecological justification for future, more robust shoreline protection projects

Feeding Blueberry Diets in Early Life Prevent Senescence of Osteoblasts and Bone Loss in Ovariectomized Adult Female Rats

Appropriate nutrition during early development is essential for maximal bone mass accretion; however, linkage between early nutrition, childhood bone mass, peak bone mass in adulthood, and prevention of bone loss later in life has not been studied.In this report, we show that feeding a high quality diet supplemented with blueberries (BB) to pre-pubertal rats throughout development or only between postnatal day 20 (PND20) and PND34 prevented ovariectomy (OVX)-induced bone loss in adult life. This protective effect of BB is due to suppression of osteoblastic cell senescence associated with acute loss of myosin expression after OVX. Early exposure of pre-osteoblasts to serum from BB-fed rats was found to consistently increase myosin expression. This led to maintenance osteoblastic cell development and differentiation and delay of cellular entrance into senescence through regulation of the Runx2 gene. High bone turnover after OVX results in insufficient collagenous matrix support for new osteoblasts and their precursors to express myosin and other cytoskeletal elements required for osteoblast activity and differentiation.These results indicate: 1) a significant prevention of OVX-induced bone loss from adult rats can occur with only 14 days consumption of a BB-containing diet immediately prior to puberty; and 2) the molecular mechanisms underlying these effects involves increased myosin production which stimulates osteoblast differentiation and reduces mesenchymal stromal cell senescence