Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Inflammatory pathways”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 253 records · Page 14Linked to original sources
PubMed2006

Nonendothelial mesenchymal cell-derived MCP-1 is required for FGF-2-mediated therapeutic neovascularization: critical role of the inflammatory/arteriogenic pathway.

OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1) is a C-C chemokine that is known as an inflammatory/arteriogenic factor. Angiogenesis contributes to the inflammatory process; however, the molecular and cellular mechanisms of the links among the inflammatory pathway, arteriogenesis, and angiogenesis have not been well elucidated. METHODS AND RESULTS: Using murine models of fibroblast growth factor-2 (FGF-2)-mediated therapeutic neovascularization, we here show that FGF-2 targets nonendothelial mesenchymal cells (NEMCs) enhancing both angiogenic (vascular endothelial growth factor [VEGF]) and arteriogenic (MCP-1) signals via independent signal transduction pathways. Severe hindlimb ischemia stimulated MCP-1 expression that was strongly enhanced by FGF-2 gene transfer, and a blockade of MCP-1 activity via a dominant negative mutant as well as a deficiency of its functional receptor CCR2 resulted in the diminished recovery of blood flow attributable to adaptive and therapeutic neovascularization. Tumor necrosis factor (TNF)-alpha stimulated MCP-1 expression in all cell types tested, whereas FGF-2-mediated upregulation of MCP-1 was found only in NEMCs but not in others, a finding that was not affected by VEGF in vitro and in vivo. CONCLUSIONS: These results indicate that FGF-2 targets NEMCs independently, enhancing both angiogenic (VEGF) as well as inflammatory/arteriogenic (MCP-1) pathways. Therefore, MCP-1/CCR2 plays a critical role in adaptive and FGF-2-mediated therapeutic neovascularization.

Adaptation, Physiological↗
PubMed2005

To be or not to be (inflamed)--is that the question in anti-inflammatory drug therapy of neurodegenerative disorders?

A sustained inflammatory reaction is present in acute (e.g. stroke) and chronic (e.g. Alzheimer's disease, Parkinson's disease and multiple sclerosis) neurodegenerative disorders. Inflammation, which is fostered by both residential glial cells and blood-circulating cells that infiltrate the diseased brain, probably starts as a time- and site-specific defense mechanism that could later evolve into a destructive and uncontrolled reaction. In this article, we review the crucial dichotomy of brain inflammation, where failure to resolve an acute beneficial response could lead to a vicious and anarchic state of chronic activation. The possible use of non-steroidal anti-inflammatory drugs for the management of neurodegenerative diseases is discussed in light of recent data demonstrating a neuroprotective role of local innate and adaptive immune responses. Novel therapeutic approaches must rely on potentiation of endogenous anti-inflammatory pathways, identification of early markers of neuronal deterioration and a combination treatment involving immune modulation and anti-inflammatory therapies.

Animals↗
PubMed2006

[Chronic inflammation increases the risk of cardiovascular disease in patients with rheumatoid arthritis].

Rheumatoid arthritis is associated with increased cardiovascular morbidity and mortality due to atherosclerosis. This cannot be explained by an increased presence of traditional risk factors but seems to depend on inflammatory mechanisms. The association of inflammatory pathways with atherosclerosis is complex, and more research is required to optimise preventative measures against cardiovascular complications in inflammatory rheumatic diseases.

Anti-Inflammatory Agents↗
PubMed1997

Sepsis and septic shock.

Focal infectious processes may produce a systemic syndrome whose description has been recently standardized by the definitions of sepsis, severe sepsis and septic shock. This classification should only be used as an adjunct to the microbiological and clinical diagnosis of a given infection. The incidence of sepsis and septic shock has been increasing over recent decades, but the ratio of gram-negative to gram-positive causative organisms has remained largely similar (most often between 1:1 and 3:2). Recent advances in understanding of the pathophysiology of sepsis and septic shock have made it possible to delineate more clearly the role of bacterial products such as lipopolysaccharide, exotoxins or cell wall fragments. These products are able either to directly trigger inflammatory pathways, or to stimulate target cells (such as monocytic cells, PMN or endothelial cells) to produce pro-inflammatory cytokines. Management of the infectious process itself with antibiotics, and with surgery if needed, is the cornerstone of the therapy of sepsis and septic shock. More recent approaches aim at inhibiting the bioactivity of bacterial or pro-inflammatory mediators. Up to now, however, none of these approaches has led to therapeutic modalities that can be applied routinely to patients.

Anti-Bacterial Agents↗
PubMed2006

The importance of disease associations and concomitant therapy for the long-term management of psoriasis patients.

It is well established that several inflammatory-type conditions, such as arthritis, diabetes, cardiovascular disease, and irritable bowel disease exist comorbidly and at an increased incidence in patients with psoriasis. Psoriasis and other associated diseases are thought to share common inflammatory pathways. Conditions such as these, with similar pathogenic mechanisms involving cytokine dysregulation, are referred to as immune-mediated inflammatory diseases (IMIDs). Considerable evidence for the genetic basis of comorbidities in psoriasis exists. The WHO has reported that the occurrence of chronic diseases, including IMIDs, are a rising global burden. In addition, conditions linked with psoriasis have been associated with increasing rates of considerable morbidity and mortality. The presence of comorbid conditions in psoriasis patients has important implications for clinical management. QoL, direct health care expenditures and pharmacokinetics of concomitant therapies are impacted by the presence of comorbid conditions. For example, methotrexate is contraindicated in hepatic impairment, while patients on cyclosporin should be monitored for kidney function. In addition, some agents, such as beta blockers, lithium, synthetic antimalarial drugs, NSAIDs and tetracycline antibiotics, have been implicated in the initiation or exacerbation of psoriasis. Consequently, collaboration between physicians in different specialties is essential to ensuring that psoriasis treatment benefits the patient without exacerbating associated conditions.

Comorbidity↗
PubMed2005

Endurance training reduces circulating inflammatory markers in persons at risk of coronary events: impact on plaque stabilization?

Inflammatory pathways are involved in destabilization of atherosclerotic plaques. We assessed the hypothesis that endurance training decreases circulating concentrations of inflammatory markers in persons with coronary artery disease (CAD) and cardiovascular risk factors (CVRFs). Thirty-two subjects with CAD and/or CVRFs joined a 12-week supervised endurance training. We found a significant decrease of the chemokines interleukin (IL)-8 (pre: 3.9+/-0.6, change: -1.2+/-0.4 pg/ml, -21%, p=0.002) and monocyte chemoattractant protein-1 (pre: 213+/-9, change: -20.4+/-8.2 pg/ml, -5%, p=0.03). Diabetes mellitus (DM) significantly influenced changes of IL-8 (p=0.002). IL-8 substantially dropped by 39% in diabetics. Moreover, matrix metalloproteinase-9 (MMP-9) highly significantly decreased in response to training (pre: 750+/-98, change: -278+/-77 ng/ml, -18%, p=0.005). Exercise-induced changes of MMP-9 were influenced by concomitant use of statins (p=0.038). We observed a particularly strong MMP-9 reduction of 44% in patients treated with statins. Acute phase reactants IL-6 (pre: 1.7+/-0.3, change: +0.25+/-0.7 pg/ml, +4%, p=0.58) and high sensitivity C-reactive protein (pre: 2.1+/-0.5, change: -0.25+/-0.4 mg/l, -9%, p=0.54) did not change in response to training. In conclusion, endurance training decreased circulating chemokines and MMP-9, which may in part explain its beneficial effect on coronary risk. Patients with DM or treated with statins because of hypercholesterolemia may particularly take advantage.

Chemokine CCL2↗
PubMed2005

The role and modulation of the oxidative balance in pregnancy.

Oxidative processes exert a fundamental regulatory function during pregnancy. It depends on the influence of oxygen, nitric oxide, reactive oxygen species and reactive nitrogen species metabolic pathways upon the vascular changes in the maternal organism, as well as on the regulation of uterine and cervical tone throughout gestation and delivery. These functions are strictly linked with the mediators of the inflammatory pathway. At the beginning of pregnancy, when a certain grade of inflammatory change is necessary to the trophoblast invasion of maternal tissue, the activation of the process by nitric oxide and reactive nitrogen species is welcome. Indeed, these products modulate the metalloproteinases, which are responsible for the remodelling of uterine extracellular matrix. At this stage estrogens are involved as well in the regulation of the delicate balance of pro-oxidant and anti-oxidant effects. Furthermore, reactive oxygen and nitrogen species appear to play an important role both in normal and pathologic embryogenesis. During advanced pregnancy, a derangement of the oxidative balance can lead to the improper activation of inflammatory changes, thus triggering premature labour as well as other complications, such as foetal growth restriction and preeclampsia. Although a number of pro- and anti-oxidant agents are available to influence the above-mentioned processes, there is no way to adequately measure the oxidative needs in single cases, in order to modulate the oxidative balance in clinical practice. Pharmacological research should be addressed to the development of new drugs, as well as to selective methods of delivery to the gestational tissues.

Antioxidants↗
PubMed2006

TLR signaling pathways: opportunities for activation and blockade in pursuit of therapy.

The identification of the TLRs as key sensors of microbial infection has presented a series of new targets for drug development. The TLRs are linked to the most powerful inflammatory pathways in mammals. The question arises from the start: do we wish to stimulate TLR signaling in order to eradicate specific infections and/or neoplastic diseases? Or do we wish to block TLR signaling to treat inflammatory diseases? If we accept that it would be useful to modulate TLR signaling, the next step is to identify the correct molecular target(s) for the task. Perhaps it might even be possible to exercise selectivity, modulating some aspects of TLR signaling and not others. Classical and reverse genetic analyses offer insight into the possibilities that exist, and point to specific checkpoints within signaling pathways at which modulation might normally be imposed.

Anti-Inflammatory Agents↗
PubMed2026

Methylation profiling of normal tissue adjacent to breast tumors reveals two distinct groups with divergent tumor microenvironment features.

We previously identified diverse genetic evolutionary patterns in whole-genome sequencing of paired normal tissue adjacent to tumor (NAT) and tumor tissues from Hong Kong breast cancer (HKBC) patients. Here, we investigated whether DNA methylation (DNAm) contributes to NAT heterogeneity and shapes the tumor microenvironment (TME). Genome-wide DNAm profiling was performed on paired NAT and tumor tissues from 188 HKBC patients using the Infinium 850 K array. RNA-seq data were available for 76 NATs and 177 tumors. Cellular composition was inferred using MethylCIBERSORT, CIBERSORTx, and EpiDISH, and histopathologic features were assessed on 115 H&E-stained sections. Unsupervised clustering identified two distinct NAT subtypes with divergent TME characteristics. Cluster 1 (N = 139) showed higher epithelial and fibroblast content and enrichment of estrogen response pathways. Cluster 2 (N = 49) exhibited an immune-metabolic phenotype characterized by increased fat and immune cells, stromal disruption, inflammatory pathway activation, and greater macrophage infiltration. Cluster 2 patients also demonstrated significantly younger epigenetic age estimated using multiple epigenetic clocks. These DNAm-defined NAT subtypes and associated TME features were validated in 97 NAT samples from TCGA breast cancer patients. Overall, our findings identify DNAm-driven NAT heterogeneity with distinct TME landscapes, providing new insights into field cancerization and tumor evolution in breast cancer.

Journal Article↗
PubMed2006

Pathways leading to muscle insulin resistance--the muscle--fat connection.

Type 2 diabetes is a heterogeneous disease characterized by hyperglycemia and insulin resistance in peripheral tissues such as adipose tissue and skeletal muscle. This review focuses on obesity as one of the major environmental factors contributing to the development of diabetes. It has become evident that adipose tissue represents an active secretory organ capable of releasing a variety of cytokines such as TNFalpha, IL-6, adiponectin and other still unknown factors that might constitute the missing link between adipose tissue and insulin resistance. In fact, adipocyte-derived factors are significantly increased in obesity and represent good predictors of the development of type 2 diabetes. The negative crosstalk between adipocytes and skeletal muscle cells leads to disturbances in muscle cell insulin signalling and insulin resistance involving major pathways in inflammation, cellular stress and mitogenesis. Positive regulators of insulin sensitivity include the adipocyte hormone adiponectin and inhibitors of inflammatory pathways such as JNK-, IKK- and ERK-inhibitors. In summary, a better knowledge of intracellular and intercellular mechanisms by which adipose tissue affects skeletal muscle cell physiology may help to develop new strategies for diabetes treatment.

Adipocytes↗
PubMed2006

Nicotine and serotonin in immune regulation and inflammatory processes: a perspective.

Nicotine and serotonin modulate the innate and adaptive immune responses and the inflammatory states. Several nicotinic cholinergic and serotonergic receptor subtypes have been characterized in B and T lymphocytes, monocytes, macrophages, and dendritic cells. The use of knockout mice has allowed a better characterization of nicotinic receptors and their role in anti-inflammatory processes in these cells. Cytokines play a crucial role in controlling inflammatory reactions. Nicotine and serotonin have been reported to regulate cytokine release. Cholinergic mechanisms also play an important role in inflammation through endogenous acetylcholine. Nicotine mimics this effect by activating the cholinergic anti-inflammatory pathways. New concepts of reciprocal interactions between nicotine and serotonin are emerging. The role of nicotine as an anti-inflammatory agent has been established, whereas that of serotonin remains more controversial.

Animals↗
PubMed2005

Brain damage in preterm infants: etiological pathways.

Preterm newborns represent a high-risk population for brain damage, primarily affecting the white matter, and for related neurodevelopmental disabilities. Determinants of brain damage have been extensively investigated, but there are still many controversies on how these factors can influence the developing brain and provoke damage. The concept of etiological pathway, instead of a single determinant, appears to better explain pathogenetic mechanisms: the brain damage may represent the final outcome of exposure to several combinations of risk factors in the same pathway or in different pathways and can change according to the gestational age. The aim of this article is to review the current knowledge on the pathogenesis of brain damage in preterm infants, within the frame of two main theoretical models, the ischemic and the inflammatory pathway. The relationship between the two pathways and the contribution of genetic susceptibility to ischemic and/or inflammatory insult, in modulating the extent and severity of brain damage, is also discussed.

Adult↗
PubMed1995

Intercellular adhesion molecule 1 gene associations with immunologic subsets of inflammatory bowel disease.

BACKGROUND & AIMS: Inflammatory bowel disease is characterized by a failure to down-regulate the usual self-limited gut inflammatory response, suggesting that one or more of the predisposing genes could be those that determine the level of the immune response along the inflammatory pathway. The aim of this study was to examine potential associations of intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms with inflammatory bowel disease or subsets of inflammatory bowel disease. METHODS: One hundred eighteen patients with ulcerative colitis (UC) and 130 patients with Crohn's disease (CD) as well as 77 ethnically matched controls were tested for antineutrophil cytoplasmic antibodies (ANCAs) and genotyped by polymerase chain reaction and allele-specific oligonucleotide techniques for ICAM-1 polymorphisms at codon 241 (exon 4) and codon 469 (exon 6). RESULTS: There was no significant difference between all patients with UC, patients with CD, and controls in either polymorphism. However, when stratified by ANCA status, ANCA-negative UC showed a significantly increased frequency of allele R241 compared with ANCA-positive UC (16.0% vs. 6.6%; P = 0.047, Fisher's Exact Test). In contrast, it was ANCA-positive CD that had an increased allele frequency compared with ANCA-negative CD (19.6% vs. 8.4%; P = 0.027, Fisher's Exact Test). CONCLUSIONS: Because the codon 241 polymorphism is in a functionally important domain III of ICAM-1, we may have identified an actual responsible genetic variation for genetically heterogeneous subsets of both UC and CD.

Alleles↗
PubMed2004

Bifunctional compounds eliciting both anti-inflammatory and cholinergic activity as potential drugs for neuroinflammatory impairments.

We tested two novel bifunctional compounds: ibuprofen-N-octyl-pyridostigmine bromide (IBU-PO) and ibuprofen-N-decyl-pyridostigmine bromide (IBU-PD). They both contain a non-steroidal anti-inflammatory drug (NSAID), ibuprofen (IBU) and pyridostigmine (PO), a cholinesterase inhibitor that acts as a cholinergic up-regulator (CURE). The two moieties are conjugated by a hydrocarbon spacer consisting of 8 (octyl) and 10 (decyl) carbons, respectively. The compounds were tested for their efficiency in reducing the neurological symptoms observed in experimental autoimmune encephalomyelitis induced in mice by myelin oligodendrocyte glycoprotein (MOG). IBU-PO and IBU-PD significantly ameliorated the clinical score (a 40-50% reduction in disease severity) over a period of 30 days, following daily administration of 1 and 0.1mg/kg, i.p., respectively. Clinical improvement was accompanied by reduced responsiveness of MOG-specific T-cells. In addition, IBU-PO and IBU-PD down-regulated the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in cultured astrocytes. To determine which moiety was responsible for these effects, we tested each of the two components, IBU and PO. Our findings indicate that combining NSAID with cholinergic intervention contributes an added therapeutic value for each distinct entity and that these bifunctional compounds act both on the peripheral immunological system and on the central nervous system (CNS) inflammatory pathways.

Animals↗
PubMed2003

Gene transfer approaches for the treatment of inflammatory bowel disease.

The pathogenesis of Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease, involves a complex interplay between certain genetic, environmental and immunological factors. Considerable research progress in the last decade defined key inflammatory pathways in the inflamed gut and identified new potential therapeutic targets. Since the current medical treatment with corticosteroids and anti-inflammatory drugs is often associated with undesired side effects and cannot completely cure IBD, these current advances in our understanding of intestinal pathology may now allow the development of new biologic treatment strategies including gene therapy. In this review, we will give a brief overview of potential gene therapy target molecules related to chronic intestinal inflammation. Furthermore, we summarize the results of recent preclinical studies for intestinal gene transfer and discuss future perspectives.

Adenoviridae↗
PubMed2003

Recent advances on the role of CD40 and dendritic cells in immunity and tolerance.

CD40 is a key signaling pathway for the function of B cells, monocytes, and dendritic cells in the immune system, and plays an important role in inflammatory pathways of nonhemopoietic cells. The NFkappaB family of transcription factors is a critical mediator in inflammation. NFkappaB is involved both in the regulation of CD40 expression and in cell signaling after CD40 ligation. This positive feedback loop linking NFkappaB and CD40 plays an important role in the control of the adaptive immune response, with fundamental implications for immunity and tolerance in vivo.

CD40 Antigens↗
PubMed2000

Human amylin stimulates inflammatory cytokine secretion from human glioma cells.

Chronic neurodegeneration in the brains of Alzheimer's disease (AD) patients may be mediated, at least in part, by the ability of amyloid beta (Abeta) to exacerbate inflammatory pathways in a conformation-dependent manner. In this regard, we previously reported that the Abeta-peptide-mediated potentiation of inflammatory cytokine secretion from interleukin-1beta (IL-1beta)-stimulated human astrocytoma cells was conformation dependent. Other amyloidogenic peptides, such as human amylin, which display similar conformation-dependent neurotoxic effects, may also elicit inflammatory cytokine secretion from glial cells. To test this hypothesis, we compared human and rat amylin for the effects on cytokine production in U-373 MG human astrocytoma cells. Human amylin alone stimulated U-373 MG cells to secrete IL-6 and IL-8 in a concentration-dependent manner with maximum effects seen at 10-25 microM peptide. In addition, human amylin markedly potentiated IL-1beta-stimulated cytokine production with a similar concentration dependence. In contrast, nonamyloidogenic rat amylin modestly stimulated cytokine secretion, either alone or combined with IL-1beta. Aging human amylin resulted in diminished cytokine secretion, probably due to the formation of large, less active aggregates. In agreement with our previous studies using Abeta, extracellular Ca(2+) was necessary for human amylin stimulation of cytokine secretion. Our data suggest that amyloidogenic peptides promote cytokine secretion through similar beta-sheeted secondary-structure- and extracellular-Ca(2+)-dependent mechanisms.

Aging↗
PubMed2006

Expression of nicotinic acetylcholine receptors on murine alveolar macrophages.

Neuronal nicotinic acetylcholine receptors (nAChRs) play an essential role in immunomodulation of macrophages. In particular, the alpha7 subunit confers inhibition of the systemic inflammatory response to bacterial lipopolysaccharide, thereby being the crucial element of the cholinergic anti-inflammatory pathway (Borovikova et al., 2000; Pavlov et al., 2003; Wang et al., 2003). In the murine lung, nicotine also exerts anti-inflammatory effects (Blanchet et al., 2004), but at least in murine alveolar macrophage cell lines the alpha7 subunit has not been detected (Matsunaga et al., 2001). On this background we investigated the expression of the nAChR subunits (alpha2-alpha7, alpha9, alpha10, beta2-beta4) on freshly isolated murine alveolar macrophages by immunohistochemistry and RT-PCR.

Animals↗