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Mutant forms of transthyretin (TTR) deposit in tissues of patients presenting with familial amyloidotic polyneuropathy (FAP). The cellular consequences of tissue TTR deposition have only been addressed recently and are summarized here. Inflammatory and oxidative stress pathways are triggered by fibrillar and non-fibrillar TTR deposits, a fact to take into account in future forms of FAP treatment.
BACKGROUND: The risk of colorectal carcinoma development is elevated in chronic, longstanding ulcerative colitis. The changes of such regenerative and immortalizing pathways caused by the inflammatory process that are proved to be carcinogenic in other human tissues have not been fully and uniformly described. Aim of the study was to describe the expression alterations of regenerative signal receptors and cell aging inhibitory systems within colonic crypts considering the histological activity of the disease. MATERIALS AND METHODS: I-type insulin-like growth factor receptor (IGF1R), hepatocyte derived growth factor receptor (HGFR), telomerase reverse transcriptase (TERT) and telomerase associated protein (TP-1) expression were evaluated immunohistochemically on formalin fixed paraffin embedded biopsy specimen from 10 mild, 10 moderate, and 10 severe active inflammation of ulcerative colitis and from 10 normal colonic tissue. RESULTS: In mild inflammation all observed parameter showed significantly elevated protein expression in protein level compared to normal (p <0.005). In moderately active inflammation only IGF1R expression was significantly higher compared to normal and to mild inflammation (p <0.005). There were no regenerative signal expression alteration in severe inflammation compared to normal, and epithelial telomerase expression was not detectable in these cases. CONCLUSION: The expression of regenerative signal receptors and immortalizing factors is elevated in mildly (and moderately) inflamed ulcerative colitis. This phenomenon let the genetically defected epithelial cells to pathologically survive and proliferate, so thus favours the development of tumors.
A number of stimuli known to induce acid hydrolase secretion from cultured macrophages were examined for their ability to activate C3 via the alternative pathway of the complement system. Loss of haemolytically active C3 was checked in normal and C4-deficient guinea-pig serum. For comparison the interactions of cultured macrophages with other agents well known as potent activators of the alternative pathway of the complement system have been investigated. As judged by their activity in these assays, group A streptococcal cell walls, different carrageenan preparations, dental plaque and Actinomyces viscosus were all capable of initiating the alternative pathway but differed with respect to their potency and their ability to inhibit C3 turnover at high concentrations. Zymosan, some carrageenans, polyanethol sulphonate, and Corynebacterium parvum all induce the release of hydrolytic enzymes from macrophages in culture, even in the absence of serum in the medium. The release is time- and dose-dependent and is not associated with loss of the cytoplasmic enzyme lactate dehydrogenase or any other sign of cell death. The parallelism between the capacity of several agents to activate the complement system via the alternative pathway and to induce inflammatory responses in vivo and selective lysosoma enzyme secretion from cultures of macrophages is discussed.
By initial 3H-thymidine labelling an enhanced monocyte proliferation in the bone marrow of patients with rheumatoid arthritis is demonstrated. The significant monocyte proliferation correlates positively with the erythrocyte sedimentation rate but shows a negative correlation with age. The high significance of the mononuclear phagocyte (MNP) system in the pathogenesis of rheumatoid arthritis is seriously underlined by the experimental findings in our allergic arthritis model. Benoxaprofen as an inhibitor of the lipoxygenase pathway and of the inflammatory monocyte influx significantly suppresses the experimental allergic synovitis. These findings stress upon the important role of the MNP-system in the pathogenesis of rheumatoid arthritis and demonstrate the significance of the monocytes/macrophages as an important target-cell system for antirheumatic drugs.
Since high-molecular-weight levan is known to reduce capillary permeability to large molecules, an experiment was designed to investigate whether this agent may attenuate the glomerulonephritis associated with acute serum sickness in rabbits. The study, in fact, demonstrated an enhancing effect of levan, which caused increased glomerular proliferative changes and leucocyte infiltration and, possibly, increased IgG deposition in this experimental model. In addition, rabbits injected only with levan also demonstrated mild glomerulitis and C3 deposition. In one of four rabbits examined, this was accompanied by a marked fall in the serum level of total haemolysing complement. Levan was demonstrated to cause activation of complement when incubated with normal rabbit serum in vitro. We believe that these findings are best explained on the basis of complement activation in situ by levan in the glomeruli, probably via the alternative pathway, with the resulting inflammatory response. In the case of BSA-injected rabbits, this response is believed to be additive to that of the classical immune complex-mediated complement activation.
Superoxide anion (0(-2)), hydrogen peroxide (H2O2) and hydroxyl radical (OH.) are products of the biological reduction of 0(2). They are very reactive and poorly tolerated within living systems and enzymes that catalytically scavenge these products have been evolved as defense mechanisms. These include superoxide dismutases (SOD), catalase and peroxidases. Large amounts of O-2 are produced by different enzymatic and non enzymatic biological processes. Large amounts of activated oxygens are produced by phagocytosing cells such as macrophages and polymorphonuclear cells. This production is associated with the bactericidal actions of these cells but it also largely contributes to exacerbate and sustain the inflammation where these cells congregate. The arachidonic acid pathway triggered by the inflammatory stimuli is also a source for these oxidizing radicals. The production of activated oxygens has been associated with the normal aging process but also with various toxic reactions (e.g. the toxicity of the herbicide paraquat, of the ionizing radiations, of certain antibiotics such as streptonigrin, etc. . . .). O-2 induces the depolymerization of hyaluronic acid which lends viscosity and lubricating properties to synovial fluids. SOD possess antiinflammatory properties and a bovine SOD, orgotein, has now been largely investigated by intramuscular and intraarticular injections in the treatment of rheumatic diseases. Various antiinflammatory compounds (e.g. the salicylates) are able either to inhibit the production of these oxygen radicals or to scavenge them which seems of importance for their antiinflammatory properties. Singlet oxygen, another activated oxygen, might also play a role in the inflammatory process.
Mouse peritoneal macrophages in culture exposed to mouldy hay dust, Micropolyspora faeni or glycopeptide or protein/glycoprotein fractions from this organism show marked biochemical changes. For comparison the interaction of cultured macrophages with zymosan has been investigated. All these agents induce the release of hydrolytic enzymes from macrophages, even in the absence of serum in the medium. The release is time- and dose-dependent and is not associated with loss of the cytoplasmic enzyme lactate dehydrogenase or any other sign of cell death. The parallelism between the capacity of these agents to activate the complement system via the alternative pathway and to induce inflammatory responses in vivo and selective lysosomal enzyme secretion from cultures of macrophages is discussed. The in vitro phenomena seen with mouldy hay dust, M. faeni, the protein/glycoprotein and the glycopeptide derived from it, may be relevant to understanding the role of mononuclear phagocytes in the disease farmer's lung and other inflammatory reactions.
Secretion of the eicosanoids, nitric oxide (NO.) and superoxide anion (O2.-) was evaluated in human embryonic astrocytes and microglia. An inducible form of cyclo-oxygenase (COX 2) was demonstrated in astrocytes and microglia after IL-1 beta plus IFN-gamma stimulation; since 1) large amounts of PGF2 alpha were released; 2) PGF2 alpha secretion required protein synthesis and was blocked by indomethacin; and 3) the response was delayed and persistent. Using the same inducers, astrocytes, but not microglial cells, produced NO. and had an inducible form of nitric oxide synthase. Conversely, microglial cells were induced by IL-1 beta and IFN-gamma to generate superoxide anions (O2.-) through an NADPH oxidase-dependent pathway. We then investigated interactions between these different pathways of synthesis by inhibition experiments. The cytokine-induced production of PGF2 alpha in astrocytes was not affected by exposure to N-omega-monomethyl-L-arginine, which inhibits NO. production, whereas it was reduced by 40% in microglia. Since microglia did not secrete any detectable NO. in their supernatant, intracellular production of NO. could occur in these cells that positively regulated PGF2 alpha production. Exposure to indomethacin, which prevented PGF2 alpha production in both astrocytes and microglia, resulted in a 64% increase in cytokine-induced NO. production by astrocytes and a 70% inhibition of O2.- generation by stimulated microglia. Finally, superoxide dismutase depletion of O2.- in astrocytes and microglia had no effect on PGF2 alpha production in these cells. These results demonstrate that there are important interactions between the pathways of synthesis of inflammatory mediators in glial cells that could unveil additional regulatory mechanisms.
Respiratory virus are the most frequent cause of asthma attacks, and are responsible for more than 80% of episodes of wheezing in children. Atopic subjects have a higher risk of respiratory virus infections, benign or severe, than healthy persons. In children older than 8 years, most respiratory infections are caused by rhinovirus (RV). RV colonizes the respiratory epithelium and provokes a symptomatic rhinitis by non-inflammatory routes (with non involvement of leucocytes). In the nose the most importance of these routes are nerves. In the lower respiratory airways, infection with RV causes an inflammatory reaction with persistence of eosinophils. IL-8 and the other cytokines produced by the infected epithelium extend the action of eosinophils and the inflammatory reaction. The viral/inflammatory pathway is an important new target for development of strategies for the prevention of asthma.
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Generation of mixtures of small interfering (si) RNAs by recombinant dicer avoids selection of efficient target sites within mRNAs but little is known about off-target effects of this approach. Using recombinant human dicer we generated siRNA mixtures (dsiRNA) directed against the protein kinase TAK1 and its subunit TAB1, important upstream molecules in the pathways activated by IL-1, TNF, and toll-like receptors (TLR). dsiRNA against TAK1 or TAB1 significantly suppressed their target proteins as well as TAK1-mediated activation of NFkappaB, p38 MAPK, and JNK, and of IL-8 transcription. However, microarray analysis of 136 endogenous inflammatory genes revealed that dsiRNA against TAB1 or TAK1 did not suppress IL-1 or TNF-induced genes but rather induced a broader range of 15 inflammatory genes as well as seven known interferon-response genes. The same genes were induced by dsiRNA directed against luciferase but not by a synthetic control siRNA molecule. Hence, our results show that complex mixtures of siRNA induce an inflammatory gene response that is independent from TAK1-mediated signal transduction. In the light of the increasing usage of enzymatically prepared libraries of siRNA these results provide important insight into potential off-target effects of this approach.
Fas/FasL signaling is best known for induction of apoptosis. However, there is an alternate pathway of Fas signaling that induces inflammatory cytokines, particularly tumor necrosis factor (TNF)-alpha and interleukin (IL)-8. This pathway is prominent in cells that express high levels of anti-apoptotic molecules such as Bcl-xL. Because TNF-alpha is central to the pathogenesis of psoriasis and psoriatic epidermis has a low apoptotic index with high expression of Bcl-xL, we hypothesized that inflammatory Fas signaling mediates induction of psoriasis by activated lymphocytes. Noninvolved skin from psoriasis patients was grafted to beige-severe combined immunodeficiency mice, and psoriasis was induced by injection of FasL-positive autologous natural killer cells that were activated by IL-2. Induction of psoriasis was inhibited by injection of a blocking anti-Fas (ZB4) or anti-FasL (4A5) antibody on days 3 and 10 after natural killer cell injection. Anti-Fas monoclonal antibody significantly reduced cell proliferation (Ki-67) and epidermal thickness, with inhibition of epidermal expression of TNF-alpha, IL-15, HLA-DR, and ICAM-1. Fas/FasL signaling is an essential early event in the induction of psoriasis by activated lymphocytes and is necessary for induction of key inflammatory cytokines including TNF-alpha and IL-15.
We performed this study to determine the relationship between activation of nuclear factor (NF)-kappaB and inhibition of keratinocyte growth by anthralin, which not only might be useful for a better understanding of the role of NF-kappaB in the pathogenesis of psoriasis, but also indicate whether the inflammatory reaction induced by anthralin is inseparable from its antipsoriatic activity. The involvement of NF-kappaB was assessed using the antipsoriatic drugs leflunomide and triptolide (T0) as effectors, since they can inhibit NF-kappaB activation induced by anthralin. The results showed that the inhibition of keratinocyte growth by anthralin was not related to the activation of NF-kappaB. Using sodium salicylate, a known NF-kappaB inhibitor, further confirmed this conclusion. Thus it might be possible to inhibit the inflammatory response induced by anthralin via repression of NF-kappaB activation. We found that leflunomide or T0 could significantly inhibit the mRNA overexpression of interleukin-8 and intercellular adhesion molecule-1 in keratinocytes induced by anthralin. Taken together, our data indicate that the growth inhibition of anthralin is related to the NF-kappaB-independent signaling pathway, and that leflunomide or T0 could control proinflammatory cytokine expression induced by anthralin via inhibiting the activation of NF-kappaB.
Upon activation, basophilic granulocytes release inflammatory mediators such as histamine. We studied histamine release of human basophils (64.1 +/- 9.6% pure) after cross-linking of membrane-bound IgE via anti-IgE, or after binding of the chemoattractant formyl-methionyl-leucyl-phenylalanine (fMLP). A variability in the extent of histamine release upon stimulation by either anti-IgE or fMLP was found between donors. Kinetic studies revealed that the histamine release induced by anti-IgE (t1/2 greater than 240 s) was more than 20-fold slower than the almost instantaneous release upon stimulation with fMLP (t1/2 less than 10 s). Differences in the cell activation pathways triggered by these stimuli were further analyzed with staurosporine, an inhibitor of protein kinase C (PKC) and with wortmannin, an inhibitor of a PKC-independent pathway. Inhibition of PKC resulted in a partial inhibition of the anti-IgE-induced release, whereas the fMLP-induced release was slightly potentiated. The anti-IgE-induced release was completely inhibited in the presence of wortmannin. This inhibitor too, had no effect on the fMLP-induced release. We conclude that major differences exist in the signal-response coupling between the anti-IgE and fMLP-induced histamine release in human basophils. The so-called releasability of human basophils may be due to the availability of different cell activation pathways.
Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce the risk of colorectal cancer (CRC). They are also known to induce the regression of colorectal adenomas, which are precursors to CRC. Despite these evidences, the exact mechanism by which NSAIDs exerts its anti-oncogenic effect is not completely understood. Using a focus formation assay, here we show that sulindac sulfide, a NSAID, specifically inhibits cell transformation mediated by oncogenic Ha-Ras, but not by other established oncogene products such as v-Src, Galpha12, and Galpha13. Our results suggest that the ability of sulindac sulfide to suppress transformation is confined to specific oncogenic pathways. Further studies of the sulindac-resistant oncogenic pathways may lead to identification of novel therapeutic agents that are effective in the prevention or treatment of CRC.
INTRODUCTION: PCOS is a common endocrine disorder with elevated cardiometabolic risk, yet the role of the renin-angiotensin system (RAS)-iron metabolism axis in this comorbidity remains unclear. We explored its underlying mechanisms and evaluated the therapeutic potential of gentiopicroside. METHODS: Integrated multi-omics analyses combining transcriptomics, single-cell RNA sequencing, Mendelian randomization, machine learning, molecular docking, and in vitro functional assays were performed to identify shared molecular pathways and therapeutic targets across PCOS, hypertension, NAFLD, and T2DM. RESULTS: SLC11A2 was consistently dysregulated in PCOS transcriptomic datasets, and associated with iron metabolism, inflammatory response and oxidative stress pathways. Genetic analyses validated RAS-related regulation in hypertension susceptibility and revealed shared genetic architecture between PCOS and cardiometabolic traits. Network and single-cell analyses characterized SLC11A2-associated molecular patterns in disease-relevant cell types; machine learning identified disease-classifying molecular signatures. Gentiopicroside alleviated inflammatory and oxidative stress phenotypes, including reduced IL-6 expression and reactive oxygen species accumulation. CONCLUSION: This study defines an RAS-SLC11A2 molecular framework linking iron metabolism dysregulation to PCOS-related cardiometabolic risk, elucidating the mechanisms connecting ovarian dysfunction, inflammation, oxidative stress and hypertension, and supports gentiopicroside as a promising therapeutic candidate.
Ischemic stroke is a devastating global public health problem and the leading cause of acute death and chronic disability. Despite being the diagnostic cornerstone, limitations in neuroimaging, including availability, cost, and therapeutic window, have rekindled interest in biomarker-based approaches. Biomarkers will be employed to facilitate the eventual prediction, early diagnosis, and prognosis of strokes, as well as to inform person-centered medicine. This review summarizes recent advances in the search for biomarkers related to inflammatory, endothelial, metabolic, and neuroaxonal pathways. Interleukin-6 (IL-6), asymmetric dimethylarginine (ADMA), endothelial microparticles (EMP), and homocysteine serve as predictive biomarkers corresponding to vascular risk and inflammatory priming. Glial fibrillary acidic protein (GFAP), D-dimer, and neuron-specific enolase (NSE) are diagnostic markers that can already subtype stroke and estimate lesion burden. Prognostic biomarkers, such as serum neurofilament light chain (sNfL), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP), and growth differentiation factor 15 (GDF-15), are associated with infarct size and long-term outcomes. The -omic sciences (genomic, proteomic, and metabolomic) have discovered defined molecular signatures and panels with high specificity to describe heterogeneity in stroke. Cerebrospinal fluid (CSF) biomarkers and newer imaging modalities, such as those provided through positron emission tomography/computed tomography (PET/CT), offer valuable adjuncts to blood biomarkers in the diagnosis of conditions. Translational potential is hindered by heterogeneity in the transcriptional landscape.
The ubiquitin-proteasome pathway is regarded as playing a crucial role in protein breakdown in inflammation and sepsis as well as in the regulation of inflammatory cell responses. In this pathway, ubiquitylation of target proteins is believed to act as a recognition signal for degradation by the 26S proteasome. As yet neither the ubiquitylation rate of cytosolic proteins, as a result of the total ubiquitin-protein ligase (tUbPL) activity, nor the specific ubiquitylation of calmodulin (ubiquitin-calmodulin ligase, uCaM-synthetase) has been determined in human mononuclear cells. Therefore, we studied cytosolic protein ubiquitylation in normal and in endotoxin (LPS)-stimulated human peripheral blood mononuclear cells (PBMNCs).PBMNCs from healthy volunteers were incubated with 0 or 100 ng/ml LPS for 18 h. Cytosolic extracts were obtained by hypotonic lysis and ultracentrifugation. TUbPL was measured as [(125)I]-[CT]-ubiquitin incorporation into the sum of cytosolic proteins. UCaM-synthetase activity was quantified with the fluphenazine (FP)-Sepharose affinity adsorption test. Endotoxin stimulation appears to inhibit tUbPL 3.7 +/- 2.7-fold to 48 +/- 43 fkat/mg (n = 6). UCaM-synthetase in cultures (n = 5) without endotoxin was determined to be 91 +/- 32 fkat/mg +Ca(2+) and 29 +/- 23 fkat/mg -Ca(2+). With endotoxin uCaM-synthetase was 138 +/- 73 fkat/mg +Ca(2+) and 14 +/- 22 fkat/mg -Ca(2+). Ca(2+)-specificity (ratio +/- Ca(2+)) of uCaM-synthetase increases from 3.1 without LPS to 10 after LPS stimulation, which was caused by a 2-fold decrease in minus Ca(2+) activity and a 1.5-fold increase in plus Ca(2+) activity. The data indicate specific regulatory effects of endotoxin on the cytosolic ubiquitylation systems in human PBMNCs.