Overexpression Of Proinflammatory Cytokines Research Articles

Serum interleukin‐6 levels in response to methotrexate treatment in psoriatic patients

BackgroundPsoriasis is a chronic autoimmune hyperproliferative skin disease. In psoriasis, the cutaneous and systemic overexpression of various proinflammatory cytokines, such as interleukin-6 (IL-6) has been demonstrated. Methotrexate (MTX) has been used in the treatment of psoriasis. The aim of this study is to assess the effect of MTX on serum IL-6 levels and also to find the association between PASI score and IL-6 levels in psoriatic patients during MTX therapy. MethodsWe recruited 20 control subjects and 22 Psoriasis vulgaris patients for this study. The patients were treated with 7.5mg of methotrexate per week for 12weeks. Folic acid was given at 5mg once daily except on the day of MTX for 12weeks. There were 2 dropouts, because of increased liver enzyme levels. Blood samples were collected at three intervals (i.e., Day 0, 6weeks, 12weeks) from psoriatic patients and only once from control subjects. PASI score, biochemical and hematological parameters were assessed. Serum IL-6 level was analyzed by using ELISA. ResultsBiochemical and hematological parameters showed no significant changes. Serum IL-6 level and PASI score declined significantly (p<0.001) from Day 0 to 12weeks of MTX treatment and also showed positive correlation before (r=0.992; p<0.000) and after (r=0.987; p<0.000) treatment with MTX. Out of 4 clinical indices of PASI, only 2 indices namely Infiltration (I) and Desquamation (D) showed positive correlation with IL-6 before and after MTX treatment. ConclusionThe treatment response with MTX in psoriatic patients can be seen both at clinical and molecular levels.

Abstract 145: Epigenetic Modifications of Bone-Marrow Progenitor Cells Promote an M1 Phenotype in Peripheral Macrophages in Diabetes

Introduction: Diabetic wounds are characterized by a chronic inflammatory state that is maintained by overexpression of pro-inflammatory cytokines generated by immune cells, namely macrophages. To understand this imbalance, it is critical of understand how changes in immune cells at the systemic level influence the peripheral immune cells. Work from our lab has shown that cytokines induce a histone post-translational “epigenetic signature” at promoter sites of specific genes. However, the role of histone modification of DNA on diabetic progenitor and differentiated immune cells and their impact on chronic inflammation in the periphery has not been studied. We hypothesized that epigenetic changes to bone marrow cells influences peripheral macrophage phenotypes. Methods: Bone marrow was harvested from 7 diet-induced obese mice (DIO) (mean glucose= 290) and 7 wildtype (WT) controls. In some of the mice, lin -/ckit+ population was isolated and flow cytometry (FACS) analysis was performed to isolate hematopoietic stem cells (HSC) and myeloid progenitor cells (MYP). HSC were defined as cells expressing sca1+/CD150+/flt3+ and MYP co-expression of sca1+/CD150+/FcgR-/CD105low. HSC and MYP were analyzed via FACS for the presence of chromatin marks. In other mice, BMD macrophages were isolated and propagated in cell culture. Macrophages were either untreated or skewed towards an M1 or M2 phenotype with IF-gamma or IL-4, respectively. Levels of protein and mRNA of M1/M2 products were analyzed. Additionally, at 6, 24 and 72 hours the macrophages were assessed for expression of chromatin remodeling marks via FACS analysis. Results: HSC had a 2 fold decrease in the expression of H3K9 histone methylation marks in the DIO mice as compared to WT. (Figure 1A) This pattern was also observed in the more differentiated MYP cells. (Fig 1B) Macrophages isolated from diabetic mice also reflected these histone changes, supporting the role of histone methylation on fully-differentiated macrophage gene expression. (Fig 1C) DIO macrophages demonstrated increased levels of TNF-alpha and CCL3, classic M1 phenotype markers. (Fig 1D) Conclusions: Epigenetic changes initiated in the bone marrow progenitor cells effect immune cells in the periphery, and may contribute to the chronic inflammation seen in diabetics. Manipulation of these histone modifications at the bone marrow level could allow for the development of therapies to prevent chronic inflammation in the periphery of diabetics.

Metabolites of Lactobacillus plantarum 2142 Prevent Oxidative Stress-Induced Overexpression of Proinflammatory Cytokines in IPEC-J2 Cell Line

Probiotics have already proven beneficial effects in the treatment of several intestinal infections, but the underlying mechanisms how the probiotics can affect responses of porcine IPEC-J2 enterocytes to oxidative stress remained to be elucidated. The immunomodulatory effect of five bacterial strains (Lactobacillus plantarum 2142, Lactobacillus casei Shirota, Bifidobacterium animalis subsp. lactis BB-12, Bacillus amyloliquefaciens CECT 5940 and Enterococcus faecium CECT 4515) on 1 mM peroxide-triggered upregulation of interleukin (IL)-8 and tumor necrosis factor alpha (TNF-α) level was screened by q RT-PCR. Our data revealed that spent culture supernatant (SCS) of L. plantarum 2142 had significant lowering effect on IL-8 and TNF-α level with concomitant promoting activity on protective Hsp70 gene expression. According to our results, lactic acid (racemic, D: - and L: -lactic acid) and acetic acid produced by lactobacilli had no protective effect in quenching upregulation of proinflammatory cytokines. Furthermore, L. plantarum 2142-specific supernatant peptides were detected by gel electrophoresis and capillary zone electrophoresis.

Systemic inflammation and priming of peripheral blood leukocytes persist during clinical remission in horses with heaves

ObjectiveTo compare innate immune responses of peripheral blood leukocytes from healthy and asymptomatic heaves-affected horses. AnimalsHeaves-affected horses (n=5-6) and healthy controls (n=4–5) kept under low dust environments (pasture or shavings and pellets). MethodsBlood neutrophil and neutrophil-depleted cell populations were isolated using MACS system. Cells were incubated with or without bacterial products (lipopolysaccharide (LPS), 100ng/mL and fMLP, 5ng/mL, 5h). Cytokine (IL-1β, IL-8, TNF, IL-4, INFγ and IL-10) and receptor (TLR4) mRNA expression was assessed by qPCR. TNF concentration in culture supernatants and serum samples was assessed using equine specific ELISA. Apoptotic rate of resting and stimulated neutrophils was assessed by flow cytometry using AnnexinV and 7-AAD (18h) and correlated with early pro-inflammatory cytokine expression in the same cells (5h). ResultsStimulation with bacterial-derived products resulted in overexpression of pro-inflammatory cytokines in both neutrophils (IL-1β and TNF) and neutrophil-depleted leukocytes (IL-1β and IL-8) from heaves-affected horses. Neutrophil survival (18h) was associated with their early TNF expression, but not IL-8. Neutrophil-depleted leukocytes from these horses also had significantly increased basal TNF mRNA levels. Serum TNF concentration was also significantly higher in heaves-affected horses compared to healthy horses kept in similar environment. ConclusionsAltered innate immune response to bacterial products is observable ex vivo in peripheral blood leukocytes from asymptomatic heaves-susceptible horses and is associated with high serum TNF concentration. It remains to be determined if this phenomenon is caused by intrinsic differences in innate immune responses or to cellular priming caused by systemic inflammation.

Metabolic and immune risk factors for dementia and their modification by flavonoids: New targets for the prevention of cognitive impairment?

A number of contributory factors have been implicated in the pathogenesis of Alzheimer's disease. One of these factors is chronic inflammation, with the over expression of pro-inflammatory cytokines and acute phase reactants consistently observed in the post mortem brain and plasma of AD patients. Furthermore, cardiovascular risk factors, such as hypertension, impaired vascular function and elevated LDL cholesterol, also appear to be predictive of increased dementia risk. Although classically associated with cardiovascular disease risk, both vascular and immune mediators may have direct deleterious effects on the brain, which contribute to the development of vascular dementia and Alzheimer's disease, as well as impairments in memory and neuro-cognitive function. Dietary agents previously noted for their ability to modulate these cardiovascular risk factors leading to reductions in chronic, low-grade inflammation and/or vascular dysfunction, may also possess an ability to moderate the progression of dementia. Flavonoid-rich foods such as tea, berries and cocoa have been reported to attenuate age-related deficits in memory and cognition, although the precise mechanisms of their action are unclear. As these flavonoid rich-foods/beverages also appear to mediate inflammatory processes, attenuate endothelial dysfunction and reduce hypertension, such actions may contribute to their efficacy in the brain. This review will explore these concepts with the view to further unravelling the actions of flavonoids and flavonoid-rich foods against brain disease and to highlight the importance measuring such factors in future clinical studies.

Insights into Behçet’s disease

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Shahneh F, Babalo Z, Baradaran B, Sepehr K. Review paperInsights into Behçet’s disease. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii. 2012;29(6):461-466. doi:10.5114/pdia.2012.32395. APA Shahneh, F., Babalo, Z., Baradaran, B., & Sepehr, K. (2012). Review paperInsights into Behçet’s disease. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, 29(6), 461-466. https://doi.org/10.5114/pdia.2012.32395 Chicago Shahneh, Fatemeh Zare, Zohreh Babalo, Behzad Baradaran, and Koushan Sineh Sepehr. 2012. "Review paperInsights into Behçet’s disease". Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii 29 (6): 461-466. doi:10.5114/pdia.2012.32395. Harvard Shahneh, F., Babalo, Z., Baradaran, B., and Sepehr, K. (2012). Review paperInsights into Behçet’s disease. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, 29(6), pp.461-466. https://doi.org/10.5114/pdia.2012.32395 MLA Shahneh, Fatemeh Zare et al. "Review paperInsights into Behçet’s disease." Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, vol. 29, no. 6, 2012, pp. 461-466. doi:10.5114/pdia.2012.32395. Vancouver Shahneh F, Babalo Z, Baradaran B, Sepehr K. Review paperInsights into Behçet’s disease. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii. 2012;29(6):461-466. doi:10.5114/pdia.2012.32395.

Chemical genetics of neuroinflammation: natural and synthetic compounds as microglial inhibitors

Chemical genetics is a new field of study that employs diverse small-molecule compounds to interrogate specific biological functions. The chemical genetics approach has been recently applied to microglial biology. Microglial cells are the primary immune cells of the brain, and are believed to play a major role in both host defense and tissue repair in the central nervous system. However, excessive microglial activation with overexpression of proinflammatory cytokines and oxidative stress products is linked to the progression of several neurodegenerative diseases. Therefore, suppression of microglial activation and subsequent neuroinflammation may be a potential therapeutic approach against these diseases. From microglia cell-based assays, the natural compound obovatol and several synthetic compounds were identified as inhibitors of microglial activation. They showed strong anti-neuroinflammatory activities in various in vitro and in vivo studies. Nuclear factor-κB and mitogen-activated protein kinase pathways were found to be related to the effects of these compounds on microglia. In particular, based on the affinity purification approach, peroxiredoxin 2 was identified as a microglial target of obovatol. Thus, natural and synthetic compounds are not only important biological tools for the study of microglial physiology and pathology, but they are also attractive candidates for the development of therapeutic drugs against neuroinflammatory and neurodegenerative diseases.

Role of Islet Culture on Angiogenic and Inflammatory Mechanisms

Early events hampering islet engraftment may relate to instant blood-mediated inflammatory reaction (IBMIR) and to insufficient islet revascularization inducing β-cell death. We evaluated the influence of time of culture on angiogenic and inflammatory cellular mechanisms in islet loss in vitro. Rat pancreatic islets cultured for 0, 12, 24, and 48 hours were assessed for functionality using glucose stimulation tests and identification of signaling pathways using polymerase chain reaction (PCR) arrays. Islet functionality decreased significantly immediately. Index of stimulation (IS) was decreased to 2.29 ± 1.05 after 48 hours of culture versus 18.47 ± 4.84 at 0 hours ( P < .001). Gene expression studies at 12 hours of culture showed significant overexpression of proinflammatory cytokines and chemokines — interleukin (IL)-6 884.22 ± 282.58 ( P < .001) and Cxcl-1 448.09 ± 196.05-fold change ( P < .01). Moreover, islets exhibited significant under-expression after 48 hours of genes encoding angiogenic growth factors, such as epidermal growth factor, vascular endothelial growth factor, platelet endothelial cell adhesion molecule 1, a major protein involved in angiogenesis: 0.07 ± 0.02, 0.11 ± 0.08 ( P < .001), and 0.17 ± 0.15-fold change ( P < .01) respectively. Moreover, tissue inhibitor of metalloproteinases 1, an inhibitor of metallopeptidase, was significantly more over-expressed, namely 54.58 ± 18.08 at 12 hours of culture versus 0.93 ± 0.15/fold change at 0 hours. This study revealed current culture conditions to be deleterious for islet engraftment, possibly due to expression of angiogenic genes and proinflamatory genes during culture.

Exaggerated inflammatory response affects endometrial receptivity in women with idiopathic recurrent spontaneous miscarriage

Exaggerated inflammatory response affects endometrial receptivity in women with idiopathic recurrent spontaneous miscarriage

Resveratrol ameliorates TNFα‐mediated suppression of erythropoiesis in human CD34+ cells via modulation of NF‐κB signalling

Overexpression of pro-inflammatory cytokines, including tumour necrosis factor alpha (TNFα), has been implicated in the pathogenesis of anaemia of inflammation. TNFα suppresses erythroid colony formation via both direct and indirect effects on haematopoietic progenitors, often involving activation of nuclear factor (NF)-κB signalling resulting in downregulation of transcription factors critical for erythropoiesis. There is a dearth of effective and safe therapies for many patients with inflammatory anaemia. Resveratrol is a flavanol found in red wine grapes that possesses potent anti-inflammatory properties, but studies of its impact on human erythropoiesis have proven contradictory. We investigated whether resveratrol ameliorates TNFα-mediated suppression of erythropoiesis in human CD34(+) haematopoietic progenitors. We found that resveratrol partially reverses the erythroid suppressive effects of TNFα, leading to significant recovery in burst forming unit-erythroid colony formation in human CD34(+) cells. CD34(+) cells pre-incubated with resveratrol for 72 h in the presence of TNFα inhibited NF-κB activation via decreased NF-κB nuclear localization without altering total NF-κB protein levels and independent of IκB degradation. Resveratrol also significantly restored the baseline expression of erythroid transcription factors NFE2 and the GATA1/GATA2 ratio in CD34(+) cells treated with TNFα. In conclusion, resveratrol may inhibit TNFα-mediated NF-κB activation and promote erythropoiesis in primary human CD34(+) cells.

Quantitative trait loci in a bacterially induced model of inflammatory bowel disease.

Inflammatory bowel diseases (IBDs) are complex disorders caused by a combination of environmental, microbial, and genetic factors. Genome-wide association studies in humans have successfully identified multiple genes and loci associated with disease susceptibility, but the mechanisms by which these loci interact with each other and/or with environmental factors (i.e., intestinal microbiota) to cause disease are poorly understood. Helicobacter hepaticus-induced intestinal inflammation in mice is an ideal model system for elucidating the genetic basis of IBD susceptibility in a bacterially induced system, as there are significant differences in H. hepaticus-induced disease susceptibility among inbred mouse strains. Infected A/J mice develop acute overexpression of proinflammatory cytokines followed 2-3 months later by chronic cecal inflammation, whereas infected C57BL/6 mice fail to develop cecal inflammation or increased cytokine expression. The goal of this project was to use quantitative trait locus (QTL) mapping to evaluate genetic factors that contribute to the differential disease susceptibility between these two mouse strains. Using acute cecal IL-12/23p40 expression as a biomarker for disease susceptibility, QTL analysis of H. hepaticus-infected F(2) mice revealed involvement of multiple loci. The loci with the strongest association were located on Chromosome 3 and Chromosome 17, with logarithm of odds (LOD) scores of 6.89 and 3.09, respectively. Cecal expression of IL-12/23p40 in H. hepaticus-infected C57BL/6J-Chr3(A/J)/NaJ chromosome substitution mice had an intermediate phenotype, significantly higher than in resistant C57BL/6 but lower than in susceptible A/J mice, confirming the importance of this locus to the immune response to H. hepaticus infection.

Anti-inflammatory effect of transduced PEP-1-heme oxygenase-1 in Raw 264.7 cells and a mouse edema model

Heme oxygenase-1 (HO-1), which catalyzes the degradation of free heme to biliverdin, carbon monoxide (CO), and free iron (Fe2+), is up-regulated by several cellular stress and cell injuries, including inflammation, ischemia and hypoxia. In this study, we examined whether fusion of HO-1 with PEP-1, a protein transduction domain that is able to deliver exogenous molecules to living cells or tissues, would facilitate HO-1 delivery to target cells and tissues, and thereby effectively exert a therapeutically useful response against inflammation. Western blot analysis demonstrated that PEP-1-HO-1 fusion proteins were transduced into Raw 264.7 cells in time- and dose-dependent manners, and were stably maintained in the cells for about 60h. In addition, fluorescence analysis revealed that only PEP-1-HO-1 fusion proteins were significantly transduced into the cytoplasm of cells, while HO-1 proteins failed to be transduced. In lipopolysaccharide (LPS)-stimulated Raw 264.7 cells and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse edema model, transduced PEP-1-HO-1 fusion proteins effectively inhibited the overexpression of pro-inflammatory mediators and cytokines. Also, histological analysis demonstrated that PEP-1-HO-1 remarkably suppressed ear edema. The results suggest that the PEP-1-HO-1 fusion protein can be used as a therapeutic molecule against reactive oxygen species-related inflammatory diseases.

Involvement of Axl receptor tyrosine kinase in the pathogenesis of DSS-induced IBD (166.14)

Abstract To elucidate the role of Axl receptor tyrosine kinase on the pathogenesis of inflammatory bowel disease (IBD), IBD-associated prognostic factors were examined in dextran sulfate sodium (DSS)-treated wild type and Axl-/- mice. We found that body weight and colon length were decreased in DSS-treated Axl-/- mice compared to those in DSS-treated WT mice. In addition, the reduced number of regulatory T cells was observed in the large intestine, mesenteric lymph node, and peritoneal cavity of DSS-treated Axl-/- mice. Expression of the proinflammatory cytokines was overexpressed in the large intestine of DSS-treated Axl-/- mice. These results suggest that the overexpression of proinflammatory cytokines may be due to the reduced number of regulatory T cells by Axl deficiency. Taken together, it suggests that Axl may be involved in the pathogenesis of IBD, and the regulation of its signaling may be helpful to ameliorate the progression of IBD.

Nfat1 regulates adult articular chondrocyte function through its age-dependent expression mediated by epigenetic histone methylation

The development of disease-modifying pharmacologic therapy for osteoarthritis (OA) currently faces major obstacles largely because the regulatory mechanisms for the function of adult articular chondrocytes remain unclear. We previously demonstrated that lack of Nfat1, one of the nuclear factor of activated T cells (NFAT) transcription factors, causes OA-like changes in adult mice. This study aimed to identify whether Nfat1 specifically regulates adult articular chondrocyte function and its age-dependent regulatory mechanism using both Nfat1-deficient and wild-type mice. Deletion of Nfat1 did not induce OA-like articular chondrocyte dysfunction (e.g., overexpression of proinflammatory cytokines and matrix-degrading proteinases) until the adult stage. RNAi-mediated Nfat1 knockdown caused dysfunction of wild-type adult articular chondrocytes. Nfat1 expression in wild-type articular chondrocytes was low in the embryonic but high in the adult stage. Chromatin immunoprecipitation assays demonstrated that an increase in Nfat1 expression in articular chondrocytes was associated with increased H3K4me2 (a histone modification linked to transcriptional activation), whereas a decrease in Nfat1 expression in articular chondrocytes was correlated with increased H3K9me2 (a histone modification linked to transcriptional repression). Knockdown of lysine-specific demethylase-1 (Lsd1) in embryonic articular chondrocytes upregulated Nfat1 expression concomitant with increased H3K4me2 at the Nfat1 promoter. Knockdown of Jmjc-containing histone demethylase-2a (Jhdm2a) in 6-month articular chondrocytes downregulated Nfat1 expression concomitant with increased H3K9me2 at the Nfat1 promoter. These results suggest that Nfat1 is an essential transcriptional regulator of chondrocyte homeostasis in adult articular cartilage. Age-dependent Nfat1 expression in articular chondrocytes is regulated by dynamic histone methylation, one of the epigenetic mechanisms that regulate gene transcription.

Molecular regulation of articular chondrocyte function and its significance in osteoarthritis.

Osteoarthritis (OA) is the most common form of joint disease. Histopathologically, OA is characterized by a progressive loss of articular cartilage, osteophyte formation, thickening of subchondral bone, and subchondral cyst formation. All current therapies are aimed at symptomatic control and have limited impacts on impeding or reversing the histopathologic progression to advanced OA. Previous studies have shown that overexpression of matrix-degrading proteinases and proinflammatory cytokines is associated with osteoarthritic cartilage degradation. However, clinical trials applying an inhibitor of proteinases or proinflammatory cytokines have been unsuccessful. A more sophisticated understanding of the regulatory mechanisms that control the function of articular chondrocytes is paramount to developing effective treatments. Since multiple catabolic factors and pathological chondrocyte hypertrophy are involved in the development of OA, it is important to identify which upstream factors regulate the expression of catabolic molecules and/or chondrocyte hypertrophy in articular cartilage. This review summarizes the current studies on the molecular regulation, with a main focus on transcriptional regulation, of the function of adult articular chondrocytes and its significance in the pathogenesis and treatment of OA. Recent studies have discovered that transcription factor Nfat1 may play an important role in maintaining the physiological function of adult articular chondrocytes. Nfat1-deficient mice exhibit normal skeletal development but display most of the features of human OA as adults, including chondrocyte hypertrophy with overexpression of specific matrix-degrading proteinases and proinflammatory cytokines in adult articular cartilage. ß-catenin transcriptional signaling in articular chondrocytes may also be involved in the pathogenesis of OA. Activation of ß-catenin leads to OA-like phenotypes with overexpression of specific matrix-degrading proteinases in articular cartilage of adult mice. These and other regulatory mechanisms described in this review may provide new insights into the pathogenesis of OA and the development of novel therapeutic targets for the treatment of OA.

The sign of psoriasis in mesenchymal stem cells of the skin

Psoriasis is a chronic inflammatory and immune-mediated skin disease, characterized by epidermal hyperproliferation, abnormal keratinocyte differentiation and angiogenesis, whose skin lesions are promoted by exogenous and endogenous factors. The cutaneous and systemic over-expression of several pro-inflammatory cytokines, observed in the initiation, maintenance and recurrence of skin lesions, is known to be caused also by reactive oxygen species (ROS). For this reason it has been postulated that ROS production and compromised function of antioxidant system may be involved in the pathogenesis of psoriasis. Some typical features of psoriasis, like growth rate, expression of VEGF and iNOS as well as the production of VEGF and nitric oxide (NO) and some antioxidant responses, have already been extensively evaluated in differentiated cells of psoriatic skin, but no indications are still available about, the mesenchymal stem, that may be isolated from skin (S-MSCs).

Visfatin levels and intima-media thicknesses in rheumatic diseases

Chronic inflammatory rheumatic diseases lead to increased prevalence of atherosclerosis. However, this early and accelerated atherosclerosis cannot be explained by traditional cardiovascular risk factors alone. The permanent overexpression of cellular adhesion molecules and pro-inflammatory cytokines in chronic inflammatory conditions may participate in accelerated atherosclerosis. Visfatin, a novel adipocytokine, has a potential insulin-like action and pro-inflammatory effects. Therefore, the aim of the study was to determine serum visfatin level and its association with common carotid intima-media thickness (IMT), which is a predictor of atherosclerosis, in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and Behçet's disease (BD). The study involved 29 RA, 26 SLE, 25 SSc, 30 BD patients, and 29 healthy controls (HC). Serum levels of TNF-α, IL-6, and visfatin were analyzed using enzyme-linked immunosorbent assay method and homeostasis model assessment for insulin resistance (HOMA-IR) indexes, and IMTs were determined. Serum visfatin level was higher in the RA group than all the other groups. In addition, visfatin level was higher in the active BD subgroup than the inactive BD subgroup. In the study groups, visfatin levels were not correlated with HOMA-IR indexes and IMTs. Whereas visfatin serum concentration was not associated with insulin resistance and carotid atherosclerosis in selected rheumatic diseases, it was higher in the RA and active BD groups, but not in the SLE and SSc groups. Visfatin levels may be associated with Th1/Th2 balance. Further studies are needed for more precise elucidation of the pro-inflammatory activities of visfatin.

Neuronal hyperexcitability and seizures are associated with changes in glial–neuronal interactions in the hippocampus of a mouse model of epilepsy with mental retardation

Hippocampal excitability and the metabolic glial-neuronal interactions were investigated in 22-week-old mice with motor neuron degeneration (mnd), a model of progressive epilepsy with mental retardation. Mnd mice developed spontaneous spikes in the hippocampus and were more susceptible to kainate-induced seizures compared with control mice. Neuronal hyperexcitability in their hippocampus was confirmed by the selective increase of c-Fos positive nuclei. Glial activation and pro-inflammatory cytokines over-expression were observed in the hippocampus of mnd mice, even in the absence of marked hippocampal neurodegeneration, as suggested by unchanged amounts of neuroactive amino acids and N-acetyl aspartate. Concentration of other amino acids, including GABA and glutamate, was not changed as well. However, ex vivo(13) C magnetic resonance spectroscopy, after simultaneous injection of [1-(13) C]glucose and [1,2-(13) C]acetate, followed by decapitation, showed decreased [1,2-(13) C]GABA formation from hippocampal astrocytic precursors and a marked reduction in [4,5-(13) C]glutamate derived from glutamine. We suggest that astrocyte dysfunction plays a primary role in the pathology and that mnd mice are of value to investigate early pathogenetic mechanism of progressive epilepsy with mental retardation.

The correlation between NF-κB inhibition and disease activity by coadministration of silibinin and ursodeoxycholic acid in experimental colitis

NF-κB is one of the most important nuclear factors responsible for overexpression of proinflammatory cytokines. This is demonstrated by increased NF-κB activity and other dependent immune factors in inflammatory bowel disease (IBD). Anti-inflammatory effects of silibinin and ursodeoxycholic acid (UDCA) along with their NF-κB inhibitory property are thought to be beneficial in colitis. Trinitrobenzene sulfonic acid was used to induce colitis rat models. After instillation, 48 rats were treated with oral silibinin, UDCA alone or a combination of both. Intraperitoneal dexamethasone was used in the control group. After 12 days of treatment, colonic samples were tested for the severity of mucosal damage macroscopically and microscopically. The levels of activated NF-κB, IL-1β, TNF-α, myeloperoxidase, thiobarbituric acid reactive substances (TBARS), protein carbonyl, and the antioxidant power of the bowel homogenates were determined. The results indicated a significant reduction in NF-κB activity as well as the levels of IL-1β, TNF-α, TBARS, protein carbonyl, myeloperoxidase activity, and an improvement in antioxidant power of colitis in treated rats. Combination therapy resulted in a more prominent improvement in bowel antioxidant power and myeloperoxidase activity. In conclusion, combination of silibinin and UDCA by inhibition of NF-κB and other relevant inflammatory factors of colitis is a good candidate for management of Crohn's disease.

Expression of pro-inflammatory TACE-TNF-α-amphiregulin axis in Sjögren’s syndrome salivary glands

The tumor-necrosis-factor-converting-enzyme (TACE)-TNF-α-Amphiregulin (AREG) axis plays an important pathogenic role in inflammatory and autoimmune disorders. However, the pathological roles of these proteins in the chronic autoimmune disease Sjögren's syndrome (SS) remain to be elucidated. It is known that the TACE-AREG axis is clearly part of a larger cascade of signals that starts with the activation of Furin, responsible for maturation of TACE that, in turn, determines the production of active TNF-α, directly involved in the up-regulation of AREG expression. This study showed that Furin, TACE, TNF-α, and AREG proteins, detected in acinar and ductal cells of human salivary glands from SS patients, increased remarkably in comparison with biopsies of labial salivary glands from healthy controls. The changes in Furin, TACE, TNF- α, and AREG proteins' level detected in salivary glands biopsies of SS patients could be responsible for pro-inflammatory cytokines overexpression characterizing Sjögren's syndrome.