Subcellular injuries in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia occurring in the elderly. Several hypotheses have been proposed to explain the pathophysiology of AD, including amyloidogenesis, disruption of calcium homeostasis, energetic failure, induction of oxidative stress, and hyperphosphorylation of tau protein. This review examines associations between cellular and subcellular injuries, neurodegeneration, and cell death in experimental models, clinical symptoms, and autopsy reports of AD to identify the subcellular events leading to disease onset and progression.

[Ischemia reperfusion: an unavoidable phase of transplant procedures].

Transplanted organs are inevitably exposed to ischemia-reperfusion injury. Cold preservation is also used to reduced metabolic processes during ex vivo transport but triggers a complex pathophysiological syndrome which is responsible for delayed graft function after reperfusion. Ischemia-reperfusion injury is also associated with chronic graft dysfunction.

[French national health insurance. The current situation].

An audit of the French national health insurance system would be justified by economic considerations alone, but this would risk overlooking the notions of solidarity and freedom to which the French are rightly attached. European comparisons suggest, however, that our system could be made more efficient without undermining public health. The national health insurance system allows each member of the population to receive high-quality medical care.

Amyloidosis and neurodegenerative diseases: current treatments and new pharmacological options.

Most neurodegenerative diseases share several clinical, genetic and pathophysiological features, and an irreversible evolution as well. They are characterized by an endogenous production of abnormal proteins called amyloid proteins (AP), which are not hydrosoluble, form depots, and are only partly cleared by autophagy and the ubiquitin-protease system. Despite their different structures, they are probably generated by a common pathological pathway, a misfolding process.

Renal protective effect of metabolic therapy in patients with coronary artery disease and diabetes: from bench to bed side.

Coronary artery disease (CAD) is due to subintimal deposition of atheromatous plaques in large and medium-sized coronary arteries. Different risk factors have been identified such as hypertension, hypercholesterolemia, diabetes and smoking. Both hypertension and diabetes mellitus affect the same major target organs.

Caprospinol: moving from a neuroactive steroid to a neurotropic drug.

In search of new drugs for Alzheimer's disease, we departed from the classic concepts and investigated the ability of normal and Alzheimer's disease brain to convert cholesterol to steroids, otherwise known as neurosteroids. We identified 22R-hydroxycholesterol to be present in much lower levels in the hippocampus and frontal cortex of Alzheimer's disease than in tissue from age-matched controls. 22R-hydroxycholesterol was shown to protect against beta-amyloid (A beta(42))-induced neurotoxicity and block the formation of A beta oligomers.

Concentration-dependent plasma protein binding of the novel dipeptidyl peptidase 4 inhibitor BI 1356 due to saturable binding to its target in plasma of mice, rats and humans.

Objectives: The purpose of this study was to characterise the plasma protein binding of BI 1356.

Methods: BI 1356 (proposed trade name ONDERO) is a novel dipeptidyl peptidase 4 (DPP-4) inhibitor, which is under clinical development for the treatment of type 2 diabetes. DPP-4 is expressed in various tissues but soluble DPP-4 is also present in plasma.

[Self-medication and safety].

Most drugs used for self-medication act on pain, diarrhea, constipation, gastric acid hypersecretion, or allergic diseases. They are generally well-tolerated, provided the recommended dose regimen is respected. Most adverse effects result from misuse (wrong indication, overdose, interactions, etc.

Trimetazidine reduces early and long-term effects of experimental renal warm ischemia: a dose effect study.

Objective: Renal ischemia reperfusion (IR) injury (IRI) is an important mechanism of acute renal failure (ARF) and a crucial factor of tissue damage during vascular surgery. IR may lead to tissue destruction and influence the early and long-term outcome of organs. The anti-anginal medication trimetazidine (TMZ) is a drug, the protective effects of which have been already assessed during cold preservation and warm ischemia (WI).

Protection of cellular and mitochondrial functions against liver ischemia by N-benzyl-N'-(2-hydroxy-3,4-dimethoxybenzyl)-piperazine (BHDP), a sigma1 ligand.

We investigated the antiischemic properties of a new compound N-benzyl-N'-(2-hydroxy-3,4-dimethoxybenzyl)-piperazine (BHDP), having high affinity and selectivity for the sigma(1) receptor, in two different models of ischemia. The first was an experimental model of rat liver normothermic ischemia-reperfusion. Rats were pretreated with different doses of BHDP (0.

Comparison of protective effects of trimetazidine against experimental warm ischemia of different durations: early and long-term effects in a pig kidney model.

Acute renal failure (ARF) is often the consequence of an ischemia-reperfusion injury (IRI) and associated with high mortality. Warm ischemia (WI) is a crucial factor of tissue damage, and tissue destruction led by ischemia-reperfusion (I/R) can impact the early and long-term functional outcome. Trimetazidine (TMZ) is an anti-ischemic drug.

[Drug binding to blood proteins: characteristics, roles and pathophysiological changes].

HSA and AGP are the only plasma proteins capable of binding drugs through specific sites with high affinity. As such, they can limit drug distribution and, sometimes, drug elimination. Such binding is called restrictive.

Implication of mitochondrial dysfunction and cell death in cold preservation--warm reperfusion-induced hepatocyte injury.

Cold ischemia--warm reperfusion (CI/WR) injury of liver transplantation involves hepatocyte cell death, the nature and underlying mechanisms of which remain unclear. Isolated hepatocytes and isolated perfused livers were used to determine the prevalence of necrosis and apoptosis as well as mitochondrial dysfunction. In isolated cells, propidium iodide and Hoechst 33342 staining showed a cold-storage, time-dependent increase in necrosis, whereas apoptosis was minimal even after 48 h of hypothermia.

Effect of the mitochondrial transition pore inhibitor, S-15176, on rat liver mitochondria: ATP synthase modulation and mitochondrial uncoupling induction.

S-15176 is a new inhibitor of the permeability transition pore (PTP) which has been shown to display anti-ischemic properties. We show here that S-15176 prevented PTP, cytochrome c release and maintained mitochondrial membrane potential when low concentrations of S-15176 were used (not exceeding 50 nmol/mg protein). For higher concentrations S-15176 is able to collapse mitochondrial potential.

Resveratrol protects against cold ischemia-warm reoxygenation-induced damages to mitochondria and cells in rat liver.

Ischemia-reperfusion is a critical event in the development of primary graft dysfunctions after liver transplantations. Ischemia-reperfusion causes cell injuries which are related to the successive cold preservation-warm reperfusion (CPWR) periods required by the graft. Recent evidences suggest that oxidative stress plays an important role in the development of these injuries and that mitochondrial dysfunctions are involved.

Effect of ethanol and red wine on ochratoxin a-induced experimental acute nephrotoxicity.

Ochratoxin A (OTA), is a nephrotoxic mycotoxin present in wine, which is nephrotoxic in humans. Our working hypothesis is that natural substances in wine may counteract OTA toxicity. Thirty-six rats were randomized to OTA dissolved in saline, red wine, or 13.

Role of the permeability transition pore in cytochrome C release from mitochondria during ischemia-reperfusion in rat liver.

Ischemia and reperfusion cause mitochondrial dysfunctions that initiate the mitochondrial apoptosis pathway. They involve the release of cytochrome C and the activation of the caspase cascade but the mechanism(s) leading to cytochrome C release is(are) poorly understood. The aim of this study was to analyse the relation between cytochrome C release and the opening of the permeability transition pore (PTP) during in situ liver ischemia and reperfusion.

Long-term exposure to nicotine modulates the level and activity of acetylcholine receptors in white blood cells of smokers and model mice.

Long-term consumption of tobacco by smokers causes addiction and increases the level of neuronal nicotinic acetylcholine receptors (nAChRs) in the brain, a phenomenon known as up-regulation. Here, we show that up-regulation of specific nAChR subunits takes place in white blood cells (WBCs) of smokers and mice subjected to long-term administration of nicotine. The basal level of alpha-bungarotoxin binding site, which corresponds to the homomeric alpha7 nAChR subtype, was not affected in WBCs of both smokers and mice administered nicotine.

Protection by cyclosporin A of mitochondrial and cellular functions during a cold preservation-warm reperfusion of rat liver.

Liver transplantation is an effective therapeutic option for end-stage liver disease, but initial poor graft function still occurs, often related to cold preservation-warm reperfusion (CPWR) conditions. Damages to mitochondria could be implicated in hepatocyte cell death since opening of the permeability transition pore (PTP) can lead to necrosis and apoptosis. The purpose of this study was to test the hypothesis that inhibition of mitochondrial permeability transition by cyclosporin A could improve rat liver mitochondrial and hepatocellular parameters after 24-h cold preservation followed by a warm reperfusion in Krebs-Henseleit Buffer.

Fluoride curcumin derivatives: new mitochondrial uncoupling agents.

The mitochondrial effects of two fluoride curcumin derivatives were studied. They induced the collapse of mitochondrial membrane potential (DeltaPsi), increased mitochondrial respiration, and decreased O(2)*- production and promoted Ca(2+) release. These effects were reversed by the recoupling agent 6-Ketocholestanol, but not by cyclosporin A, an inhibitor of the permeability transition pore (PTP), suggesting that these compounds act as uncoupling agents.

Evidence for protective roles of polyethylene glycol plus high sodium solution and trimetazidine against consequences of renal medulla ischaemia during cold preservation and reperfusion in a pig kidney model.

Background: The renal medulla is particularly sensitive to oxidant stress and to ischaemia-reperfusion injury (IRI). In organ transplantation, delayed graft function is an important problem and cold ischaemia is thought to be the most important factor in short- and long-term complications. Our aim was to study cold-induced damage in proximal tubular segments and renal medulla osmolite excretion during use of various preservation solutions, and to clarify the role of trimetazidine (TMZ) in limiting renal dysfunction.

Evidence for a mitochondrial impact of trimetazidine during cold ischemia and reperfusion.

In organ transplantation, ischemia-reperfusion injury (IRI) has been implicated in delayed graft function (DGF) as well as in short- and long-term complications. Using an autotransplant pig kidney model, changes in renal function and morphology were determined after different periods of cold ischemia in kidneys preserved in the University of Wisconsin solution (UW), high-Na(+) version of UW (HEH) or Celsior (CEL) a newly developed high-Na(+) solution, with or without trimetazidine (TMZ). Kidney function was better preserved in CEL, UW and particularly HEH in combination with TMZ, particularly after 48 and 72 h.

Protective roles of polyethylene glycol and trimetazidine against cold ischemia and reperfusion injuries of pig kidney graft.

Ischemia-reperfusion injury (IRI) represents an allo-independent risk factor which favors chronic allograft nephropathy (CAN). Here we analyzed the influence of preservation solutions on the function of autotransplanted pig kidneys over 1-16 weeks after surgery. Kidneys were cold-flushed and cold-stored for 24 or 48 h either in University of Wisconsin (UW), modified-UW Hôpital Edouard Herriot, polyethylene glycol 20 kDa (PEG)-supplemented preservation solutions with low K+ (ECPEG) or high K+ (ICPEG) content.

Effects of curcumin and curcumin derivatives on mitochondrial permeability transition pore.

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a natural compound with antiproliferative properties. Recent studies suggest that these properties might be due to the ability of curcumin to induce apoptosis in tumor cells by increasing the permeability of the mitochondrial membrane. In the present study, we confirm these observations and provide a molecular mechanism for the action of curcumin in rat liver mitochondria.