Saxagliptin mitigates airway inflammation in a mouse model of acute asthma via modulation of NF-kB and TLR4
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...
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| Veröffentlicht in: | Life sciences (1973) 2019-12, Vol.239, p.117017, Article 117017 |
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| creator | Helal, Manar G. Megahed, Nermeen A. Abd Elhameed, Ahmed G. |
| description | 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.
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.
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.
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. |
| doi_str_mv | 10.1016/j.lfs.2019.117017 |
| format | Article |
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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.
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.
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.</description><identifier>ISSN: 0024-3205</identifier><identifier>EISSN: 1879-0631</identifier><identifier>DOI: 10.1016/j.lfs.2019.117017</identifier><identifier>PMID: 31678284</identifier><language>eng</language><publisher>Netherlands: Elsevier Inc</publisher><subject>Acute asthma ; Acute Disease ; Adamantane - analogs & derivatives ; Adamantane - therapeutic use ; Alveoli ; Animals ; Asthma ; Asthma - chemically induced ; Asthma - drug therapy ; Asthma - pathology ; Bronchoalveolar Lavage Fluid - cytology ; Bronchus ; Chemical compounds ; Dexamethasone ; Dexamethasone - therapeutic use ; Diabetes mellitus ; Diabetes mellitus (non-insulin dependent) ; Dipeptidase ; Dipeptides - therapeutic use ; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use ; Dual energy X-ray absorptiometry ; Glutathione ; Immunomodulation ; Inflammation ; L-Lactate dehydrogenase ; L-Lactate Dehydrogenase - metabolism ; Lactate dehydrogenase ; Lactic acid ; Leukocytes ; Levels ; Lung - metabolism ; Lung - pathology ; Lungs ; Male ; Mice ; Modulation ; MPO ; NF-kappa B - drug effects ; NF-κB ; NF-κB protein ; Nitric Oxide - metabolism ; Oral administration ; Ovalbumin ; Oxidative stress ; Peroxidase ; Peroxidase - metabolism ; Pharmacology ; Proteins ; Respiratory tract ; Respiratory tract diseases ; Saxagliptin ; TLR4 ; TLR4 protein ; Toll-Like Receptor 4 - drug effects ; Toll-like receptors</subject><ispartof>Life sciences (1973), 2019-12, Vol.239, p.117017, Article 117017</ispartof><rights>2019 Elsevier Inc.</rights><rights>Copyright © 2019 Elsevier Inc. All rights reserved.</rights><rights>Copyright Elsevier BV Dec 15, 2019</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c447t-13d728e659fe56ea1e75c6948afcedfee7e5c5180b630284dd67382af76bb5ff3</citedby><cites>FETCH-LOGICAL-c447t-13d728e659fe56ea1e75c6948afcedfee7e5c5180b630284dd67382af76bb5ff3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.lfs.2019.117017$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31678284$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Helal, Manar G.</creatorcontrib><creatorcontrib>Megahed, Nermeen A.</creatorcontrib><creatorcontrib>Abd Elhameed, Ahmed G.</creatorcontrib><title>Saxagliptin mitigates airway inflammation in a mouse model of acute asthma via modulation of NF-kB and TLR4</title><title>Life sciences (1973)</title><addtitle>Life Sci</addtitle><description>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.
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.
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.
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.</description><subject>Acute asthma</subject><subject>Acute Disease</subject><subject>Adamantane - analogs & derivatives</subject><subject>Adamantane - therapeutic use</subject><subject>Alveoli</subject><subject>Animals</subject><subject>Asthma</subject><subject>Asthma - chemically induced</subject><subject>Asthma - drug therapy</subject><subject>Asthma - pathology</subject><subject>Bronchoalveolar Lavage Fluid - cytology</subject><subject>Bronchus</subject><subject>Chemical compounds</subject><subject>Dexamethasone</subject><subject>Dexamethasone - therapeutic use</subject><subject>Diabetes mellitus</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Dipeptidase</subject><subject>Dipeptides - therapeutic use</subject><subject>Dipeptidyl-Peptidase IV Inhibitors - therapeutic use</subject><subject>Dual energy X-ray absorptiometry</subject><subject>Glutathione</subject><subject>Immunomodulation</subject><subject>Inflammation</subject><subject>L-Lactate dehydrogenase</subject><subject>L-Lactate Dehydrogenase - metabolism</subject><subject>Lactate dehydrogenase</subject><subject>Lactic acid</subject><subject>Leukocytes</subject><subject>Levels</subject><subject>Lung - metabolism</subject><subject>Lung - pathology</subject><subject>Lungs</subject><subject>Male</subject><subject>Mice</subject><subject>Modulation</subject><subject>MPO</subject><subject>NF-kappa B - drug effects</subject><subject>NF-κB</subject><subject>NF-κB protein</subject><subject>Nitric Oxide - metabolism</subject><subject>Oral administration</subject><subject>Ovalbumin</subject><subject>Oxidative stress</subject><subject>Peroxidase</subject><subject>Peroxidase - metabolism</subject><subject>Pharmacology</subject><subject>Proteins</subject><subject>Respiratory tract</subject><subject>Respiratory tract diseases</subject><subject>Saxagliptin</subject><subject>TLR4</subject><subject>TLR4 protein</subject><subject>Toll-Like Receptor 4 - drug effects</subject><subject>Toll-like receptors</subject><issn>0024-3205</issn><issn>1879-0631</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1P3DAQhi3UChbKD-gFWeo5ix3HdiJOBQGttCoShbM1G4-pl3wstgPl39erUI5cbFnzzDueh5CvnC054-p0s-xcXJaMN0vONeN6jyx4rZuCKcE_kQVjZVWIkskDchjjhjEmpRb75EBwpeuyrhbk8Tf8hYfOb5MfaO-Tf4CEkYIPL_BK_eA66HtIfhzygwLtxyliPi12dHQU2ikhhZj-9ECf_a5up27mc_nXVfF4TmGw9G51W30hnx10EY_f7iNyf3V5d_GjWN1c_7z4viraqtKp4MLqskYlG4dSIXDUslVNVYNr0TpEjbKVvGZrJVhewlqlRV2C02q9ls6JI_Jtzt2G8WnCmMxmnMKQR5pSCNFUUso6U3ym2jDGGNCZbfA9hFfDmdnpNRuT9ZqdXjPrzT0nb8nTukf73vHfZwbOZgDzfs8eg4mtxyH_2wdsk7Gj_yD-H9VzitE</recordid><startdate>20191215</startdate><enddate>20191215</enddate><creator>Helal, Manar G.</creator><creator>Megahed, Nermeen A.</creator><creator>Abd Elhameed, Ahmed G.</creator><general>Elsevier Inc</general><general>Elsevier BV</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20191215</creationdate><title>Saxagliptin mitigates airway inflammation in a mouse model of acute asthma via modulation of NF-kB and TLR4</title><author>Helal, Manar G. ; Megahed, Nermeen A. ; Abd Elhameed, Ahmed G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c447t-13d728e659fe56ea1e75c6948afcedfee7e5c5180b630284dd67382af76bb5ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acute asthma</topic><topic>Acute Disease</topic><topic>Adamantane - analogs & derivatives</topic><topic>Adamantane - therapeutic use</topic><topic>Alveoli</topic><topic>Animals</topic><topic>Asthma</topic><topic>Asthma - chemically induced</topic><topic>Asthma - drug therapy</topic><topic>Asthma - pathology</topic><topic>Bronchoalveolar Lavage Fluid - cytology</topic><topic>Bronchus</topic><topic>Chemical compounds</topic><topic>Dexamethasone</topic><topic>Dexamethasone - therapeutic use</topic><topic>Diabetes mellitus</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Dipeptidase</topic><topic>Dipeptides - therapeutic use</topic><topic>Dipeptidyl-Peptidase IV Inhibitors - therapeutic use</topic><topic>Dual energy X-ray absorptiometry</topic><topic>Glutathione</topic><topic>Immunomodulation</topic><topic>Inflammation</topic><topic>L-Lactate dehydrogenase</topic><topic>L-Lactate Dehydrogenase - metabolism</topic><topic>Lactate dehydrogenase</topic><topic>Lactic acid</topic><topic>Leukocytes</topic><topic>Levels</topic><topic>Lung - metabolism</topic><topic>Lung - pathology</topic><topic>Lungs</topic><topic>Male</topic><topic>Mice</topic><topic>Modulation</topic><topic>MPO</topic><topic>NF-kappa B - drug effects</topic><topic>NF-κB</topic><topic>NF-κB protein</topic><topic>Nitric Oxide - metabolism</topic><topic>Oral administration</topic><topic>Ovalbumin</topic><topic>Oxidative stress</topic><topic>Peroxidase</topic><topic>Peroxidase - metabolism</topic><topic>Pharmacology</topic><topic>Proteins</topic><topic>Respiratory tract</topic><topic>Respiratory tract diseases</topic><topic>Saxagliptin</topic><topic>TLR4</topic><topic>TLR4 protein</topic><topic>Toll-Like Receptor 4 - drug effects</topic><topic>Toll-like receptors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Helal, Manar G.</creatorcontrib><creatorcontrib>Megahed, Nermeen A.</creatorcontrib><creatorcontrib>Abd Elhameed, Ahmed G.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Life sciences (1973)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Helal, Manar G.</au><au>Megahed, Nermeen A.</au><au>Abd Elhameed, Ahmed G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Saxagliptin mitigates airway inflammation in a mouse model of acute asthma via modulation of NF-kB and TLR4</atitle><jtitle>Life sciences (1973)</jtitle><addtitle>Life Sci</addtitle><date>2019-12-15</date><risdate>2019</risdate><volume>239</volume><spage>117017</spage><pages>117017-</pages><artnum>117017</artnum><issn>0024-3205</issn><eissn>1879-0631</eissn><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.
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.
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.
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.</abstract><cop>Netherlands</cop><pub>Elsevier Inc</pub><pmid>31678284</pmid><doi>10.1016/j.lfs.2019.117017</doi></addata></record> |
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| ispartof | Life sciences (1973), 2019-12, Vol.239, p.117017, Article 117017 |
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| subjects | Acute asthma Acute Disease Adamantane - analogs & derivatives Adamantane - therapeutic use Alveoli Animals Asthma Asthma - chemically induced Asthma - drug therapy Asthma - pathology Bronchoalveolar Lavage Fluid - cytology Bronchus Chemical compounds Dexamethasone Dexamethasone - therapeutic use Diabetes mellitus Diabetes mellitus (non-insulin dependent) Dipeptidase Dipeptides - therapeutic use Dipeptidyl-Peptidase IV Inhibitors - therapeutic use Dual energy X-ray absorptiometry Glutathione Immunomodulation Inflammation L-Lactate dehydrogenase L-Lactate Dehydrogenase - metabolism Lactate dehydrogenase Lactic acid Leukocytes Levels Lung - metabolism Lung - pathology Lungs Male Mice Modulation MPO NF-kappa B - drug effects NF-κB NF-κB protein Nitric Oxide - metabolism Oral administration Ovalbumin Oxidative stress Peroxidase Peroxidase - metabolism Pharmacology Proteins Respiratory tract Respiratory tract diseases Saxagliptin TLR4 TLR4 protein Toll-Like Receptor 4 - drug effects Toll-like receptors |
| title | Saxagliptin mitigates airway inflammation in a mouse model of acute asthma via modulation of NF-kB and TLR4 |
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