Inflammatory stimuli increase local cortisol production in osteoblasts in vitro and in vivo.

: In vivo and in vitro studies reveal that ursolic acid (UA) is able to counteract endogenous and exogenous inflammatory stimuli, and has favorable anti-inflammatory effects. The anti-inflammatory mechanisms mainly include decreasing the release of histamine in mast cells, suppressing the activities of lipoxygenase, cyclooxygenase and phospholipase, and reducing the production of nitric oxide and reactive oxygen species, blocking the activation of signal pathway, down-regulating the expression of inflammatory factors, and inhibiting the activities of elastase and complement. These mechanisms can open up new avenues for the scientific community to develop or improve novel therapeutic approaches to tackle inflammatory diseases such as arthritis, atherosclerosis, neuroinflammation, liver diseases, kidney diseases, diabetes, dermatitis, bowel diseases, cancer. The anti-inflammatory activity, the anti-inflammatory mechanism of ursolic acid and its therapeutic applications are reviewed in this paper.

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Resistin Is Increased in Periodontal Cells and Tissues: In Vitro and In Vivo Studies

Mediators of Inflammation ◽

10.1155/2020/9817095 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Andressa V. B. Nogueira ◽

Marjan Nokhbehsaim ◽

Sema Tekin ◽

Rafael S. de Molon ◽

Luis C. Spolidorio ◽

...

Keyword(s):

Bone Loss ◽

Inflammatory Diseases ◽

Inflammatory Cells ◽

Male Rats ◽

In Vivo Studies ◽

Hard Tissue ◽

Tissue Metabolism ◽

Inflammatory Stimuli

Resistin, a proinflammatory adipokine, is elevated in many inflammatory diseases. However, little is known about its performance in periodontitis. The present study is aimed at evaluating resistin expression and synthesis in periodontal cells and tissues under inflammatory/microbial stress in addition to its effects on the periodontium. In vivo, 24 male rats were randomly divided into two groups: control and ligature-induced periodontal disease. After 6 and 12 days, animals were sacrificed to analyze gene expression of adipokines, bone loss, inflammation, and resistin synthesis. In vitro, human periodontal ligament (PDL) fibroblasts were used to evaluate the expression of resistin after inflammatory stimuli. In addition, PDL fibroblasts were exposed to resistin to evaluate its role on soft and hard tissue metabolism markers. The periodontitis group demonstrated significant bone loss, an increase in the number of inflammatory cells and vascular structures, an increase in resistin expression and synthesis, and a decrease in the expression of adiponectin, leptin, and its functional receptor. PDL fibroblasts showed a significant increase in resistin expression and synthesis in response to the inflammatory stimulus by IL-1β. Resistin induced an increase in cytokine expression and a decrease in the regulation of some hard tissue and matrix formation genes in PDL fibroblasts. These data indicate that resistin is produced by periodontal cells and tissues, and this effect is enhanced by inflammatory stimuli. Moreover, resistin seems to interfere with soft and hard tissue metabolism during periodontitis by reducing markers related to matrix formation and bone tissue.

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Vascular wall–produced prostaglandin E2 exacerbates arterial thrombosis and atherothrombosis through platelet EP3 receptors

Journal of Experimental Medicine ◽

10.1084/jem.20061617 ◽

2007 ◽

Vol 204 (2) ◽

pp. 311-320 ◽

Cited By ~ 108

Author(s):

Sabrina Gross ◽

Peggy Tilly ◽

Didier Hentsch ◽

Jean-Luc Vonesch ◽

Jean-Etienne Fabre

Keyword(s):

Prostaglandin E2 ◽

Arterial Thrombosis ◽

Blood Platelets ◽

Vascular Wall ◽

Bioactive Lipids ◽

Arterial Walls ◽

Inflammatory Stimuli ◽

Ep3 Receptor

Prostanoids, bioactive lipids derived from arachidonic acid (AA), are important for vascular homeostasis. Among them, prostaglandin E2 (PGE2) enhances aggregation of platelets submaximally stimulated in vitro. This results from activation of EP3, one of the four PGE2 receptors, which decreases the threshold at which agonists activate platelets to aggregate. Although PGE2 altered venous thrombosis induced by administration of AA, its role in pathophysiopathological conditions has remained speculative. We report that arterial walls subjected to inflammatory stimuli produce PGE2. In several models, we show that PGE2 produced by the arterial wall facilitates arterial thrombosis. Next, we detected PGE2 in mouse atherosclerotic plaques. We demonstrate that this plaque-produced PGE2 is not altered and is still able to activate EP3. In addition, we present evidence that PGE2 can leave the plaque and activate EP3 on blood platelets. Consistent with these findings, we observed that atherothrombosis induced in vivo by mechanical rupture of the plaque was drastically decreased when platelets lacked EP3. In conclusion, PGE2 facilitates the initiation of arterial thrombosis and, hence, contributes to atherothrombosis. Inhibition of the platelet EP3 receptor should improve prevention of atherothrombosis.

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Endotoxin-stimulated production of rat hypothalamic interleukin-1β in vivo and in vitro, measured by specific immunoradiometric assay

Journal of Molecular Endocrinology ◽

10.1677/jme.0.0110031 ◽

1993 ◽

Vol 11 (1) ◽

pp. 31-36 ◽

Cited By ~ 71

Author(s):

P Hagan ◽

S Poole ◽

A F Bristow

Keyword(s):

Acute Phase ◽

Acute Phase Response ◽

Interleukin 1 ◽

Phase Response ◽

Inflammatory Stimuli ◽

Quantitative Immunoassay ◽

Time Courses ◽

A Site

ABSTRACT Regulation of a number of aspects of the acute-phase response, including induction of fever and activation of the hypothalamo-pituitary-adrenal axis, occurs within the hypothalamus. The acute-phase response appears to be co-ordinated by the inflammatory cytokine interleukin-1 (IL-1). A number of studies using hybridization techniques to measure IL-1 gene expression and immunocyto-chemistry to localize immunoactive IL-1 have established the concept that the central nervous system, and in particular the hypothalamus, is a site of IL-1 production, and that levels increase in response to inflammatory stimuli. In this report we present data on the levels of IL-1β produced in the rat hypothalamus using quantitative immunoassay techniques. Bacterial endotoxin, administered to rats in vivo, evoked increases in hypothalamic IL-1β levels which were significant within 1 h, and reached maximum levels at 5–10 h. The response to endotoxin was dose-related, and levels reached in hypothalamic extracts corresponded to intra-hypothalamic levels of the order of 20 ng/ml. During short-term in-vitro culture of rat hypothalami, endotoxin stimulated a dose-related increase in both the synthesis and the secretion of IL-1β, which reached similar levels to those seen after in-vivo stimulation. Hypothalami obtained from animals stimulated with endotoxin in vivo did not, however, show any evidence of persistent stimulation of IL-1β production when subsequently cultured in vitro. These data support the concept that production of hypothalamic IL-1 is an essential step in regulating the activity of the hypothalamus during the acute-phase response, and provide for the first time quantitative data on the magnitude, dose—response relationships and time-courses of rat hypothalamic IL-1β production in vivo and in vitro.

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Dendritic cells require NIK for CD40-dependent cross-priming of CD8+ T cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1520627112 ◽

2015 ◽

Vol 112 (47) ◽

pp. 14664-14669 ◽

Cited By ~ 22

Author(s):

Anand K. Katakam ◽

Hans Brightbill ◽

Christian Franci ◽

Chung Kung ◽

Victor Nunez ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd8 T Cells ◽

Lymphoid Organs ◽

Serine Threonine Kinase ◽

Cross Presentation ◽

Inflammatory Stimuli ◽

Dc Maturation

Dendritic cells (DCs) link innate and adaptive immunity and use a host of innate immune and inflammatory receptors to respond to pathogens and inflammatory stimuli. Although DC maturation via canonical NF-κB signaling is critical for many of these functions, the role of noncanonical NF-κB signaling via the serine/threonine kinase NIK (NF-κB–inducing kinase) remains unclear. Because NIK-deficient mice lack secondary lymphoid organs, we generated transgenic mice with targeted NIK deletion in CD11c+ cells. Although these mice exhibited normal lymphoid organs, they were defective in cross-priming naive CD8+ T cells following vaccination, even in the presence of anti-CD40 or polyinosinic:polycytidylic acid to induce DC maturation. This impairment reflected two intrinsic defects observed in splenic CD8+ DCs in vitro, namely antigen cross-presentation to CD8+ T cells and secretion of IL-12p40, a cytokine known to promote cross-priming in vivo. In contrast, antigen presentation to CD4+ T cells was not affected. These findings reveal that NIK, and thus probably the noncanonical NF-κB pathway, is critical to allow DCs to acquire the capacity to cross-present antigen and prime CD8 T cells after exposure to licensing stimuli, such as an agonistic anti-CD40 antibody or Toll-like receptor 3 ligand.

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Stauntonia hexaphylla leaf extract (YRA-1909) suppresses inflammation by modulating Akt/NF-κB signaling in lipopolysaccharide-activated peritoneal macrophages and rodent models of inflammation

Food & Nutrition Research ◽

10.29219/fnr.v65.7666 ◽

2021 ◽

Author(s):

Jaeyong Kim ◽

Gyuok Lee ◽

Huwon Kang ◽

Ji-Seok Yoo ◽

Yongnam Lee ◽

...

Keyword(s):

Leaf Extract ◽

Inflammatory Diseases ◽

Vascular Diseases ◽

Peritoneal Macrophages ◽

Inflammatory Activity ◽

Dependent Manner ◽

Inflammatory Stimuli ◽

Anti Inflammatory

Background: Inflammation is emerging as a key contributor to many vascular diseases and furthermore plays a major role in autoimmune diseases, arthritis, allergic reactions, and cancer. Lipopolysaccharide (LPS), which is a component constituting the outer membrane of Gram-negative bacteria, is commonly used for an inflammatory stimuli to mimic inflammatory diseases. Nuclear factor-kappa B (NF-κB) is a transcription factor and regulates gene expression particularly related to the inflammatory process. Stauntonia hexaphylla (Lardizabalaceae) is widely used as a traditional herbal medicine for rheumatism and osteoporosis and as an analgesic, sedative, and diuretic in Korea, Japan, and China. Objective: The purpose of this study was to investigate the anti-inflammatory activity of YRA-1909, the leaf aqueous extract of Stauntonia hexaphylla using LPS-activated rat peritoneal macrophages and rodent inflammation models. Results: YRA-1909 inhibited the LPS-induced nitric oxide (NO) and proinflammatory cytokine production in rat peritoneal macrophages without causing cytotoxicity and reduced inducible NO synthase and prostaglandin E2 levels without affecting the cyclooxygenase-2 expression. YRA-1909 also prevented the LPS-stimulated Akt and NF-κB phosphorylation and reduced the carrageenan-induced hind paw edema, xylene-induced ear edema, acetic acid-induced vascular permeation, and cotton pellet-induced granuloma formation in a dose-dependent manner in mice and rats. Conclusions: S. hexaphylla leaf extract YRA-1909 had anti-inflammatory activity in vitro and in vivo that involves modulation of Akt/NF-κB signaling. Thus, YRA-1909 is safe and effective for the treatment of inflammation.

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A Novel, Nonpeptidic, Orally Active Bivalent Inhibitor of Human β-Tryptase

Pharmacology ◽

10.1159/000492078 ◽

2018 ◽

Vol 102 (5-6) ◽

pp. 233-243 ◽

Cited By ~ 2

Author(s):

Sarah F. Giardina ◽

Douglas S. Werner ◽

Maneesh Pingle ◽

Donald E. Bergstrom ◽

Lee D. Arnold ◽

...

Keyword(s):

Active Sites ◽

Rational Design ◽

Therapeutic Potential ◽

X Ray Crystallography ◽

Inflammatory Stimuli ◽

Invaluable Tool ◽

Xenograft Models ◽

Orally Bioavailable

β-Tryptase is released from mast cells upon degranulation in response to allergic and inflammatory stimuli. Human tryptase is a homotetrameric serine protease with 4 identical active sites directed toward a central pore. These active sites present an optimized scenario for the rational design of bivalent inhibitors, which bridge 2 adjacent active sites. Using (3-[1-acylpiperidin-4-yl]phenyl)methanamine as the pharmacophoric core and a disiloxane linker to span 2 active sites we have successfully produced a novel bivalent tryptase inhibitor, compound 1a, with a comparable profile to previously described inhibitors. Pharmacological properties of compound 1a were studied in a range of in vitro enzymic and cellular screening assays, and in vivo xenograft models. This non-peptide inhibitor of tryptase demonstrated superior activity (IC50 at 100 pmol/L tryptase = 1.82 nmol/L) compared to monomeric modes of inhibition. X-ray crystallography validated the dimeric mechanism of inhibition, and 1a demonstrated good oral bioavailability and efficacy in HMC-1 xenograft models. Furthermore, compound 1a demonstrated extremely slow off rates and high selectivity against-related proteases. This highly potent, orally bioavailable and selective inhibitor of human tryptase will be an invaluable tool in future studies to explore the therapeutic potential of attenuating the activity of this elusive target.

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Indirect regulation of HMGB1 release by gasdermin D

Nature Communications ◽

10.1038/s41467-020-18443-3 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Allen Volchuk ◽

Anna Ye ◽

Leon Chi ◽

Benjamin E. Steinberg ◽

Neil M. Goldenberg

Keyword(s):

Bone Marrow ◽

Knockout Mice ◽

Extracellular Space ◽

High Mobility ◽

High Mobility Group ◽

Inflammasome Activation ◽

Inflammatory Stimuli ◽

Lps Treatment

Abstract The protein high-mobility group box 1 (HMGB1) is released into the extracellular space in response to many inflammatory stimuli, where it is a potent signaling molecule. Although research has focused on downstream HMGB1 signaling, the means by which HMGB1 exits the cell is controversial. Here we demonstrate that HMGB1 is not released from bone marrow-derived macrophages (BMDM) after lipopolysaccharide (LPS) treatment. We also explore whether HMGB1 is released via the pore-forming protein gasdermin D after inflammasome activation, as is the case for IL-1β. HMGB1 is only released under conditions that cause cell lysis (pyroptosis). When pyroptosis is prevented, HMGB1 is not released, despite inflammasome activation and IL-1β secretion. During endotoxemia, gasdermin D knockout mice secrete HMGB1 normally, yet secretion of IL-1β is completely blocked. Together, these data demonstrate that in vitro HMGB1 release after inflammasome activation occurs after cellular rupture, which is probably inflammasome-independent in vivo.

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Neutrophil recruitment inhibitory factor: a possible candidate for a novel cytokine

Mediators of Inflammation ◽

10.1155/s0962935192000103 ◽

1992 ◽

Vol 1 (1) ◽

pp. 49-54 ◽

Cited By ~ 1

Author(s):

W. M. S. C. Tamashiro ◽

B. M. Tavares-Murta ◽

F. Q. Cunha ◽

M. C. Roque-Barreira ◽

R. M. D. Nogueira ◽

...

Keyword(s):

Inhibitory Activity ◽

Inflammatory Responses ◽

Neutrophil Migration ◽

Gel Filtration ◽

Inhibitory Effect ◽

Neutrophil Recruitment ◽

Tnf Α ◽

Inflammatory Stimuli

Inhibitory effect upon neutrophil migration to the inflammatory focus was previously detected in the cell-free incubation fluid of lipopolysaccharide (LPS)-stimulated macrophage monolayers. In the present study we showed that the neutrophil recruitment inhibitory activity from this supernatant was mainly detected in a fraction (P2) obtained by gel filtration chromatography on Sephacryl S-300. P2 fraction was able to inhibit ‘in vivo’ neutrophil emigration induced by different inflammatory stimuli, but it did not affect ‘in vitro’ neutrophil chemotaxis induced by FMLP. When injected intravenously, P2 inhibited oedema induced by carrageenin or immunological stimulus but not the oedema induced by dextran, thus affecting cell-dependent inflammatory responses. It was observed that P2 also induced neutrophil migration when injected locally in peritoneal cavities. This activity was significantly reduced by pretreatment of the animals with dexamethasone. Cytokines, such as IL-8 and TNF-α that are known to exhibit inhibitory effect upon neutrophil migration, were not detected in P2 fraction by highly sensitive assays. Overall the results suggest the existence of a novel cytokine exhibiting ‘in vivo’ neutrophil inhibitory activity, referred as NRIF.

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Gas6 promotes inflammation by enhancing interactions between endothelial cells, platelets, and leukocytes

Blood ◽

10.1182/blood-2007-05-089565 ◽

2008 ◽

Vol 111 (8) ◽

pp. 4096-4105 ◽

Cited By ~ 102

Author(s):

Marc Tjwa ◽

Lola Bellido-Martin ◽

Yuan Lin ◽

Esther Lutgens ◽

Stéphane Plaisance ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Heart Transplantation ◽

Mouse Models ◽

Inflammatory Stimuli ◽

Leukocyte Extravasation

AbstractThe role of Gas6 in endothelial cell (EC) function remains incompletely characterized. Here we report that Gas6 amplifies EC activation in response to inflammatory stimuli in vitro. In vivo, Gas6 promotes and accelerates the sequestration of circulating platelets and leukocytes on activated endothelium as well as the formation and endothelial sequestration of circulating platelet-leukocyte conjugates. In addition, Gas6 promotes leukocyte extravasation, inflammation, and thrombosis in mouse models of inflammation (endotoxinemia, vasculitis, heart transplantation). Thus, Gas6 amplifies EC activation, thereby playing a key role in enhancing the interactions between ECs, platelets, and leukocytes during inflammation.

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