The results suggest that the technique for preservation which is most widely used for ophthalmological amniotic membrane transplantation significantly impairs viability and proliferative capacity. This supports the clinical finding that neither immunological reactions nor signs of ingrowth of amniotic cells are observed in patients. Furthermore amniotic membrane grafts seem to function primarily as matrix and not by virtue of transplanted functional cells.
Endoplasmic reticulum (ER) stress leads to activation of the unfolded protein response (UPR) that results in transient suppression of protein translation to allow recovery but leads to cell death when stress cannot be resolved. Central to initiation of the UPR is the activation of the ER transmembrane kinase protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). Here we report that the thiol oxidoreductase ERp57 and protein disulfide isomerase-A1 (PDI), which belong to the same family of luminal ER oxidoreductases, have strikingly opposing roles in the regulation of PERK function. In HCT116 colon carcinoma cells, lentiviral depletion of ERp57 resulted in oxidation of PDI and activation of PERK, whereas depletion or chemical inhibition of PDI reduced PERK signaling and sensitized the cancer cells to hypoxia and ER stress. We conclude that oxidized PDI acts as a PERK activator, whereas ERp57 keeps PDI in a reduced state in the absence of ER stress. Thus, our study defines a new interface between metabolic redox signaling and PERK-dependent activation of the UPR and has the potential to influence future cancer therapies that target PERK signaling.
Baseline lung function is related to symptoms and precludes EIB in some rink athletes, suggesting that EIB and its development is a heterogeneous and may involve fibrotic as well as inflammatory processes. Small airway dysfunction in ice arena athletes is likely related to internal combustion pollutants emitted from ice resurfacing machines.
Background: Exercise induced bronchoconstriction (EIB) is common in elite athletes. Eucapnic voluntary hyperventilation (EVH) is a laboratory test recommended for the identification of EIB in athletes, secondary to a field exercise challenge. Montelukast attenuates EIB, but its protective effect against airway narrowing from EVH has not been investigated. Objective: To examine the effectiveness of montelukast after exercise and after EVH. Methods: A randomised, placebo controlled, double blind, crossover study was performed with 11 physically active EIB positive subjects (eight men, three women; mean (SD) age 22.8 (6.8) years). Six hours before each of the following challenges 10 mg montelukast or placebo was ingested: (a) a six minute, cold air (23˚C) maximal effort work accumulation cycle ergometer exercise; (b) EVH, breathing 5% CO 2 compressed air at 85% maximal voluntary ventilation for six minutes. Spirometry was performed before and 5, 10, and 15 minutes after the challenge. At least 48 hours was observed between challenges. Results: No differences in forced expiratory volume in one second (FEV 1 ) were found after the two challenges. Exercise and EVH resulted in falls in FEV 1 of 22.4 (18.0) and 25.6 (16.8) respectively. Falls in FEV 1 after montelukast were less than after placebo (10.6 (10.6) and 14.3 (11.3) after exercise and EVH respectively; p,0.05). Montelukast provided protection against bronchoconstriction (59% and 53%; p,0.05) for eight exercising subjects and 10 EVH subjects; no protection was afforded for three exercising and one EVH challenged subject. Conclusions: Both exercise and EVH were potent stimuli of airway narrowing. A single dose of montelukast provided reasonable protection in attenuating bronchoconstriction from either exercise or EVH. The similar protection by montelukast suggests that EVH is a suitable laboratory surrogate for EIB evaluation.
Similar postchallenge percent falls in FEV1 for room- and cold-temperature EVH and exercise suggest that dryness is essential to test conditions, as cold temperature did not have an additive effect to the EIB response.
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