Chronic obstructive pulmonary disease: molecular and cellular mechanisms.

Chronic obstructive pulmonary disease is a leading cause of death and disability, but has only recently been extensively explored from a cellular and molecular perspective. There is a chronic inflammation that leads to fixed narrowing of small airways and alveolar wall destruction (emphysema). This is characterised by increased numbers of alveolar macrophages, neutrophils and cytotoxic T-lymphocytes, and the release of multiple inflammatory mediators (lipids, chemokines, cytokines, growth factors). A high level of oxidative stress may amplify this inflammation. There is also increased elastolysis and evidence for involvement of several elastolytic enzymes, including serine proteases, cathepsins and matrix metalloproteinases. The inflammation and proteolysis in chronic obstructive pulmonary disease is an amplification of the normal inflammatory response to cigarette smoke. This inflammation, in marked contrast to asthma, appears to be resistant to corticosteroids, prompting a search for novel anti-inflammatory therapies that may prevent the relentless progression of the disease.     

Mitochondria in aging and Alzheimer's disease

Two significant risk factors are inextricably linked with Alzheimer's disease: advancing age, and accumulation of the amyloid-beta peptide. Over the age of 65 the risk of developing Alzheimer's disease increases almost exponentially with age, and the amyloid-beta rich neuritic plaques of the Alzheimer's disease brain are a histopathological hallmark of the disease. Since its identification as a major constituent of neuritic plaques amyloid-beta has attracted intense research focus as the primary causative agent in the development of Alzheimer's disease. As a result, numerous reports now exist to propose potential neurotoxic mechanisms mediated by amyloid-beta. Despite these research efforts, there is still a scarcity of information on the biologic link between aging and amyloid-beta in Alzheimer's disease, and although increasing evidence indicates that intracellular amyloid-beta is acutely toxic, there is also a paucity of information on the mechanisms of neurotoxicity mediated by intracellular amyloid-beta. Functional decline of mitochondria with aging is well established, and growing evidence attributes this decline to loss of mitochondrial DNA integrity in postmitotic cells including neurons. Oxidative stress due to mitochondrial failure may drive increased amyloidogenic processing of the amyloid-beta precursor protein, contributing to a loss of amyloid-beta precursor protein functionality and increased amyloid-beta production. Importantly, recent data show that amyloid-beta accumulates within mitochondria of the Alzheimer's disease brain. We speculate that age-related somatic mutation of mitochondrial DNA may be an important factor underlying sporadic Alzheimer's disease.     

Synovial xanthomatosis: are there clues to mechanisms for this rare disease?

We report a 64-year-old man with arthritis and nodules to describe that this picture can be caused by normo-lipidemic xanthomas. Light and electron microscopy (EM) plus polymerase chain reaction (PCR) studies were performed for diagnosis and investigation. These showed features typical of xanthomas plus PCR and EM evidence of possible infection with Chlamydia pneumoniae as a pathogenetic mechanism deserving consideration. With such rare diseases, any clues to possible mechanisms seem important to record and thus to encourage future investigations. This uncommon cause of arthritis and nodules had been confused with rheumatoid arthritis by others in this case.     

Androgens, aging, and Alzheimer's disease

Testoterone depletion is a normal consequence of aging in men that is associated with senescent effects in androgen-responsive tissues. We discuss new evidence that one consequence of testosterone depletion in men is an increased risk for the development of Alzheimer's disease (AD). Furthermore, we discuss two candidate mechanisms by which test osterone may affect AD pathogenesis. First, testosterone has been identified as an endogenous regulator of β-amyloid, a protein that abnormally accumulates in AD brain and is implicated as a causal factor in the disease. Second, findings from several different paradigms indicate that testosterone has both neurotrophic and neuroprotective functions. These new findings support the clinical evaluation of androgen-based therapies for the prevention and treatment of AD.     

Neurovascular dysfunction and vascular amyloid accumulation as early events in Alzheimer's disease

Metabolic Brain Disease - Alzheimer's disease (AD) is clinically characterized by a progressive loss of cognitive functions and short-term memory. AD patients present two distinctive...     

Mechanisms of disease: autoantigens as clues to the pathogenesis of myositis

Autoimmune inflammatory myopathies, referred to as myositis, comprise a heterogeneous group of chronic inflammatory muscle diseases that present with various clinical phenotypes, histologic changes and autoantibodies, resulting in progressive inflammatory muscle damage and weakness. In up to 20% of myositis patients, particularly those with dermatomyositis, there is an association with cancer that is most frequently diagnosed within 1 year of presentation of myositis. Accumulating data show that autoantibodies in myositis target a specific group of intracellular molecules that are not muscle-specific in their expression. The striking association between autoantibodies recognizing ubiquitously expressed molecules and distinct clinical phenotypes suggests that the target tissues themselves might regulate and shape the phenotype-specific immune response in myositis. Studies indicate that changes in phenotype-specific autoantigens, such as altered structure, enhanced expression, and acquisition of adjuvant properties during various forms of cellular stress, apoptosis, and transformation, might be mechanistically important in this regard. This Review discusses these developments and highlights a central role of autoantigens themselves as a critical partner in driving autoimmune diseases, and the potential for their therapeutic manipulation. In addition, we will highlight insights that the cancer-autoimmunity interface in this group of diseases provides into the relationship between the anticancer immune response and autoimmune diseases.     

Oxidation as a possible mechanism of cellular aging: vitamin E deficiency causes premature aging and IgG binding to erythrocytes.

Senescent-cell antigen is a "neo-antigen" that appears on the surface of senescent cells and initiates IgG binding and cellular removal. As an approach to evaluating oxidation as a possible mechanism for generation of senescent-cell antigen, we studied erythrocytes from vitamin E-deficient rats. Vitamin E is localized primarily in cellular membranes. Its major role is the termination of free-radical chain reactions propagated by the polyunsaturated fatty acids of membrane propagated by the polyunsaturated fatty acids of membrane phospholipids. Results of our studies indicate that erythrocytes of all ages from vitamin E-deficient rats behave like old erythrocytes from normal rats, as determined by their susceptibility to phagocytosis, IgG binding, anion transport ability, and glyceraldehyde-3-phosphate dehydrogenase activity. Increased breakdown products of band 3 were observed with immunoblotting in membranes of erythrocytes from vitamin E-deficient rats. Breakdown products of band 3 are known to increase as cells age in normal individuals. The data suggest that oxidation may be a possible mechanism for erythrocyte aging and generation of senescent-cell antigen in vivo.     

Dimensionality of parkinsonian signs in aging and Alzheimer's disease

BACKGROUND: Parkinsonian signs are commonly found on the neurologic examination of older persons and are associated with morbidity and mortality. The extent to which parkinsonian signs in aging and Alzheimer's disease cluster in groups typical of Parkinson's disease has not been investigated previously. METHODS: The motor portion of the Unified Parkinson's Disease Rating Scale (UPDRS), or a version with minor modifications, was administered to more than 2,800 persons in three cohorts: (a) 637 older persons with a wide range of neurologic conditions participating in the Chicago Health and Aging Project, a study of common health problems of a random sample of older persons from a geographically defined biracial community population; (b) 638 relatively healthy and highly educated older persons from 25 Catholic religious communities participating in the Religious Orders Study, a longitudinal clinical-pathologic study of aging; and (c) 1,546 older persons undergoing evaluation for possible dementia at the Rush Alzheimer's Disease Center, an urban, tertiary care center that evaluates persons for possible dementia. Separate factor analyses were performed on each data set. Additional analyses examined the factor structure in subsets by gender and race. RESULTS: A similar grouping of items emerged in each cohort and did not differ substantially by gender or race. The factors corresponded closely with the traditional grouping of parkinsonian signs into bradykinesia, gait disturbance, rigidity, and tremor. CONCLUSIONS: The grouping of parkinsonian signs is consistent in diverse samples of older persons and does not vary substantially across gender or race. The results provide an empirical basis for summarizing the principal motoric manifestations of parkinsonism.     

The pupillary light reflex in aging and Alzheimer's disease

The pupillary light reflex is reported to be reduced in amplitude in Alzheimer's disease (AD). The purpose of this study was to determine whether this effect is measurable under conditions typical of clinical rather than laboratory settings. A head-mounted infra-red videopupillometer was used to measure the amplitude of pupillary constriction in 12 patients with probable AD, 12 healthy age-matched older adults and 12 young adults. The constriction to the onset of bright light relative to the resting amplitude was significantly reduced in AD compared with both control groups. This result is consistent with an acetylcholine-related deficit in AD and supports the findings of Prettyman et al. and Fotiou et al. The impairment is likely to be caused by degeneration in relays in the midbrain but cholinergic deficits in the peripheral parasympathetic pathway cannot be excluded. The variation in pupillary response between individuals may preclude its use for diagnostic purposes. However, if the changes in pupillary response in AD are related to change in neurotransmitter status, then the value of such a technique may be in its use in providing an objective, non-invasive monitor of physiological abnormality with which to follow disease progression and treatment efficacy.     

Molecular and cellular events in alcohol-induced muscle disease

Alcohol consumption induces a dose-dependent noxious effect on skeletal muscle, leading to progressive functional and structural damage of myocytes, with concomitant reductions in lean body mass. Nearly half of high-dose chronic alcohol consumers develop alcoholic skeletal myopathy. The pathogenic mechanisms that lie between alcohol intake and loss of muscle tissue involve multiple pathways, making the elucidation of the disease somewhat difficult.
This review discusses the recent advances in basic and clinical research on the molecular and cellular events involved in the development of alcohol-induced muscle disease. The main areas of recent research interest on this field are as follows: (i) molecular mechanisms in alcohol exposed muscle in the rat model; (ii) gene expression changes in alcohol exposed muscle; (iii) the role of trace elements and oxidative stress in alcoholic myopathy; and (iv) the role of apoptosis and preapoptotic pathways in alcoholic myopathy. These aforementioned areas are crucial in understanding the pathogenesis of this disease. For example, there is overwhelming evidence that both chronic alcohol ingestion and acute alcohol intoxication impair the rate of protein synthesis of myofibrillar proteins, in particular, under both postabsorptive and postprandial conditions. Perturbations in gene expression are contributory factors to the development of alcoholic myopathy, as ethanol-induced alterations are detected in over 400 genes and the protein profile (i.e., the proteome) of muscle is also affected.There is supportive evidence that oxidative damage is involved in the pathogenesis of alcoholic myopathy. Increased lipid peroxidation is related to muscle fibre atrophy, and reduced serum levels of some antioxidants may be related to loss of muscle mass and muscle strength. Finally, ethanol induces skeletal muscle apoptosis and increases both pro- and antiapoptotic regulatory mechanisms.     

Alzheimer's disease: pathological mechanisms and the beneficial role of melatonin

Alzheimer's disease (AD) is a highly complex neurodegenerative disorder of the aged that has multiple factors which contribute to its etiology in terms of initiation and progression. This review summarizes these diverse aspects of this form of dementia. Several hypotheses, often with overlapping features, have been formulated to explain this debilitating condition. Perhaps the best-known hypothesis to explain AD is that which involves the role of the accumulation of amyloid-β peptide in the brain. Other theories that have been invoked to explain AD and summarized in this review include the cholinergic hypothesis, the role of neuroinflammation, the calcium hypothesis, the insulin resistance hypothesis, and the association of AD with peroxidation of brain lipids. In addition to summarizing each of the theories that have been used to explain the structural neural changes and the pathophysiology of AD, the potential role of melatonin in influencing each of the theoretical processes involved is discussed. Melatonin is an endogenously produced and multifunctioning molecule that could theoretically intervene at any of a number of sites to abate the changes associated with the development of AD. Production of this indoleamine diminishes with increasing age, coincident with the onset of AD. In addition to its potent antioxidant and anti-inflammatory activities, melatonin has a multitude of other functions that could assist in explaining each of the hypotheses summarized above. The intent of this review is to stimulate interest in melatonin as a potentially useful agent in attenuating and/or delaying AD.     

Cellular vulnerability in brain aging and Alzheimer's disease. Clinical correlates and molecular background

The neuropathological changes associated with normal brain aging and Alzheimer's disease involve specific cortical circuits. Extensive hippocampal alterations are correlated with age-associated memory impairment, while substantial neurofibrillary tangle formation in neocortical association areas of the temporal lobe is a prerequisite for the development of Alzheimer's disease. Several lines of evidence indicate that there is no correlation between senile plaque densities and the degree of dementia in this disorder. The cortical involvement in the ninth and tenth decades of life is different from that observed in younger patients in that parietal and cingulate areas are affected early in the course of Alzheimer's disease, and neocortical senile plaques densities are strongly correlated with the severity of dementia. Moreover, Alzheimer's disease pathology is characterized in these very old patients by high neurofibrillary tangle densities in the anterior CA1 field, but not in the entorhinal cortex and inferior temporal cortex. These patterns of lesion distribution are discussed in respect to the neurochemical, genetic and metabolic factors which may influence the neuronal vulnerability in Alzheimer's disease.     

Dendritic BC200 RNA in aging and in Alzheimer's disease

Small untranslated BC1 and BC200 RNAs are translational regulators that are selectively targeted to somatodendritic domains of neurons. They are thought to operate as modulators of local protein synthesis in postsynaptic dendritic microdomains, in a capacity in which they would contribute to the maintenance of long-term synaptic plasticity. Because plasticity failure has been proposed to be a starting point for the neurodegenerative changes that are seen in Alzheimer's disease (AD), we asked whether somatodendritic levels of human BC200 RNA are deregulated in AD brains. We found that in normal aging, BC200 levels in cortical areas were reduced by >60% between the ages of 49 and 86. In contrast, BC200 RNA was significantly up-regulated in AD brains, in comparison with age-matched normal brains. This up-regulation in AD was specific to brain areas that are involved in the disease. Relative BC200 levels in those areas increased in parallel with the progression of AD, as reflected by Clinical Dementia Rating scores. In more advanced stages of the disease, BC200 RNA often assumed a clustered perikaryal localization, indicating that dendritic loss is accompanied by somatic overexpression. Mislocalization and overexpression of BC200 RNA may be reactive-compensatory to, or causative of, synaptodendritic deterioration in AD neurons.     

Experimental evidence for a unifying concept of the molecular mechanisms of the cellular aging and the cellular neoplastic transformation.

Experimental data supporting a Unifying Concept of the molecular mechanisms of cellular aging and cellular neoplastic transformation of dividing cells in mass culture and clonal culture systems will be described. The Unifying Concept combines the hitherto antithetically presented Differentiation Theory, the Mutation Theory, the Error Catastrophy Theory and the Degradation Deficiency Theory with a newly worked out Virus Theory of the cellular aging and the cellular neoplastic transformation. Quantitative in vitro studies of embryonic fibroblast cell systems of two closely related inbred rat strains L.BN and Lewis were undertaken. The data obtained from the experimental analysis of the molecular mechanisms of the cellular aging and the cellular neoplastic transformation demonstrate, that the cellular aging of dividing cells is a Three-Stage-Differentiation Sequence under the control of three different genetic programs. The genetic constitution of the senescent cell regulates the expression of virogenes and oncogenes of the endogenous RNA tumor viruses of the C-type, resulting either in the cellular degeneration of the senescent cell under the control of the virogenes or in the cellular neoplastic transformation regulated by the oncogenes.