MHTP, a synthetic alkaloid, attenuates combined allergic rhinitis and asthma syndrome through downregulation of the p38/ERK1/2 MAPK signaling pathway in mice
•CARAS is an airway syndrome that affects a large part of the world population.•MHTP synthetic alkaloid by oral and intranasal route inhibits eosinophils.•MHTP reduces the signs of rhinitis by acting on the H1 receptor.•MHTP reduces airway tissue remodeling of CARAS.•MHTP inhibits signal transductio...
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| Veröffentlicht in: | International immunopharmacology 2021-07, Vol.96, p.107590-107590, Article 107590 |
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| creator | Paiva Ferreira, Laércia K.D. Paiva Ferreira, Larissa A.M. Bezerra Barros, Grasiela C. Mozzini Monteiro, Talissa de Araújo Silva, Luiz A. Pereira, Ramon de A. Figueiredo, Pedro T.R. Alves, Adriano Francisco Rodrigues, Luís Cezar Piuvezam, Marcia Regina |
| description | •CARAS is an airway syndrome that affects a large part of the world population.•MHTP synthetic alkaloid by oral and intranasal route inhibits eosinophils.•MHTP reduces the signs of rhinitis by acting on the H1 receptor.•MHTP reduces airway tissue remodeling of CARAS.•MHTP inhibits signal transduction of the p38/ERK1/2 MAPK pathways in granulocytes.
The combined allergic rhinitis and asthma syndrome (CARAS) is a chronic airway inflammation of allergic individuals, with a type 2 immune response. Pharmacotherapy is based on drugs with relevant side effects. Thus, the goal of this study was to evaluate the synthetic alkaloid, MHTP in the experimental model of CARAS. Therefore, BALB/c mice were ovalbumin (OVA) -sensitized and -challenged and treated with MHTP by intranasal or oral routes. Treated animals showed a decrease (p |
| doi_str_mv | 10.1016/j.intimp.2021.107590 |
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The combined allergic rhinitis and asthma syndrome (CARAS) is a chronic airway inflammation of allergic individuals, with a type 2 immune response. Pharmacotherapy is based on drugs with relevant side effects. Thus, the goal of this study was to evaluate the synthetic alkaloid, MHTP in the experimental model of CARAS. Therefore, BALB/c mice were ovalbumin (OVA) -sensitized and -challenged and treated with MHTP by intranasal or oral routes. Treated animals showed a decrease (p < 0.05) of sneezing, nasal rubbings, and histamine nasal hyperactivity. Besides, MHTP presented binding energy and favorable interaction for adequate anchoring in the histamine H1 receptor. MHTP treatment inhibited the eosinophil migration into the nasal (NALF) and the bronchoalveolar (BALF) fluids. Histological analysis showed that the alkaloid decreased the inflammatory cells in the subepithelial and perivascular regions of nasal tissue and in the peribronchiolar and perivascular regions of lung tissue. The MHTP treatment also reduced the pulmonary hyperactivity by decreasing the smooth muscle layer hypertrophy and the collagen fiber deposition in the extracellular matrix. The immunomodulatory effect of the alkaloid was due to the decrease of cytokines like IL-5 and IL-17A (type 2 and 3), TSLP (epithelial), and the immunoregulatory cytokine, TGF-β. These MHTP effects on granulocytes were dependent on the p38/ERK1/2 MAP kinase signaling pathway axis. Indeed, the synthetic alkaloid reduced the frequency of activation of both kinases independent of the NF-κB (p65) pathway indicating that the molecule shut down the intracellular transduction signals underlie the cytokine gene transcription.</description><identifier>ISSN: 1567-5769</identifier><identifier>EISSN: 1878-1705</identifier><identifier>DOI: 10.1016/j.intimp.2021.107590</identifier><identifier>PMID: 33857802</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Airway inflammation ; Alkaloid ; Alkaloids ; Allergens - immunology ; Allergic rhinitis ; Animals ; Anti-Asthmatic Agents - therapeutic use ; Asthma ; Asthma - drug therapy ; Bronchus ; Collagen ; Computational fluid dynamics ; Cytokines ; Cytokines - metabolism ; Disease Models, Animal ; Drug therapy ; Eosinophils ; Extracellular matrix ; Extracellular signal-regulated kinase ; Female ; Histamine ; Histamine H1 receptors ; Humans ; Hyperactivity ; Hypertrophy ; Immune response ; Immune system ; Immunomodulation ; Immunoregulation ; Immunosuppressive agents ; Inflammation ; Interleukin 5 ; Kinases ; Leukocyte migration ; Leukocytes (eosinophilic) ; Leukocytes (granulocytic) ; MAP kinase ; MAP Kinase Signaling System ; MHTP ; Mice ; Mice, Inbred BALB C ; Molecular Docking Simulation ; Muscles ; NF-κB protein ; Ovalbumin ; Ovalbumin - immunology ; p38 Mitogen-Activated Protein Kinases - metabolism ; p38/ERK1/2 MAP kinase ; Receptors, Histamine H1 - metabolism ; Respiratory tract diseases ; Rhinitis ; Rhinitis, Allergic - drug therapy ; Shutdowns ; Side effects ; Signal transduction ; Signaling ; Smooth muscle ; Sneezing ; Tetrahydroisoquinolines - therapeutic use ; Transcription</subject><ispartof>International immunopharmacology, 2021-07, Vol.96, p.107590-107590, Article 107590</ispartof><rights>2021 Elsevier B.V.</rights><rights>Copyright © 2021 Elsevier B.V. All rights reserved.</rights><rights>Copyright Elsevier BV Jul 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c436t-97aebd6a63776d2c8d0f3e1caaf49c57a34911eae7ce9e20837516b949d232203</citedby><cites>FETCH-LOGICAL-c436t-97aebd6a63776d2c8d0f3e1caaf49c57a34911eae7ce9e20837516b949d232203</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.intimp.2021.107590$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3548,27923,27924,45994</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33857802$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Paiva Ferreira, Laércia K.D.</creatorcontrib><creatorcontrib>Paiva Ferreira, Larissa A.M.</creatorcontrib><creatorcontrib>Bezerra Barros, Grasiela C.</creatorcontrib><creatorcontrib>Mozzini Monteiro, Talissa</creatorcontrib><creatorcontrib>de Araújo Silva, Luiz A.</creatorcontrib><creatorcontrib>Pereira, Ramon de A.</creatorcontrib><creatorcontrib>Figueiredo, Pedro T.R.</creatorcontrib><creatorcontrib>Alves, Adriano Francisco</creatorcontrib><creatorcontrib>Rodrigues, Luís Cezar</creatorcontrib><creatorcontrib>Piuvezam, Marcia Regina</creatorcontrib><title>MHTP, a synthetic alkaloid, attenuates combined allergic rhinitis and asthma syndrome through downregulation of the p38/ERK1/2 MAPK signaling pathway in mice</title><title>International immunopharmacology</title><addtitle>Int Immunopharmacol</addtitle><description>•CARAS is an airway syndrome that affects a large part of the world population.•MHTP synthetic alkaloid by oral and intranasal route inhibits eosinophils.•MHTP reduces the signs of rhinitis by acting on the H1 receptor.•MHTP reduces airway tissue remodeling of CARAS.•MHTP inhibits signal transduction of the p38/ERK1/2 MAPK pathways in granulocytes.
The combined allergic rhinitis and asthma syndrome (CARAS) is a chronic airway inflammation of allergic individuals, with a type 2 immune response. Pharmacotherapy is based on drugs with relevant side effects. Thus, the goal of this study was to evaluate the synthetic alkaloid, MHTP in the experimental model of CARAS. Therefore, BALB/c mice were ovalbumin (OVA) -sensitized and -challenged and treated with MHTP by intranasal or oral routes. Treated animals showed a decrease (p < 0.05) of sneezing, nasal rubbings, and histamine nasal hyperactivity. Besides, MHTP presented binding energy and favorable interaction for adequate anchoring in the histamine H1 receptor. MHTP treatment inhibited the eosinophil migration into the nasal (NALF) and the bronchoalveolar (BALF) fluids. Histological analysis showed that the alkaloid decreased the inflammatory cells in the subepithelial and perivascular regions of nasal tissue and in the peribronchiolar and perivascular regions of lung tissue. The MHTP treatment also reduced the pulmonary hyperactivity by decreasing the smooth muscle layer hypertrophy and the collagen fiber deposition in the extracellular matrix. The immunomodulatory effect of the alkaloid was due to the decrease of cytokines like IL-5 and IL-17A (type 2 and 3), TSLP (epithelial), and the immunoregulatory cytokine, TGF-β. These MHTP effects on granulocytes were dependent on the p38/ERK1/2 MAP kinase signaling pathway axis. Indeed, the synthetic alkaloid reduced the frequency of activation of both kinases independent of the NF-κB (p65) pathway indicating that the molecule shut down the intracellular transduction signals underlie the cytokine gene transcription.</description><subject>Airway inflammation</subject><subject>Alkaloid</subject><subject>Alkaloids</subject><subject>Allergens - immunology</subject><subject>Allergic rhinitis</subject><subject>Animals</subject><subject>Anti-Asthmatic Agents - therapeutic use</subject><subject>Asthma</subject><subject>Asthma - drug therapy</subject><subject>Bronchus</subject><subject>Collagen</subject><subject>Computational fluid dynamics</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Disease Models, Animal</subject><subject>Drug therapy</subject><subject>Eosinophils</subject><subject>Extracellular matrix</subject><subject>Extracellular signal-regulated kinase</subject><subject>Female</subject><subject>Histamine</subject><subject>Histamine H1 receptors</subject><subject>Humans</subject><subject>Hyperactivity</subject><subject>Hypertrophy</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunomodulation</subject><subject>Immunoregulation</subject><subject>Immunosuppressive agents</subject><subject>Inflammation</subject><subject>Interleukin 5</subject><subject>Kinases</subject><subject>Leukocyte migration</subject><subject>Leukocytes (eosinophilic)</subject><subject>Leukocytes (granulocytic)</subject><subject>MAP kinase</subject><subject>MAP Kinase Signaling System</subject><subject>MHTP</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Molecular Docking Simulation</subject><subject>Muscles</subject><subject>NF-κB protein</subject><subject>Ovalbumin</subject><subject>Ovalbumin - immunology</subject><subject>p38 Mitogen-Activated Protein Kinases - metabolism</subject><subject>p38/ERK1/2 MAP kinase</subject><subject>Receptors, Histamine H1 - metabolism</subject><subject>Respiratory tract diseases</subject><subject>Rhinitis</subject><subject>Rhinitis, Allergic - drug therapy</subject><subject>Shutdowns</subject><subject>Side effects</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Smooth muscle</subject><subject>Sneezing</subject><subject>Tetrahydroisoquinolines - therapeutic use</subject><subject>Transcription</subject><issn>1567-5769</issn><issn>1878-1705</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc9u1DAQxiMEoqXwBghZ4sKh2fWfOE4uSFXVUtRWVKicLa89Sbwk9tZ2qPZheFe8pHDgwGlG3_zmszVfUbwleEUwqdfblXXJTrsVxZRkSfAWPyuOSSOakgjMn-ee16Lkom6PilcxbjHOekVeFkeMNVw0mB4XP2-v7u9OkUJx79IAyWqkxu9q9NZkNSVws0oQkfbTxjoweTpC6DMWButsshEpl9WYhum3iQl-ApSG4Od-QMY_ugD9PKpkvUO-yxNAO9asL75ekzVFt2d31yja3qnRuh7tVBoe1R5Zhyar4XXxolNjhDdP9aT4dnlxf35V3nz59Pn87KbUFatT2QoFG1OrmglRG6obgzsGRCvVVa3mQrGqJQQUCA0tUNwwwUm9aavWUEYpZifFh8V3F_zDDDHJyUYN46gc-DlKyknFW9pyntH3_6BbP4f8_QPFD3dlrM5UtVA6-BgDdHIX7KTCXhIsD_HJrVzik4f45BJfXnv3ZD5vJjB_l_7klYGPCwD5Gj8sBBm1BafB2AA6SePt_1_4BQzergU</recordid><startdate>202107</startdate><enddate>202107</enddate><creator>Paiva Ferreira, Laércia K.D.</creator><creator>Paiva Ferreira, Larissa A.M.</creator><creator>Bezerra Barros, Grasiela C.</creator><creator>Mozzini Monteiro, Talissa</creator><creator>de Araújo Silva, Luiz A.</creator><creator>Pereira, Ramon de A.</creator><creator>Figueiredo, Pedro T.R.</creator><creator>Alves, Adriano Francisco</creator><creator>Rodrigues, Luís Cezar</creator><creator>Piuvezam, Marcia Regina</creator><general>Elsevier B.V</general><general>Elsevier BV</general><scope>6I.</scope><scope>AAFTH</scope><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>7QO</scope><scope>7T5</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>202107</creationdate><title>MHTP, a synthetic alkaloid, attenuates combined allergic rhinitis and asthma syndrome through downregulation of the p38/ERK1/2 MAPK signaling pathway in mice</title><author>Paiva Ferreira, Laércia K.D. ; Paiva Ferreira, Larissa A.M. ; Bezerra Barros, Grasiela C. ; Mozzini Monteiro, Talissa ; de Araújo Silva, Luiz A. ; Pereira, Ramon de A. ; Figueiredo, Pedro T.R. ; Alves, Adriano Francisco ; Rodrigues, Luís Cezar ; Piuvezam, Marcia Regina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c436t-97aebd6a63776d2c8d0f3e1caaf49c57a34911eae7ce9e20837516b949d232203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Airway inflammation</topic><topic>Alkaloid</topic><topic>Alkaloids</topic><topic>Allergens - immunology</topic><topic>Allergic rhinitis</topic><topic>Animals</topic><topic>Anti-Asthmatic Agents - therapeutic use</topic><topic>Asthma</topic><topic>Asthma - drug therapy</topic><topic>Bronchus</topic><topic>Collagen</topic><topic>Computational fluid dynamics</topic><topic>Cytokines</topic><topic>Cytokines - metabolism</topic><topic>Disease Models, Animal</topic><topic>Drug therapy</topic><topic>Eosinophils</topic><topic>Extracellular matrix</topic><topic>Extracellular signal-regulated kinase</topic><topic>Female</topic><topic>Histamine</topic><topic>Histamine H1 receptors</topic><topic>Humans</topic><topic>Hyperactivity</topic><topic>Hypertrophy</topic><topic>Immune response</topic><topic>Immune system</topic><topic>Immunomodulation</topic><topic>Immunoregulation</topic><topic>Immunosuppressive agents</topic><topic>Inflammation</topic><topic>Interleukin 5</topic><topic>Kinases</topic><topic>Leukocyte migration</topic><topic>Leukocytes (eosinophilic)</topic><topic>Leukocytes (granulocytic)</topic><topic>MAP kinase</topic><topic>MAP Kinase Signaling System</topic><topic>MHTP</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Molecular Docking Simulation</topic><topic>Muscles</topic><topic>NF-κB protein</topic><topic>Ovalbumin</topic><topic>Ovalbumin - immunology</topic><topic>p38 Mitogen-Activated Protein Kinases - metabolism</topic><topic>p38/ERK1/2 MAP kinase</topic><topic>Receptors, Histamine H1 - metabolism</topic><topic>Respiratory tract diseases</topic><topic>Rhinitis</topic><topic>Rhinitis, Allergic - drug therapy</topic><topic>Shutdowns</topic><topic>Side effects</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Smooth muscle</topic><topic>Sneezing</topic><topic>Tetrahydroisoquinolines - therapeutic use</topic><topic>Transcription</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Paiva Ferreira, Laércia K.D.</creatorcontrib><creatorcontrib>Paiva Ferreira, Larissa A.M.</creatorcontrib><creatorcontrib>Bezerra Barros, Grasiela C.</creatorcontrib><creatorcontrib>Mozzini Monteiro, Talissa</creatorcontrib><creatorcontrib>de Araújo Silva, Luiz A.</creatorcontrib><creatorcontrib>Pereira, Ramon de A.</creatorcontrib><creatorcontrib>Figueiredo, Pedro T.R.</creatorcontrib><creatorcontrib>Alves, Adriano Francisco</creatorcontrib><creatorcontrib>Rodrigues, Luís Cezar</creatorcontrib><creatorcontrib>Piuvezam, Marcia Regina</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology 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>MEDLINE - Academic</collection><jtitle>International immunopharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Paiva Ferreira, Laércia K.D.</au><au>Paiva Ferreira, Larissa A.M.</au><au>Bezerra Barros, Grasiela C.</au><au>Mozzini Monteiro, Talissa</au><au>de Araújo Silva, Luiz A.</au><au>Pereira, Ramon de A.</au><au>Figueiredo, Pedro T.R.</au><au>Alves, Adriano Francisco</au><au>Rodrigues, Luís Cezar</au><au>Piuvezam, Marcia Regina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MHTP, a synthetic alkaloid, attenuates combined allergic rhinitis and asthma syndrome through downregulation of the p38/ERK1/2 MAPK signaling pathway in mice</atitle><jtitle>International immunopharmacology</jtitle><addtitle>Int Immunopharmacol</addtitle><date>2021-07</date><risdate>2021</risdate><volume>96</volume><spage>107590</spage><epage>107590</epage><pages>107590-107590</pages><artnum>107590</artnum><issn>1567-5769</issn><eissn>1878-1705</eissn><abstract>•CARAS is an airway syndrome that affects a large part of the world population.•MHTP synthetic alkaloid by oral and intranasal route inhibits eosinophils.•MHTP reduces the signs of rhinitis by acting on the H1 receptor.•MHTP reduces airway tissue remodeling of CARAS.•MHTP inhibits signal transduction of the p38/ERK1/2 MAPK pathways in granulocytes.
The combined allergic rhinitis and asthma syndrome (CARAS) is a chronic airway inflammation of allergic individuals, with a type 2 immune response. Pharmacotherapy is based on drugs with relevant side effects. Thus, the goal of this study was to evaluate the synthetic alkaloid, MHTP in the experimental model of CARAS. Therefore, BALB/c mice were ovalbumin (OVA) -sensitized and -challenged and treated with MHTP by intranasal or oral routes. Treated animals showed a decrease (p < 0.05) of sneezing, nasal rubbings, and histamine nasal hyperactivity. Besides, MHTP presented binding energy and favorable interaction for adequate anchoring in the histamine H1 receptor. MHTP treatment inhibited the eosinophil migration into the nasal (NALF) and the bronchoalveolar (BALF) fluids. Histological analysis showed that the alkaloid decreased the inflammatory cells in the subepithelial and perivascular regions of nasal tissue and in the peribronchiolar and perivascular regions of lung tissue. The MHTP treatment also reduced the pulmonary hyperactivity by decreasing the smooth muscle layer hypertrophy and the collagen fiber deposition in the extracellular matrix. The immunomodulatory effect of the alkaloid was due to the decrease of cytokines like IL-5 and IL-17A (type 2 and 3), TSLP (epithelial), and the immunoregulatory cytokine, TGF-β. These MHTP effects on granulocytes were dependent on the p38/ERK1/2 MAP kinase signaling pathway axis. Indeed, the synthetic alkaloid reduced the frequency of activation of both kinases independent of the NF-κB (p65) pathway indicating that the molecule shut down the intracellular transduction signals underlie the cytokine gene transcription.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>33857802</pmid><doi>10.1016/j.intimp.2021.107590</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Airway inflammation Alkaloid Alkaloids Allergens - immunology Allergic rhinitis Animals Anti-Asthmatic Agents - therapeutic use Asthma Asthma - drug therapy Bronchus Collagen Computational fluid dynamics Cytokines Cytokines - metabolism Disease Models, Animal Drug therapy Eosinophils Extracellular matrix Extracellular signal-regulated kinase Female Histamine Histamine H1 receptors Humans Hyperactivity Hypertrophy Immune response Immune system Immunomodulation Immunoregulation Immunosuppressive agents Inflammation Interleukin 5 Kinases Leukocyte migration Leukocytes (eosinophilic) Leukocytes (granulocytic) MAP kinase MAP Kinase Signaling System MHTP Mice Mice, Inbred BALB C Molecular Docking Simulation Muscles NF-κB protein Ovalbumin Ovalbumin - immunology p38 Mitogen-Activated Protein Kinases - metabolism p38/ERK1/2 MAP kinase Receptors, Histamine H1 - metabolism Respiratory tract diseases Rhinitis Rhinitis, Allergic - drug therapy Shutdowns Side effects Signal transduction Signaling Smooth muscle Sneezing Tetrahydroisoquinolines - therapeutic use Transcription |
| title | MHTP, a synthetic alkaloid, attenuates combined allergic rhinitis and asthma syndrome through downregulation of the p38/ERK1/2 MAPK signaling pathway in mice |
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