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1.
Life Sci ; 239: 117017, 2019 Dec 15.
Article in English | MEDLINE | ID: mdl-31678284

ABSTRACT

Saxagliptin (Saxa), a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, is widely used for the treatment of type 2 diabetes mellitus. It has been documented to have immunomodulatory and anti-inflammatory actions. Our objective was to delineate the protective effect and the underlying mechanism of Saxa-in comparison with Dexamethasone (Dexa) - in airway inflammation induced by ovalbumin (OVA) in mice. METHODS: Mice were OVA-sensitized and challenged for the induction of acute asthma. Mice were orally administrated Saxa or Dexa. Total and differential cell counts, lactate dehydrogenase (LDH) and total protein concentrations were assessed in bronchoalveolar lavage fluid (BALF). The toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-kB), reduced glutathione (GSH), and total nitrate/nitrite products (NOx) levels as well as myeloperoxidase (MPO) activity in lung tissues were measured. Histopathological examination of the lung specimens was carried out using the hematoxylin and eosin (H & E) staining. RESULTS: Histopathological examination revealed that both Saxa and Dexa ameliorated OVA-induced inflammatory changes and significantly reduced total and differential leukocyte counts, LDH and total protein level in BALF upon comparison with OVA group. In addition, both treatments significantly mitigated OVA-induced oxidative stress as evidenced by diminished lung NOx level and MPO activity and elevated GSH level. The elevation of TLR4 and NF-kB levels in lung tissue were ameliorated by Saxa and Dexa administration. CONCLUSION: Saxa had marked antiasthmatic effect in OVA-induced allergic asthma through modulation of TLR4 and NF-κB signaling. Also, Saxa may represent a promising therapeutic agent for acute allergic asthma.


Subject(s)
Adamantane/analogs & derivatives , Asthma/drug therapy , Dipeptides/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , NF-kappa B/drug effects , Toll-Like Receptor 4/drug effects , Acute Disease , Adamantane/therapeutic use , Animals , Asthma/chemically induced , Asthma/pathology , Bronchoalveolar Lavage Fluid/cytology , Dexamethasone/therapeutic use , L-Lactate Dehydrogenase/metabolism , Lung/metabolism , Lung/pathology , Male , Mice , Nitric Oxide/metabolism , Ovalbumin , Peroxidase/metabolism
2.
Environ Toxicol Pharmacol ; 50: 175-182, 2017 Mar.
Article in English | MEDLINE | ID: mdl-28189063

ABSTRACT

Acute hepatic dysfunction associating sepsis is mediated mainly by toll-like receptor-4 (TLR-4)/nuclear factor kappa-B (NF-κB) inflammatory pathway. This study explores potential hepatoprotective effect of the NF-κB inhibitor celastrol in cecal ligation and puncture (CLP) model in rats. Protective effect of celastrol (1mg/kg, i.p., 1h before CLP) was illustrated after 24h by preventing CLP-induced hepatic histopathological changes and elevation in serum hepatic biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB) and gamma aminotransferase (γ-GT)] without affecting mortality. Celastrol anti-inflammatory effect was illustrated by inhibiting increased serum and hepatic mRNA expression of interleukin-6 (IL-6) without affecting IL-10 elevation. Furthermore, celastrol inhibited CLP-induced elevations in hepatic mRNA expression of nuclear factor inhibitory protein kappa-B alpha (NFκBia), TLR-4, 5-lipoxygenase (5-LOX) and prevented NF-κB/p65 nuclear translocation and activation. In conclusion, celastrol prevented CLP-induced acute hepatic dysfunction through its anti-inflammatory effect by attenuating NF-κB activation, TLR-4 and 5-LOX expression with subsequent reduction in pro-inflammatory IL-6.


Subject(s)
Anti-Inflammatory Agents/administration & dosage , Liver Diseases/prevention & control , NF-kappa B/antagonists & inhibitors , Triterpenes/administration & dosage , Animals , Anti-Inflammatory Agents/pharmacology , Cecum/surgery , Disease Models, Animal , Gene Expression Regulation/drug effects , Interleukin-10/blood , Interleukin-10/genetics , Interleukin-6/blood , Interleukin-6/genetics , Liver Diseases/etiology , Liver Diseases/genetics , Liver Diseases/metabolism , Male , Pentacyclic Triterpenes , Rats , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Triterpenes/pharmacology
3.
Naunyn Schmiedebergs Arch Pharmacol ; 390(4): 361-368, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28035464

ABSTRACT

Sepsis is a systemic inflammatory response associating severe infection leading to multi-organ failure, such as hepatic dysfunction. This study investigates the possible hepatoprotective effect of the lipoxin A4 agonist (BML-111) in cecal ligation and puncture (CLP) model in rats. Pretreatment with BML-111 (1 mg/kg, i.p., 1 h before CLP) protected against CLP-induced mortality after 24 h. BML-111 prevented marked inflammatory cells in liver tissues and decreased elevation in serum hepatic biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), gamma-glutamyl transferase (γ-GT)] induced by CLP. Additionally, BML-111 attenuated elevated serum level of interleukin-6 (IL-6) and downregulated hepatic IL-6 mRNA expression. Meanwhile, BML-111 further increased serum IL-10 and upregulated hepatic IL-10 mRNA expression, while it downregulated hepatic mRNA expression of nuclear factor inhibitory protein kappa-B alpha (NFκBia), toll-like receptor-4 (TLR-4), and 5-lipooxygenase (5-LOX). Moreover, BML-111 prevented NF-κB/p65 nuclear translocation and activation. In conclusion, BML-111 attenuated CLP-induced acute hepatic dysfunction through its anti-inflammatory effect by decreasing NF-κB activity, TLR-4, and 5-LOX expression with subsequent decrease in pro-inflammatory IL-6 and elevation in anti-inflammatory IL-10.


Subject(s)
Heptanoic Acids/therapeutic use , Lipoxins/agonists , Liver Diseases/drug therapy , Protective Agents/therapeutic use , Alanine Transaminase/blood , Animals , Arachidonate 5-Lipoxygenase/genetics , Aspartate Aminotransferases/blood , Bilirubin/blood , Cecum/injuries , Cecum/surgery , Heptanoic Acids/pharmacology , Interleukin-10/blood , Interleukin-10/genetics , Interleukin-6/blood , Interleukin-6/genetics , Ligation , Liver/drug effects , Liver/metabolism , Liver/pathology , Liver Diseases/etiology , Liver Diseases/metabolism , Liver Diseases/pathology , Male , NF-kappa B/genetics , NF-kappa B/metabolism , Protective Agents/pharmacology , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Toll-Like Receptor 4/genetics , gamma-Glutamyltransferase/blood
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