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Results for “Protein Aggregation, Pathological”

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PubMed2006

Reduction of soluble Abeta and tau, but not soluble Abeta alone, ameliorates cognitive decline in transgenic mice with plaques and tangles.

Increasing evidence points to soluble assemblies of aggregating proteins as a major mediator of neuronal and synaptic dysfunction. In Alzheimer disease (AD), soluble amyloid-beta (Abeta) appears to be a key factor in inducing synaptic and cognitive abnormalities. Here we report the novel finding that soluble tau also plays a role in the cognitive decline in the presence of concomitant Abeta pathology. We describe improved cognitive function following a reduction in both soluble Abeta and tau levels after active or passive immunization in advanced aged 3xTg-AD mice that contain both amyloid plaques and neurofibrillary tangles (NFTs). Notably, reducing soluble Abeta alone did not improve the cognitive phenotype in mice with plaques and NFTs. Our results show that Abeta immunotherapy reduces soluble tau and ameliorates behavioral deficit in old transgenic mice.

Alzheimer Disease↗

PubMed1986

Vascular aspects and hemodynamic consequences of central nervous system injury.

We document here microvascular alterations occurring in models of mild, moderate, and severe cerebral ischemic injury. The relationship of the vascular abnormalities to the generation of hemodynamic alterations was also evaluated. Following periods of severe incomplete ischemia, scanning electron microscopic analysis of cerebral microvessels revealed the widespread production of cerebral endothelial microvilli. These microvilli increased in frequency as the ischemic insult was prolonged and remained prominent during periods of recirculation. Although these luminal projections would not be expected to inhibit reperfusion completely, they might increase microvascular resistance, leading to moderate hemodynamic impediments extending into the post-ischemic period. Similar periods of complete ischemia resulted in more severe microvascular alterations. Light and electron microscopic studies revealed a high frequency of compressed capillary lumina with vascular stasis. These compressed vessels were consistently surrounded by swollen astrocytic foot processes. When recirculation was instituted for 1 hr following 1 hr of complete ischemia, regions of non-perfusion were detected autoradiographically within brain regions destined to undergo ischemic infarction. Finally, in an attempt to determine the consequences of a primary microvascular insult on brain structure and function, the endothelial layer of microvessels in the cerebral cortex was injured using a noninvasive photochemical method. Endothelial damage led to platelet aggregation in both pial and intraparenchymal vessels. Occlusive thrombi were frequently detected with perivascular edema associated with vascular compression and severe focal ischemia. Ultrastructural blood-brain barrier studies using the horseradish peroxidase tracer demonstrated that protein leakage at the site of primary vascular injury resulted in tracer material in brain regions remote from the pathological lesion. The widespread leakage of protein tracer was associated with decreased blood flow in remote brain regions at several postirradiation periods. These data emphasize the importance of injury-induced microvascular dysfunction in the generation of brain lesions and hemodynamic abnormalities.

Animals↗

PubMed2006

Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.

Protein aggregation is an established pathogenic mechanism in Alzheimer's disease, but little is known about the initiation of this process in vivo. Intracerebral injection of dilute, amyloid-beta (Abeta)-containing brain extracts from humans with Alzheimer's disease or beta-amyloid precursor protein (APP) transgenic mice induced cerebral beta-amyloidosis and associated pathology in APP transgenic mice in a time- and concentration-dependent manner. The seeding activity of brain extracts was reduced or abolished by Abeta immunodepletion, protein denaturation, or by Abeta immunization of the host. The phenotype of the exogenously induced amyloidosis depended on both the host and the source of the agent, suggesting the existence of polymorphic Abeta strains with varying biological activities reminiscent of prion strains.

Aged↗

PubMed2004

Influence of cell-specific factors on red blood cell aggregation.

The reversible aggregation of red blood cells (RBC) into linear and three-dimensional structures continues to be of basic science and clinical interest: RBC aggregation affects low shear blood viscosity and microvascular flow dynamics, and can be markedly enhanced in several clinical states. Until fairly recently, most research efforts were focused on relations between suspending medium composition (i.e., protein levels, polymer type and concentration) and aggregate formation. However, there is now an increasing amount of experimental evidence indicating that RBC cellular properties can markedly affect aggregation, with the term "RBC aggregability" coined to describe the cell's intrinsic tendency to aggregate. Variations of aggregability can be large, with some changes of aggregation substantially greater than those resulting from pathologic states. The present review provides a brief overview of this topic, and includes such areas as donor-to-donor variations, polymer-plasma correlations, effects of RBC age, effects of enzymatic treatment, and current developments related to the mechanisms involved in RBC aggregation.

Adult↗

PubMed2003

On noxious desmin: functional effects of a novel heterozygous desmin insertion mutation on the extrasarcomeric desmin cytoskeleton and mitochondria.

Recent studies in desmin (-/-) mice have shown that the targeted ablation of desmin leads to pathological changes of the extrasarcomeric intermediate filament cytoskeleton, as well as structural and functional abnormalities of mitochondria in striated muscle. Here, we report on a novel heterozygous single adenine insertion mutation (c.5141_5143insA) in a 40-year-old patient with a distal myopathy. The insertion mutation leads to a frameshift and a truncated desmin (K239fs242). Using transfection studies in SW13 and BHK21 cells, we show that the K239fsX242 desmin mutant is incapable of forming a desmin intermediate filament network. Furthermore, it induces the collapse of a pre-existing desmin cytoskeleton, alters the subcellular distribution of mitochondria and leads to abnormal cytoplasmic protein aggregates reminiscent of desmin-immunoreactive granulofilamentous material seen in the ultrastructural analysis of the patient's muscle. Analysis of mitochondrial function in isolated saponin-permeablized skeletal muscle fibres from our patient showed decreased maximal rates of respiration with the NAD-dependent substrate combination glutamate and malate, as well as a higher amytal sensitivity of respiration, indicating an in vivo inhibition of complex I activity. Our findings suggest that the heterozygous K239fsX242 desmin insertion mutation has a dominant negative effect on the polymerization process of desmin intermediate filaments and affects not only the subcellular distribution, but also biochemical properties of mitochondria in diseased human skeletal muscle. As a consequence, the intermediate filament pathology-induced mitochondrial dysfunction may contribute to the degeneration/regeneration process leading to progressive muscle dysfunction in human desminopathies.

Adenine↗

PubMedDate not supplied

Effect of serum amyloid A, HDL-apolipoprotein, on endothelial cell proliferation. Implication of an enigmatic protein to atherosclerosis.

The possible contribution of apo-HDL serum amyloid A (SAA) to the protective effect of HDL against atherosclerosis was studied by evaluating its effect on bovine aortic endothelial cell (BAEC) proliferation. Our results suggest that human SAA, both purified and recombinant, in concentrations relevant to mild acute phase events, significantly inhibit endothelial cell proliferation in a dose-dependent manner (e.g., 50 micrograms/ml causes approximately 88% inhibition; p < 0.001). This inhibition was attenuated by addition of fibroblast growth factor (FGF), which antagonized the SAA-mediated effect. As levels of TNF may be highly elevated during the acute phase response, its effect on BAEC proliferation was evaluated and found, at concentrations of > 1 pg/ml, to be substantially inhibitory Co-incubation of cells with both SAA and TNF was inhibitory, albeit neither additive nor synergistic. FGF antagonized the effect of both proteins. Amyloidic deposit (AA, i.e. SAA 1-76), derived from pathological proteolysis of SAA, practically retains the inhibitory activity (e.g. 50 micrograms/ml causes approximately 66% inhibition; p < 0.001) but apparently lacks the regulatory site towards FGF. In contrast to the above inhibitory effect, synthetic SAA-related peptide corresponding to the sequence 29-33 of SAA enhances BAEC proliferation (50 micrograms/ml causes approximately 64% increase; p < 0.001). The present data, coupled with our previous observations in which SAA was found to induce endothelial PGI2 formation and to inhibit overproduction of PGI2 by TNF and LPS as well as platelet aggregation, may suggest that SAA contributes to the protective effect of HDL against atherosclerosis. This, by means of its modulatory effect on endothelial cell and platelet activation, primarily in the presence of other regulatory proteins. SAA-derived peptides may, potentially, be used as therapeutic agents in the treatment of atherosclerosis and cardiovascular diseases.

Amino Acid Sequence↗

PubMed2006

Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson's disease.

To date there is no accepted clinical diagnostic test for Parkinson's disease (PD) based on biochemical analysis of blood or cerebrospinal fluid (CSF). alpha-Synuclein (alpha-syn) protein has been linked to the pathogenesis of PD with the discovery of mutations in the gene encoding alpha-syn in familial cases with early-onset PD. Lewy bodies and Lewy neurites, which constitute the main pathological features in the brains of patients with sporadic PD and dementia with Lewy bodies, are formed by the conversion of soluble monomers of alpha-syn into insoluble aggregates. We recently reported the presence of alpha-syn in normal human blood plasma and in postmortem CSF. Here, we investigated whether alpha-syn can be used as a biomarker for PD. We have developed a novel ELISA method that detects only oligomeric "soluble aggregates" of alpha-syn. Using this ELISA, we report the presence of significantly elevated (P=0.002) levels of oligomeric forms of alpha-syn in plasma samples obtained from 34 PD patients compared with 27 controls; 52% (95% confidence intervals 0.353-0.687) of the PD patients displayed signals >0.5 OD with our ELISA assay in comparison to only 14.8% (95% confidence intervals 0.014-0.281) for the control cases. An analysis of the test's diagnostic value revealed a specificity of 0.852 (95% confidence intervals 0.662-0.958), sensitivity of 0.529 (95% confidence intervals 0.351-0.702) and a positive predictive value of 0.818 (95% confidence intervals 0.597-0.948). These observations offer new opportunities for developing diagnostic tests for PD and related diseases and for testing therapeutic agents aimed at preventing or reversing the aggregation of alpha-syn.

Aged↗

PubMed2005

Tissue plasminogen activator mediates amyloid-induced neurotoxicity via Erk1/2 activation.

Tissue plasminogen activator (tPA) is the main activator of plasminogen into plasmin in the brain where it may have beneficial roles but also neurotoxic effects that could be plasmin dependent or not. Little is known about the substrates and pathways that mediate plasmin-independent tPA neurotoxicity. Here we show in primary hippocampal neurons that tPA promotes a catalytic-independent activation of the extracellular regulated kinase (Erk)1/2 signal transduction pathway through the N-methyl-D-aspartate receptor, G-proteins and protein kinase C. This results in GSK3 activation in a process that requires de novo synthesis of proteins, and leads to tau aberrant phosphorylation, microtubule destabilization and apoptosis. Similar effects are produced by amyloid aggregates in a tPA-dependent manner, as demonstrated by pharmacological treatments and in wt and tPA-/- mice neurons. Consistently, in Alzheimer's disease (AD) patients' brains, high levels of tPA colocalize with amyloid-rich areas, activated Erk1/2 and phosphorylated tau. This is the first demonstration of an intracellular pathway by which tPA triggers kinase activation, tau phosphorylation and neurotoxicity, suggesting a key role for this molecule in AD pathology.

Alzheimer Disease↗

PubMed2006

Abnormal prion accumulation associated with retinal pathology in experimentally inoculated scrapie-affected sheep.

The purpose of this study was to characterize the patterns of PrP(Sc) immunoreactivity in the retinae of scrapie-affected sheep and to determine the extent of retinal pathology as indicated by glial fibrillary acidic protein immunoreactivity (GFAP-IR) of Müller glia. Sections from the retina of 13 experimentally inoculated scrapie-affected and 2 negative control sheep were examined with immunohistochemical staining for PrP(Sc), GFAP, and PrP(Sc)/GFAP double staining. GFAP-IR of Müller glia is suggestive of retinal pathology in the absence of morphologic abnormality detected by light microscopy. Sheep with the least amount of PrP(Sc) in the retina have multifocal punctate aggregates of prion staining in the outer half of the inner plexiform layer and rarely in the outer plexiform layer. In these retinae, GFAP-IR is not localized with prion accumulation, but rather is present in moderate numbers of Müller glia throughout the sections of retina examined. The majority of sheep with retinal accumulation of PrP(Sc) have intense, diffuse PrP(Sc) staining in both plexiform layers, with immunoreactivity in the cytoplasm of multiple ganglion cells and lesser amounts in the optic fiber layer and between nuclei in nuclear layers. This intense PrP(Sc) immunoreactivity is associated with diffuse, intense GFAP-IR that extends from the inner limiting membrane to the outer limiting membrane. This is the first report of a prion disease in a natural host that describes the accumulation of PrP(Sc) in retina associated with retinal pathology in the absence of overt morphologic changes indicative of retinal degeneration.

Animals↗

PubMed2005

Isoform-specific interactions of human apolipoprotein E to an intermediate conformation of human Alzheimer amyloid-beta peptide.

Brain plaque deposits of amyloid-beta peptide (Abeta) is a pathological hallmark of Alzheimer's disease (AD) and apolipoprotein E (apoE) is thought to be involved in its deposition. One hypothesis for the role of apoE in the pathogenesis of AD is that apoE may be involved in deposition or clearance of Abeta by direct protein-to-protein interaction. Lipidated apoE4 bound preferentially to an intermediate aggregated form of Abeta and formed two- to three-fold more binding complexes than isoforms apoE2 or apoE3. The interaction was detected by a sandwich ELISA with capture antibodies specific for the N-terminus of apoE, whereas the interaction was not recognized with a C-terminal antibody. The observations indicate that the C-terminus of apoE4 interacts with the intermediate form of Abeta. The differential risk of AD related to apoE genotype may be the result of an enhanced capacity of apoE4 binding to an intermediate aggregated form of Abeta.

Amyloid beta-Peptides↗

PubMed2001

DNA technology, the clinical laboratory, and the future.

OBJECTIVE: To review the advances in clinically useful molecular biological techniques and their applications in clinical practice as presented at the Ninth Annual William Beaumont Hospital DNA Symposium. DATA SOURCES: The 10 manuscripts submitted were reviewed and their major findings were compared with literature on the same topic. STUDY SELECTION: One manuscript reviewed the development of pharmacogenetics, 3 described analytic approaches to detect aneuploidy or cancer, 1 described transcription factor E2F-1 increase during apoptosis, 2 reported on genetic and pharmacologic factors that influence platelet aggregation, 2 described molecular methods for detecting long QT syndrome or mycobacteria, and 1 reported a modification in collection of buccal DNA. DATA SYNTHESIS: Genomic and proteomic approaches to develop clinically useful assays have been successful. Aneuploidy can be easily detected by comparative genomic hybridization, which does not require cell culture like cytogenetics. Mutations have been characterized for a variety of hereditary cancer syndromes, 2 inherited long QT syndromes, and thromboembolism. PlA1 and PlA2 polymorphisms in platelets are associated with a difference in aggregation inhibition by estrogen, another example of genotypic pharmacogenetics. Protein expression differences may define colorectal cancer stage and explain apoptotic signal transduction. Mycobacterial detection by nucleic acid amplification and simplified buccal DNA collection demonstrate cost-effective strategies. CONCLUSION: The working draft of the Human Genome Project is completed and the number of clinically useful molecular pathologic techniques and assays will expand as additional disease-associated mutations are defined. Expanded use of database software for genomic and proteomic screening should increase the efficiency of clinical useful assay development.

Biotechnology↗

PubMed1990

[Study on the variation of relaxation time in diabetic cataractous lenses of rats by using NMRA].

Nuclear magnetic resonance analysis (NMRA) was used to measure the relaxation time T1 and T2 of the protons in the different-stage-diseased lenses of rats with diabetic cataract caused by the streptozotocin, and the results were put in comparison with those obtained from the control group, showing that after one month of medication the values of T1 and T2 in the cataractous lenses are greater than those gained from the control group. The variation, as time goes on, becomes greater and greater. T1 and T2 indicate the speed of the free induction decay (FID) signals, and the variation of the FID signals are in direct proportion to that of the proton content of the samples. This shows that an increase in T1 and T2 indicates an increase in the water content in the diseased lenses, and the changes in ratio of "bound" water to free water. Such changes may be explained that the space for "bound" water is occupied by some other macromolecules, causing the alteration of the macromolecular structure, and consequently the aggregation of protein and the degeneration or dehydration or dehydration of the membrane occur, which may give rise to another scattering centre. So the scattering of the lens increases and its transparency decreases. This result is in agreement with some reports in the medical literature. As T1 and T2 are quite different in the normal and pathological tissues, and the protons are the most extensive nucleus in all biological tissues, NMR is a very important method to determine the proton relaxation time in the biological tissue and to judge if it is normal or not.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Protein fluorescence and its relationship to free radical activity.

Evidence for free radical involvement in pathological processes is often indirect and frequently depends upon the detection of characteristic changes in tissue constituents, particularly polyunsaturated lipids. Free radical attack on protein leads to specific oxidative changes in their constituent amino acids, principally cysteine, tryptophan and tyrosine. This is associated with the induction of characteristic fluorescence (excitation 360 nm, emission 454 nm) and protein aggregation. This observation leads to a suitable assay for studying protein oxidation, and such fluorescent proteins may be relevant in the pathogenesis of diabetic microangiopathy and rheumatoid arthritis.

Arthritis, Rheumatoid↗

PubMed1995

Extracellular matrix, supramolecular organisation and shape.

Connective tissue function is defined as the formation and maintenance of shape, without which centralised physiologies (circulatory, digestive or nervous) could not have evolved. Two elements, inextensible (collagenous) fibrils and compression-resistant interfibrillar soluble polymers (proteoglycans), cope with all usual stresses. Relationships between the two are highly specific, as demonstrated by electron histochemistry based on Cupromeronic blue and critical electrolyte concentration (CEC) methodologies. Recent ideas on (1) the protofibrillar or modular structure of collagen fibrils, (2) the nature of specific binding sites for proteoglycans on fibrils, and (3) fundamental similarities in secondary and tertiary structures of the glycosaminoglycans (hyaluronan, chondroitin, keratan and dermatan sulphates) are described. They have greatly illuminated the study of extracellular matrix structure and function in normal, pathological (osteogenesis imperfecta) and ageing tissues. The small proteoglycans are proposed to be tissue organisers, orienting and ordering the collagen fibrils--thus shaping the tissue at a molecular and ultimately macro level. These interfibrillar structures are based on their bifunctional character, the protein parts binding to collagen fibrils at specific sites and the glycosaminoglycans duplexing and aggregating to hold the proteins and hence the collagen fibrils at defined distances from each other, rather like yardsticks. Examples of the way these functions work in specific tissues are drawn from the cornea and vitreous humour of the eye and developing tendon.

Animals↗

PubMed2005

LDL receptor-related protein and the vascular wall: implications for atherothrombosis.

LDL receptor-related protein 1 (LRP1) is highly expressed in the vascular wall and is mainly associated with macrophages and vascular smooth muscle cells (VSMCs). Overexpression of LRP1 in atherosclerotic lesions has been demonstrated in several animal models and human lesions. Clinical studies have suggested a relation between alterations in LRP1 expression and coronary heart disease. Indeed, it has been demonstrated that LRP1 gene expression is increased in blood mononuclear cells from patients with coronary obstruction and that the LRP1 mRNA-protein expression ratio is altered in coronary patients. Taken together, these results seem to suggest that LRP1 may be a pivotal receptor in the etiology of atherosclerosis. Our group has contributed to the elucidation of the physiopathologic role of LRP1 in the vascular wall by demonstrating that LRP1-mediated, matrix-retained LDL internalization could be crucial for VSMC-foam cell formation, that LRP1 is upregulated by lipid during human atherosclerotic lesion progression, and that LRP1-mediated aggregated LDL uptake causes the prothrombotic transformation of the vascular wall. Therefore, LRP1 seems to play a pathologic function during atherosclerotic lesion progression; however, LRP1 also seems to be essential for embryonic development and for the maintenance of vascular integrity. The protective effect of LRP1 in the vessel wall seems to be mainly due to its role in controlling certain signaling pathways. In this review, we will focus on the description of the main physiopathologic functions of LRP1 in the vascular wall.

Arteriosclerosis↗

PubMed1998

What do we learn from a few familial Alzheimer's disease cases?

Alzheimer's disease is the most common form of dementia. About 90% of the cases occur sporadically whereas in 10% of the cases mutations were found within three different genes. Mutations in the gene encoding the beta-Amyloid precursor protein (beta APP) are located in the ultimate neighborhood of the three proteases (secretases) involved in proteolytic processing of beta APP. These mutations cause an increased production of the long form of Amyloid beta-peptide (A beta) the major component of Amyloid plaques. In contrast to the 40 amino acid form (A beta 40), the 42 amino acid form (A beta 42) aggregates more rapidly, kills cultured neurons more efficiently, and precipitates preferentially in amyloid plaques. Interestingly, mutations in the Presenilin genes which are responsible for more then 40% of all familial AD cases also cause enhanced production of the elongated form of A beta. Therefore mutations in three different genes directly effect A beta production in a pathological manner, which strongly supports the amyloid cascade hypothesis.

Alzheimer Disease↗

PubMed2005

Trehalose differentially inhibits aggregation and neurotoxicity of beta-amyloid 40 and 42.

A key event in Alzheimer's disease (AD) pathogenesis is the conversion of the peptide beta-amyloid (Abeta) from its soluble monomeric form into various aggregated morphologies in the brain. Preventing aggregation of Abeta is being actively pursued as a primary therapeutic strategy for treating AD. Trehalose, a simple disaccharide, has been shown to be effective in preventing the deactivation of numerous proteins and in protecting cells against stress. Here, we show that trehalose is also effective in inhibiting aggregation of Abeta and reducing its cytotoxicity, although it shows differential effects toward Abeta40 and Abeta42. When co-incubated with Abeta40, trehalose inhibits formation of both fibrillar and oligomeric morphologies as determined by fluorescence staining and atomic force microscopy (AFM). However, when co-incubated with Abeta42, trehalose inhibits formation only of the fibrillar morphology, with significant oligomeric formation still present. When aggregated mixtures were incubated with SH-SY5Y cells, trehalose was shown to reduce the toxicity of Abeta40 mixtures, but not Abeta42. These results provide additional evidence that aggregation of Abeta into soluble oligomeric forms is a pathological step in AD and that Abeta42 in particular is more susceptible to forming these toxic oligomers than Abeta40. These results also suggest that the use of trehalose, a highly soluble, low-priced sugar, as part of a potential therapeutic cocktail to control Abeta peptide aggregation and toxicity warrants further study.

Alzheimer Disease↗

PubMed1997

Relation of neuronal endoplasmic reticulum calcium homeostasis to ribosomal aggregation and protein synthesis: implications for stress-induced suppression of protein synthesis.

Results from experiments performed with permanent non-neuronal cell lines suggest that endoplasmic reticulum (ER) calcium homeostasis plays a key role in the control of protein synthesis (PS). It has been concluded that disturbances in ER calcium homeostasis may contribute to the suppression of PS triggered by a severe metabolic stress (W. Paschen, Med. Hypoth., 47 (1996) 283-288). To elucidate how an emptying of ER calcium stores of these cells would effect PS and ribosomal aggregation of non-transformed fully differentiated cells, experiments were run on primary neuronal cell cultures. ER calcium stores were depleted by treating cells with thapsigargin (TG, a selective, irreversible inhibitor of ER Ca(2+)-ATPase), cyclopiazonic acid (CPA, a reversible inhibitor of ER Ca(2+)-ATPase), or caffeine (an agonist of ER ryanodine receptor). Changes in intracellular calcium activity were evaluated by fluorescence microscopy using fura-2-loaded cells. Protein synthesis was determined by measuring the incorporation of [3H]leucine into proteins. The degree of aggregation of ribosomes was evaluated by electron microscopy. TG induced a permanent inhibition of PS to about 10% of control which was only partially reversed within 2 h of recovery. CPA caused about 70% inhibition of PS, and PS recovered completely 60 min after treatment. Caffeine produced an inhibition of PS to about 50% of control. Loading cells with the calcium chelator BAPTA-AM (33.3 microM) alone suppressed PS without reversing TG- or caffeine-induced inhibition of PS, indicating that the suppression of PS was caused by a depletion of ER calcium stores and not by an increase in cytosolic calcium activity. TG-treatment of cells induced a complete disaggregation of polysomes which was not reversed within the 4 h recovery period following TG-treatment. After caffeine treatment of cells, we observed a heterogenous pattern of ribosomal aggregation: in some neurons ribosomes were almost completely aggregated while in other cells a significant portion of polyribosomes were disaggregated. The results indicate that a depletion of neuronal ER calcium stores disturbs protein synthesis in a similar way to the effects of transient forms of metabolic stress (ischemia, hypoglycemia or status epilepticus), thus implying that a disturbance in ER calcium homeostasis may contribute to the pathological process of stress-induced cell injury.

Animals↗