Vitamin D Combined with Pioglitazone Mitigates Type-2 Diabetes-induced Hepatic Injury Through Targeting Inflammation, Apoptosis, and Oxidative Stress
— Inflammation is a major pathophysiological factor in development of type-2 diabetes mellitus (T2DM). Vitamin D (VITD) plays an imperative role in modulation of several inflammatory responses. The current study aimed to investigate the possible beneficial effects of coadministration of VITD with pi...
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| Veröffentlicht in: | Inflammation 2022-02, Vol.45 (1), p.156-171 |
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| creator | Hamouda, Hend A. Mansour, Suzan M. Elyamany, Mohammed F. |
| description | —
Inflammation is a major pathophysiological factor in development of type-2 diabetes mellitus (T2DM). Vitamin D (VITD) plays an imperative role in modulation of several inflammatory responses. The current study aimed to investigate the possible beneficial effects of coadministration of VITD with pioglitazone (PIO), a PPAR-γ agonist, in fructose/streptozotocin (F/STZ) T2DM model in male
Wistar
rats. T2DM was induced by maintaining rats on 10% (w/v) fructose in drinking water for 9 weeks with an intraperitoneal injection of sub-diabetogenic dose of STZ (35 mg/kg) by the end of the fourth week. One week after STZ injection, PIO (10 mg/kg/day) alone or with VITD (500 IU/kg/day) was administered orally to diabetic rats till the end of the experiment. Blood samples were collected, livers were homogenized to determine biochemical parameters, and samples of livers were fixed in 10% formalin in saline for histological examination. Administration of PIO alone improved diabetes-induced inflammatory and oxidative states besides controlling hyperglycemia and decreasing apoptosis. Coadministration of VIT D with PIO promoted additional improvement in glycemic and lipid profiles, provided further control on diabetic-induced hepatic inflammation evident by downregulating TLR2, TLR4, and IKK-β while upregulating IκB-α expression and reducing inflammatory cytokines namely; NF-κB, TNF-α, IL-6, and IL-1β, decreasing apoptosis and oxidative stress by hampering caspase-3 and MDA contents, respectively, and improved liver histology than PIO alone. These beneficial effects of VIT D may expand its use by diabetics combined with antidiabetic drugs due to its anti-inflammatory, antioxidant, and antiapoptotic properties.
Graphical Abstract |
| doi_str_mv | 10.1007/s10753-021-01535-7 |
| format | Article |
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Inflammation is a major pathophysiological factor in development of type-2 diabetes mellitus (T2DM). Vitamin D (VITD) plays an imperative role in modulation of several inflammatory responses. The current study aimed to investigate the possible beneficial effects of coadministration of VITD with pioglitazone (PIO), a PPAR-γ agonist, in fructose/streptozotocin (F/STZ) T2DM model in male
Wistar
rats. T2DM was induced by maintaining rats on 10% (w/v) fructose in drinking water for 9 weeks with an intraperitoneal injection of sub-diabetogenic dose of STZ (35 mg/kg) by the end of the fourth week. One week after STZ injection, PIO (10 mg/kg/day) alone or with VITD (500 IU/kg/day) was administered orally to diabetic rats till the end of the experiment. Blood samples were collected, livers were homogenized to determine biochemical parameters, and samples of livers were fixed in 10% formalin in saline for histological examination. Administration of PIO alone improved diabetes-induced inflammatory and oxidative states besides controlling hyperglycemia and decreasing apoptosis. Coadministration of VIT D with PIO promoted additional improvement in glycemic and lipid profiles, provided further control on diabetic-induced hepatic inflammation evident by downregulating TLR2, TLR4, and IKK-β while upregulating IκB-α expression and reducing inflammatory cytokines namely; NF-κB, TNF-α, IL-6, and IL-1β, decreasing apoptosis and oxidative stress by hampering caspase-3 and MDA contents, respectively, and improved liver histology than PIO alone. These beneficial effects of VIT D may expand its use by diabetics combined with antidiabetic drugs due to its anti-inflammatory, antioxidant, and antiapoptotic properties.
Graphical Abstract</description><identifier>ISSN: 0360-3997</identifier><identifier>EISSN: 1573-2576</identifier><identifier>DOI: 10.1007/s10753-021-01535-7</identifier><identifier>PMID: 34468908</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Animal models ; Animals ; Anti-Inflammatory Agents - pharmacology ; Anti-Inflammatory Agents - therapeutic use ; Antidiabetics ; Antioxidants ; Apoptosis ; Apoptosis - drug effects ; Biomarkers - metabolism ; Biomedical and Life Sciences ; Biomedicine ; Caspase-3 ; Diabetes ; Diabetes mellitus ; Diabetes Mellitus, Experimental - drug therapy ; Diabetes Mellitus, Experimental - metabolism ; Diabetes Mellitus, Experimental - physiopathology ; Diabetes Mellitus, Type 2 - drug therapy ; Diabetes Mellitus, Type 2 - metabolism ; Diabetes Mellitus, Type 2 - physiopathology ; Drinking water ; Drug Therapy, Combination ; Fructose ; Hyperglycemia ; Hypoglycemic Agents - pharmacology ; Hypoglycemic Agents - therapeutic use ; IL-1β ; Immunology ; Inflammation ; Inflammation - drug therapy ; Inflammation - etiology ; Inflammation - metabolism ; Injection ; Interleukin 6 ; Internal Medicine ; Liver ; Liver Diseases - etiology ; Liver Diseases - metabolism ; Liver Diseases - prevention & control ; Male ; NF-κB protein ; Oral administration ; Original Article ; Oxidative stress ; Oxidative Stress - drug effects ; Pathology ; Peroxisome proliferator-activated receptors ; Pharmacology/Toxicology ; Pioglitazone ; Pioglitazone - pharmacology ; Pioglitazone - therapeutic use ; Rats ; Rats, Wistar ; Rheumatology ; Rodents ; Streptozocin ; TLR2 protein ; TLR4 protein ; Toll-like receptors ; Treatment Outcome ; Tumor necrosis factor-α ; Vitamin D ; Vitamin D - pharmacology ; Vitamin D - therapeutic use</subject><ispartof>Inflammation, 2022-02, Vol.45 (1), p.156-171</ispartof><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.</rights><rights>The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-3aed93731750fcc9de00212254afd6af10e1366391f00e548a96489b514cecef3</citedby><cites>FETCH-LOGICAL-c375t-3aed93731750fcc9de00212254afd6af10e1366391f00e548a96489b514cecef3</cites><orcidid>0000-0003-3229-4771</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s10753-021-01535-7$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s10753-021-01535-7$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34468908$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hamouda, Hend A.</creatorcontrib><creatorcontrib>Mansour, Suzan M.</creatorcontrib><creatorcontrib>Elyamany, Mohammed F.</creatorcontrib><title>Vitamin D Combined with Pioglitazone Mitigates Type-2 Diabetes-induced Hepatic Injury Through Targeting Inflammation, Apoptosis, and Oxidative Stress</title><title>Inflammation</title><addtitle>Inflammation</addtitle><addtitle>Inflammation</addtitle><description>—
Inflammation is a major pathophysiological factor in development of type-2 diabetes mellitus (T2DM). Vitamin D (VITD) plays an imperative role in modulation of several inflammatory responses. The current study aimed to investigate the possible beneficial effects of coadministration of VITD with pioglitazone (PIO), a PPAR-γ agonist, in fructose/streptozotocin (F/STZ) T2DM model in male
Wistar
rats. T2DM was induced by maintaining rats on 10% (w/v) fructose in drinking water for 9 weeks with an intraperitoneal injection of sub-diabetogenic dose of STZ (35 mg/kg) by the end of the fourth week. One week after STZ injection, PIO (10 mg/kg/day) alone or with VITD (500 IU/kg/day) was administered orally to diabetic rats till the end of the experiment. Blood samples were collected, livers were homogenized to determine biochemical parameters, and samples of livers were fixed in 10% formalin in saline for histological examination. Administration of PIO alone improved diabetes-induced inflammatory and oxidative states besides controlling hyperglycemia and decreasing apoptosis. Coadministration of VIT D with PIO promoted additional improvement in glycemic and lipid profiles, provided further control on diabetic-induced hepatic inflammation evident by downregulating TLR2, TLR4, and IKK-β while upregulating IκB-α expression and reducing inflammatory cytokines namely; NF-κB, TNF-α, IL-6, and IL-1β, decreasing apoptosis and oxidative stress by hampering caspase-3 and MDA contents, respectively, and improved liver histology than PIO alone. These beneficial effects of VIT D may expand its use by diabetics combined with antidiabetic drugs due to its anti-inflammatory, antioxidant, and antiapoptotic properties.
Graphical Abstract</description><subject>Animal models</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Anti-Inflammatory Agents - therapeutic use</subject><subject>Antidiabetics</subject><subject>Antioxidants</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biomarkers - metabolism</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Caspase-3</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetes Mellitus, Experimental - drug therapy</subject><subject>Diabetes Mellitus, Experimental - metabolism</subject><subject>Diabetes Mellitus, Experimental - physiopathology</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Diabetes Mellitus, Type 2 - metabolism</subject><subject>Diabetes Mellitus, Type 2 - physiopathology</subject><subject>Drinking water</subject><subject>Drug Therapy, Combination</subject><subject>Fructose</subject><subject>Hyperglycemia</subject><subject>Hypoglycemic Agents - pharmacology</subject><subject>Hypoglycemic Agents - therapeutic use</subject><subject>IL-1β</subject><subject>Immunology</subject><subject>Inflammation</subject><subject>Inflammation - drug therapy</subject><subject>Inflammation - etiology</subject><subject>Inflammation - metabolism</subject><subject>Injection</subject><subject>Interleukin 6</subject><subject>Internal Medicine</subject><subject>Liver</subject><subject>Liver Diseases - etiology</subject><subject>Liver Diseases - metabolism</subject><subject>Liver Diseases - prevention & control</subject><subject>Male</subject><subject>NF-κB protein</subject><subject>Oral administration</subject><subject>Original Article</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - drug effects</subject><subject>Pathology</subject><subject>Peroxisome proliferator-activated receptors</subject><subject>Pharmacology/Toxicology</subject><subject>Pioglitazone</subject><subject>Pioglitazone - pharmacology</subject><subject>Pioglitazone - therapeutic use</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Rheumatology</subject><subject>Rodents</subject><subject>Streptozocin</subject><subject>TLR2 protein</subject><subject>TLR4 protein</subject><subject>Toll-like receptors</subject><subject>Treatment Outcome</subject><subject>Tumor necrosis factor-α</subject><subject>Vitamin D</subject><subject>Vitamin D - pharmacology</subject><subject>Vitamin D - therapeutic use</subject><issn>0360-3997</issn><issn>1573-2576</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp9kUFv1DAUhC1ERZfCH-CALHGt6XMcx_Gx2lJaqahILFwjb_KS9WpjB9spXf4H_xfDFnrrybLmmxnpDSFvOLznAOosclBSMCg4Ay6FZOoZWXCpBCukqp6TBYgKmNBaHZOXMW4BoNa1eEGORVlWtYZ6QX59s8mM1tELuvTj2jrs6A-bNvSz9cMuaz-9Q_rJJjuYhJGu9hOygl5Ys8b8Z9Z1c5s9VziZZFt67bZz2NPVJvh52NCVCQMm64Ys9Dszjhny7pSeT35KPtp4So3r6O297bJyh_RLChjjK3LUm13E1w_vCfl6-WG1vGI3tx-vl-c3rBVKJiYMdloowZWEvm11h5CPURSyNH1XmZ4DclFVQvMeAGVZG12VtV5LXrbYYi9OyLtD7hT89xljarZ-Di5XNkVVlCBkIXmmigPVBh9jwL6Zgh1N2Dccmj9LNIclmlze_F2iUdn09iF6Xo_Y_bf8O30GxAGIWXIDhsfuJ2J_Awa7lWw</recordid><startdate>20220201</startdate><enddate>20220201</enddate><creator>Hamouda, Hend A.</creator><creator>Mansour, Suzan M.</creator><creator>Elyamany, Mohammed F.</creator><general>Springer US</general><general>Springer Nature B.V</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>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><orcidid>https://orcid.org/0000-0003-3229-4771</orcidid></search><sort><creationdate>20220201</creationdate><title>Vitamin D Combined with Pioglitazone Mitigates Type-2 Diabetes-induced Hepatic Injury Through Targeting Inflammation, Apoptosis, and Oxidative Stress</title><author>Hamouda, Hend A. ; Mansour, Suzan M. ; Elyamany, Mohammed F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-3aed93731750fcc9de00212254afd6af10e1366391f00e548a96489b514cecef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Anti-Inflammatory Agents - therapeutic use</topic><topic>Antidiabetics</topic><topic>Antioxidants</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Biomarkers - metabolism</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Caspase-3</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetes Mellitus, Experimental - drug therapy</topic><topic>Diabetes Mellitus, Experimental - metabolism</topic><topic>Diabetes Mellitus, Experimental - physiopathology</topic><topic>Diabetes Mellitus, Type 2 - drug therapy</topic><topic>Diabetes Mellitus, Type 2 - metabolism</topic><topic>Diabetes Mellitus, Type 2 - physiopathology</topic><topic>Drinking water</topic><topic>Drug Therapy, Combination</topic><topic>Fructose</topic><topic>Hyperglycemia</topic><topic>Hypoglycemic Agents - pharmacology</topic><topic>Hypoglycemic Agents - therapeutic use</topic><topic>IL-1β</topic><topic>Immunology</topic><topic>Inflammation</topic><topic>Inflammation - drug therapy</topic><topic>Inflammation - etiology</topic><topic>Inflammation - metabolism</topic><topic>Injection</topic><topic>Interleukin 6</topic><topic>Internal Medicine</topic><topic>Liver</topic><topic>Liver Diseases - etiology</topic><topic>Liver Diseases - metabolism</topic><topic>Liver Diseases - prevention & control</topic><topic>Male</topic><topic>NF-κB protein</topic><topic>Oral administration</topic><topic>Original Article</topic><topic>Oxidative stress</topic><topic>Oxidative Stress - drug effects</topic><topic>Pathology</topic><topic>Peroxisome proliferator-activated receptors</topic><topic>Pharmacology/Toxicology</topic><topic>Pioglitazone</topic><topic>Pioglitazone - pharmacology</topic><topic>Pioglitazone - therapeutic use</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Rheumatology</topic><topic>Rodents</topic><topic>Streptozocin</topic><topic>TLR2 protein</topic><topic>TLR4 protein</topic><topic>Toll-like receptors</topic><topic>Treatment Outcome</topic><topic>Tumor necrosis factor-α</topic><topic>Vitamin D</topic><topic>Vitamin D - pharmacology</topic><topic>Vitamin D - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hamouda, Hend A.</creatorcontrib><creatorcontrib>Mansour, Suzan M.</creatorcontrib><creatorcontrib>Elyamany, Mohammed F.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><jtitle>Inflammation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hamouda, Hend A.</au><au>Mansour, Suzan M.</au><au>Elyamany, Mohammed F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Vitamin D Combined with Pioglitazone Mitigates Type-2 Diabetes-induced Hepatic Injury Through Targeting Inflammation, Apoptosis, and Oxidative Stress</atitle><jtitle>Inflammation</jtitle><stitle>Inflammation</stitle><addtitle>Inflammation</addtitle><date>2022-02-01</date><risdate>2022</risdate><volume>45</volume><issue>1</issue><spage>156</spage><epage>171</epage><pages>156-171</pages><issn>0360-3997</issn><eissn>1573-2576</eissn><abstract>—
Inflammation is a major pathophysiological factor in development of type-2 diabetes mellitus (T2DM). Vitamin D (VITD) plays an imperative role in modulation of several inflammatory responses. The current study aimed to investigate the possible beneficial effects of coadministration of VITD with pioglitazone (PIO), a PPAR-γ agonist, in fructose/streptozotocin (F/STZ) T2DM model in male
Wistar
rats. T2DM was induced by maintaining rats on 10% (w/v) fructose in drinking water for 9 weeks with an intraperitoneal injection of sub-diabetogenic dose of STZ (35 mg/kg) by the end of the fourth week. One week after STZ injection, PIO (10 mg/kg/day) alone or with VITD (500 IU/kg/day) was administered orally to diabetic rats till the end of the experiment. Blood samples were collected, livers were homogenized to determine biochemical parameters, and samples of livers were fixed in 10% formalin in saline for histological examination. Administration of PIO alone improved diabetes-induced inflammatory and oxidative states besides controlling hyperglycemia and decreasing apoptosis. Coadministration of VIT D with PIO promoted additional improvement in glycemic and lipid profiles, provided further control on diabetic-induced hepatic inflammation evident by downregulating TLR2, TLR4, and IKK-β while upregulating IκB-α expression and reducing inflammatory cytokines namely; NF-κB, TNF-α, IL-6, and IL-1β, decreasing apoptosis and oxidative stress by hampering caspase-3 and MDA contents, respectively, and improved liver histology than PIO alone. These beneficial effects of VIT D may expand its use by diabetics combined with antidiabetic drugs due to its anti-inflammatory, antioxidant, and antiapoptotic properties.
Graphical Abstract</abstract><cop>New York</cop><pub>Springer US</pub><pmid>34468908</pmid><doi>10.1007/s10753-021-01535-7</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-3229-4771</orcidid></addata></record> |
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| ispartof | Inflammation, 2022-02, Vol.45 (1), p.156-171 |
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| language | eng |
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| subjects | Animal models Animals Anti-Inflammatory Agents - pharmacology Anti-Inflammatory Agents - therapeutic use Antidiabetics Antioxidants Apoptosis Apoptosis - drug effects Biomarkers - metabolism Biomedical and Life Sciences Biomedicine Caspase-3 Diabetes Diabetes mellitus Diabetes Mellitus, Experimental - drug therapy Diabetes Mellitus, Experimental - metabolism Diabetes Mellitus, Experimental - physiopathology Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - metabolism Diabetes Mellitus, Type 2 - physiopathology Drinking water Drug Therapy, Combination Fructose Hyperglycemia Hypoglycemic Agents - pharmacology Hypoglycemic Agents - therapeutic use IL-1β Immunology Inflammation Inflammation - drug therapy Inflammation - etiology Inflammation - metabolism Injection Interleukin 6 Internal Medicine Liver Liver Diseases - etiology Liver Diseases - metabolism Liver Diseases - prevention & control Male NF-κB protein Oral administration Original Article Oxidative stress Oxidative Stress - drug effects Pathology Peroxisome proliferator-activated receptors Pharmacology/Toxicology Pioglitazone Pioglitazone - pharmacology Pioglitazone - therapeutic use Rats Rats, Wistar Rheumatology Rodents Streptozocin TLR2 protein TLR4 protein Toll-like receptors Treatment Outcome Tumor necrosis factor-α Vitamin D Vitamin D - pharmacology Vitamin D - therapeutic use |
| title | Vitamin D Combined with Pioglitazone Mitigates Type-2 Diabetes-induced Hepatic Injury Through Targeting Inflammation, Apoptosis, and Oxidative Stress |
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