The protective effect of solidagenone from Solidago chilensis Meyen in a mouse model of airway inflammation

Solidagenone is the main active constituent present in Solidago chilensis Meyen which is used in folk medicine to treat pain and inflammatory diseases. This study aimed to evaluate the anti-inflammatory activity of solidagenone in vitro and in a model of allergic airway inflammation. In vitro studies were performed in activated macrophages and lymphocytes. BALB/c mice were sensitized and challenged with ovalbumin and treated with solidagenone orally (30 or 90 mg/kg body weight) or dexamethasone, as a positive control in our in vivo analysis. Supernatant concentrations of nitrite, TNF and IL-1β, as well as gene expression of pro-inflammatory mediators in macrophages cultures, were reduced after solidagenone treatment, without affecting macrophages viability. Besides, solidagenone significantly decreased T cell proliferation and secretion of IFNγ and IL-2. Th2 cytokine concentrations and inflammatory cell counts, especially eosinophils, in bronchoalveolar lavage fluid were reduced in mice treated with solidagenone. Histopathological evaluation of lung tissue was performed, and morphometrical analyses demonstrated reduction of cellular infiltration and mucus hypersecretion. Altogether, solidagenone presented anti-inflammatory activity in vitro and in vivo in the OVA-induced airway inflammation model, suggesting its promising pharmacological use as an anti-inflammatory agent for allergic hypersensitivity.     

Oral administration of alkaloid fraction from Ruta graveolens inhibits oxidative stress and inflammation in hypercholesterolemic rabbits

Abstract

Context: The anti-atherogenic effect of alkaloid fraction from Ruta graveolens Linn (Rutaceae) extract is suspected to be related to its activities of antioxidation and anti-inflammation.

Objective: This study investigated the efficacy of alkaloid fraction isolated from Ruta graveolens (AFR) in reducing oxidative damage and inflammation in hypercholesteremic rabbits.

Materials and methods: The New Zealand white rabbits were randomly divided into three groups: Group I rabbits were fed with normal chow diet for 90?d. Group II rabbits were fed with 1% cholesterol-enriched diet. Group III rabbits were fed with 1% cholesterol-enriched diet together with AFR (10?mg/kg/daily for 90?d).

Results and discussion: The results showed that on treatment with AFR significantly lowered the level of total cholesterol and LDL-C and showed an increment in the level of HDL-C. LD₅₀ of the AFR in rats is greater than 525?mg/kg. Activities of antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase and GSH level were decreased in cholesterol-fed rabbit and supplementation of AFR significantly enhanced the activities of these antioxidant enzymes and GSH level. Increased activities of enzymes such as cyclooxygenase-2, 15-lipoxygenase and myeloperoxidase were significantly suppressed by AFR administration. The acute phase proteins, total WBC count and TBARS concentrations were significantly increased by hypercholesteromic diet, which were significantly decreased by AFR treatment. Histopathological studies of aorta in cholesterol-fed rabbit showed plaque formation and significant changes in aortic wall. Administration of AFR showed no changes in aortic wall.

Conclusion: AFR reduces oxidative stress and inflammation and reduces the aortic pathology in hypercholesteromic rabbits.     

Investigation into potent inflammation inhibitors from traditional Chinese medicine

Microsomal prostaglandin E synthase-1 (mPGES-1) is the key enzyme for prostaglandin E2 (PGE2) generation during inflammation and is a potential target for designing anti-inflammatory drugs. Potential inhibitors of m-PGES-1 were selected from traditional Chinese medicine (TCM Database@Taiwan) based on the pharmacophore map generated by the top HypoGen hypothesis and validated using structure- and ligand-based analysis. Key features for potential m-PGES-1 inhibitors include pi-interactions and H-bond donors. TCM compounds, shanciol B, shanciol A, castilliferol, and aurantiamide acetate, contoured to the quantitative structure-activity relationship pharmacophore and exhibited high docking scores and binding stability with m-PGES-1. Bioactivity models multiple linear regression (MLR) and support vector machine also supported activity predictions for the candidate compounds. Our results indicate that the investigated TCM compounds could be of use for development into mPGES-1 inhibitors.     

Cytoprotective effects of endothelin‐1 on mesenchymal stem cells: an in vitro study

Stem cell‐based therapies is a promising approach for regenerative therapy in various diseases. Some obstacles remain to be solved before clinical application of the cell therapy is realized, including increasing the survival of transplanted stem cells, reducing loss of transplanted cells, and maintaining adequate vascular supply. Recently, stem cell preconditioning with chemical and pharmacological agents has been shown to increase therapeutic efficacy. The present study investigated the effect of endothelin‐1 (ET‐1) on survival, angiogenesis, and migration of mesenchymal stem cells (MSCs), in vitro. MSCs were treated with various concentrations of ET‐1 and the expression of cyclooxygenase‐2 (COX‐2), hypoxia‐inducible factor‐1 (HIF‐1), C‐X‐C chemokine receptor type 4 (CXCR4), C‐C chemokine receptor type 2 (CCR2), vascular endothelial growth factor (VEGF), angiopoietin‐2 (Ang‐2), angiopoietin‐4 (Ang‐4) and matrix metalloproteinase‐2 (MMP‐2) were examined. Caspase 3 activity and prostaglandin E2 (PGE2) were determined by ELISA assay. MSCs migration and tube formation potential were assessed using scratch test and three dimensional vessel formation assay. ET‐1 enhanced the MSCs viability. In ET‐1‐ treated MSCs, expression of COX‐2, HIF‐1, CXCR4, CCR2, VEGF, Ang‐2, Ang‐4 and MMP‐2 were increased compared to control groups. Elevation of all these genes were reversed by celecoxib (50 μmol/L), a selective COX‐2 inhibitor. PGE2 generation, MSCs migration and tube formation were enhanced by ET‐1 conditioning, whereas caspase‐3 activity was reduced in these cells, compared to the control group. The results presented here reveal that preconditioning of MSCs with ET‐1 has strong cytoprotective effects through activation of survival signalling molecules and trophic factors.     

Analysing the role of COX-2 in acute oesophagitis and in melatonin-exerted protection against experimental reflux oesophagitis in rats

Objectives Cyclooxygenase(COX)‐2 is implicated in variety of pathophysiological processes, although its role in acute reflux oesophagitis is debatable. This study was designed to evaluate the role of COX‐2 during oesophagitis and in melatonin‐elicited protection in rats. Methods Reflux oesophagitis was induced in rats by ligating the pyloric end and the limiting ridge of the stomach for 5 h. Celecoxib (COX‐2 blocker; 10 mg/kg), 16,16‐dimethyl prostaglandinE₂ (dmPGE₂; a synthetic analogue of PGE₂; 10 µg/kg), melatonin (20 and 40 mg/kg) and omeprazole (10 mg/kg) were given intra‐peritoneally 45 min before induction of oesophagitis in rats. Alterations in COX‐1 and 2 gene expression and protein levels level were analysed via RT‐PCR and Western blotting, respectively. Mucosal PGE₂ level and myeloperoxidase (MPO) activity were measured using an enzyme immunoassay (EIA) kit and spectrophotometrically, respectively. Key findings COX‐2 over‐expression during reflux oesophagitis promotes inflammation of the oesophagus as celecoxib pretreatment significantly reduced tissue damage and MPO activity in rats with reflux oesophagitis (RE‐rats). By contrast, dmPGE₂ pretreatment significantly exacerbated tissue injury and simultaneously increased COX‐2 expression, PGE₂ levels and MPO activity in RE‐rats. Further, melatonin pretreatment significantly reduced the tissue injury, COX‐2 over‐expression, PGE₂ level and MPO activity in RE‐rats. Melatonin offered more potent suppression of COX‐2, PGE₂ and MPO activity than the proton‐pump inhibitor omeprazole; however, both reduced the lesion injury to a similar extent. Melatonin at a dose of 20 mg/kg failed to inhibit significantly the dmPGE₂‐induced tissue damage, COX‐2 expression, PGE₂ level and MPO activity in RE‐rats while at a higher dose of 40 mg/kg it significantly attenuated these changes. Conclusion Our results suggest that COX‐2 plays an important pro‐inflammatory role during acute reflux oesophagitis in rats and its inhibition contributes significantly to melatonin‐exerted protection against reflux oesophagitis.     

Synthesis,biological evaluation,and docking studies of some 5‐chloro‐2(3H)‐benzoxazolone Mannich bases derivatives as cholinesterase inhibitors

A series of N‐substituted‐5‐chloro‐2(3H)‐benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory, and antioxidant activities. The structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The free radical scavenging activity was also determined by in vitro ABTS (2,2‐azinobis(3‐ethylbenzothiazoline‐6‐sulfonic acid)) assay. The biological activity results revealed that all of the title compounds displayed higher AChE inhibitory activity than the reference compound, rivastigmine, and were selective for AChE. Among the tested compounds, compound 7 exhibited the highest inhibition against AChE (IC₅₀ = 7.53 ± 0.17 μM), while compound 11 was found to be the most active compound against BuChE (IC₅₀ = 17.50 ± 0.29 μM). The molecular docking study of compound 7 showed that this compound can interact with the catalytic active site (CAS) of AChE and also has potential metal chelating ability and a proper log P value. On the other hand, compound 2 bearing a methyl substituent at the ortho position on the phenyl ring showed better radical scavenging activity (IC₅₀ = 1.04 ± 0.04 mM) than Trolox (IC₅₀ = 1.50 ± 0.05 mM).

     

Doxazosin down‐regulates sodium‐glucose cotransporter‐2 and exerts a renoprotective effect in rat models of acute renal injury

Sodium‐glucose cotransporter‐2 (SGLT2) is known to be involved in the progression of acute renal injury (ARI) and is regulated by different mediators in the kidneys including extracellular signal‐regulated kinase (ERK), hypoxia‐inducible factor 1 alpha (HIF1α) and prostaglandin E2 (PGE2). In the present study, we investigated the possible protective effect of doxazosin on renal ischaemia/reperfusion (IR) and glycerol‐induced ARI by determining its effect on SGLT2 via modifying ERK‐HIF1α pathway and/or PGE2. Rats were divided into control, sham or IR where the rats received the vehicle, doxazosin (8 mg/kg) or the SGLT2 inhibitor, dapagliflozin (10 mg/kg) for 3 days followed by 45 minutes bilateral renal ischaemia then 24 hours reperfusion. Another group of rats received the vehicle, doxazosin or dapagliflozin for three days followed by injection of 50% glycerol (8 mL/kg, IM) or saline. Kidney function tests, systolic blood pressure (SBP), oxidative stress markers (malondialdehyde [MDA] and NADPH oxidase), nitric oxide (NO), inducible nitric oxide synthase (iNOS), HIF1α, ERK phosphorylation and PGE2 levels were determined. Additionally, renal sections were used for immunological expression of SGLT2. ARI rats showed significantly increased SBP; worsened kidney function tests; increased oxidative stress, iNOS, NO, HIF1α levels; and decreased PGE2 and ERK phosphorylation along with up‐regulated SGLT2. Doxazosin treatment protected against the kidney damage and attenuated the associated biochemical changes. Doxazosin has a direct renoprotective effect possibly by down‐regulating SGLT2.     

Chronic restraint stress induces intestinal inflammation and alters the expression of hexose and lipid transporters

相似文献   

Role of nitric oxide in allergic inflammation and bronchial hyperresponsiveness

The role of nitric oxide (NO) in allergic inflammation and bronchial hyperresponsiveness is unclear. We studied a selective prodrug nitric oxide synthase (NOS)-2 inhibitor, L-N(6)-(1-iminoethyl)lysine 5-tetrazole amide (SC-51). In ovalbumin-sensitized and challenged rats, exhaled NO levels increased by 3 h following challenge (3.73 +/- 0.74 ppb; P < 0.05), peaking at 9 h (11.0 +/- 2.75; P < 0.01) compared to saline controls (1.87 +/- 0.26; P < 0.05 and 2.81 +/- 0.18; P < 0.01). Immunoreactive lung NOS2 expression was increased in ovalbumin-challenged rats compared with ovalbumin-sensitized, saline-challenged rats at 8 h post-challenge. SC-51 (10 mg/kg; p.o.) inhibited allergen-induced increase in exhaled NO levels to 1.3 +/- 0.17 ppb. SC-51 inhibited bronchial hyperresponsiveness in ovalbumin-sensitized and challenged rats (P < 0.05). In sensitized non-exposed rats, SC-51 increased bronchial responsiveness (P < 0.05). SC-51 reduced the allergen-induced increase in bronchoalveolar lavage neutrophils, but caused a nonsignificant reduction in bronchial mucosal eosinophil numbers. NO generated through NOS2 contributes to allergen-induced bronchial hyperresponsiveness but not to bronchial eosinophilia, indicating that these are independently expressed.     

Molecular Docking and in Vitro Antileishmanial Evaluation of Chromene-2-thione Analogues

相似文献   

金茵颗粒剂抗豚鼠胆囊炎分子机制

 目的: 探讨金茵颗粒剂抗豚鼠胆色素结石性胆囊炎的分子机制。方法: 构建豚鼠胆色素结石性胆囊炎模型,然后用金茵颗粒剂连续治疗15 d。治疗结束后,采用酶联免疫吸附法（ELISA）检测血清、胆汁中前列腺素E2（prostaglandin E2,PGE2）的含量,免疫组化法检测胆囊组织内环氧化酶-2（cycloxygenase-2,COX-2）和核因子-κB （nuclear factor-kappa B ,NF-κB）的表达量及活化细胞数量。结果: 与模型对照组比较,金茵颗粒剂治疗组豚鼠血清和胆汁中PGE2的含量以及胆囊组织内COX-2和NF-κB的表达量及活化细胞数量明显减少,有统计学显著差异（P＜0.01）。结论: 金茵颗粒剂治疗胆囊炎可能的分子机制是通过抑制NF-κB的活化及表达量进而抑制COX-2的表达和PGE2的合成。     

The efficacy of oleuropein against non‐steroidal anti‐inflammatory drug induced toxicity in rat kidney

Indomethacin is generally used in clinical therapeutics as a non‐steroidal anti‐inflammatory drug. However, its use has been limited due to the gastrointestinal and renal toxic effects of this drug. These toxic effects were associated with not only the inhibition of prostaglandin synthesis but also drug‐elevated oxidative stress. To ameliorate these toxicities, natural antioxidants can be used as an alternative and/or combination therapies. Therefore, the current study was conducted to assess the renoprotective effects of oleuropein against indomethacin‐induced renal damages. Male Sprague‐Dawley rats were pretreated with oleuropein (75, 150, and 300 mg/kg), and then treated with indomethacin (25 mg/kg). To evaluate kidney function, serum blood urea nitrogen, uric acid, and creatinine were measured. In addition, prostaglandin E₂, tumor necrosis factor‐alpha, endothelial nitric oxide synthase, caspase‐3, oxidant/antioxidant status, and 8‐Oxo‐2′‐deoxyguanosine levels were determined for the antioxidative and anti‐inflammatory effects of oleuropein. Tissue sections were also histopathologically assessed. The biochemical and histopathological analysis proved the toxic effects of indomethacin on kidney. However, the pretreatment with oleuropein (300 mg/kg) protects kidney from indomethacin‐induced damages. Our study proved that prior administration of oleuropein has renoprotective activity against indomethacin‐associated toxicities.     

Protective effect of curcumin,a Curcuma longa constituent,in early colonic inflammation in rats

Curcumin, a polyphenol derived from the plant, Curcuma longa, has a variety of pharmacological effects, including chemotherapeutic, anti‐inflammatory, antiangiogenic, and antioxidant activities. To gain a better understanding of the effects and mechanisms of action of curcumin on the acute injury caused by intra‐colonic administration of acetic acid (AA) in rats, inflammation was assessed by histology and myeloperoxidase activity (MPO; an index of neutrophil infiltration in the mucosa); Th1 and Th2 cytokine production; histological and histochemical analysis of the lesions; nitrite production in colon mucosa; and the expression of iNOS, COX‐1 and ‐2 using Western blotting and inmmunohistochemistry. We also studied the involvement of the p38 MAPK/JNK signalling pathway in the protective effect of curcumin in acute colonic inflammation. Curcumin (50–100 mg/kg/day) reduced the degree of colonic injury, the index of neutrophil infiltration and Th1 cytokine secretion, and increased IL‐10 production, reduced colonic levels of nitrites, and reduced COX‐2 and iNOS overexpression. A reduction in the activation of p38 and JNK MAPKs was also observed. Thus, we show that the widely used food additive, curcumin reduced the development of AA‐induced colitis and alleviated the inflammatory response. Inhibition of MAPK signalling by curcumin could explain the changes on the cytokine Th1/Th2 profile, the reduction of COX‐2 and iNOS signaling, as well as the decreased nitrite production in colonic mucosa, suggesting that curcumin may be useful in the treatment of ulcerative colitis. Drug Dev Res, 2009. © 2009 Wiley‐Liss, Inc.     

Possible participation of cyclooxygenase-2 in the recurrence of allergic inflammation in rats

In the recurrence of allergic inflammation in a rat air pouch model, pouch fluid volume, prostaglandin E₂ concentration in the pouch fluid, leukocyte infiltration into the pouch fluid, and granulation tissue weight were markedly increased by the antigen challenge. To clarify the role of cyclooxygenase-2 in the recurrence of allergic inflammation, the time-course of changes in protein levels of cyclooxygenase-1 and cyclooxygenase-2 in the granulation tissue and in the infiltrated leukocytes was examined by Western blot analysis. It was shown that cyclooxygenase-1 levels in the granulation tissue and in the infiltrated leukocytes were not changed by the antigen challenge, but cycoloxygenase-2 levels were increased. Furthermore, treatment with the selective cyclooxygenase-2 inhibitor, NS-398 ([N-2(cyclohexyloxy-4-nitrophenyl]-methanesulfonamide), suppressed the recurrence of allergic inflammation as did the non-selective cyclooxygenase-1/cyclooxygenase-2 inhibitor, indomethacin. The steroidal anti-inflammatory drug, dexamethasone, inhibited the induction of cyclooxygenase-2, and suppressed the allergic inflammation. These findings strongly suggested that cyclooxygenase-2 induced by the antigen challenge plays a role in the recurrence of inflammation induced by the allergic mechanism.     

N‐[9‐(ortho‐Fluorobenzyl)‐2‐Phenyl‐8‐Azapurin‐6‐yl]‐Amides as Potent and Selective Ligands for A1 Adenosine Receptors

A series of N‐[9‐(ortho‐fluorobenzyl)‐2‐phenyl‐8‐azapurin‐6‐yl]‐amides were synthesized and tested for their affinity toward A₁, A_2A, and A₃ adenosine receptor subtypes. Biological results demonstrated that the introduction of a fluorine atom at the ortho position of the 9‐benzyl group generally enhanced affinity toward A₁ subtype and did not significantly affect A_2A and A₃ affinity. Very interesting is the compound bearing a meta‐fluorophenyl substituent on the carbonyl carbon of the amide group, which shows significantly high A₁/A_2A‐A₃ selectivity. Compounds of this new series, together with the previously published analogs without the fluorine atom on the 9‐benzyl group, constituted the starting dataset for the development of QSAR models. The models obtained were able to rationally describe the affinity trends resulting from biological testing and to enable investigation of the role of different substituents on the 8‐azapurine scaffold, as well as the influence of the newly introduced fluorine atom on the benzyl moiety. The said QSAR models can also assist in the design of new compounds selectively active on A₁ adenosine receptors. Furthermore, a molecular docking study was carried out to assess hypothetical binding mode of N‐[9‐(ortho‐fluorobenzyl)‐2‐phenyl‐8‐azapurin‐6‐yl]‐amides to A₁ adenosine receptors.     

Histone Deacetylase Inhibition Activity and Molecular Docking of (E )‐Resveratrol: Its Therapeutic Potential in Spinal Muscular Atrophy

Spinal muscular atrophy is an autosomal recessive motor neuron disease that is caused by mutation of the survival motor neuron gene (SMN1) but all patients retain a nearly identical copy, SMN2. The disease severity correlates inversely with increased SMN2 copy. Currently, the most promising therapeutic strategy for spinal muscular atrophy is induction of SMN2 gene expression by histone deacetylase inhibitors. Polyphenols are known for protection against oxidative stress and degenerative diseases. Among our candidate prodrug library, we found that (E )‐resveratrol, which is one of the polyphenolic compounds, inhibited histone deacetylase activity in a concentration‐dependent manner and half‐maximum inhibition was observed at 650 μm . Molecular docking studies showed that (E )‐resveratrol had more favorable free energy of binding (?9.09 kcal/mol) and inhibition constant values (0.219 μm ) than known inhibitors. To evaluate the effect of (E )‐resveratrol on SMN2 expression, spinal muscular atrophy type I fibroblast cell lines was treated with (E )‐resveratrol. The level of full‐length SMN2 mRNA and protein showed 1.2‐ to 1.3‐fold increase after treatment with 100 μm (E )‐resveratrol in only one cell line. These results indicate that response to (E )‐resveratrol treatment is variable among cell lines. This data demonstrate a novel activity of (E )‐resveratrol and that it could be a promising candidate for the treatment of spinal muscular atrophy.     

Effect of atovastatin treatment on porcine circovirus 2 infection in BALB/c mice

The HMG‐CoA reductase (HMGCR) pathway is an important metabolic route, which is not only present in almost every organism, but also involves virus infection. It has recently been shown that expression levels of IFN‐responsive genes were significantly increased in HMGCR‐downregulated cells and HMGCR inhibitor‐treated cells. The aim of this study was to determine whether inhibition of HMGCR by atovastatin would significantly affect Porcine circovirus type 2 (PCV2) infection and immunological reaction in BALB/c mice. The results showed atovastatin significantly stimulated PCV2 replication in vivo. Immunological reaction in atovastatin‐treated mice was also significantly enhanced during PCV2 infection. Atovastatin also enhanced PCV2‐induced illness in mice. The results of this study will provide new insight into the role of atovastatin in PCV2 infection.