血小板膜糖蛋白（GP）ⅢaPLA、Ⅰa807C/T基因多态性与阿司匹林抵抗的相关性研究

目的：探讨青岛地区汉族人群阿司匹林抵抗与血小板膜糖蛋白GPⅢaPLA、Ⅰa807C/T基因多态性之间的关系。方法：筛选150例动脉粥样硬化患者服用阿司匹林（100mg/d）至少14d以上,根据血小板聚集功能测定将其分为阿司匹林抵抗（AR）组、阿司匹林半抵抗（ASR）组,阿司匹林敏感（AS）组。用PCR-RFLP法确定各组GPⅢaPLA、GPⅠa 807C/T基因型。结果：仅于ASR组检出1例PLA1/A2基因型,其余均为PLA1/A1基因型,未发现PLA2/A2基因型,差异无统计学意义（P〉0.005）;GPⅠa807C/T基因位点AR组、ASR组的T等位基因频率均显著高于AS组,有统计学意义（P〈0.005）。结论：GPⅢaPLA2基因可能不是阿司匹林抵抗的遗传危险因素。而GPⅠa 807C/T基因位点的T等位基因与阿司匹林抵抗的发生相关联,可能是阿司匹林抵抗遗传易感因素。     

COX-2 is not involved in thromboxane biosynthesis by activated human platelets.

The occurrence of aspirin resistance has been inferred by the assessment of platelet aggregation ex vivo in patients with ischemic vascular syndromes taking aspirin. Since aspirin is a weak inhibitor of the inducible isoform of prostaglandin H synthase (COX-2), it was suggested that COX-2 may play a role in aspirin resistance. However the cellular source(s) of COX-2 possibly responsible for aspirin resistance remains unknown. Recently, the expression of the inducible isoform of COX-2 in circulating human platelets was reported. To investigate the possible contribution of COX-2 expression in platelet thromboxane (TX) biosynthesis, we have compared the inhibitory effects of NS-398 and aspirin, selective inhibitors of COX-2 and COX-1, respectively, on prostanoid biosynthesis by thrombin-stimulated platelets vs lipopolysaccharide (LPS)stimulated monocytes (expressing high levels of COX-2) isolated from whole blood of healthy subjects. NS-398 was 180-fold more potent in inhibiting monocyte COX-2 activity than platelet TXB2 production. In contrast, aspirin (55 micromol/L) largely suppressed platelet TXB2 production without affecting monocyte COX-2 activity. By using specific Western blot techniques, we failed to detect COX-2 in platelets while COX-1 was readily detectable. Our results argue against the involvement of COX-2 in TX biosynthesis by activated platelets and consequently dispute platelet COX-2 expression as an important mechanism of aspirin resistance.     

Effect of aspirin on nasal resistance to airflow.

The effect of aspirin on nasal resistance to airflow was investigated by rhinomanometry in 25 healthy subjects before and after ingestion of aspirin or vitamin C in a double blind crossover trial. Aspirin caused a significant increase in nasal resistance compared with vitamin C. The effect of aspirin may be due to its inhibition of the synthesis of prostaglandins.     

Aspirin resistance and its implications in clinical practice

Recent studies have suggested that some patients may not obtain the full benefits of aspirin's antiplatelet effects. An international roundtable of experts was held November 6, 2004, in New Orleans, Louisiana, to address the concept of aspirin resistance and its clinical implications. Panelists discussed various definitions and possible mechanisms of aspirin resistance, along with several tests currently available to measure platelet function. They recommended that until the clinical importance of these tests is known, physicians should continue to prescribe low-dose aspirin therapy for individuals at high risk for cardiovascular events and patients currently taking aspirin should continue to comply with their prescribed therapy.     

Controversies and future perspectives of antiplatelet therapy in secondary stroke prevention

Antiplatelet agents are a cornerstone in the treatment of acute arterial thrombotic events and in the prevention of thrombus formation. However, existing antiplatelet agents (mainly aspirin, the combination of aspirin and dipyridamole and clopidogrel) reduce the risk of vascular events only by about one quarter compared with placebo. As a consequence, more efficacious antiplatelet therapies with a reduced bleeding risk are needed. We give an overview of several new antiplatelet agents that are currently investigated in secondary stroke prevention: adenosine 5′-diphosphonate receptor antagonists, cilostazol, sarpogrelate, terutroban and SCH 530348. There are unique features in secondary stroke prevention that have to be taken into account: ischaemic stroke is a heterogeneous disease caused by multiple aetiologies and the blood–brain barrier is disturbed after stroke which may result in a higher intracerebral bleeding risk. Several small randomized trials indicated that the combination of aspirin and clopidogrel might be superior to antiplatelet monotherapy in the acute and early post-ischaemic phase. There is an ongoing debate about antiplatelet resistance. Decreasing response to aspirin is correlated independently with an increased risk of cardiovascular events. However, there is still no evidence from randomized trials linking aspirin resistance and recurrent ischaemic events. Similarly, randomized trials have not demonstrated a clinical significantly decreased antiplatelet effect by the concomitant use of clopidogrel and proton pump inhibitors. Nevertheless, a routine use of this drug combination is not recommended.     

Acetylation and glycation of fibrinogen in vitro occur at specific lysine residues in a concentration dependent manner: a mass spectrometric and isotope labeling study

Aspirin may exert part of its antithrombotic effects through platelet-independent mechanisms. Diabetes is a condition in which the beneficial effects of aspirin are less prominent or absent - a phenomenon called "aspirin resistance". We investigated whether acetylation and glycation occur at specific sites in fibrinogen and if competition between glucose and aspirin in binding to fibrinogen occurs. Our hypothesis was that such competition might be one explanation to "aspirin resistance" in diabetes. After incubation of fibrinogen in vitro with aspirin (0.8 mM, 24 h) or glucose (100 mM, 5-10 days), we found 12 modified sites with mass spectrometric techniques. Acetylations in the α-chain: αK191, αK208, αK224, αK429, αK457, αK539, αK562, in the β-chain: βK233, and in the γ-chain: γK170 and γK273. Glycations were found at βK133 and γK75, alternatively γK85. Notably, the lysine 539 is a site involved in FXIII-mediated cross-linking of fibrin. With isotope labeling in vitro, using [(14)C-acetyl]salicylic acid and [(14)C]glucose, a labeling of 0.013-0.084 and 0.12-0.5 mol of acetylated and glycated adduct/mol fibrinogen, respectively, was found for clinically (12.9-100 μM aspirin) and physiologically (2-8 mM glucose) relevant plasma concentrations. No competition between acetylation and glycation could be demonstrated. Thus, fibrinogen is acetylated at several lysine residues, some of which are involved in the cross-linking of fibrinogen. This may mechanistically explain why aspirin facilitates fibrin degradation. We find no support for the idea that glycation of fibrin(ogen) interferes with acetylation of fibrinogen.     

冠心病患者阿司匹林抵抗发生率与正常人的比较

目的:观察冠心病患者阿司匹林抵抗的发生率是否与正常人群有差异。方法:心内科住院的冠心病病人50例和正常对照组30例每天服用阿司匹林100mg,7天后用二磷酸腺苷(ADP)、花生四烯酸(AA)作为血小板聚集诱导剂检测定血小板聚集率。结果:在50例冠心病患者中,阿司匹林完全抵抗发生率为12%(6/50);阿司匹林半抵抗发生率为26(13/50),阿司匹林敏感率为62%(31/50)。在30例正常对照组中,阿司匹林完全抵抗发生率为13.3%(4/30);阿司匹林半抵抗发生率为26.6%(8/30),阿司匹林敏感率为60.1%(18/30)。结论:冠心病患者阿司匹林抵抗的发生率是与正常人群没有差异。     

Aspirin inhibits serine phosphorylation of IRS-1 in muscle and adipose tissue of septic rats

Whole body insulin resistance has been demonstrated in septic patients and in infected animals. In this study, we demonstrate that sepsis induces insulin resistance and that pretreatment with aspirin inhibits sepsis-induced insulin resistance. Sepsis was observed to lead to serine phosphorylation of IRS-1, a phenomenon which was reversed by aspirin in muscle and WAT, in parallel with a reduction in JNK activity. In addition, our data show an impairment of insulin activation of IR and IRS-1 tyrosine phosphorylation in septic rats and, consistent with the reduction of IRS-1 serine phosphorylation observed in septic animals pretreated with aspirin, there was an increase in IRS-1 protein levels and tyrosine phosphorylation in muscle and WAT. Overall, these results provide important new insights into the mechanism of sepsis-induced insulin resistance.     

Aspirin “resistance” and risk of cardiovascular morbidity: systematic review and meta-analysis

Objective To determine if there is a relation between aspirin “resistance” and clinical outcomes in patients with cardiovascular disease.Design Systematic review and meta-analysis.Data source Electronic literature search without language restrictions of four databases and hand search of bibliographies for other relevant articles.Review methods Inclusion criteria included a test for platelet responsiveness and clinical outcomes. Aspirin resistance was assessed, using a variety of platelet function assays.Results 20 studies totalling 2930 patients with cardiovascular disease were identified. Most studies used aspirin regimens, ranging from 75-325 mg daily, and six studies included adjunct antiplatelet therapy. Compliance was confirmed directly in 14 studies and by telephone or interviews in three. Information was insufficient to assess compliance in three studies. Overall, 810 patients (28%) were classified as aspirin resistant. A cardiovascular related event occurred in 41% of patients (odds ratio 3.85, 95% confidence interval 3.08 to 4.80), death in 5.7% (5.99, 2.28 to 15.72), and an acute coronary syndrome in 39.4% (4.06, 2.96 to 5.56). Aspirin resistant patients did not benefit from other antiplatelet treatment.Conclusion Patients who are resistant to aspirin are at a greater risk of clinically important cardiovascular morbidity long term than patients who are sensitive to aspirin.     

Fault-il mettre en examen les antiplaquettaires et rechercher une résistance à l’aspirine?

Aspirin resistance leading to thrombotic recurrence has been extensively reported in the literature. However, its precise mechanisms and clinical outcomes are largely unknown. In this review, we report the conditions governing this resistance and the various tests proposed to explore it. The usefulness of monitoring aspirin therapy remains a debate.     

Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in growth hormone treated animals

In this study, we demonstrate that pretreatment with aspirin inhibits GH-induced insulin resistance. GH was observed to lead to serine phosphorylation of IRS-1, a phenomenon which was reversed by aspirin in liver, muscle and WAT in parallel with a reduction in JNK activity. In addition, our data show an impairment of insulin activation in the IR/IRS/PI(3)kinase pathway and a reduction in IRS-1 protein levels in rats treated with GH, which was also reversed in the animals pretreated with aspirin. Overall, these results provide new insights into the mechanism of GH-induced insulin resistance.     

Lunasin,a novel seed peptide,sensitizes human breast cancer MDA-MB-231 cells to aspirin-arrested cell cycle and induced apoptosis

Breast cancer is one of the most common tumors in women of Western countries. The high aggressiveness and therapeutic resistance of estrogen-independent breast tumors have motivated the development of new strategies for prevention and/or treatment. Combinations of two or more chemopreventive agents are currently being used to achieve greater inhibitory effects on breast cancer cells. This study reveals that both aspirin and lunasin inhibit, in a dose-dependent manner, human estrogen-independent breast cancer MDA-MB-231 cell proliferation. These compounds arrest the cell cycle in the S- and G1-phases, respectively, acting synergistically to induce apoptosis. To begin elucidating the mechanism(s) of action of these compounds, different molecular targets involved in cell cycle control, apoptosis and signal transduction have been evaluated by real-time polymerase chain reaction (RT-PCR) array. The cell growth inhibitory effect of a lunasin/aspirin combination is achieved, at least partially, by modulating the expression of genes encoding G1 and S-phase regulatory proteins. Lunasin/aspirin therapy exerts its potent pro-apoptotic effect is at least partially achieved through modulating the extrinsic-apoptosis dependent pathway. Synergistic down-regulatory effects were observed for ERBB2, AKT1, PIK3R1, FOS and JUN signaling genes, whose amplification has been reported as being responsible for breast cancer cell growth and resistance to apoptosis. Therefore, our results suggest that a combination of these two compounds is a promising strategy to prevent/treat breast cancer.     

Aspirin promotes tenogenic differentiation of tendon stem cells and facilitates tendinopathy healing through regulating the GDF7/Smad1/5 signaling pathway

Tendinopathy is a common musculoskeletal system disorder in sports medicine, but regeneration ability of injury tendon is limited. Tendon stem cells (TSCs) have shown the definitive treatment evidence for tendinopathy and tendon injuries due to their tenogenesis capacity. Aspirin, as the representative of nonsteroidal anti-inflammatory drugs for its anti-inflammatory and analgestic actions, has been commonly used in treating tendinopathy in clinical, but the effect of aspirin on tenogenesis of TSCs is unclear. We hypothesized that aspirin could promote injury tendon healing through inducing TSCs tenogenesis. The aim of the present study is to make clear the effect of aspirin on TSC tenogenesis and tendon healing in tendinopathy, and thus provide new treatment evidence and strategy of aspirin for clinical practice. First, TSCs were treated with aspirin under tenogenic medium for 3, 7, and 14 days. Sirius Red staining was performed to observe the TSC differentiation. Furthermore, RNA sequencing was utilized to screen out different genes between the induction group and aspirin treatment group. Then, we identified the filtrated molecules and compared their effect on tenogenesis and related signaling pathway. At last, we constructed the tendinopathy model and compared biomechanical changes after aspirin intake. From the results, we found that aspirin promoted tenogenesis of TSCs. RNA sequencing showed that growth differentiation factor 6 (GDF6), GDF7, and GDF11 were upregulated in induction medium with the aspirin group compared with the induction medium group. GDF7 increased tenogenesis and activated Smad1/5 signaling. In addition, aspirin increased the expression of TNC, TNMD, and Scx and biomechanical properties of the injured tendon. In conclusion, aspirin promoted TSC tenogenesis and tendinopathy healing through GDF7/Smad1/5 signaling, and this provided new treatment evidence of aspirin for tendinopathy and tendon injuries.     

Dual antiplatelet therapy in patients with aspirin resistance following coronary artery bypass grafting: study protocol for a randomized controlled trial [NCT01159639

ABSTRACT: BACKGROUND: Coronary artery disease remains the dominant cause of mortality in developed countries. While platelets have been recognized to play a pivotal role in atherothrombosis, the ideal antiplatelet regime after coronary artery surgery remains elusive.The evolution of CABG has presently moved beyond technical improvements to involve modulation of pharmacologic management designed to improve patient outcomes. The aim of this trial will be to test the hypothesis that the addition of clopidogrel to patients with documented postoperative aspirin resistance will reduce the incidence of major cardiovascular events. METHODS: Patients scheduled for isolated coronary artery surgery will be eligible for the study. Patients in whom postoperative multiple electrode aggregometry documents aspirin resistance will be randomized into two groups. The control group will receive 300 mg of aspirin. The dual antiplatelet group will receive 75 mg of clopidogrel in addition to 300 mg of aspirin. Patients will be followed for 6 months. Major adverse cardiac and cerebrovascular events (death from any cause, myocardial infarction, stroke, hospitalization due to cardiovascular pathology) as well as bleeding events will be recorded. DISCUSSION: This will be the first trial that will specifically address the issue of dual antiplatelet therapy in patients undergoing coronary artery surgery who have been found to be aspirin resistant. In the event that the addition of clopidogrel proves to be beneficial in this subset of surgical patients, this study could significantly impact their future antiplatelet management.This randomized controlled trial has been registered at the ClinicalTrials.gov website (Identifier NCT01159639).     

Combination of aspirin with telmisartan suppresses the augmented TGFβ/smad signaling during the development of streptozotocin-induced type I diabetic nephropathy

Diabetic nephropathy (DN) is the most common indication for the development of end stage renal diseases. Inflammation is increasingly seen as the core process in the development of diabetes. Inflammatory markers e.g. NFκB (p65 levels), TNFα, COX-2 and TGFβ–smad signaling are the key elements in the development of DN. Renin–angiotensin system suppressors like telmisartan have been used to treat DN, but they are not able to prevent completely because of development of resistance against them. Anti-inflammatory agents like, aspirin acts through both COX dependent and COX independent pathways. Hence, we thought that combining aspirin with telmisartan will be better therapeutic option in preventing the progression of nephropathy in diabetes. In the present study we studied the effect of this combination on inflammatory markers [COX-2, NFκB (p65 levels), TNFα], TGFβ–smad expression in preventing the progression of streptozotocin-induced type I diabetic nephropathy. Treatment of aspirin significantly prevented the progression of nephropathy and inhibited the augmented COX-2, NFκB (p65 levels), TNFα, and TGFβ–smad expression. Combination of aspirin with telmisartan resulted in a further decrease in the development of nephropathy and inflammatory markers in comparison to aspirin alone treatment. This is the first report which shows that aspirin in combination with telmisartan is more proficient in the treatment of diabetic nephropathy than any single drug therapy and involves the change in expression of inflammatory markers and TGFβ–smad signaling.     

Cost effectiveness of primary stroke prevention in atrial fibrillation: Swedish national perspective.

OBJECTIVE--To assess the potential effects of primary prevention with anticoagulants or aspirin in atrial fibrillation on Swedish population. DESIGN--Analysis of cost effectiveness based on the following assumptions: about 83,000 people have atrial fibrillation in Sweden, of whom 22,000 would be potential candidates for treatment with anticoagulants and 55,000 for aspirin treatment; the annual 5% stroke rate is reduced by 64% (with anticoagulants) and 25% (with aspirin); incidence of intracranial haemorrhage of 0.3%, 1.3%, or 2.0% per year; direct and indirect costs of a stroke of Kr180,000 and Kr90,000; estimated annual cost of treatment is Kr5030 for anticoagulants and Kr100 for aspirin. SETTING--Total Swedish population. MAIN OUTCOME MEASURES--Direct and indirect costs of stroke saved, number of strokes prevented, and cost of preventive treatment. RESULTS--Depending on the rate of haemorrhagic complications 34 to 83 patients would need to be treated annually with anticoagulants to prevent one stroke; 83 patients would need to be treated with aspirin. Giving anticoagulant treatment only would reduce costs by Kr60 million if the incidence of intracranial haemorrhage were 0.3% but would imply a net expense if the complication rate exceeded 1.3%. The total savings from giving anticoagulant (22,000 patients) and aspirin (55,000 patients) treatment would be Kr175 million per year corresponding to 2 million pounds per million inhabitants each year. CONCLUSIONS--Treatment with anticoagulants and, if contraindications exist, with aspirin is cost effective provided that the risk of serious haemorrhage complications due to anticoagulants is kept low.     

中国老年心脑血管疾病患者阿司匹林抵抗与环氧化酶-1单体型关联分析

目的:旨在研究老年心脑血管病患者阿司匹林抵抗与阿司匹林作用靶点环氧化酶-1(COX-1)基因单体型的关联性。方法:入选北京地区服用阿司匹林的老年汉族心脑血管疾病患者431例,通过花生四烯酸诱导光比浊法,筛选出阿司匹林抵抗患者59例作为病例组,372例阿司匹林不抵抗者作为对照组,使用美国Sequenom系统SNP分型技术鉴定了COX-1基因6个常见单核苷酸多态性位点(SNP)与阿司匹林抵抗的关联性。6个SNP分别是:rs1888943(8759C/T)、rs1330344(1676A/G)、rs3842787(exon 2,50C/T,p.Pro17Leu)、rs5787(exon 4,323G/A,p.Arg108Gln)、rs5789(exon7,709C/A,p.Leu237Met)和rs5794(exon10,1330G/A,p.Val481Ile)。结果:突变COX-1单体型CGCGCC,在病例组频率为0.48(57/118),对照组频率为0.39(286/742),显著高于对照组(P≤0.05)。结论:中国老年汉族心脑血管疾病患者阿司匹林抵抗与COX-1单体型相关联,突变COX-1单体型CGCGCC显著增加了阿司匹林抵抗的发病风险。     

Aspirin inhibits adipogenesis of tendon stem cells and lipids accumulation in rat injury tendon through regulating PTEN/PI3K/AKT signalling

Tendon injury repairs are big challenges in sports medicine, and fatty infiltration after tendon injury is very common and hampers tendon injury healing process. Tendon stem cells (TSCs), as precursors of tendon cells, have shown promising effect on injury tendon repair for their tenogenesis and tendon extracellular matrix formation. Adipocytes and lipids accumulation is a landmark event in pathological process of tendon injury, and this may induce tendon rupture in clinical practice. Based on this, it is important to inhibit TSCs adipogenesis and lipids infiltration to restore structure and function of injury tendon. Aspirin, as the representative of non‐steroidal anti‐inflammatory drugs (NSAIDs), has been widely used in tendon injury for its anti‐inflammatory and analgesic actions, but effect of aspirin on TSCs adipogenesis and fatty infiltration is still unclear. Under adipogenesis conditions, TSCs were treated with concentration gradient of aspirin. Oil red O staining was performed to observe changes of lipids accumulation. Next, we used RNA sequencing to compare profile changes of gene expression between induction group and aspirin‐treated group. Then, we verified the effect of filtrated signalling on TSCs adipogenesis. At last, we established rat tendon injury model and compared changes of biomechanical properties after aspirin treatment. The results showed that aspirin decreased lipids accumulation in injury tendon and inhibited TSCs adipogenesis. RNA sequencing filtrated PTEN/PI3K/AKT signalling as our target. After adding the signalling activators of VO‐Ohpic and IGF‐1, inhibited adipogenesis of TSCs was reversed. Still, aspirin promoted maximum loading, ultimate stress and breaking elongation of injury tendon. In conclusion, by down‐regulating PTEN/PI3K/AKT signalling, aspirin inhibited adipogenesis of TSCs and fatty infiltration in injury tendon, promoted biomechanical properties and decreased rupture risk of injury tendon. All these provided new therapeutic potential and medicine evidence of aspirin in treating tendon injury and tendinopathy.     

The Association of Four Common Polymorphisms from Four Candidate Genes (COX-1, COX-2, ITGA2B,ITGA2) with Aspirin Insensitivity: A Meta-Analysis

Objective

Evidence is mounting suggesting that a strong genetic component underlies aspirin insensitivity. To generate more information, we aimed to evaluate the association of four common polymorphisms (rs3842787, rs20417, rs201184269, rs1126643) from four candidate genes (COX-1, COX-2, ITGA2B, ITGA2) with aspirin insensitivity via a meta-analysis.

Methods and Results

In total, there were 4 (353/595), 6 (344/698), 10 (588/878) and 7 (209/676) articles (patients/controls) qualified for rs3842787, rs20417, rs20118426 and rs1126643, respectively. The data were extracted in duplicate and analyzed by STATA software (Version 11.2). The risk estimate was expressed as odds ratio (OR) and 95% confidence interval (95% CI). Analyses of the full data set indicated significant associations of rs20417 (OR; 95% CI; P: 1.86; 1.44–2.41; <0.0005) and rs1126643 (2.37; 1.44–3.89; 0.001) with aspirin insensitivity under allelic model. In subgroup analyses, the risk estimate for rs1126643 was greatly potentiated among patients with aspirin semi-resistance relative to those with aspirin resistance, especially under dominant model (aspirin semi-resistance: 5.44; 1.42–20.83; 0.013 versus aspirin resistance: 1.96; 1.07–3.6; 0.03). Further grouping articles by ethnicity observed a stronger prediction of all, but rs20417, examined polymorphisms for aspirin insensitivity in Chinese than in Caucasians. Finally, meta-regression analyses observed that the differences in percentage of coronary artery disease (P = 0.034) and averaged platelet numbers (P = 0.012) between two groups explained a large part of heterogeneity for rs20417 and rs1126643, respectively.

Conclusion

Our findings provide strong evidence that COX-2 and ITGA2 genetic defects might increase the risk of having aspirin insensitivity, especially for aspirin semi-resistance and in Chinese populations.     

Resistance to apoptosis is a mechanism of adaptation of rat stomach to aspirin

Adaptation of the gastric mucosa to nonsteroidal anti-inflammatory drug-induced injury is a well-documented phenomenon, but the mechanisms are not known. We investigated whether changes in stress protein expression and apoptosis play roles in adaptation of rat stomach to aspirin. RT-PCR and Western blotting techniques were used to analyze mRNA and protein expression of HSP72 and HSP90 and cleavage of caspase 3 protein. Apoptosis was detected by the TUNEL method and quantified. HSP72 mRNA and protein expression was unchanged in adapted mucosa, whereas HSP90 mRNA and protein levels decreased. Caspase 3 protein was activated, and the number of apoptotic cells increased in mucosa after one aspirin dose. However, in adapted mucosa after aspirin, activated caspase 3 and the number of apoptotic cells had returned to basal levels. Induction of the stress response was found not to be a mechanism of mucosal adaptation against multiple doses of aspirin. Our results lead us to propose instead that resistance to aspirin-induced apoptosis plays a role in the protective phenomenon of adaptation.