Anti-inflammatory Activity In Model Research Articles

Crystal Structure of Cleaved Serp-1, a Myxomavirus-Derived Immune Modulating Serpin: Structural Design of Serpin Reactive Center Loop Peptides with Improved Therapeutic Function.

The Myxomavirus-derived protein Serp-1 has potent anti-inflammatory activity in models of vasculitis, lupus, viral sepsis, and transplant. Serp-1 has also been tested successfully in a Phase IIa clinical trial in unstable angina, representing a "first-in-class" therapeutic. Recently, peptides derived from the reactive center loop (RCL) have been developed as stand-alone therapeutics for reducing vasculitis and improving survival in MHV68-infected mice. However, both Serp-1 and the RCL peptides lose activity in MHV68-infected mice after antibiotic suppression of intestinal microbiota. Here, we utilize a structure-guided approach to design and test a series of next-generation RCL peptides with improved therapeutic potential that is not reduced when the peptides are combined with antibiotic treatments. The crystal structure of cleaved Serp-1 was determined to 2.5 Å resolution and reveals a classical serpin structure with potential for serpin-derived RCL peptides to bind and inhibit mammalian serpins, plasminogen activator inhibitor 1 (PAI-1), anti-thrombin III (ATIII), and α-1 antitrypsin (A1AT), and target proteases. Using in silico modeling of the Serp-1 RCL peptide, S-7, we designed several modified RCL peptides that were predicted to have stronger interactions with human serpins because of the larger number of stabilizing hydrogen bonds. Two of these peptides (MPS7-8 and -9) displayed extended activity, improving survival where activity was previously lost in antibiotic-treated MHV68-infected mice (P < 0.0001). Mass spectrometry and kinetic assays suggest interaction of the peptides with ATIII, A1AT, and target proteases in mouse and human plasma. In summary, we present the next step toward the development of a promising new class of anti-inflammatory serpin-based therapeutics.

Omega-3-carboxylic acids provide efficacious anti-inflammatory activity in models of crystal-mediated inflammation

This study assesses the efficacy and exposure–response relationship of omega-3-carboxylic acids (OM-3 CA) in models of crystal-based inflammation. Human THP-1 macrophages and primary peripheral blood mononuclear cells exposed to multiple inflammatory crystal types were used to determine the anti-inflammatory potential of omega-3 (OM-3) fatty acids in vitro. Anti-inflammatory effects of OM-3 CA in vivo were tested in rat monosodium urate (MSU) crystal air pouch and rat knee intra-articular MSU injection models. Acute treatment with the OM-3 fatty acid docosahexaenoic acid suppressed MSU-, cholesterol crystal-, and calcium pyrophosphate crystal-mediated interleukin-1β (IL-1β) production in vitro. In vivo, OM-3 CA dose-dependently reduced crystal-mediated cell migration, exudate volume, and levels of IL-1β and prostaglandin E2. Following intra-articular injection of MSU, treatment with OM-3-CA (1 mL/kg) and indomethacin (1 mg/kg) resulted in similar mean reductions in pain (23% and 41%, respectively) and swelling (58% and 50%, respectively), compared with controls. Additionally, in complex formulations of OM-3 fatty acids, high levels of palmitic acid could reduce the in vivo effect on crystal-mediated IL-1β elevation. OM-3 CA has a broadly efficacious anti-inflammatory effect with a strong exposure–response relationship that could be beneficial in prevention and treatment of crystal arthritis, with potential applications in other IL-1β-mediated diseases.

ОГЛЯД НАУКОВИХ ДОСЛІДЖЕНЬ З МЕТОЮ ОДЕРЖАННЯ НОВИХ ФІТОПРЕПАРАТІВ НА ОСНОВІ ГЕРАНІ СИБІРСЬКОЇ

В огляді літератури узагальнено дані про ботанічну характеристику, розповсюдження, хімічний склад і застосування герані сибірської.

Pereskia aculeata Miller leaves present in vivo topical anti-inflammatory activity in models of acute and chronic dermatitis

Ethnopharmacological relevance: The leaves of Pereskia aculeata Miller (Cactaceae), known as Barbados gooseberry, are used in Brazilian traditional medicine as emollients and to treat skin wounds and inflammation. This study investigated the topical anti-inflammatory activity of the hexane fraction (HF) obtained from the methanol extract of the leaves of this species in models of acute and chronic ear dermatitis in mice.Material and methods: Mice ear edema was induced by topical application of croton oil, arachidonic acid, capsaicin, ethyl-phenylpropiolate and phenol; and by subcutaneous injection of histamine. Ear biopsies were obtained to determine the levels of IL-1β, IL-6 and TNF-α cytokines by ELISA assay. Histopathological analysis was also performed to evaluate the HF activity in croton oil multiple application test. In addition, acute dermal irritation/corrosion test in rats was accomplished. HF chemical characterization was performed by GC–MS analysis.Results: HF intensively reduced the inflammatory process induced by all irritant agents used, except for arachidonic acid. This activity is related, at least in part, to the reduction of IL-6 and TNF-α cytokines levels. Moreover, when the glucocorticoid receptor antagonist mifepristone was used, HF failed to respond to the croton oil application.The results strongly suggested a glucocorticoid-like effect, which was reinforced by the presence of considerable amounts of sterol compounds identified in HF. The acute dermal irritaton/corrosion test showed no signs of toxicity.Conclusions: This study showed that the acute and chronic anti-inflammatory activity of P. aculeata leaves is very promising, and corroborates to better understand their ethnopharmacological applications.

Synthesis and Biological Evaluation of a Novel Series of Pyrazolylcoumarins as Anti-Inflammatory and Antioxidant Agents

A new series of pyrazolylcoumarins (4a-k) was synthesized by reaction of appropriate dibromochalcones (3a-k) with phenyl hydrazine in ethanol. Structures of all new synthesized compounds were characterized on the basis of elemental analysis and spectral data (UV, IR and 1H NMR). The title compounds were screened for in vivo anti-inflammatory activities at a dose of 200 mg/kg b.w. Among the 11 prepared compounds, Compounds 4c, d, h and i exhibited significant anti-inflammatory activity in model of acute inflammation such as carrageenan-induced rat edema paw while compound 4d showed considerable activity in model of chronic inflammation such as adjuvant-induced arthritis along with minimum ulcerogenic index and were compared with diclofenac (13.5 mg/kg b.w.) as a standard drug. Additionally, the synthesized compounds were evaluated for their in vitro antioxidant activity. Compound 4k was found to be the most active antioxidant in the series compared with standard vitamin C.

Topical anti-inflammatory activity of quillaic acid from Quillaja saponaria Mol. and some derivatives

Quillaic acid is the major aglycone of the widely studied saponins of the Chilean indigenous tree Quillaja saponaria Mol. The industrial availability of quillaja saponins and the extensive functionalization of this triterpenoid provide unique opportunities for structural modification and pose a challenge from the standpoint of selectivity in regard to one or the other secondary alcohol group, the aldehyde, and the carboxylic acid functions. The anti-inflammatory activity of this sapogenin has not been studied previously and it has never been used to obtain potential anti-inflammatory derivatives. A series of quillaic acid derivatives were prepared and subjected to topical assays for the inhibition of inflammation induced by arachidonic acid or phorbol ester. Quillaic acid exhibited strong topical anti-inflammatory activity in both models. Most of its derivatives were less potent, but the hydrazone 8 showed similar potency to quillaic acid in the TPA assay. The structural modifications performed and the biological results suggest that the aldehyde and carboxyl groups are relevant to the anti-inflammatory activity in these models.

Evaluation of the anti-inflammatory activity of Aegle marmelos (Bilwa) root

Aims and objectives:The purpose of this study was to evaluate and compare the anti-inflammatory activity of the aqueous root bark extract of Aegle marmelos (Bilwa) in experimental acute and chronic inflammatory animal models.Materials and Methods:Aqueous extract of root bark of Bilwa was prepared and tested for anti-inflammatory activity in albino rats weighing 150-280 grams. The animals were randomly divided into 3 groups of 6 each; one group served as control and other two groups received indomethacin and Bilwa orally 1 hour prior to experimentation. The in vivo anti-inflammatory activity was studied using the acute (Carrageenan induced paw edema) and chronic (Cotton pellet induced granuloma) animal models. Anti-inflammatory activity was expressed as Percent inhibition (PI). Statistical analysis was performed using One-way analysis of variance (ANOVA) followed by Scheffe's post hoc test. P < 0.05 was considered statistically significant.Results:The PI with indomethacin and Bilwa in carrageenan induced paw edema were 52.7% and 46% and in cotton pellet induced granuloma were 24.7% and 9.2% respectively. Indomethacin showed highly significant anti-inflammatory activity in both the models. However, Bilwa showed highly significant activity in acute model and but a trend of anti-inflammatory activity in chronic model studied.Conclusions:As Bilwa showed significant anti-inflammatory activity in the models studied, it can be a promising anti-inflammatory agent.

Bovine Glycomacropeptide Has Intestinal Antiinflammatory Effects in Rats with Dextran Sulfate-Induced Colitis1–3

Milk κ-casein-derived bovine glycomacropeptide (GMP) has immunomodulatory and bacterial toxin-binding effects, and it has been shown to exert intestinal antiinflammatory activity in the trinitrobenzenesulfonic acid-induced model of colitis. However, its mechanism of action is not well characterized, and it is not known whether GMP is effective in other experimental models. The intestinal antiinflammatory activity of GMP was assessed in the dextran sulfate sodium (DSS)-induced model of rat colitis. DSS was applied at a starting concentration of 5% (wt:v) in drinking water and adjusted when the disease activity index (DAI) increased substantially for 10 d. There were 3 experimental groups: control (no inflammation), DSS, and GMP (GMP-treated rats with DSS-induced colitis). GMP pretreatment (500 mg · kg−1 · d−1, starting 2 d before DSS treatment) reduced the DAI by 60% and lowered the colonic damage score by 44% (P < 0.05). GMP fully normalized the colonic expression of interleukin (IL) 1β, IL17, IL23, IL6, transforming growth factor β, IL10, and Foxp3 as assessed by quantitative RT-PCR. The production of interferon-γ by mesenteric lymph node cells ex vivo was also normalized by GMP treatment. In contrast, GMP did not change colonic thickening, myeloperoxidase, cyclooxygenase 2, or alkaline phosphatase. Histology analysis showed better preservation of the epithelium and attenuated infiltration and submucosal thickening in rats treated with GMP. We conclude that GMP exerts intestinal antiinflammatory activity in this model, which may be primarily related to actions on Th1 and Th17 lymphocytes and perhaps macrophages.

Synthesis and pharmacological evaluation of a novel series of 5-(substituted)aryl-3-(3-coumarinyl)-1-phenyl-2-pyrazolines as novel anti-inflammatory and analgesic agents

A novel series of 5-(substituted)aryl-3-(3-coumarinyl)-1-phenyl-2-pyrazolines ( 3a– l) were synthesized by reacting various substituted 3-aryl-1-(3-coumarinyl)propan-1-ones ( 2a– l) with phenylhydrazine in the presence of hot pyridine. Structures of all new synthesized compounds were characterized on the basis of elemental analysis and spectral data (IR, 1H NMR and 13C NMR). The title compounds were screened for in vivo anti-inflammatory and analgesic activities at a dose of 200 mg/kg b.w. Among the 12 prepared compounds, Compounds 3d, e, i and j exhibited significant anti-inflammatory activity in model of acute inflammation such as carrageenan-induced rat edema paw while compounds 3d and e showed considerable activity in model of chronic inflammation such as adjuvant-induced arthritis and were compared with diclofenac (13.5 mg/kg b.w.) as a standard drug. These compounds were also found to have significant analgesic activity in the acetic acid induced writhing model and antipyretic activity in yeast-induced pyrexia model along with minimum ulcerogenic index.

THE EFFECTS OF GRANULOCYTE COLONY-STIMULATING FACTOR IN PRECLINICAL MODELS OF INFECTION AND ACUTE INFLAMMATION

The cytokine granulocyte colony-stimulating factor (G-CSF) is a potent endogenous trigger for the release of neutrophils from bone marrow stores and for their activation for enhanced antimicrobial activity. G-CSF has been widely evaluated in preclinical models of acute illness, with generally promising though divergent results. A recombinant G-CSF molecule has recently undergone clinical trials to assess its efficacy as an adjuvant therapy in community-acquired and nosocomial pneumonia, however, these studies failed to provide convincing evidence of benefit. We undertook a systematic review of the published literature reporting the effects of modulation of G-CSF in preclinical in vivo models to determine whether evidence of differential efficacy might explain the disappointing results of human studies and point to disease states that might be more likely to benefit from G-CSF therapy. G-CSF has been evaluated in 86 such studies involving a variety of different models. The strongest evidence of benefit was seen in studies involving intraperitoneal challenge with live organisms; benefit was evident whether the agent was given before or after challenge. G-CSF demonstrates anti-inflammatory activity in models of systemic challenge with viable organisms or endotoxin, but only when the agent is given before challenge; evidence of benefit after challenge was minimal. Preclinical models of intrapulmonary challenge only show efficacy when the cytokine is administered before the infectious challenge, and suggested harm in gram-negative pneumonia resulting from challenge with Escherichia coli or Klebsiella. There is little evidence for therapeutic efficacy in noninfectious models of acute illness. We conclude that the most promising populations for evaluation of G-CSF are neutropenic patients with invasive infection and patients with intra-abdominal infection, particularly those with the syndrome of tertiary, or recurrent, peritonitis. Significant variability in the design and reporting of studies of preclinical models of acute illness precludes more sophisticated data synthesis.

Up-regulation of cyclooxygenase-2 expression by TSG-6 protein in macrophage cell line

TNF-stimulated gene 6 (TSG-6) encodes a 35 kDa inducible secreted glycoprotein important in inflammation and female fertility. Previous studies have shown that TSG-6 has anti-inflammatory activity in models of acute and chronic inflammation. In the present study, we show that treatment of the RAW 264.7 murine macrophage cell line with TSG-6 protein up-regulates the expression of inducible cyclooxygenase-2 (COX-2), a key enzyme in inflammation and immune responses. This action of TSG-6 protein was abolished by heat denaturation, trypsin digestion, or anti-TSG-6 antibodies. TSG-6 treatment also resulted in a rapid increase in COX-2 mRNA levels, suggesting that TSG-6 up-regulates COX-2 gene expression. Up-regulation of COX-2 was accompanied by an increase in the production of prostaglandins, especially PGD 2. As the PGD 2 metabolite, 15-deoxy-Δ 12,14-PGJ 2, can act as a negative regulator of inflammation, these TSG-6 actions may explain, at least in part, the anti-inflammatory effect of TSG-6 observed in the intact organism.

Correlation of Toxicity and Pharmacokinetic Properties of a Phosphorothioate Oligonucleotide Designed to Inhibit ICAM-1

ISIS 2302 is a phosphorothioate oligodeoxynucleotide with a sequence complementary to the mRNA of human intercellular adhesion molecule 1 (ICAM-1). Hybridization of ISIS 2302 to the mRNA inhibits expression of the ICAM-1 protein in response to inflammatory stimuli. A murine active antisense oligonucleotide, ISIS 3082, has been used for in vivo pharmacology studies and has anti-inflammatory activity in models of organ transplant rejection, ulcerative colitis, and collagen-induced arthritis at doses ranging from 0.03 to 5 mg/kg. The safety assessment for ISIS 2302 includes general toxicity studies up to 6 mo in duration in mice and monkeys, genetic toxicity studies, and reproductive/fertility studies. ISIS 3082 was examined in parallel with ISIS 2302 in mouse toxicity and reproductive studies. The toxicities observed following systemic administration of ISIS 2302 and ISIS 3082 were similar and consistent with those observed for other compounds in this chemical class and, therefore, are independent of the suppression of ICAM-1 expression. Toxicokinetic evaluation demonstrated that toxicities occurred in organs containing the highest concentrations of ISIS 2302. Evidence of immune stimulation. including dose-dependent splenomegaly, lymphoid hyperplasia, and multiorgan mixed mononuclear cell infiltrates, was the most common finding in rodent studies. Monkeys were much less sensitive than mice to immune stimulation. Kidney contained the highest concentrations of ISIS 2302. Morphologic changes observed in kidney included atrophic and regenerative changes in proximal tubular epithelium; however, there was no evidence of functional abnormalities. Additional histologic changes noted in proximal tubular epithelium included basophilic granules, which were reflective of oligonucleotide distribution and uptake in these cells. Liver also contained high concentrations of oligonucleotide, which were associated with Kupffer cell hypertrophy in mice. Changes in serum transaminases, cholesterol, and triglycerides were reflective of hepatic alterations. In monkeys, high concentrations of oligonucleotide caused a transient increase in clotting times and activation of the alternative complement pathway. All toxicities associated with ISIS 2302 were reversible and occurred at doses well above those required for pharmacologic activity or currently used in clinical trials. In addition, there has been no evidence of genetic toxicity associated with ISIS 2302, and no changes in reproductive performance, fertility, or fetal development have been noted in animals treated with ISIS 2302 or ISIS 3082.

Reduced anti-inflammatory activity of acetylsalicylic acid maltol ester, aspalatone

The anti-inflammatory activity of acetylsalicylic acid maltol ester (aspalatone), a potential antithrombotic agent, was studied using the several experimental animal models of inflammation. By oral administration, aspalatone was found to possess the weak anti-inflammatory activity in models of an acute inflammation, in which aspalatone showed approximately one-third to one-fourth of the anti-inflammatory activity of aspirin. Aspalatone (200 mg/kg/day) and aspirin (50 mg/kg/day), however, did not show the inhibitory activity against granuloma formation and adjuvant-induced arthritis.