The oxidative stress theory of disease: levels of evidence and epistemological aspects

The theory stating that oxidative stress (OS) is at the root of several diseases is extremely popular. However, so far, no antioxidant is recommended or offered by healthcare systems neither approved as therapy by regulatory agencies that base their decisions on evidence-based medicine (EBM). This is simply because, so far, despite many preclinical and clinical studies indicating a beneficial effect of antioxidants in many disease conditions, randomised clinical trials have failed to provide the evidence of efficacy required for drug approval. In this review, we discuss the levels of evidence required to claim causality in preclinical research on OS, the weakness of the oversimplification associated with OS theory of disease and the importance of the narrative in its popularity. Finally, from a more translational perspective, we discuss the reasons why antioxidants acting by scavenging reactive oxygen species (ROS) might not only prevent their detrimental effects but also interfere with essential signalling roles. We propose that ROS have a complex metabolism and are generated by different enzymes at diverse sites and with different timing. Aggregating this plurality of systems in a single theory of disease may not be the best way to develop new drugs, and future research may need to focus on specific oxygen-toxifying pathways rather than on non-specific ROS scavengers. Finally, similarly to what is nowadays required for clinical trials, we recommend making unpublished data available in repositories (open data), as this will allow big data approaches or meta-analyses without the blinders of the publication bias

The Persistent Sodium Current Blocker Riluzole Is Antiarrhythmic and Anti-Ischaemic in a Pig Model of Acute Myocardial Infarction

Background The potential of the cardiac persistent sodium current as a target for protection of the myocardium from ischaemia and reperfusion injury is gaining increasing interest. We have investigated the anti-ischaemic and antiarrhythmic effects of riluzole, a selective INaP blocker, in an open chest pig model of infarction. Methods and Principal Findings The left anterior descending coronary artery (LAD) was ligated in 27 anesthetised pigs (landrace or large white, either sex, 20–35 kg) which had received riluzole (8 mg/kg IP; n = 6), lidocaine (2.5–12 mg/kg bolus plus 0.05–0.24 mg/kg/min; n = 11) or vehicle (n = 10) 50 min prior. Arrhythmias could be delineated into phase 1a (0 to 20 min), phase 1b (20 to 50 min) and phase 2 (from 50 min to termination at 180 min) and were classified as premature ventricular contractions (PVCs), non-sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) (spontaneously reverting within 15 s) or sustained VT or VF (ie. requiring cardioversion at 15 s). Riluzole reduced the average number of all arrhythmias in Phase 2 (PVCs from 484+/−119 to 32+/−13; non sustained arrhythmias from 8.9+/−4.4 to 0.7+/−0.5; sustained arrhythmias from 3.9+/−2.2 to 0.5+/−0.4); lidocaine reduced the average number of non-sustained and sustained arrhythmias (to 0.4+/−0.3 and 0.4+/−0.3 respectively) but not PVCs (to 390+/−234). Riluzole and lidocaine reduced the average number of sustained arrhythmias in phase 1b (from 1.8+/−0.4 to 0.17+/−0.13 (p<0.02) and to 0.55+/−0.26 (p = ns) respectively). Neither lidocaine or riluzole changed the ECG intervals: there was no statistical significance between groups at time zero (just before ligation) for any ECG measure. During the course of the 3 hour period of the ischaemia R-R, and P-R intervals shortened slightly in control and riluzole groups (not significantly different from each other) but not in the lidocaine group (significantly different from control). QRS and QTc did not change appreciably in any group Riluzole reduced the degree of histopathological tissue damage across the infarct zone considerably more than did lidocaine. Conclusions At the doses used, riluzole was at least as effective as lidocaine at reducing the number of episodes of ischaemic VT or VF in pigs, and much more effective at reducing the number of PVCs. We propose that this is related to the ability of riluzole to block cardiac persistent sodium currentSteven M. Weiss and David A. Sain

Numerical computations of facetted pattern formation in snow crystal growth

Facetted growth of snow crystals leads to a rich diversity of forms, and exhibits a remarkable sixfold symmetry. Snow crystal structures result from diffusion limited crystal growth in the presence of anisotropic surface energy and anisotropic attachment kinetics. It is by now well understood that the morphological stability of ice crystals strongly depends on supersaturation, crystal size and temperature. Until very recently it was very difficult to perform numerical simulations of this highly anisotropic crystal growth. In particular, obtaining facet growth in combination with dendritic branching is a challenging task. We present numerical simulations of snow crystal growth in two and three space dimensions using a new computational method recently introduced by the authors. We present both qualitative and quantitative computations. In particular, a linear relationship between tip velocity and supersaturation is observed. The computations also suggest that surface energy effects, although small, have a larger effect on crystal growth than previously expected. We compute solid plates, solid prisms, hollow columns, needles, dendrites, capped columns and scrolls on plates. Although all these forms appear in nature, most of these forms are computed here for the first time in numerical simulations for a continuum model.Comment: 12 pages, 28 figure

Non-canonical chemical feedback self-limits nitric oxide-cyclic GMP signaling in health and disease

Nitric oxide (NO)-cyclic GMP (cGMP) signaling is a vasoprotective pathway therapeutically targeted, for example, in pulmonary hypertension. Its dysregulation in disease is incompletely understood. Here we show in pulmonary artery endothelial cells that feedback inhibition by NO of the NO receptor, the cGMP forming soluble guanylate cyclase (sGC), may contribute to this. Both endogenous NO from endothelial NO synthase and exogenous NO from NO donor compounds decreased sGC protein and activity. This effect was not mediated by cGMP as the NO-independent sGC stimulator, or direct activation of cGMP-dependent protein kinase did not mimic it. Thiol-sensitive mechanisms were also not involved as the thiol-reducing agent N-acetyl-L-cysteine did not prevent this feedback. Instead, both in-vitro and in-vivo and in health and acute respiratory lung disease, chronically elevated NO led to the inactivation and degradation of sGC while leaving the heme-free isoform, apo-sGC, intact or even increasing its levels. Thus, NO regulates sGC in a bimodal manner, acutely stimulating and chronically inhibiting, as part of self-limiting direct feedback that is cGMP independent. In high NO disease conditions, this is aggravated but can be functionally recovered in a mechanism-based manner by apo-sGC activators that re-establish cGMP formatio

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

A Cahn-Hilliard-Darcy model for tumour growth with chemotaxis and active transport

Using basic thermodynamical principles we derive a Cahn--Hilliard--Darcy model for tumour growth including nutrient diffusion, chemotaxis, active transport, adhesion, apoptosis and proliferation. The model generalise earlier models and in particular include active transport mechanisms which ensures thermodynamical consistency. We perform a formally matched asymptotic expansion and develop several sharp interface models. Some of them are classical and some new ones which for example include a jump in the nutrient density at the interface. A linear stability analysis for a growing nucleus is performed and in particular the role of the new active transport term is analysed. Numerical computations are performed to study the influence of the active transport term for specific growth scenarios

Nitric oxide-independent vasodilator rescues heme-oxidized soluble guanylate cyclase from proteosomal degradation

Background: Nitric oxide (NO) is an essential vasodilator. In vascular diseases, oxidative stress attenuates NO signaling by both chemical scavenging of free NO and oxidation and down-regulation of its major intracellular receptor, the alpha/beta heterodimeric heme-containing soluble guanylate cyclase (sGC). Oxidation can also induce loss of sGC's heme and responsiveness to NO. Results: sGC activators such as BAY 58-2667 bind to oxidized/heme-free sGC and reactivate the enzyme to exert disease-specific vasodilation. Here we show that oxidation-induced down-regulation of sGC protein extends to isolated blood vessels. Mechanistically, degradation was triggered through sGC ubiquitination and proteasomal degradation. The heme-binding site ligand, BAY 58-2667, prevented sGC ubiquitination and stabilized both alpha and beta subunits. Conclusion: Collectively, our data establish oxidation-ubiquitination of sGC as a modulator of NO/cGMP signaling and point to a new mechanism of action for sGC activating vasodilators by stabilizing their receptor, oxidized/heme-free sGC