Elevation Of Inflammatory Mediators Research Articles

Effect of ethyl gallate and propyl gallate on dextran sulfate sodium (DSS)-induced ulcerative colitis in C57BL/6J mice: preventive and protective.

Inflammatory bowel disease (IBD) is an idiopathic inflammatory condition of the digestive system marked by oxidative stress, leukocyte infiltration, and elevation of inflammatory mediators. In this study, we demonstrate the protective effect of ethyl gallate (EG), a phytochemical, and propyl gallate (PG), an anti-oxidant, given through normal drinking water (DW) and copper water (CW) in various combinations, which had a positive effect on the amelioration of DSS-induced ulcerative colitis in C57BL/6J mice. We successfully determined the levels of proinflammatory cytokines and anti-oxidant enzymes by ELISA, tracked oxidative/nitrosative stress (RO/NS) by in vivo imaging (IVIS) using L-012 chemiluminescent probe, disease activity index (DAI), and histopathological and morphometric analysis of colon in DSS-induced colitis in a model. The results revealed that oral administration of ethyl gallate and propyl gallate at a dose of 50mg/kg considerably reduced the severity of colitis and improved both macroscopic and microscopic clinical symptoms. The level of proinflammatory cytokines (TNF-α, IL-6, IL-1β, and IFN-γ) in colonic tissue was considerably reduced in the DSS + EG-treated and DSS + PG-treated groups, compared to the DSS alone-treated group. IVIS imaging of animals from the DSS + EG and DSS + PG-treated groups showed a highly significant decrease in RO/NS species relative to the DSS control group, with the exception of the DSS + PG/CW and DSS + EG + PG/CW-treated groups. We also observed lower levels of myeloperoxidase (MPO), nitric oxide (NO), and lipid peroxidation (LPO), and restored levels of GST and superoxide dismutase (SOD) in DSS + EG-DW/CW, DSS + PG/DW, and DSS + EG + PG/DW groups compared to DSS alone-treated group. In addition, we showed that the EG, PG, and EG + PG treatment significantly reduced the DAI score, and counteracted the body weight loss and colon shortening in mice compared to DSS alone-treated group. In this 21-day study, mice were treated daily with test substances and were challenged to DSS from day-8 to 14. Our study highlights the protective effect of ethyl gallate and propyl gallate in various combinations which, in pre-clinical animals, serve as an anti-inflammatory drug against the severe form of colitis, indicating its potential for the treatment of IBD in humans. In addition, propyl gallate was investigated for the first time in this study for its anti-colitogenic effect with normal drinking water and reduced effect with copper water.

Autophagy-mediated circHIPK2 promotes lipopolysaccharide-induced astrocytic inflammation via SIGMAR1.

Circular RNAs (circRNAs) are a subclass of noncoding RNAs and widely involve in the occurrence of multiple human diseases. It is an urgent task to clarify circRNA upstream regulation mechanism and seek their biofunction. Our previous study has confirmed that circular RNA HIPK2 (circHIPK2) promotes astrocyte activation via SIGMAR1, sigma non-opioid intracellular receptor 1, in a mouse model of single high-dose lipopolysaccharide (LPS) injection. However, what mechanism circHIPK2 is regulated by and whether it is involved in the inflammatory response of astrocytes remain unclear. In this study, we reported that circHIPK2 and SIGMAR1 were significantly increased in mouse prefrontal cortex after multiple intraperitoneal injection of LPS, with the elevation of inflammatory mediators. Knockdown circHIPK2 in primary astrocytes suppressed the SIGMAR1 expression and inflammation. Pretreatment of autophagy inducer rapamycin on astrocytes suppressed the circHIPK2 expression and inactivated inflammatory response. These results implied that autophagy inducer rapamycin could suppress astrocytic inflammation by inactivating circHIPK2-SIGMAR1 axis. Autophagy may be a promising upstream administrator of circHIPK2 and therapeutic target for central nervous system inflammation.

Study of exopolysaccharide produced by Streptomyces rochie strain OF1 and its effect as ameliorative on osteoarthritis in rats via inhibiting TNF-α/COX2 pathway

BackgroundCarbohydrates are known as the main natural products of life activities. ResultsStreptomyces rochie strain OF1 isolated from a mangrove tree produced exopolysaccharide S5 (EPSS5) (14.2 gl−1) containing uronic acid 21.98% sulfate content of 11.65 mg/ml, and a viscosity of 1.35 mm2/s. while total hexose amine content was 24.72%. The high performance liquid chromatography (HPLC) analysis of mono sugars revealed that EPS was composed of manouronic acid, glucuronic acid, xylose, and fructose at a molar ratio of 1.0:0.5:1.0:2.0, respectively. It showed that the whole antioxidant activity was 92.06%. It showed antibacterial activity against Staphylococcus aureus, and E. coli, MRSA and Klebsiella pneumoniae. But, EPSS5 displayed low antifungal activity against Candida albicans. While no antifungal activity has been detected against Aspergillus niger. EPSS5 has antibiofilm action that is noticeable toward S. aureus with an inhibition ratio of biofilm up to 50%. Effect of EPS on serum levels of TNF-α and COX2 by 2 fold and 1.9 fold of EPS reduced serum levels of Tumor necrosis factor-α (TNF-α) by 38%, 12%, 49%, and Cyclooxygenase-2 (COX2) by 61%, 34%, and 62%, respectively. By affected of EPSS5 on arthritis in rats stimulated by carrageenan. ConclusionsAdministration of EPS ameliorated carrageen-induced elevation in inflammatory mediators; TNF-α/COX and suppressed the expressions of metalloproteinase 9 (MMP9) by 68%, 86%, and 75% correspondingly in comparison to the group of carrageenans. Then again, therapy involving a high dose only reduced MMP9 level by 57%, compared to free drug suggesting that EPSS5 is a good inhibitor of the MMP9, as it brought MMP9 back to normal levels via the signaling pathway.

High Dose Methylprednisolone versus Low Dose in Correction of Congenital Acyanotic Heart Disease

ABSTRACT Background A large number of pediatric patients undergoing congenital heart disease corrective procedures receive peri-operative corticosteroids, aiming to reduce post-operative inflammation and capillary leak following cardiopulmonary bypass (CPB). This study aimed to compare the effect of different doses of methylprednisolone on inflammatory mediators’ production and effect on myocardium. Methods A trial was conducted on pediatric patients undergoing surgical correction for congenital acyanotic lesion needing CPB machine. Patients were divided into 3 groups: group A patients received 10 mg/kg methylprednisolone (MP) after induction, group B received 30 mg/kg MP and group C patients received placebo. Results Serial measurement of serum troponin, IL6 and random blood sugar showed no differences in the 3 studied groups at the first measurement, and random blood glucose at ICU admission and hour-24 were highest in the high-dose group (IL6 was lowest) with P value <0.001. Troponin showed no difference at ICU admission, while at hour-24, it was lowest in the high-dose group with p value<0.001, followed by the low-dose group and the highest in control. The ejection fraction (EF) at hour-6 was highest in the high-dose group with p value<0.001, followed by the low-dose group and lowest in control. The vasoactive inotrope score was lowest in high-dose followed by low-dose groups followed by control. As regards complications, there was no different significance between groups. Conclusion High-dose MP (30 mg/kg) given to pediatric patients undergoing surgical correction of congenital acyanotic heart disease showed better outcomes such as less elevation of inflammatory mediators, lower level of troponin, vasoactive score and higher ejection fraction, with no additional complications recorded.

Anti-Inflammatory Effects of Conditioned Medium of Periodontal Ligament-Derived Stem Cells on Chondrocytes, Synoviocytes, and Meniscus Cells.

Osteoarthritis (OA) is the most common type of arthritis, afflicting millions of people in the world. Elevation of inflammatory mediators and enzymatic matrix destruction is often associated with OA. Therefore, the objective of this study was to investigate the effects of conditioned medium from periodontal ligament-derived stem cells (PDLSCs) on inflammatory and catabolic gene expressions of chondrocytes, synoviocytes, and meniscus cells under in vitro inflammatory condition. Stem cells were isolated from human periodontal ligaments. Conditioned medium was collected and concentrated 20 × . Chondrocytes, synoviocytes, and meniscus cells were isolated from pig knees and divided into four experimental groups: serum-free media, serum-free media+interleukin-1β (IL-1β) (10 ng/mL), conditioned media (CM), and CM+IL-1β. Protein content and extracellular vesicle (EV) miRNAs of CM were analyzed by liquid chromatography-tandem mass spectrometry and RNA sequencing, respectively. It was found that the IL-1β treatment upregulated the expression of IL-1β, tumor necrosis factor-α (TNF-α), MMP-13, and ADAMTS-4 genes in the three cell types, whereas PDLSC-conditioned medium prevented the upregulation of gene expression by IL-1β in all three cell types. This study also found that there was consistency in anti-inflammatory effects of PDLSC CM across donors and cell subcultures, while PDLSCs released several anti-inflammatory factors and EV miRNAs at high levels. OA has been suggested as an inflammatory disease in which all intrasynovial tissues are involved. PDLSC-conditioned medium is a cocktail of trophic factors and EV miRNAs that could mediate different inflammatory processes in various tissues in the joint. Introducing PDLSC-conditioned medium to osteoarthritic joints could be a potential treatment to prevent OA progression by inhibiting inflammation.

Studies in a Murine Granuloma Model of Instilled Carbon Nanotubes: Relevance to Sarcoidosis.

Poorly soluble environmental antigens, including carbon pollutants, are thought to play a role in the incidence of human sarcoidosis, a chronic inflammatory granulomatous disease of unknown causation. Currently, engineered carbon products such as multiwall carbon nanotubes (MWCNT) are manufactured commercially and have been shown to elicit acute and chronic inflammatory responses in experimental animals, including the production of granulomas or fibrosis. Several years ago, we hypothesized that constructing an experimental model of chronic granulomatosis resembling that associated with sarcoidosis might be achieved by oropharyngeal instillation of MWCNT into mice. This review summarizes the results of our efforts to define mechanisms of granuloma formation and identify potential therapeutic targets for sarcoidosis. Evidence is presented linking findings from the murine MWCNT granuloma model to sarcoidosis pathophysiology. As our goal was to determine what pulmonary inflammatory pathways might be involved, we utilized mice of knock-out (KO) backgrounds which corresponded to deficiencies noted in sarcoidosis patients. A primary example of this approach was to study mice with a myeloid-specific knock-out of the lipid-regulated transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) which is strikingly depressed in sarcoidosis. Among the major findings associated with PPARγ KO mice compared to wild-type were: (1) exacerbation of granulomatous and fibrotic histopathology in response to MWCNT; (2) elevation of inflammatory mediators; and (3) pulmonary retention of a potentially antigenic ESAT-6 peptide co-instilled with MWCNT. In line with these data, we also observed that activation of PPARγ in wild-type mice by the PPARγ-specific ligand, rosiglitazone, significantly reduced both pulmonary granuloma and inflammatory mediator production. Similarly, recognition of a deficiency of ATP-binding cassette (ABC) lipid transporter ABCG1 in sarcoidosis led us to study MWCNT instillation in myeloid-specific ABCG1 KO mice. As anticipated, ABCG1 deficiency was associated with larger granulomas and increased levels of inflammatory mediators. Finally, a transcriptional survey of alveolar macrophages from MWCNT-instilled wild-type mice and human sarcoidosis patients revealed several common themes. One of the most prominent mediators identified in both human and mouse transcriptomic analyses was MMP12. Studies with MMP12 KO mice revealed similar acute reactions to those in wild-type but at chronic time points where wild-type maintained granulomatous disease, resolution occurred with MMP12 KO mice suggesting MMP12 is necessary for granuloma progression. In conclusion, these studies suggest that the MWCNT granuloma model has relevance to human sarcoidosis study, particularly with respect to immune-specific pathways.

Inflammatory mediator modulation by Short- and Long-Acting β2 Agonists in Induced Bronchial Asthma in Rats

Background: Bronchial asthma is an inflammatory lung disease characterized by hyper-responsiveness and bronchoconstriction. Beta2 agonists are bronchodilator drugs that possess anti-inflammatory properties. Aim: The present study aimed to investigate the anti-inflammatory and anti-oxidant effects of short-acting (salbutamol) and long-acting(bambuterol) as beta 2 agonists combination. Also, the effect of these drugs, singly and in combination with prednisolone was measured in asthma-induced rats in both lung tissue and broncho-alveolar lavage. Materials and Methods:Wistar rats were sensitized with intraperitoneal (I.P) administration of ovalbumin/Al(OH)3, twenty days later, animals were treated orally with salbutamol 2mg/kg or bambuterol 10 mg/kg or prednisolone 3mg/kg or a combination. Results: Ovalbumin/Al(OH)3-sensitized rats showed a significant elevation in inflammatory mediators (IL-4, MIP1α, PGE2, TNFα) and other oxidative parameters such as MDA, NO in both lung tissue and bronchial alveolar lavage (BAL). Moreover, salbutamol and bambuterol decreased inflammatory mediators and alleviated oxidative stress. These inhibitory effects were greatest when both short and long-acting β2 agonists were used in combination. Also, co-administration of β2 agonists with prednisolone revealed pronounced decreases in all parameters compared to β2 agonists alone. Conclusion: The combined therapy of salbutamol and bambuterol has an anti-inflammatory and anti-oxidant effect on the experimentally induced asthma in both BAL fluids and lung tissues. Also, these drugs in combination with prednisolone possess greater inhibitory effects on inflammatory mediators.

Protective role of HO-1 against acute kidney injury caused by cutaneous exposure to arsenicals.

Lewisite and many other similar arsenicals are warfare vesicants developed and weaponized for use in World Wars I and II. These chemicals, when exposed to the skin and other epithelial tissues, cause rapid severe inflammation and systemic damage. Here, we show that topically applied arsenicals in a murine model produce significant acute kidney injury (AKI), as determined by an increase in the AKI biomarkers NGAL and KIM-1. An increase in reactive oxygen species and ER stress proteins, such as ATF4 and CHOP, correlated with the induction of these AKI biomarkers. Also, TUNEL staining of CHOP-positive renal tubular cells suggests CHOP mediates apoptosis in these cells. A systemic inflammatory response characterized by a significant elevation in inflammatory mediators, such as IL-6, IFN-α, and COX-2, in the kidney could be the underlying cause of AKI. The mechanism of arsenical-mediated inflammation involves activation of AMPK/Nrf2 signaling pathways, which regulate heme oxygenase-1 (HO-1). Indeed, HO-1 induction with cobalt protoporphyrin (CoPP) treatment in arsenical-treated HEK293 cells afforded cytoprotection by attenuating CHOP-associated apoptosis and cytokine mRNA levels. These results demonstrate that topical exposure to arsenicals causes AKI and that HO-1 activation may serve a protective role in this setting.

Chronic, Active Inflammation in Patients With Failed Total Knee Replacements Undergoing Revision Surgery.

ABSTRACTChronic pain and restricted knee motion is a significant problem following the total knee arthroplasty (TKA). The molecular pathogenesis of pain post‐TKA is not known and no targeted therapeutic intervention is available. The aim of this study was to investigate whether pro‐inflammatory mediators are elevated in revision knee patients, indicating an active, ongoing inflammatory process that may contribute to pain. Twelve key markers (pro‐inflammatory cytokines granulocyte‐macrophage colony‐stimulating factor [GM‐CSF], interleukin 5 [IL‐5], IL‐8 and IL‐10, chemokines CCL2, CCL3, CCL4, and CCL13, mediators of angiogenesis Flt‐1, vascular endothelial growth factor, and cell migration vascular cell adhesion molecule 1 and intercellular adhesion molecule 1) were measured in knee tissue and synovial fluid (SF) from primary TKA (n = 29) and revision patients (n = 32). Indications for surgery were osteoarthritis (OA) for primary TKA, and component loosening (n = 11), stiffness (n = 11), laxity pattern (n = 8), or progression of OA in patella resurfacing (n = 3) for revision surgery. Pain levels (WOMAC score) were higher in revision than primary patients (p ≤ 0.05). Time from primary to revision ranged from 8 months to 30 years (median 10 years). All markers were elevated in revision TKA; there was no trend toward decreasing levels with greater time from primary surgery for any marker studied in SF. Similar results were seen in knee tissue. We found no differences comparing indications for revision surgery (p ≥ 0.05). The elevation of inflammatory mediators in painful post‐TKA knees requiring revision suggests active, chronic inflammation. Characterization of upregulated markers provides rationale for targeted therapy, even many years from the primary surgery. © 2019 The Authors. Journal of Orthopaedic Research ® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2316–2324, 2019

Mechanistic perspective of protective effects of resveratrol against cisplatin-induced ovarian injury in rats: emphasis on anti-inflammatory and anti-apoptotic effects.

Chemotherapeutic platinum-containing drugs are widely used to treat a variety of cancer types; however, they cause ovarian failure and infertility. The aim of this study is to investigate the molecular mechanism underlying the potential protective effect of resveratrol against cisplatin-induced ovarian damage in a rat model. Female rats were given either cisplatin (6mg/kg, i.p., once per week for two consecutive weeks) and/or resveratrol (10mg/kg, orally for 17days). Follicular development, ovarian function markers, as well as apoptotic and inflammatory markers were assessed 24h after the last resveratrol dose. Resveratrol ameliorated the marked follicular loss and the significant reduction in anti-Müllerian hormone (AMH) level triggered by cisplatin. Mechanistically, cisplatin elicited a potent inflammatory response in ovarian tissue as evidenced by the elevated expression of tumor necrosis factor, nuclear factor kappa-B, and proinflammatory enzymes. Co-treatment with resveratrol inhibited the elevation in inflammatory mediators induced by cisplatin. Further, cisplatin switched on the apoptotic machinery in ovarian tissues via increasing the expression of both cytochrome c and caspase-3 which was reversed upon resveratrol co-treatment. Resveratrol also counteracts the upregulating poly(ADP-ribose) polymerase expression which could attribute to the inflammatory and apoptotic effects of cisplatin. Resveratrol protects the ovary from cisplatin-induced toxicity through preventing the loss of the AMH-secreting granulosa cells, diminishing PARP-1 expression, and downregulating the inflammatory and apoptotic events implicated in cisplatin toxicity.

Effects of vitamin A and vitamin E on attenuation of titanium dioxide nanoparticles-induced toxicity in the liver of male Wistar rats.

The increasing application of titanium dioxide nanoparticles (NTiO2) in life and the toxicity potential of these nanoparticles have raised concerns about their detrimental effects on human health. This study was conducted to investigate the hepatoprotective effects of vitamin E and vitamin A against hepatotoxicity induced by NTiO2 in rats. Thirty-six male Wistar rats were randomly divided into six groups of six rats each. Intoxicated group received 300mg/kg NTiO2 for two weeks by gavage. Groups treated with vitamin E (100IU/kg), vitamin A (100IU/kg) and mixture of these vitamins were orally administered for 3weeks (started 7days before NTiO2 administration). In order to investigate the redox changes, total antioxidant capacity, total oxidant status, and lipid peroxidation were determined in liver tissue as well as activity of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and catalase. In addition, inflammatory responses were assessed by measuring the expression of NF-κB (mRNA) and TNF-α (mRNA and protein). Histopathological analysis and measurement of liver enzymes (ALP, ALT, AST, and LDH in serum) were also done to determine hepatic injury. In liver, NTiO2 caused hepatic injury, redox perturbation, and reduction of antioxidant enzymes and elevation of inflammatory mediators, significantly. However, treatment with vitamins was able to significantly ameliorate these alterations. This study highlights the antioxidant and anti-inflammatory properties of vitamins A and E against toxicity of NTiO2 and poses the use of these vitamins to mitigate the toxic effects of this nanoparticles in NTiO2-contained products.

Monocyte-to-HDL-cholesterol ratio as a prognostic marker in cardiovascular diseases.

Inflammation and lipid accumulation are two basic hallmarks of atherosclerosis as a chronic disease. Inflammation not only is a local response but can also be considered as a systemic process followed by an elevation of inflammatory mediators. Monocytes are a major source of proinflammatory species during atherogenesis. In atherosclerosis, modified low-density lipoproteins (LDLs) are removed by macrophages; these are recruited in the vessel wall, inducing the release of inflammatory cytokines in inflamed tissue. Hence, inflammatory cholesterol ester-loaded plaque is generated. High-density lipoprotein-cholesterol (HDL-C) exhibits antiatherosclerotic effects by neutralizing the proinflammatory and pro-oxidant effects of monocytes via inhibiting the migration of macrophages and LDL oxidation in addition to the efflux of cholesterol from these cells. Furthermore, HDL plays a role in suppressing the activation of monocytes and proliferation-differentiation of monocyte progenitor cells. Thus, accumulation of monocytes and reduction of HDL-C may participate in atherosclerosis and cardiovascular diseases (CVD). Given that the relationship between the high number of monocytes and low HDL-C levels has been reported in inflammatory disorders, this review focused on understanding whether the monocyte-to-HDL ratio could be a convenient marker to predict atherosclerosis development and progression, hallmarks of CV events, instead of the individual monocyte count or HDL-C level.

Copper oxide nanoparticles induce collagen deposition via TGF-β1/Smad3 signaling in human airway epithelial cells

Use and application of nanoparticles has increased in recent years. Copper oxide nanoparticles (CuONPs) are one of the most common types of nanoparticles, and they are mainly used as catalysts and preservatives. However, limited toxicity data are available on the toxicity of CuONPs to the respiratory system. We investigated fibrotic responses induced by CuONPs in the respiratory tract and elucidated its underlying mechanism of action in vivo and in vitro experiments. In the mouse model, CuONPs exposure markedly increased transforming growth factor-β1 (TGF-β1) and collagen I expression and Smad3 phosphorylation, combined with elevation of inflammatory mediators including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). These alterations were also observed in histological analysis of lung tissue. CuONPs markedly increased inflammatory responses and collagen deposition, accompanied by the elevation of TGF-β1 and collagen I expression in lung tissue. In addition, CuONPs-treated H292 cells showed significantly increased mRNA and protein production of TGF-β1, collagen I, IL-6, and TNF-α; this response was markedly decreased by treatment of a TGF-β1 inhibitor (SB-431542). Taken together, CuONPs induced fibrotic responses in the respiratory tract, closely related to TGF-β1/Smad3 signaling. Therefore, our results raise the necessity of further investigation for the present state of its risk by providing useful information of the toxicity of CuONPs.

Low Vs. High Alcohol: Central Benefits Vs. Detriments.

The dose-dependent effects of alcohol, where the initial euphoric and stimulant effects initiated by the exposure to low ethanol levels can quickly lead to a deadly consequence are well established. Thus, high blood alcohol concentration (BAC), as seen in alcoholics, can cause significant damage to various organs. At low concentrations (e.g., 10mg% or lower), however, beneficial effects of alcohol, particularly on cardiovascular function have been reported. Although, the latter assertion has been challenged by recent epidemiological studies, protective effects of low alcohol concentrations in vitro and in vivo relevant to the central nervous system (CNS) is well documented. In this review, the mechanism(s) leading to the detrimental effects of high BAC, as well as the beneficial effects of low BAC will be discussed. In addition, gender consideration is touched upon. Although further investigation is clearly warranted, it may be concluded that at least some of the beneficial outcomes of low BAC, including possible neuroprotection and antidepressant-like effects, may be due to elevation of the neurotropic factors and reduction of inflammatory mediators, whereas detrimental outcomes associated with high BAC, including neurotoxicity and depressive-like behavior may be due to reduction in neurotropic factors and elevation of inflammatory mediators. Furthermore, new research strategies are suggested.

IFN-gamma priming of adipose-derived stromal cells at "physiological" hypoxia.

Multipotent mesenchymal stromal cells (MSCs) are considered cue regulators of tissue remodeling. Their activity is strongly governed by local milieu, where O2 level is most important. The elevation of inflammatory mediators and acute O2 lowering may additionally modulate MSC activity. In present paper the priming effects of IFN-gamma on adipose tissue-derived MSCs (ASCs) at tissue-related O2 level (5%) and acute hypoxic stress (0.1% O2 ) were assessed as alterations of ASCs' CFU-F, proliferation, migration, osteo-commitment. IFN-gamma priming provoked ROS elevation, cell growth slowdown, attenuation of both spontaneous and induced osteodifferentiation of tissue O2 -adapted ASCs. The prominent changes in ASC cytoskeleton-related gene transcription was detected. IFN-gamma exposure shifted the ASC paracrine profile, suppressing the production of VEGF and IL-8, while MCP-1 and IL-6 were stimulated. Conditioned medium of IFN-gamma-primed ASCs did not activate vessel growth in the CAM assay, but induced endothelial cell migration in "wound closure." Short-term hypoxia suppressed CFU-F number, IFN-gamma-induced elevation of IL-6 and endothelial cell migration, while it abolished IFN-gamma-provoked VEGF inhibition. After N-acetyl cysteine treatment ROS level was partly abolished providing additional enhancement of IL-6 and suppression of IL-8 and VEGF production. These findings demonstrated that paracrine activity of ASCs in part may be governed by ROS level. Thus, this study first demonstrated that IFN-gamma priming itself and in combination with acute O2 deprivation could supply dual effects on ASC functions providing both stimulatory and hampering effects. The equilibrium of these factors is a substantial requirement for the execution of MSC remodeling functions.

Antioxidant and Anti-Inflammatory Effects of Rhei Rhizoma and Coptidis Rhizoma Mixture on Reflux Esophagitis in Rats.

The purpose of this study was to investigate the antioxidant and anti-inflammatory effects of the combined extract of Rhei rhizoma and Coptidis rhizoma (RC-mix) in experimental model of acute reflux esophagitis. The antioxidant activity was assessed by in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assays. RC-mix was given at 100, 200, and 400 mg/kg body weight 2 h prior to induction of reflux esophagitis (RE). After 5 h, the effects of RC-mix treated rats were compared with those of normal and control rats. The representative flavonoid contents of RC-mix, such as sennoside A, epiberberine, coptisine, palmatine, and berberine, were detected using HPLC. The elevated esophageal mucosa damage was markedly ameliorated by RC-mix treatment in a dose-dependent manner. Furthermore, the administration of RC-mix reduced the increase of serum reactive oxygen species (ROS) and peroxynitrite (ONOO−). The improvement of superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) levels were marked in the group given RC-mix. Moreover, the elevation of inflammatory mediators and cytokines by nuclear factor-kappa B (NF-κB) activation in control rats decreased by RC-mix pretreatment. These results indicate that RC-mix treatment reduces the pathological states of esophagitis via regulating NF-κB mediated inflammation related to oxidative stress.

Decidualized Human Endometrial Stromal Cells Are Sensors of Hormone Withdrawal in the Menstrual Inflammatory Cascade1

Menstruation is a complex process dependent on premenstrual release of inflammatory mediators and proteolytic enzymes from endometrial cells. Endometrial leukocytes are traditionally considered to be the major source of the inflammatory factors. However, evidence is emerging to suggest a role for decidualized endometrial stromal cells in the premenstrual inflammatory cascade. We sought to determine if withdrawal of hormone support (estrogen and progesterone) from decidualized endometrial stromal cells, in a model mimicking the precise timing leading to menstruation, activated inflammatory signaling pathways and downstream release of inflammatory mediators. Human endometrial stromal cells decidualized gradually over 12 days of estradiol and progestin treatment as evidenced by an increase in prolactin secretion. Withdrawal of hormone support from decidualized stromal cells resulted in a decrease in cytoplasmic IkappaB and a progressive increase in nuclear accumulation of NF-kappaB, as demonstrated by Western immunoblot and immunocytochemical analyses. Concomitant with nuclear translocation of NF-kappaB, hormone withdrawal led to production of a host of inflammatory mediators by the decidualized stromal cells, including IFN-alpha, IL-6, CCL11, GM-CSF, CCL2, IL1-RA, CXCL10, CXCL8, IL-12, IL-15, VEGF, and CCL5. Elevation of inflammatory mediators was not observed, however, upon hormone withdrawal in cells treated with the NF-kappaB inhibitor BAY 11-7085. Decidualized stromal cells are likely highly sensitive sensors of changing hormone levels. This provides a mechanism by which decidualized stromal cells may recruit inflammatory leukocytes into the premenstrual endometrium and contribute to the intense inflammation underlying this unique physiological process.

Characterization of MMP-9 and -12 KO mice in a model of acute smoke exposure

Short-term cigarette smoke exposure in mice has been shown to exhibit some similarities to cell and cell-mediated inflammation seen in COPD patients. We sought to identify biomarkers in the lungs and bronchoalveolar lavage fluid (BALF) that would characterize this inflammation. Mice were exposed; nose only, to 600 mg/m3 of cigarette smoke from 2R4F Kentucky Reference cigarettes twice daily for three consecutive days. Sham smoked animals were exposed to room air. Short-term cigarette smoke exposure induced a mild but statistically significant increase in total BAL cells in addition to a significant increase in neutrophils as compared with sham-exposed animals. Oral administration of dexamethasone did not attenuate total BAL cell or neutrophil counts. However, administration of an oral PDE4 inhibitor, significantly reduced percent neutrophil and macrophage counts. To assess expression of genes involved in this model, transcriptional profiling was performed on whole lungs harvested on day 4. Genes with the greatest fold increase included SAA3, CXCL1, 2 and 5 and NOXO1. In addition, multiplex analysis of BALF collected on day 4, revealed significant elevation in inflammatory mediators including cytokines, chemokines and metalloproteinases. Matrix metalloproteinase (MMP)–9 and –12 knockout (KO) mice were also tested in this model to evaluate whether or not these deficiencies influence acute smoke-induced inflammation. Total BAL inflammation and neutrophil counts were decreased in smoke exposed MMP-9 and -12 KO mice compared to wild type controls. These effects, however seem to be strain dependent as they were noted only in BALB/c KO animals. Deficiencies in MMP-9 and –12 appear to be beneficial in having an anti-inflammatory effect following acute exposure to smoke.

Serum cystatin‐C levels correlate with endothelial dysfunction in patients with the metabolic syndrome

Serum cystatin‐C levels correlate with endothelial dysfunction in patients with the metabolic syndrome

Abnormally High Levels of Inflammatory Markers in Recipients of Continuous Flow Left Ventricular Assist Devices

Purpose Early activation of inflammatory markers immediately after implantation of left ventricular assist devices (LVADs) predicts multiple organ failure. Although the newer generation continuous flow (CF)-LVADs provide clinical advantages over the pulsatile pumps, the effects of low pulsatility on inflammation are not completely understood in this patient population. Under continuous-flow conditions, the levels of neurohormones, which are known to augment inflammation in heart failure (HF), are elevated. We hypothesize that in CF-LVAD recipients the levels of inflammatory markers are higher than both healthy controls and HF patients. The aim of our study was to compare the levels of inflammation in CF-LVAD recipients to those of healthy controls (HCs) and HF patients who were candidates for CF-LVADs. Methods and Materials The levels of the inflammatory markers were measured in 18 CF-LVAD recipients and compared to those of 14 HCs and 14 HF patients who were candidates for CF-LVADs. Results The levels of GM-CSF, MIP-1 beta and MDC were significantly higher in the CF-LVAD group compared to both the HC and the HF groups, whereas no significant differences were observed between the HC and the HF groups. Compared to the HC group, CRP, IP-10, MCP-1 and IL-8 levels were significantly higher in both the CF-LVAD and HF groups, while no significant differences were observed between the CF-LVAD recipients and the HF patients. [ figure 1 ] Conclusions We found that inflammation was high in CF-LVAD recipients. Further studies should investigate the time course of elevation of inflammatory mediators from pre- to post- CF-LVAD implantation and following long term CF-LVAD support.