Nanotransducers in cellular redox signaling: modification of thiols by reactive oxygen and nitrogen species.

The control of signal transduction involves post-translational modification of proteins at key amino acids. Cysteine residues are important in the control of 'redox' cell-signaling pathways, as thiol chemistry offers the possibility of modification by structurally diverse species, including those derived from oxidized lipids, peroxides or nitric oxide. An important and provocative study of the modification of thiols in the transcription factor OxyR recently extended this hypothesis.

Mitochondria: regulators of signal transduction by reactive oxygen and nitrogen species.

The functional role of mitochondria in cell physiology has previously centered around metabolism, with oxidative phosphorylation playing a pivotal role. Recently, however, this perspective has changed significantly with the realization that mitochondria are active participants in signal transduction pathways, not simply the passive recipients of injunctions from the rest of the cell. In this review the emerging role of the mitochondrion in cell signaling is discussed in the context of cytochrome c release, hydrogen peroxide formation from the respiratory chain, and the nitric oxide-cytochrome c oxidase signaling pathway.

High throughput two-dimensional blue-native electrophoresis: a tool for functional proteomics of mitochondria and signaling complexes.

The recent upsurge in proteomics research has been facilitated largely by streamlining of two-dimensional (2-D) gel technology and the parallel development of facile mass spectrometry for analysis of peptides and proteins. However, application of these technologies to the mitochondrial proteome has been limited due to the considerable complement of hydrophobic membrane proteins in mitochondria, which precipitate during first dimension isoelectric focusing of standard 2-D gels. In addition, functional information regarding protein:protein interactions is lost during 2-D gel separation due to denaturing conditions in both gel dimensions.

Nitrogen cycle: what governs nitrogen loss from forest soils?

Nitrogen is lost as dissolved organic compounds in stream waters from unpolluted South American forests, but it is lost mainly as inorganic nitrate in streams flowing from North American forests that suffer nitrogen deposition from the atmosphere. From this it has been inferred that the standard thinking about how nature deals with nitrogen in soils and waters needs to be re-evaluated and that the conventional wisdom of how nitrogen is absorbed and released by plants must be wrong. We disagree, however, on the grounds that there are other, more likely interpretations of the new results.

Mitochondrial function in response to cardiac ischemia-reperfusion after oral treatment with quercetin.

Polyphenolic compounds present in red wines, such as the flavonol quercetin, are thought capable of cardioprotection through mechanisms not yet clearly defined. It has been established that mitochondria play a critical role in myocardial recovery from ischemia-reperfusion (I-R) damage, and in vitro experiments indicate that quercetin can exert a variety of direct effects on mitochondrial function. The effects of quercetin at concentrations typically found in 1-2 glasses of red wine on cardiac I-R and mitochondrial function in vivo are not known.

Oxidation of 10-formyltetrahydrofolate to 10-formyldihydrofolate by complex IV of rat mitochondria.

We hypothesized that the unanticipated bioactivity of orally administered unnatural carbon-6 isomers, (6R)-5-formyltetrahydrofolate (5-HCO-THF) and (6S)-5,10-methenyltetrahydrofolate (5,10-CH-THF), in humans [Baggott, J. E., and Tamura, T.

Analysis of potentially mobile phosphorus in arable soils using solid state nuclear magnetic resonance.

In many intensive agroecosystems continued inputs of phosphorus (P) over many years can significantly increase soil P concentrations and the risk of P loss to surface waters. For this study we used solid-state 31P nuclear magnetic resonance (NMR) spectroscopy, high-power decoupling with magic angle spinning (HPDec-MAS) NMR, and cross polarization with magic angle spinning (CP-MAS) NMR to determine the chemical nature of potentially mobile P associated with aluminum (Al) and calcium (Ca) in selected arable soils. Three soils with a range of bicarbonate-extractable Olsen P concentrations (40-102 mg P kg(-1)) were obtained from a long-term field experiment on continuous root crops at Rothamsted, UK, established in 1843 (sampled 1958).

Specific modification of mitochondrial protein thiols in response to oxidative stress: a proteomics approach.

Mitochondria play a central role in redox-linked processes in the cell through mechanisms that are thought to involve modification of specific protein thiols, but this has proved difficult to assess. In particular, specific labeling and quantitation of mitochondrial protein cysteine residues have not been achieved due to the lack of reagents available that can be applied to the intact organelle or cell. To overcome these problems we have used a combination of mitochondrial proteomics and targeted labeling of mitochondrial thiols using a novel compound, (4-iodobutyl)triphenylphosphonium (IBTP).

Hypothesis: the mitochondrial NO(*) signaling pathway, and the transduction of nitrosative to oxidative cell signals: an alternative function for cytochrome C oxidase.

Nitric oxide (NO(*)) signaling is diverse, and involves reaction with free radicals, metalloproteins, and specific protein amino acid residues. Prominent among these interactions are the heme protein soluble guanylate cyclase and cysteine residues within several proteins such as caspases, the executors of apoptosis. Another well characterized site of NO(*) binding is the terminal complex of the mitochondrial respiratory chain, cytochrome c oxidase, although the downstream signaling effects of this interaction remain unclear.

Loss of direct and maintenance of indirect alloresponses in renal allograft recipients: implications for the pathogenesis of chronic allograft nephropathy.

Chronic allograft nephropathy (CAN) is the principal cause of late renal allograft failure. This complex process is multifactorial in origin, and there is good evidence for immune-mediated effects. The immune contribution to this process is directed by CD4(+) T cells, which can be activated by either direct or indirect pathways of allorecognition.

"Accomodated" pig endothelial cells promote nitric oxide-dependent Th-2 cytokine responses from human T cells.

Background: Cardiac and renal allo- and xenografts can become naturally resistant to vascular rejection. Understanding this process of "accommodation" would enhance our understanding of vascular inflammatory responses and have implications for immune manipulation and tolerance induction. A feature of these grafts is infiltration by leukocytes secreting a Th-2 pattern of cytokines.

Bioenergetics in cardiac hypertrophy: mitochondrial respiration as a pathological target of NO*.

A rat aortic banding model of cardiac hypertrophy was used to test the hypothesis that reversible inhibition of mitochondrial respiration by nitric oxide (NO*) elicits a bioenergetic defect in the hypertrophied heart. In support of this hypothesis, the respiration of myocytes isolated from hypertrophied hearts was more sensitive to exogenous NO* (IC(50) 200 +/- 10 nM vs. 290 +/- 30 nM in controls, P = 0.

The role of the allograft in the induction of donor-specific T cell hyporesponsiveness.

Background: With adequate immunosuppression the majority of renal allografts are accepted, despite the exceptional vigour of the T cell alloimmune response. Previous work from this laboratory has demonstrated that this is accompanied by significant reductions in the precursor frequencies of anti-donor T cells. We have also shown that parenchymal cells are tolerogenic in vitro.

Nitric oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase.

An emerging and important site of action for nitric oxide (NO) within cells is the mitochondrial inner membrane, where NO binds to and inhibits members of the electron transport chain, complex III and cytochrome c oxidase. Although it is known that inhibition of cytochrome c oxidase by NO is competitive with O2, the mechanisms that underlie this phenomenon remain unclear, and the impact of both NO and O2 partitioning into biological membranes has not been considered. These properties are particularly interesting because physiological O2 tensions can vary widely, with NO having a greater inhibitory effect at low O2 tensions (<20 microM).

Mechanisms of cell signaling by nitric oxide and peroxynitrite: from mitochondria to MAP kinases.

Many of the biological and pathological effects of nitric oxide (NO) are mediated through cell signaling pathways that are initiated by NO reacting with metalloproteins. More recently, it has been recognized that the reaction of NO with free radicals such as superoxide and the lipid peroxyl radical also has the potential to modulate redox signaling. Although it is clear that NO can exert both cytotoxic and cytoprotective actions, the focus of this overview are those reactions that could lead to protection of the cell against oxidative stress in the vasculature.

Cytomegalovirus seropositivity adversely influences outcome after T-depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft-versus-host disease prophylaxis.

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after haematopoietic stem cell transplantation from matched unrelated donors (MUD). The role of T-cell depletion (TCD) as a strategy to prevent GVHD is controversial because of the associated increased risk of leukaemic relapse, graft failure and delayed immune reconstitution. The demonstration that donor lymphocyte infusion (DLI) is effective salvage therapy if patients relapse after transplantation for chronic myeloid leukaemia (CML) prompted us to examine the proposal that TCD may be a form of GVHD prophylaxis particularly suited to this disease in patients undergoing MUD transplantation.

Increased sensitivity of mitochondrial respiration to inhibition by nitric oxide in cardiac hypertrophy.

Cardiac hypertrophy is a significant risk factor for the development of congestive heart failure (CHF). Mitochondrial defects are reported in CHF, but no consistent mitochondrial alterations have yet been identified in hypertrophy. In this study selective metabolic inhibitors were used to determine thresholds for respiratory inhibition and to reveal novel mitochondrial defects in hypertrophy.

A prospective randomised trial of tourniquet in varicose vein surgery.

A prospective randomised trial of 50 patients was carried out to assess the autoclavable Lofquist cuff (Boazal, Sweden) as a tourniquet in varicose vein surgery and determine the effect on bleeding, bruising, cosmesis and patient pain and activity. Patients undergoing unilateral long saphenous vein ligation, stripping and avulsions were randomised to tourniquet or no tourniquet. Lofquist cuffs were applied after inflation to 120 mmHg to the upper thigh for the duration of the surgery.

Concentration-dependent effects of nitric oxide on mitochondrial permeability transition and cytochrome c release.

The mitochondrial permeability transition pore (PTP) and associated release of cytochrome c are thought to be important in the apoptotic process. Nitric oxide (NO( small middle dot)) has been reported to inhibit apoptosis by acting on a variety of extra-mitochondrial targets. The relationship between cytochrome c release and PTP opening, and the effects of NO( small middle dot) are not clearly established.

The assumption that nitric oxide inhibits mitochondrial ATP synthesis is correct.

The assumption that reversible inhibition of mitochondrial respiration by nitric oxide (NO.) represents inhibition of ATP synthesis is unproven. NO.

Nitric oxide, mitochondria and neurological disease.

Damage to the mitochondrial electron transport chain has been suggested to be an important factor in the pathogenesis of a range of neurological disorders, such as Parkinson's disease, Alzheimer's disease, multiple sclerosis, stroke and amyotrophic lateral sclerosis. There is also a growing body of evidence to implicate excessive or inappropriate generation of nitric oxide (NO) in these disorders. It is now well documented that NO and its toxic metabolite, peroxynitrite (ONOO-), can inhibit components of the mitochondrial respiratory chain leading, if damage is severe enough, to a cellular energy deficiency state.