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The proteasome inhibitor, MG132, promotes the reprogramming of translation in C2C12 myoblasts and facilitates the association of hsp25 with the eIF4F complex

FEBS JOURNAL, Issue 17 2004
Joanne L. Cowan
The eukaryotic translation initiation factor (eIF) 4E, is regulated by modulating both its phosphorylation and its availability to interact with the scaffold protein, eIF4G, to form the mature eIF4F complex. Here we show that treatment of C2C12 myoblasts with the proteasomal inhibitor, MG132 (N -carbobenzoxyl-Leu-Leu-leucinal), resulted in an early decrease in protein synthesis rates followed by a partial recovery, reflecting the reprogramming of translation. The early inhibition of protein synthesis was preceded by a transient increase in eIF2, phosphorylation, followed by a sustained increase in eIF4E phosphorylation. Inhibition of eIF4E phosphorylation with CGP57380 failed to prevent translational reprogramming or the moderate decrease in eIF4F complexes at later times. Prolonged incubation with MG132 resulted in the increased expression of heat shock protein (hsp)25, ,B-crystallin and hsp70, with a population of hsp25 associating with the eIF4F complex in a p38 mitogen-activated protein kinase-dependent manner. Under these conditions, eIF4GI, and to a lesser extent eIF4E, re-localized from a predominantly cytoplasmic distribution to a more perinuclear and granular staining. Although MG132 had little effect on the colocalization of eIF4E and eIF4GI, it promoted the SB203580-sensitive association of eIF4GI and hsp25, an effect not observed with ,B-crystallin. Addition of recombinant hsp25 to an in vitro translation assay resulted in stimulation of on-going translation and a moderate decrease in de novo translation, indicating that this modified eIF4F complex containing hsp25 has a role to play in recovery of mRNA translation following cellular stress. [source]

The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia

JOURNAL OF NEUROCHEMISTRY, Issue 6 2005
Amit S. Korde
Abstract Ischemic stroke is caused by acute neuronal degeneration provoked by interruption of cerebral blood flow. Although the mechanisms contributing to ischemic neuronal degeneration are myriad, mitochondrial dysfunction is now recognized as a pivotal event that can lead to either necrotic or apoptotic neuronal death. Lack of suitable ,upstream' targets to prevent loss of mitochondrial homeostasis has, so far, restricted the development of mechanistically based interventions to promote neuronal survival. Here, we show that the uncoupling agent 2,4 dinitrophenol (DNP) reduces infarct volume approximately 40% in a model of focal ischemia,reperfusion injury in the rat brain. The mechanism of protection involves an early decrease in mitochondrial reactive oxygen species formation and calcium uptake leading to improved mitochondrial function and a reduction in the release of cytochrome c into the cytoplasm. The observed effects of DNP were not associated with enhanced cerebral perfusion. These findings indicate that compounds with uncoupling properties may confer neuroprotection through a mechanism involving stabilization of mitochondrial function. [source]

Short-term follow-up of patients with sickle cell disease and albuminuria

PEDIATRIC BLOOD & CANCER, Issue 6 2008
Ofelia Alvarez MD
Abstract Background Albuminuria with normal serum creatinine occurs frequently in patients with sickle cell disease (SCD), but the rate of progression to more advanced chronic renal disease is unknown. The purpose of this study was to investigate the rate of progression of children and young adults with SCD and albuminuria over time. Procedure Urine albumin/creatinine (A/C) ratios and serum creatinine were obtained serially. Serum cystatin C levels were determined in a subgroup of 20 patients. Results Of 38 patients with SCD who had albuminuria (30 with microalbuminuria and 8 with proteinuria), 10.5% had progressive disease during follow-up of 20,±,12 months. Progressive disease was observed in 2 of 30 patients with MA because MA worsened to either intermittent proteinuria (1 patient), or persistent proteinuria after 7 months follow-up (1 patient). Two of eight patients with proteinuria worsened to nephrotic-range after 8 and 17 months with elevations of serum creatinine. All eight patients with proteinuria were treated with angiotensin blockade and/or hydroxyurea. Of those, six patients responded to treatment with decreased albuminuria and no changes in serum creatinine. Serum cystatin C level trended to increase before serum creatinine in patients with proteinuria. Conclusions Patients with rapid progression to nephrotic-range proteinuria showed decreased kidney function. Therefore, patients with albuminuria should be monitored closely for progression, and therapy with hydroxyurea and/or angiotensin blockade should be considered for patients who develop proteinuria. Serum cystatin C appears more sensitive than serum creatinine to detect early decrease in kidney function. Pediatr Blood Cancer 2008;50:1236,1239. © 2008 Wiley-Liss, Inc. [source]

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PRESCRIBER, Issue 6 2007
Article first published online: 8 JUN 200
Initial macrolide better for pneumonia? An observational study has suggested that initial treatment with a macrolide antibiotic (such as erythromycin) may be more effective than a fluoroquinolone (like ciprofloxacin) or tetracycline as initial treatment for community acquired pneumonia and bacteraemia (Chest 2007;131:466-73). The US review of 2209 hospital episodes found that macrolide therapy was associated with a 40 per cent lower risk of death during hospital stay or within 30 days and of hospital readmission within 30 days of discharge. By contrast, no such benefit was apparent with fluoroquinolones or tetracycline. Two-year safety data for inhaled insulin Compared with sc insulin, inhaled insulin (Exubera) is associated with a small early decrease in lung function in the first three months of therapy but no further difference for up to two years (Diabetes Care 2007;30: 579-85). The comparative trial found that FEV1 declined at a mean rate of 0.051 litres per year with inhaled insulin and 0.034 litres per year with sc insulin, but there was no significant difference in the rates of decline after three months. Inhaled insulin was associated with a higher incidence of cough (37.6 vs 13.1 per cent) but a lower incidence of severe hypoglycaemic events (2.8 vs 4.1 events per 100 subject- months) and mean weight gain was 1.25kg less. Fracture risk warning with rosiglitazone GlaxoSmithKline has warned US prescribers that rosiglitazone may be associated with an increased risk of fractures. The company says information for prescribers in Europe will follow shortly. The warning comes from the ADOPT study (N Engl J Med 2006;355:2427-43), which found a significantly higher incidence of fractures of the humerus, hand and foot among women taking rosiglitazone (9.3 per cent) than with metformin (5.1 per cent) or glibenclamide (3.5 per cent). There was no difference in fracture incidence among men. The company recommends that fracture risk should be considered for women taking or about to take rosiglitazone. Oral treatment for grass pollen allergy A new treatment for allergic rhinitis due to grass pollen allergy has been introduced by ALK-Abelló. Grazax is a sublingual tablet containing a stan-dardised dose of allergen from the pollen of timothy grass. Treatment should be initiated by a specialist four months before the onset of the allergy season and continued throughout the season. Adverse effects include oral and ear pruritus, nasopharyngitis and mouth oedema. A month's treatment at the recommended dose of one tablet daily costs £67.50. Frequent analgesics linked with hypertension Men who take analgesics regularly have an increased frequency of hypertension, a US study has shown (Arch Intern Med 2007;167:394-9). The US Health Professionals Follow-Up study evaluated the use of NSAIDs, paracetamol and aspirin in 16 031 men with normal blood pressure and followed them up for four years. Compared with those who did not report analgesic use, the risk of hypertension was increased by 38 per cent for NSAID use, 34 per cent for paracetamol and 26 per cent for aspirin, all for for six or seven days a week. Similar risks were found when anal- gesic use was determined according to the number of tablets taken. The authors acknowledge the increased risk is modest, but point out that the implications may nonetheless be important because analgesics are widely used. Multiples do most pharmacist MURs Uptake of medicines use reviews (MURs) by pharmacists was modest in 2005 and most reviews were carried out by pharmacy chains rather than independent contractors, a new study has shown (Pharm J 2007;278:218-23). The survey of PCTs and SHAs in England and Wales found that, although 38 per cent of community pharmacies claimed payments for the service, 84 per cent of MURs were carried out by pharmacy chains. Uptake was low, amounting to only 7 per cent of the maximum possible number of MURs. Patients see information needs differently There is a mismatch in the perceptions of patients and health professionals about the purpose of written information about medicines, a systematic review has concluded (Health Technol Assess 2007;11:1-178). Some health professionals believe the main purpose of information is to promote compliance, whereas patients want information to help them make decisions about their treatment, including not taking it. In particular, patients want information on adverse effects, but health professionals have reservations about providing it. Aspirin for all women over 65? All women over 65 should take low-dose aspirin if the benefits are likely to outweigh the risk of adverse effects, according to new guidelines from the American Heart Association on preventing cardiovascular disease in women (published online 19 Feb 2007;doi: 10.1161/circulationaha.107.181546). The guidelines have moved away from the long-established Framingham model of risk assessment to categorising three levels of risk: high (heart disease or other relevant disease present), at risk (at least one risk factor) and optimal (healthy lifestyle, no risk factors). Low-dose aspirin is recommended for all women at high risk, for women aged 65 or over when reducing the risk of MI or ischaemic stroke outweighs the risk of adverse effects, and for younger women when reducing the risk of ischaemic stroke outweighs that of toxicity. Combination inhaler therapy Combining an inhaled long-acting bronchodilator with a steroid reduces COPD exacerbations but not all-cause mortality, a three-year trial has shown (N Engl J Med 2007;356:775-89). However, inhaled steroids appear to increase the risk of pneumonia. The TORCH trial randomised 6112 patients (FEV1<60 per cent predicted) to treatment with salmeterol 50µg plus fluticasone 500µg (Seretide) twice daily, salmeterol (Serevent) or fluticasone (Flixotide) as monotherapy, or placebo. All-cause mortality rates were 12.6, 13.5, 16.0 and 15.2 per cent respectively; the risk of death was 17 per cent lower with combined therapy, but the difference did not reach statistical significance. The combination reduced the incidence of exacerbations by 25 per cent and improved health status and FEV1. Use of fluticasone was not associated with more ocular or bone disorders, but there was an increased incidence of pneumonia among users (19.6 per cent with combined therapy and 18.3 per cent with fluticasone vs 12.3 per cent with placebo). Seretide is currently licensed in the UK for use in patients with FEV1 <50 per cent predicted. Tamoxifen long- term benefits Women with breast cancer who take tamoxifen for five to eight years continue to have a lower risk of recurrence for 10-20 years, long-term follow-up of two blinded trials has shown (J Nat Cancer Inst 2007; 99:258-60, 272-90). The frequency of adverse effects was markedly reduced when treatment ended, changing the balance of risk and benefit. Copyright © 2007 Wiley Interface Ltd [source]