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PubMed2002

Natural products as targeted modulators of the nuclear factor-kappaB pathway.

The use of plant extracts to alleviate inflammatory diseases is centuries old and continues to this day. This review assesses the current understanding of the use of such plants and natural products isolated from them in terms of their action against the ubiquitous transcription factor, nuclear factor kappa B (NF-kappaB). As an activator of many pro-inflammatory cytokines and inflammatory processes the modulation of the NF-kappaB transduction pathway is a principal target to alleviate the symptoms of such diseases as arthritis, inflammatory bowel disease and asthma. Two pathways of NF-kappaB activation will first be summarised, leading to the IKK (IkappaB kinase) complex, that subsequently initiates phosphorylation of the NF-kappaB inhibitory protein (IKB). Natural products and some extracts are reviewed and assessed for their activity and potency as NF-kappaB inhibitors. A large number of compounds are currently known as NF-kappaB modulators and include the isoprenoids, most notably kaurene diterpenoids and members of the sesquiterpene lactones class, several phenolics including curcumin and flavonoids such as silybin. Additional data on cellular toxicity are also highlighted as an exclusion principle for pursuing such compounds in clinical development. In addition, where enough data exists some conclusions on structure-activity relationship are provided.

Animals↗
PubMed1991

Hepatitis B virus X protein transactivates human interleukin-8 gene through acting on nuclear factor kB and CCAAT/enhancer-binding protein-like cis-elements.

Interleukin-8 (IL-8) is a newly described leukocyte chemotactic and activating cytokine that belongs to the novel family of inflammatory cytokines whose genes locate on human chromosome 4, q12-21 region. The production of IL-8 is usually not constitutive and can be induced rapidly and abundantly in different cell types by a variety of stimuli such as lipopolysaccharide, interleukin-1, tumor necrosis factor-alpha as well as a tumor promotor phorbol myristate acetate. We report here that in addition to these stimuli the IL-8 gene can also be induced by the protein X of the hepatitis B virus (HBV-X) as evidenced by the enhanced IL-8 mRNA expression and IL-8 production observed in HBV-X-transfected cells. Furthermore, using several deletion mutants of the 5'-flanking regulatory region of the human IL-8 gene linked to the chloramphenicol acetyl transferase gene as a reporter, we have established here that both nuclear factor kB and CCAAT/enhancer-binding protein-like cis-elements located at -94 to -71 base pairs of IL-8 gene are essential and sufficient for the induction of the IL-8 gene by HBV-X. The same elements have been identified recently by us to be interleukin-1-, tumor necrosis factor-alpha-, and phorbol myristate acetate-responsive elements on the IL-8 gene. This suggests the existence of a common pathway for these inflammatory cytokines and HBV-X to activate the IL-8 gene. These observations might be relevant to the pathogenesis of inflammation in viral hepatitis.

Base Sequence↗
PubMed2005

Mechanism of the anti-inflammatory effect of thiazolidinediones: relationship with the glucocorticoid pathway.

The glucocorticoid receptor (GR) and peroxisome proliferator-activated receptors (PPARs) play important roles in both physiological and pathological conditions such as cell differentiation, lipolysis, control of glucose metabolism, immunity, and inflammation. In fact, recent studies suggest that the thiazolidinedione (TZD) class of PPAR-gamma ligands, like glucocorticoids, may also be clinically beneficial in several inflammatory diseases, even if the molecular mechanisms responsible for these activities have not yet been clarified. In this study, by using a murine model of inflammation, the carrageenin-induced paw edema in mouse, we show that the anti-inflammatory activity exhibited by the PPAR-gamma agonists rosiglitazone and ciglitazone is reversed by the GR antagonist RU486 (17 beta-hydroxy-11 beta-[4-dimethylamino phenyl]-17 alpha-[1-propynyl]estra-4,9-dien-3-one). Moreover, by using a conditional GR null cell line, we demonstrate, for the first time to our knowledge, that one of the possible mechanisms explaining the anti-inflammatory activity of TZDs is their ability to activate GR nuclear translocation. In addition, by using J774 cell line lacking PPAR-gamma, we demonstrate that PPAR-gamma expression could not be essential for TZD-mediated GR nuclear translocation, thus explaining, at least in part, the molecular mechanism underlying their anti-inflammatory activity.

Animals↗
PubMed2004

Aminopyridazines attenuate hippocampus-dependent behavioral deficits induced by human beta-amyloid in a murine model of neuroinflammation.

The importance of glial cell-driven neuroinflammation in the pathogenesis and progression of Alzheimer's disease (AD) led us to initiate a drug discovery effort targeting the neuroinflammatory cycle that is characteristic of AD. We used our synthetic chemistry platform focused on bioavailable aminopyridazines as a new chemotype for AD drug discovery to develop novel, selective suppressors of key inflammatory and oxidative pathways in glia. We found that MW01-070C, an aminopyridazine that works via mechanisms distinct from NSAIDs and p38 MAPK inhibitors, attenuates beta-amyloid (Abeta)-induced neuroinflammation and neuronal dysfunction in a dose-dependent manner, and prevents Abeta-induced behavioral impairment. In vivo data were obtained with a murine model that uses intraventricular infusion of human Abeta1-42 peptide and replicates many of the hallmarks of AD pathology, including neuroinflammation, neuronal and synaptic degeneration, and amyloid deposition. The quantifiable endpoint pathology is robust, reproducible, and rapid in onset. Our results provide a proof of concept that targeting neuroinflammation with aminopyridazines is a viable AD drug discovery approach that has the potential to modulate disease progression and document the utility of this mouse model for preclinical screening of compounds targeting AD-relevant neuroinflammation and neuronal death.

Alzheimer Disease↗
PubMed2006

Comparison of Anti-inflammatory Activities of Six Curcuma Rhizomes: A Possible Curcuminoid-independent Pathway Mediated by Curcuma phaeocaulis Extract.

We aimed to compare the anti-inflammatory activities of six species of Curcuma drugs using adjuvant arthritis model mice. When orally administered 1 day before the injection of adjuvant, the methanol extract of Curcuma phaeocaulis significantly inhibited paw swelling and the serum haptoglobin concentration in adjuvant arthritis mice. Also when orally administered 1 day after the injection of adjuvant, the methanol extract of Curcuma phaeocaulis significantly inhibited paw swelling. Other Curcuma species (Curcuma longa, Curcuma wenyujin, Curcuma kwangsiensis, Curcuma zedoaria and Curcuma aromatica) had no significant inhibitory effects on adjuvant-induced paw swelling. Cyclooxygenase (COX)-2 activity was significantly inhibited by the methanol extract of C. phaeocaulis. Curcuminoids' (curcumin, bis-demethoxycurcumin and demethoxycurcumin) were rich in C. longa, but less in C. phaeocaulis and C. aromatica, not in C. wenyujin, C. kwangsiensis and C. zedoaria, suggesting that curcuminoids' contents do not relate to inhibition of arthritis swelling. Therefore, C. phaeocaulis may be a useful drug among Curcuma species for acute inflammation, and the active constituents of C. phaeocaulis are not curcuminoids.

Journal Article↗
PubMed2004

Inhibition of toll-like receptor and cytokine signaling--a unifying theme in ischemic tolerance.

Cerebral ischemia triggers acute inflammation, which exacerbates primary brain damage. Activation of the innate immune system is an important component of this inflammatory response. Inflammation occurs through the action of proinflammatory cytokines, such as TNF, IL-1 beta and IL-6, that alter blood flow and increase vascular permeability, thus leading to secondary ischemia and accumulation of immune cells in the brain. Production of these cytokines is initiated by signaling through Toll-like receptors (TLRs) that recognize host-derived molecules released from injured tissues and cells. Recently, great strides have been made in understanding the regulation of the innate immune system, particularly the signaling mechanisms of TLRs. Negative feedback inhibitors of TLRs and inflammatory cytokines have now been identified and characterized. It is also evident that lipid rafts exist in membranes and play a role in receptor-mediated inflammatory signaling events. In the present review, using this newly available large body of knowledge, we take a fresh look at studies of ischemic tolerance. Based on this analysis, we recognize a striking similarity between ischemic tolerance and endotoxin tolerance, an immune suppressive state characterized by hyporesponsiveness to lipopolysaccharide (LPS). In view of this analogy, and considering recent discoveries related to molecular mechanisms of endotoxin tolerance, we postulate that inhibition of TLR and proinflammatory cytokine signaling contributes critically to ischemic tolerance in the brain and other organs. Ischemic tolerance is a protective mechanism induced by a variety of preconditioning stimuli. Tolerance can be established with two temporal profiles: (i) a rapid form in which the trigger induces tolerance to ischemia within minutes and (ii) a delayed form in which development of protection takes several hours or days and requires de-novo protein synthesis. The rapid form of tolerance is achieved by direct interference with membrane fluidity, causing disruption of lipid rafts leading to inhibition of TLR/cytokine signaling pathways. In the delayed form of tolerance, the preconditioning stimulus first triggers the TLR/cytokine inflammatory pathways, leading not only to inflammation but also to simultaneous upregulation of feedback inhibitors of inflammation. These inhibitors, which include signaling inhibitors, decoy receptors, and anti-inflammatory cytokines, reduce the inflammatory response to a subsequent episode of ischemia. This novel interpretation of the molecular mechanism of ischemic tolerance highlights new avenues for future investigation into the prevention and treatment of stroke and related diseases.

Animals↗
PubMed2003

IL-1beta-mediated up-regulation of HIF-1alpha via an NFkappaB/COX-2 pathway identifies HIF-1 as a critical link between inflammation and oncogenesis.

Growing evidence indicates that inflammation is a contributing factor leading to cancer development. However, pathways involved in this progression are not well understood. To examine whether HIF-1alpha is a factor linking inflammation and tumorigenesis, we investigated whether the HIF-1 signaling pathway was stimulated by the pro-inflammatory cytokine interleukin-1beta (IL-1beta) in A549 cells. We find that IL-1beta up-regulated HIF-1alpha protein under normoxia and activated the HIF-1-responsive gene vascular endothelial growth factor (VEGF) via a pathway dependent on nuclear factor kappaB (NFkB). Interestingly, although this pathway is stimulated by upstream signaling via AKT and mTOR and requires new transcription, IL-1 mediated HIF-1alpha induction also utilizes a post-transcriptional mechanism that involves antagonism of VHL-dependent HIF-1alpha degradation, which results in increased HIF-1alpha protein stability. IL-1 mediated NFkB-dependent cyclooxygenases-2 (COX-2) expression served as a positive effector for HIF-1alpha induction. Although COX-2 inhibitors attenuated IL-1 mediated HIF-1alpha induction, prostaglandin E2 (PGE2), a physiological product of COX-2, induced HIF-1alpha protein in a dose-dependent manner. Our data, therefore, demonstrate that IL-1beta up-regulates functional HIF-1alpha protein through a classical inflammatory signaling pathway involving NFkB and COX-2, culminating in up-regulation of VEGF, a potent angiogenic factor required for tumor growth and metastasis. Thus, HIF-1 is identified as a pivotal transcription factor linking the inflammatory and oncogenic pathways.

Cell Line, Tumor↗
PubMed2001

cag+ Helicobacter pylori induce transactivation of the epidermal growth factor receptor in AGS gastric epithelial cells.

The gastric pathogen Helicobacter pylori is known to activate epithelial cell signaling pathways that regulate numerous inflammatory response genes. The aim of this study was to elucidate the pathway leading to extracellular signal-regulated kinase (ERK) 1/2 phosphorylation in H. pylori-infected AGS gastric epithelial cells. We find that H. pylori, via activation of the epidermal growth factor (EGF) receptor activates the small GTP-binding protein Ras, which in turn, mediates ERK1/2 phosphorylation. cag+ strains of H. pylori are able to induce greater EGF receptor activation than cag- strains, and studies with isogenic mutants indicate that an intact type IV bacterial secretion system is required for this effect. Blockade of EGF receptor activation using tyrphostin AG1478 prevents H. pylori-mediated Ras activation, inhibits ERK1/2 phosphorylation, and substantially decreases interleukin-8 gene expression and protein production. Investigations into the mechanism of EGF receptor activation, using heparin, a metalloproteinase inhibitor and neutralizing antibodies reveal that H. pylori transactivates the EGF receptor via activation of the endogenous ligand heparin-binding EGF-like growth factor. Transactivation of gastric epithelial cell EGF receptors may be instrumental in regulating both proliferative and inflammatory responses induced by cag+ H. pylori infection.

Antigens, Bacterial↗
PubMed1995

Modulation of mRNA expression and secretion of C1q in mouse macrophages by anti-inflammatory drugs and cAMP: evidence for the partial involvement of a pathway that includes cyclooxygenase, prostaglandin E2 and adenylate cyclase.

Isolated BALB/c mouse thioglycollate-elicited (inflammatory) peritoneal macrophages release at least 10 times more C1q than do isolated resident peritoneal macrophages. Addition of non-steroidal anti-inflammatory drugs (NSAID) to thioglycollate-elicited macrophages in culture inhibited the release of C1q and reduced levels of C1q-specific mRNA. Contrastingly, the NSAID were found to enhance C1q-specific mRNA levels in resident macrophages, although no increase in C1q levels secreted was observed. This suggests that the response of macrophages to NSAID, with respect to C1q synthesis, reflects the developmental stage of the macrophage. The gold salt auranofin (AFN) was found to enhance markedly C1q synthesis at both transcriptional and secretory levels in thioglycollate-elicited macrophages whilst, conversely, AFN reduced mRNA levels in resident macrophages. This indicates that AFN and the NSAID may work via the same or similar biochemical pathway, but with opposing effects. The glucocorticoid hydrocortisone (HC) greatly enhanced C1q-specific mRNA levels in both thioglycollate-elicited and resident macrophages, although no parallel increases in C1q secreted were observed. The data on inhibition of C1q biosynthesis by NSAID in thioglycollate-elicited macrophages are supported by the enhancement of C1q biosynthesis following addition of prostaglandin E2 (PGE2) or dibutyryl cyclic AMP (dBcAMP) to the cultures. From these experiments, it is concluded that C1q biosynthesis is controlled, at least in part, by a pathway involving cAMP.

Adenylyl Cyclases↗
PubMed1999

Priming interleukin 8 production: role of platelet-activating factor and p38.

HYPOTHESIS: Platelet-activating factor (PAF) activates p38, an important intracellular signal transduction kinase, and primes human mononuclear cells for the production of interleukin 8 (IL-8), a potent chemoattractant and activator of neutrophils. METHODS: Human mononuclear cells were isolated from healthy adults by Ficoll-paque density-gradient centrifugation. Interleukin-8 in the supernatant was measured by enzyme-linked immunosorbent assay. Dual phospho-specific p38 antibody was used to detect activated p38 by Western blotting. RESULTS: Lipopolysaccharide (LPS) and PAF activated p38. There was a shorter latency to peak p38 activation with PAF vs LPS stimulation, 5 vs 30 minutes. Platelet-activating factor-induced p38 activation was calcium dependent because it was inhibited by ethyleneglycoltetracetic acid. Lipopolysaccharide, 0.01 to 1.00 ng/mL, induced significant IL-8 production. Although PAF did not induce significant IL-8 production, it potentiated LPS-induced IL-8 production. Production of IL-8, in response to LPS alone or in combination with PAF, was inhibited by SB202190, a specific p38 inhibitor. CONCLUSIONS: Although LPS and PAF activated p38, only LPS induced IL-8 production; PAF acted as a priming agent. It seems that p38 activation is necessary but not sufficient for IL-8 production by human mononuclear cells. Identifying and evaluating the activation state of inflammatory signal transduction pathways might lead to methods for controlling and preventing neutrophil-induced tissue injury without interfering with the normal host immune response.

Adult↗
PubMed1997

Myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis is chronic/relapsing in perforin knockout mice, but monophasic in Fas- and Fas ligand-deficient lpr and gld mice.

The expression and action of Fas/Fas ligand (FasL) in multiple sclerosis has been postulated as a major pathway leading to inflammatory demyelination. To formally test this hypothesis, C57BL/6-lpr and -gld mice, which due to gene mutation express Fas and FasL in an inactive form, were immunized with myelin oligodendrocyte glycoprotein peptide(35-55). Whereas in wild-type C57BL/6 mice, experimental autoimmune encephalomyelitis (EAE), was chronic/relapsing, EAE in lpr and gld mice was characterized by a lower incidence of disease and a monophasic course. This contrasts with C57BL/6 perforin knockout mice, which showed the most severe form of EAE of all mouse strains tested, the course being chronic relapsing. The difference noted cannot be attributed to an involvement of FasL in oligodendrocyte damage since oligodendrocytes are insensitive to FasL-mediated cytotoxicity in vitro, and since in the acute phase of EAE gld mice also show CD4+ T cell infiltrates with associated demyelination in brain and spinal cord. Unlike oligodendrocytes, astrocytes were killed by FasL in vitro. It remains to be established whether this latter finding explains the different disease course of lpr and gld mice compared to wild-type and perforin knockout mice.

Animals↗
PubMed2006

CCL5 evokes calcium signals in microglia through a kinase-, phosphoinositide-, and nucleotide-dependent mechanism.

Microglia, the resident macrophages of the CNS, are responsible for the innate immune response in the brain and participate in the pathogenesis of certain neurodegenerative disorders. Chemokines initiate activation and migration of microglia. The beta-chemokine CCL5 induces an elevation in intracellular calcium concentration ([Ca(2+)](i)) in human microglia. Here, we examined the signal transduction pathway linking activation of chemokine receptor CCR5 to an elevation in [Ca(2+)](i) in cultured microglia by using pharmacological approaches in combination with Fura-2-based digital imaging. The CCL5-induced response required Janus kinase (Jak) activity and the stimulation of an inhibitory G protein. Multiple downstream signaling pathways were involved, including phosphatidylinositol 3-kinase (PI3K), Bruton's tyrosine kinase (Btk), and phospholipase C (PLC)-mediated release of Ca(2+) from inositol 1,4,5-trisphosphate (IP(3))-sensitive stores. Activation of both the kinase and the lipase pathways was required for eliciting the Ca(2+) response. However, the majority of the [Ca(2+)](i) increase was derived from sources activated by NAD metabolites. Cyclic ADP-ribose (cADPR) evoked Ca(2+) release from intracellular stores, and ADPR evoked Ca(2+) influx via a nimodipine-sensitive channel. Thus, a multistep cascade couples CCR5 activation to Ca(2+) increases in human microglia. Because changes in [Ca(2+)](i) affect chemotaxis, secretion, and gene expression, pharmacologic modulation of this pathway may alter inflammatory and degenerative processes in the CNS.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2005

Functional aspects and mechanisms of TRPV1 involvement in neurogenic inflammation that leads to thermal hyperalgesia.

Neurogenic inflammation is produced by overstimulation of peripheral nociceptor terminals by injury or inflammation of tissues. Excessive activity of sensory neurons produces vasodilation, plasma extravasation and hypersensitivity. Mechanistically, neurogenic inflammation is due to the release of substances from primary sensory nerve terminals that act directly or indirectly at the peripheral terminals, either activating or sensitizing nociceptors, endothelial cells and immunocytes. Notably, small-diameter sensory neurons that are sensitive to capsaicin play a key role in the generation of neurogenic inflammation. The cloning of the vanilloid receptor 1 (TRPV1) has been a breakthrough that has propelled our understanding of the molecular mechanisms involved in neurogenic inflammation. TRPV1 pivotally contributes to the integration of various stimuli and modulates nociceptor excitability, thus making it a true gateway for pain transduction. In addition, TRPV1 is the endpoint target of intracellular signalling pathways triggered by inflammatory mediators. Phosphorylation-induced potentiation of TRPV1 channel activity, along with an incremented TRPV1 surface expression are major events underlying the nociceptor activation and sensitization that leads to thermal hyperalgesia. The important contribution of TRPV1 receptor to the onset and maintenance of neurogenic inflammation has validated it as a therapeutic target for inflammatory pain management. As a result, the development of specific TRPV1 antagonists is a central focus of current drug discovery programs.

Animals↗
PubMed2005

Nasal cytokines as mediators of illness during the common cold.

Identification of a pharmacologically targeted mediator of the common cold is a desirable, but, to date, elusive goal of current research. The roles of various mediators, such as histamine, leukotrienes, bradykinin, and, more recently, chemokines and cytokines, in the pathophysiology and development of complications of the common cold are the subject of previous and current investigations. Establishing causality of a mediator in the common cold has been difficult for a number of reasons, including the limitations of our research tools and protocols and the complexity of the inflammatory and immune pathways that participate during the common cold. The available evidence for mediation of the common cold is the subject of this manuscript.

Common Cold↗
PubMed2005

Enhanced RAGE-mediated NFkappaB stimulation in inflamed hemodialysis patients.

Advanced glycation end-products (AGEs), a group of carbohydrate-derived compounds formed by non-enzymatic glycation and oxidation, are markedly elevated in end-stage renal disease (ESRD) and may be related to both inflammation and oxidative stress. The cellular effects of AGE are largely mediated by their interaction with specific surface receptors, such as RAGE. Measurements of biomarkers of inflammation and oxidative stress were conducted in 7 hemodialysis (HD) patients (5 males) with persistent high-grade inflammation (C-reactive protein [CRP]>10 mg/L) and 11 HD-patients (6 males) with low-grade inflammation (CRP<10 mg/L) for at least 6 months. Measured biomarkers for inflammation included hs-CRP, interleukin (IL)-6, white blood cells, neutrophils, S-albumin, peroxisome proliferator-activated receptors (PPAR alpha, beta, gamma) and nuclear factor kappaB (NFkappaB) activity. Markers for oxidative stress were advanced oxidation products (AOPP), myeloperoxidase (MPO)-activity, pentosidine and carboxymethyl lysine (CML). In addition, the effect of increasing doses of CML-modified human serum albumin on NFkappaB activity was tested in mononuclear cells isolated from each patient. As expected, HD-patients with high-grade inflammation had significantly elevated levels of IL-6 (median 9.2 pg/mL versus 2.5 pg/mL; p<0.01), MPO-activity (134.5+/-14.6 DeltaOD(630)/(min mg protein) versus 80.5+/-12.9 DeltaOD(630)/(min mg protein); p<0.05), PPAR-gamma (0.65+/-0.01 OD(655) versus 0.56+/-0.01 OD(655); p<0.01), and AOPP (269+/-54 microM versus 163+/-15 microM; p<0.05) compared with low-grade inflamed patients. Significant associations were demonstrated between hs-CRP and NFkappaB (rho=0.58; p<0.05), AOPP (rho=0.49; p<0.05) and PPAR-gamma (rho=0.62; p<0.05), respectively. In the patient group with high-grade inflammation, stimulation of mononuclear cells with CML-modified human serum albumin caused a rapid dose-dependent rise (p<0.0001) in NFkappaB activity that could be completely blocked by an anti-RAGE antibody. Inflammation and oxidative stress biomarkers are interrelated in ESRD. Inflammatory cell signal pathways, such as NFkappaB, are activated by CML-modification of proteins via RAGE.

Biomarkers↗
PubMed2004

Exip, a splicing variant of p38alpha, participates in interleukin-1 receptor proximal complex and downregulates NF-kappaB pathway.

The members of the p38 mitogen-activated protein kinase, especially specific inhibitors such as SB203580 sensitive isoforms, have been shown to play important roles in immune responses as well as in many biological events. In the course of our study to understand how p38 can be responsible for numerous biological phenomena, we have recently identified Exip, an alternative splicing variant of p38alpha. Exip retains amino acids responsible for the sensitivity to SB203580. Exip may also be involved in the intracellular signal transduction pathway different from those of conventional p38s. Though Exip is less abundant, it may play a critical role under certain circumstances. Here we report that Exip, but not p38alpha, binds to Toll interacting protein which is involved in interleukin-1 (IL-1) signaling pathway as a component of the receptor proximal complex and impaired NF-kappaB activity. Moreover, Exip binds to another component of the complex, IL-1 associating kinase. Exogenous-expression of Exip resulted in downregulation of NF-kappaB activities both in HeLa and HEK293T cells. Together, these results demonstrate that Exip can be a new component of NF-kappaB pathway, and contribute to a comprehensive understanding of the signal transduction pathway in the inflammatory responses.

Alternative Splicing↗
PubMed2005

New approaches to understanding the genetics of asthma.

Several key conditions that are necessary to identify disease susceptibility genes in common diseases such as asthma are now available, including (1) increasingly comprehensive genomic information on gene location, genomic structure, and sequence variants, from the Human Genome Project (and from other species); (2) better understanding of the biologic functions of relevant genes and inflammatory and immunity pathways important in asthma; (3) newer high throughput and accurate technologies for DNA sequencing and SNP genotyping; (4) improved statistical methods for analyzing genetic data from families and populations; and (5) availability of methods to characterize function of sequence variants and study biologic responses. Collectively, these conditions will allow the prioritization of candidate genes based on available knowledge of map position and biologic relevance; obtain genomic structure of these genes; and study sequence variants in these genes in populations to facilitate the identification of genes that are important in the development and expression (severity) of asthma and associated phenotypes. Although, it is still a labor-intensive and expensive project to identify susceptibility genes in common diseases such as asthma, the new techniques that are now being used will greatly facilitate gene mapping. The techniques discussed in this article include genome-by-genome analysis in family data, such as those listed in Box 2. This analysis has already been shown to be a powerful too in mapping genes for another common disease (prostate cancer) with interesting preliminary results for asthma. Second, the use of man-mouse homology mapping that has proven very useful in cardiovascular studies is beginning to be applied to asthma and related phenotypes. finally with new available technology, genome-wide screens using very dense SNP maps are now a reality and a significant new development in family linkage and case-control association studies. In summary, these new approaches should be considered in designing studies to detect genes that are important in asthma and allergy.

Asthma↗
PubMed2005

Neuroinflammation and regeneration in the early stages of Alzheimer's disease pathology.

The initial stages of Alzheimer's disease pathology in the neocortex show upregulation of cell cycle proteins, adhesion and inflammation related factors, indicating the early involvement of inflammatory and regenerating pathways in Alzheimer's disease pathogenesis. These brain changes precede the neurofibrillary pathology and the extensive process of neurodestruction and (astro)gliosis. Amyloid beta deposition, inflammation and regenerative mechanisms are also early pathogenic events in transgenic mouse models harbouring the pathological Alzheimer's disease mutations, while neurodegenerative characteristics are not seen in these models. This review will discuss the relationship between neuroinflammation and neuroregeneration in the early stages of Alzheimer's disease pathogenesis.

Alzheimer Disease↗