Pharmacology and clinical drug candidates in redox medicine

SIGNIFICANCE Oxidative stress is suggested to be a disease mechanism common to a wide range of disorders affecting human health. However, so far, the pharmacotherapeutic exploitation of this, for example, based on chemical scavenging of pro-oxidant molecules, has been unsuccessful. Recent Advances: An alternative emerging approach is to target the enzymatic sources of disease-relevant oxidative stress. Several such enzymes and isoforms have been identified and linked to different pathologies. For some targets, the respective pharmacology is quite advanced, that is, up to late-stage clinical development or even on the market; for others, drugs are already in clinical use, although not for indications based on oxidative stress, and repurposing seems to be a viable option. CRITICAL ISSUES For all other targets, reliable preclinical validation and drug ability are key factors for any translation into the clinic. In this study, specific pharmacological agents with optimal pharmacokinetic profiles are still lacking. Moreover, these enzymes also serve largely unknown physiological functions and their inhibition may lead to unwanted side effects. FUTURE DIRECTIONS The current promising data based on new targets, drugs, and drug repurposing are mainly a result of academic efforts. With the availability of optimized compounds and coordinated efforts from academia and industry scientists, unambiguous validation and translation into proof-of-principle studies seem achievable in the very near future, possibly leading towards a new era of redox medicine

The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm

The sperm-specific channel CatSper (cation channel of sperm) controls the intracellular Ca2+ concentration ([Ca2+]i) and plays an essential role in sperm function. It is mainly activated by the steroid progesterone (P4) but is also promiscuously activated by a wide range of synthetic and physiological compounds. These compounds include diverse steroids whose action on the channel is so far still controversial. To investigate the effect of these compounds on CatSper and sperm function, we developed a high-throughput screening (HTS) assay to measure changes in [Ca2+]i in human sperm and screened 1,280 approved and off-patent drugs including 90 steroids from the Prestwick chemical library. More than half of the steroids tested (53%) induced an increase in [Ca2+]i and reduced the P4-induced Ca2+ influx in human sperm in a dose-dependent manner. Ten of the most potent steroids (activating and P4-inhibiting) were selected for a detailed analysis of their action on CatSper and their ability to act on sperm acrosome reaction (AR) and penetration in viscous media. We found that these steroids show an inhibitory effect on P4 but not on prostaglandin E1-induced CatSper activation, suggesting that they compete for the same binding site as P4. Pregnenolone, dydrogesterone, epiandrosterone, nandrolone, and dehydroepiandrosterone acetate (DHEA) were found to activate CatSper at physiologically relevant concentrations within the nanomolar range. Like P4, most tested steroids did not significantly affect the AR while stanozolol and estropipate slightly increased sperm penetration into viscous medium. Furthermore, using a hybrid approach integrating pharmacophore analysis and statistical modelling, we were able to screen in silico for steroids that can activate the channel and define the physicochemical and structural properties required for a steroid to exhibit agonist activity against CatSper. Overall, our results indicate that not only physiological but also synthetic steroids can modulate the activity of CatSper with varying potency and if bound to CatSper prior to P4, could impair the timely CatSper activation necessary for proper fertilization to occur

Mmf1p, a novel yeast mitochondrial protein conserved throughout evolution and involved in maintenance of the mitochondrial genome

A novel protein family (p14.5, or YERO57c/YJGFc) highly conserved throughout evolution has recently been identified. The biological role of these proteins is not yet well characterized. Two members of the p14.5 family are present in the yeast Saccharomyces cerevisiae. In this study, we have characterized some of the biological functions of the two yeast proteins. Mmf1p is a mitochondrial matrix factor, and homologous Mmf1p factor (Hmf1p) copurifies with the soluble cytoplasmic fraction. Δmmf1 cells lose mitochondrial DNA (mtDNA) and have a decreased growth rate, while Δhmf1 cells do not display any visible phenotype. Furthermore, we demonstrate by genetic analysis that Mmf1p does not play a direct role in replication and segregation of the mtDNA. rho(+) Δmmf1 haploid cells can be obtained when tetrads are directly dissected on medium containing a nonfermentable carbon source. Our data also indicate that Mmf1p and Hmf1p have similar biological functions in different subcellular compartments. Hmf1p, when fused with the Mmf1p leader peptide, is transported into mitochondria and is able to functionally replace Mmf1p. Moreover, we show that homologous mammalian proteins are functionally related to Mmf1p. Human p14.5 localizes in yeast mitochondria and rescues the Δmmf1-associated phenotypes. In addition, fractionation of rat liver mitochondria showed that rat p14.5, like Mmf1p, is a soluble protein of the matrix. Our study identifies a biological function for Mmf1p and furthermore indicates that this function is conserved between members of the p14.5 family

Radiation thermo-chemical models of protoplanetary disks II. Line diagnostics

Methods. We use the recently developed disk code ProDiMo to calculate the physico-chemical structure of protoplanetary disks and apply the Monte-Carlo line radiative transfer code RATRAN to predict observable line profiles and fluxes. We consider a series of Herbig Ae type disk models ranging from 10^-6 M_Sun to 2.2 10^-2 M_Sun (between 0.5 and 700 AU) to discuss the dependency of the line fluxes and ratios on disk mass for otherwise fixed disk parameters. Results. We find the [CII] 157.7 mum line to originate in LTE from the surface layers of the disk, where Tg > Td . The total emission is dominated by surface area and hence depends strongly on disk outer radius. The [OI] lines can be very bright (> 10^-16 W/m^2) and form in slightly deeper and closer regions under non-LTE conditions. The high-excitation [OI] 145.5 mum line, which has a larger critical density, decreases more rapidly with disk mass than the 63.2 mum line. Therefore, the [OI] 63.2 mum/145.5 mum ratio is a promising disk mass indicator, especially as it is independent of disk outer radius for Rout > 200 AU. CO is abundant only in deeper layers A_V >~ 0.05. For too low disk masses (M_disk <~10^-4 M_Sun) the dust starts to become transparent, and CO is almost completely photo-dissociated. For masses larger than that the lines are an excellent independent tracer of disk outer radius and can break the outer radius degeneracy in the [OI] 63.2 mum/[CII]157.7 mum line ratio. Conclusions. The far-IR fine-structure lines of [CII] and [OI] observable with Herschel provide a promising tool to measure the disk gas mass, although they are mainly generated in the atomic surface layers. In spatially unresolved observations, none of these lines carry much information about the inner, possibly hot regions < 30 AU.Comment: accepted for publication in A&

Reactive oxygen-related diseases: therapeutic targets and emerging clinical indications

SIGNIFICANCE Enhanced levels of reactive oxygen species (ROS) have been associated with different disease states. Most attempts to validate and exploit these associations by chronic antioxidant therapies have provided disappointing results. Hence, the clinical relevance of ROS is still largely unclear. RECENT ADVANCES We are now beginning to understand the reasons for these failures, which reside in the many important physiological roles of ROS in cell signaling. To exploit ROS therapeutically, it would be essential to define and treat the disease-relevant ROS at the right moment and leave physiological ROS formation intact. This breakthrough seems now within reach. CRITICAL ISSUES Rather than antioxidants, a new generation of protein targets for classical pharmacological agents includes ROS-forming or toxifying enzymes or proteins that are oxidatively damaged and can be functionally repaired. FUTURE DIRECTIONS Linking these target proteins in future to specific disease states and providing in each case proof of principle will be essential for translating the oxidative stress concept into the clinic. Antioxid. Redox Signal. 23, 1171-1185

On the gas temperature in circumstellar disks around A stars

In circumstellar disks or shells it is often assumed that gas and dust temperatures are equal where the latter is determined by radiative equilibrium. This paper deals with the question whether this assumption is applicable for tenous circumstellar disks around young A stars. In this paper the thin hydrostatic equilibrium models described by Kamp & Bertoldi (2000) are combined with a detailed heating/cooling balance for the gas. The most important heating and cooling processes are heating through infrared pumping, heating due to the drift velocity of dust grains, and fine structure and molecular line cooling. Throughout the whole disk gas and dust are not efficiently coupled by collisions and hence their temperatures are quite different. Most of the gas in the disk models considered here stays well below 300 K. In the temperature range below 300 K the gas chemistry is not much affected by T_gas and therefore the simplifying approximation T_gas = T_dust can be used for calculating the chemical structure of the disk. Nevertheless the gas temperature is important for the quantitative interpretation of observations, like fine structure and molecular lines.Comment: 16 pages, 31 figures, A&A accepted May 4, 200

Continuum and line modeling of disks around young stars II. Line diagnostics for GASPS from the DENT grid

Aims. We want to understand the chemistry and physics of disks on the basis of a large unbiased and statistically relevant grid of disk models. One of the main goals is to explore the diagnostic power of various gas emission lines and line ratios for deriving main disk parameters such as the gas mass. Methods. We explore the results of the DENT grid (Disk Evolution with Neat Theory) that consists of 300 000 disk models with 11 free parameters. Through a statistical analysis, we search for correlations and trends in an effort to find tools for disk diagnostic. Results. All calculated quantities like species masses, temperatures, continuum and line fluxes differ by several orders of magnitude across the entire parameter space. The broad distribution of these quantities as a function of input parameters shows the limitation of using a prototype T Tauri or Herbig Ae/Be disk model. The statistical analysis of the DENT grid shows that CO gas is rarely the dominant carbon reservoir in disks. Models with large inner radii (10 times the dust condensation radius) and/or shallow surface density gradients lack massive gas phase water reservoirs. Also, 60% of the disks have gas temperatures averaged over the oxygen mass in the range between 15 and 70 K; the average gas temperatures for CO and O differ by less than a factor two. Studying the observational diagnostics, the [CII] 158 \mum fine structure line flux is very sensitive to the stellar UV flux and presence of a UV excess and it traces the outer disk radius (Rout). In the submm, the CO low J rotational lines also trace Rout. Low [OI] 63/145 line ratios (< a few) can be explained with cool atomic O gas in the uppermost surface layers leading to self-absorption in the 63 \mum line; this occurs mostly for massive non-flaring, settled disk models without UV excess. ... abbreviatedComment: 15 pages, 25 figures, accepted for publication in A&

Navigating in vitro bioactivity data by investigating available resources using model compounds.

The number of chemical compounds and associated experimental data in public databases is growing, but presently there is no simple way to access these data in a quick and synoptic manner. Instead, data are fragmented across different resources and interested parties need to invest invaluable time and effort to navigate these systems

Neonatal anthropometry: a tool to evaluate the nutritional status and predict early and late risks

Neonatal anthropometry is an inexpensive, noninvasive and convenient tool for bedside evaluation, especially in sick and fragile neonates. Anthropometry can be used in neonates as a tool for several purposes: diagnosis of foetal malnutrition and prediction of early postnatal complications; postnatal assessment of growth, body composition and nutritional status; prediction of long-term complications including metabolic syndrome; assessment of dysmorphology; and estimation of body surface. However, in this age group anthropometry has been notorious for its inaccuracy and the main concern is to make validated indices available. Direct measurements, such as body weight, length and body circumferences are the most commonly used measurements for nutritional assessment in clinical practice and in field studies. Body weight is the most reliable anthropometric measurement and therefore is often used alone in the assessment of the nutritional status, despite not reflecting body composition. Derived indices from direct measurements have been proposed to improve the accuracy of anthropometry. Equations based on body weight and length, mid-arm circumference/head circumference ratio, and upper-arm cross-sectional areas are among the most used derived indices to assess nutritional status and body proportionality, even though these indices require further validation for the estimation of body composition in neonates