Component Of Disease Pathogenesis Research Articles

Cholesterol-Dependent Cellular Processes and Peptides Containing Cholesterol-Binding Motifs: Possible Implications for Medicine

The animal cell is a unique system in which the functioning of its constituent molecules is interdependent and coordinated, and the violation of this coordination is fatal for the cell. One example of this coordination and mutual regulation is the functioning of membrane proteins, whose activity depends on their interaction with membrane lipids. This review reminds us of the crucial importance of the lipid component of cell membranes for normal cell function, and in particular looks at the role of the "cholesterol" component. Given a given genome and a corresponding set of proteins, this lipid component provides a wide range of regulation of cellular functions. The review exemplifies cholesterol-dependent membrane proteins and cellular processes and considers their role in microbial infections and some other pathologies. The concept of cholesterol-recognizing/interacting amino acid consensus (CRAC) motifs in proteins as a possible mechanism of these protein–lipid interactions is discussed. Examples of the use of peptides containing such motifs to modulate cholesterol-dependent processes are presented. In summary, consideration of the cholesterol component in disease pathogenesis and understanding the mechanisms of cholesterol–protein interactions represent a significant resource for the development of drugs that affect the protein–lipid interface. Such drugs may include cholesterol-binding peptides that target specific cholesterol-dependent proteins.

Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene that is characterized by progressive action tremor, gait ataxia, and cognitive decline. Recent studies of mitochondrial dysfunction in FXTAS have suggested that iron dysregulation may be one component of disease pathogenesis. We tested the hypothesis that iron dysregulation is part of the pathogenic process in FXTAS. We analyzed postmortem choroid plexus from FXTAS and control subjects, and found that in FXTAS iron accumulated in the stroma, transferrin levels were decreased in the epithelial cells, and transferrin receptor 1 distribution was shifted from the basolateral membrane (control) to a predominantly intracellular location (FXTAS). In addition, ferroportin and ceruloplasmin were markedly decreased within the epithelial cells. These alterations have implications not only for understanding the pathophysiology of FXTAS, but also for the development of new clinical treatments that may incorporate selective iron chelation.

Exploring the link between herpes viruses and pemphigus vulgaris: literature review and commentary

Pemphigus vulgaris (PV) is an autoimmune skin condition characterized by the presence of circulating autoantibodies specific for a subset of cellular adhesion proteins within mucosal and/or non-mucosal epidermal surfaces. Although the presence of self-directed antibodies is well established, the exact etiology of PV is still uncertain. Environmental factors have been linked to a variety of autoimmune disorders. Specifically, viral infection has been considered to act as one contributory component in disease pathogenesis. Perhaps the most studied group of pathogens is that of herpes viruses, with considerable evidence linking the herpes simplex virus and PV. These viruses have been reported to influence the course of disease and have been associated with PV flares and clinical exacerbations. However, there are significant inconsistencies amongst published data; additional analysis is required to solidify the proposed relationship. In the following article, we critically review the literature regarding the impact of the herpes viruses on PV, providing a framework for clinical application, mechanistic pathways, and future investigation.

Roles of Mitogen-Activated Protein Kinases in the Regulation of CYP Genes

Cells undergo phenotypic changes after exposure to a wide range of exogenous stimuli that include growth factors, proinflammatory cytokines and environmental chemicals. Such stimuli may arise as components of disease pathogenesis and cellular injury, or as a result of exposure to environmental chemicals and radiation. These stimuli modulate the proliferation and differentiation of cells by altering the regulation of genes that control homeostasis. A generalized response appears to be a decline in the expression and function of many cytochrome P450 (CYP) genes in liver and other tissues. Thus, individuals who have been exposed to such exogenous stimuli often exhibit a decreased capacity for drug clearance, which has important consequences for concurrent drug therapy. Several signaling pathways transduce exogenous stimuli within cells, with the mitogen-activated protein kinases (MAPKs) being one of the most important. Evidence is increasing that MAPKs may impair the expression of multiple CYP genes by modulating the activity of transcription factors, including nuclear receptors, the aryl hydrocarbon receptor, and the activator protein-1 complex. MAPKs catalyze the phosphorylation of transcription complexes that incorporate these factors, which modulates their capacity to transactivate target genes, including CYPs. An understanding of the mechanisms that account for the regulatory impact of MAPKs on the transcriptional factors that regulate CYP genes will provide critical insight into the consequences from exposure to injurious stresses that impact cellular function.

Human Benign Prostatic Hyperplasia Stromal Cells As Inducers and Targets of Chronic Immuno-Mediated Inflammation

Benign prostatic hyperplasia (BPH), a highly prevalent prostatic condition, could involve an inflammatory component in disease pathogenesis. In this study, we show that human stromal prostate cells obtained from BPH tissue can actively contribute to the inflammatory process by secreting proinflammatory cytokines as well as chemokines able to recruit lymphomonuclear cells and by acting as APCs. BPH cells express all of the TLRs and their ligation leads to the secretion of CXCL8/IL-8, CXCL10, and IL-6. In addition, BPH cells express costimulatory as well as class I and class II MHC molecules, which activate alloreactive CD4(+) cells that in turn markedly up-regulate IL-12/IL-23p40 and IL-12p75 secretion by BPH cells. Alloreactive CD4(+) cells activated by BPH cells secrete IFN-gamma and IL-17. These cytokines up-regulate IL-6, IL-8, and CXCL10 production by BPH cells, creating a positive feedback loop that can amplify inflammation. IL-8 induces autocrine/paracrine proliferation of BPH cells, indicating also a growth-promoting activity of this chemokine in disease pathogenesis. These results show that human BPH cells represent nonprofessional APCs able to induce and sustain chronic inflammatory processes, supporting the relevance of inflammation in BPH pathogenesis.

Inflammation and the mucosal microcirculation in inflammatory bowel disease: the ebb and flow

Inflammatory bowel disease pathogenesis involves the interplay of multiple biological factors, among which nonimmune cells, including the endothelium, represent a crucial component of disease pathogenesis. Endothelial cells play a key role in chronic inflammation through multiple and disparate activities. The mucosal microvasculature in inflammatory bowel disease is dysfunctional, overexpresses inflammatory molecules and undergoes intense angiogenesis, failing to exert its physiological antiinflammatory and anticoagulant activities. The mucosal microcirculation is abnormal in inflammatory bowel disease and represents a novel component of disease pathogenesis; targeting the various abnormalities of the inflammatory bowel disease microcirculation may lead to new forms of therapeutic intervention.

Soluble endoglin contributes to the pathogenesis of preeclampsia

Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction mediated by excess placenta-derived soluble VEGF receptor 1 (sVEGFR1 or sFlt1) is emerging as a prominent component in disease pathogenesis. We report a novel placenta-derived soluble TGF-beta coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery. sEng inhibits formation of capillary tubes in vitro and induces vascular permeability and hypertension in vivo. Its effects in pregnant rats are amplified by coadministration of sFlt1, leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth. sEng impairs binding of TGF-beta1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-beta signaling in the vasculature. Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia.

Epidemiology of vitiligo and associated autoimmune diseases in Caucasian probands and their families.

Generalized vitiligo is an autoimmune disorder characterized by acquired white patches of skin and overlying hair, the result of loss of melanocytes from involved areas. The most common disorder of pigmentation, vitiligo occurs with a frequency of 0.1-2.0% in various populations. Family clustering of cases is not uncommon, in a non-Mendelian pattern suggestive of multifactorial, polygenic inheritance. We surveyed 2624 vitiligo probands from North America and the UK regarding clinical characteristics, familial involvement, and association with other autoimmune disorders, the largest such survey ever performed. More than 83% of probands were Caucasians, and the frequency of vitiligo appeared approximately equal in males and females. The frequency of vitiligo in probands' siblings was 6.1%, about 18 times the population frequency, suggesting a major genetic component in disease pathogenesis. Nevertheless, the concordance of vitiligo in monozygotic twins was only 23%, indicating that a non-genetic component also plays an important role. Probands with earlier disease onset tended to have more relatives affected with vitiligo, suggesting a greater genetic component in early onset families. The frequencies of six autoimmune disorders were significantly elevated in vitiligo probands and their first-degree relatives: vitiligo itself, autoimmune thyroid disease (particularly hypothyroidism), pernicious anaemia, Addison's disease, systemic lupus erythematosus, and probably inflammatory bowel disease. These associations indicate that vitiligo shares common genetic aetiologic links with these other autoimmune disorders. These results suggest that genomic analysis of families with generalized vitiligo and this specific constellation of associated autoimmune disorders will be important to identify the mechanisms of genetic susceptibility to autoimmunity.

Suppression of pathogenesis: bacteria lead the way

Suppression of pathogenesis: bacteria lead the way

Genetics and pulmonary medicine. 3. Genetic susceptibility to tuberculosis in human populations.

Prior to the discovery of the tubercle bacillus, the observation that tuberculosis frequently occurred in many members of the same family convinced physicians that it was a hereditary disease.1 However, in 1882 when Robert Koch demonstrated that tuberculosis was caused by a microorganism,2attention turned to the importance of the pathogen and the genetic constitution of the host was largely ignored. It is estimated that only 10% of those who become infected with Mycobacterium tuberculosis will ever develop clinical disease,3 and in only a few cases is there an obvious identifiable risk factor such as diabetes, advanced age, alcohol abuse, HIV infection, or corticosteroid usage. Why then do some people succumb to the disease when most of the population can successfully fight off the tubercle bacillus? Clearly, although M tuberculosis is necessary, it is not sufficient. Determining why only some individuals are susceptible to tuberculosis is important as this will give us insight into which components of disease pathogenesis are important and hopefully assist the development of new treatment or prevention strategies. It is a common misapprehension that death from multifactorial diseases such as cancer and cardiovascular problems are influenced by genetic factors, but that death from infection is due to a bad environment or simply bad luck. In fact, a study of 960 adoptees in Denmark concluded that the genetic component of susceptibility to premature death from infectious diseases is greater than for cancer or cardiovascular causes.4 In 1949 the pioneering geneticist J B S Haldane recognised that infectious diseases have been the main agent of natural selection during the past 5000 years.5 Organisms which are widespread in the human population and which exert a high mortality will exert the most pronounced evolutionary effects.6 In the early part of the 19th century it …

Capsaicin-sensitive peptidergic neurons are involved in the zosteriform spread of herpes simplex virus infection.

The intraneuronal transport of herpes simplex virus (HSV) is an essential component in disease pathogenesis. Capsaicin, a neuropharmacologic agent lacking direct antiviral activity, has been shown to protect animals against HSV-induced disease. It has been hypothesized that capsaicin acts by interfering with the intraneuronal transport of virus. Since animal models have been useful in studying the spread of virus, we used two guinea pig models of zosteriform herpes to examine the effect of capsaicin on HSV spread. Capsaicin was subcutaneously administered to Hartley guinea pigs prior to intravaginal or cutaneous HSV-2 inoculation. Treatment did not prevent the development of herpetic vesicles at the site of inoculation but significantly reduced the zosteriform spread of lesions in male and female animals. Further, after recovery from primary infection, capsaicin-treated male guinea pigs were observed to have fewer days with recurrent herpetic lesions. These results suggest that capsaicin-sensitive nerve fibers play a role in the pathogenesis of primary and recurrent HSV infections. Capsaicin appears to reduce the severity of cutaneous HSV infections by interfering with the spread of virus.