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  1. Article ; Online: Oral mometasone furoate administration preserves anti-inflammatory action with fewer metabolic adverse effects in rats.

    Zimath, Priscila L / Almeida, Milena S / Bruxel, Maciel A / Rafacho, Alex

    Biochemical pharmacology

    2023  Volume 210, Page(s) 115486

    Abstract: Background: Exogenous glucocorticoids (CGs) possess relevant therapeutic effects but exert diabetogenic actions when in excess. Thus, ligands with potential therapeutic applications and fewer adverse effects are needed. To this, we analyzed whether ... ...

    Abstract Background: Exogenous glucocorticoids (CGs) possess relevant therapeutic effects but exert diabetogenic actions when in excess. Thus, ligands with potential therapeutic applications and fewer adverse effects are needed. To this, we analyzed whether mometasone furoate (MF), a CG expected to cause fewer side effects, given through systemic routes, could maintain the anti-inflammatory actions without relevant repercussions on metabolism.
    Methods: The anti-inflammatory effect of MF was evaluated with both peritonitis and colitis models in rodents. Glucose and lipid metabolism were investigated in male and female rats treated daily with MF with different doses and routes of administration for seven days. The involvement of glucocorticoid receptor (GR) on MF actions was assessed in animals pretreated with mifepristone. Also, the potential reversibility of the adverse effects was assessed. Dexamethasone was used as a positive control.
    Results: MF treatment resulted in glucose intolerance in male rats treated through intraperitoneal (ip) but not oral gavage route (og). In female rats, none of the routes led to glucose intolerance. MF treatment attenuated insulin sensitivity and increased pancreatic β-cell mass, regardless of the sex and route of administration. MF treatment through og route did not result in dyslipidemia, as observed in rats treated through the ip route (both sexes). The anti-inflammatory and metabolic adverse effects of MF were GR-dependent, and metabolic outcomes altered by MF administration were reversible.
    Conclusion: MF maintains anti-inflammatory activity when administered by systemic routes and exerts less impact on metabolism when administered orally in male and female rats, effects that are GR-dependent and reversible. Category: Metabolic Disorders and Endocrinology.
    MeSH term(s) Male ; Female ; Rats ; Animals ; Mometasone Furoate ; Glucose Intolerance/chemically induced ; Glucose Intolerance/drug therapy ; Pregnadienediols/adverse effects ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use ; Glucocorticoids/toxicity ; Drug-Related Side Effects and Adverse Reactions ; Administration, Inhalation
    Chemical Substances Mometasone Furoate (04201GDN4R) ; Pregnadienediols ; Anti-Inflammatory Agents ; Glucocorticoids
    Language English
    Publishing date 2023-03-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 208787-x
    ISSN 1873-2968 ; 0006-2952
    ISSN (online) 1873-2968
    ISSN 0006-2952
    DOI 10.1016/j.bcp.2023.115486
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 19: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
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  2. Article ; Online: Reduced insulin sensitivity and increased β/α cell mass is associated with reduced hepatic insulin-degrading enzyme activity in pregnant rats.

    Taschetto, Ana P D / Zimath, Priscila L / Silvério, Renata / Dos Santos, Cristiane / Boschero, Antonio C / Dos Santos, Gustavo J / Rafacho, Alex

    Life sciences

    2021  Volume 277, Page(s) 119509

    Abstract: Aims: Pregnancy is associated with the development of a transitory insulin resistance that parallels with the upregulation of pancreatic β-cell function and mass. These metabolic adaptations guarantee the higher insulin demand, but there is no evidence ... ...

    Abstract Aims: Pregnancy is associated with the development of a transitory insulin resistance that parallels with the upregulation of pancreatic β-cell function and mass. These metabolic adaptations guarantee the higher insulin demand, but there is no evidence of whether insulin clearance contributes to this process. Thus, we investigated some of the hepatic parameters related to insulin clearance during rat pregnancy. We also investigated some molecular parameters in the hypothalamus.
    Main methods: We evaluated the body mass and food intake, insulin sensitivity, β- and α-cell masses, insulin clearance based on an exogenous insulin load, hepatic insulin-degrading enzyme (IDE) activity, and hepatic and hypothalamic protein content of IDE and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) in three periods of gestation in Wistar rats.
    Key findings: In the first week of pregnancy, both insulin sensitivity and clearance increased, a pattern that inverted in the third week of gestation (reduced insulin sensitivity and clearance). Diminished insulin clearance was associated with lower hepatic IDE activity and higher pancreatic β- and α-cell masses. No alteration in the hepatic IDE and CEACAM protein content was observed throughout pregnancy, but hypothalamic IDE protein content was significantly reduced in the late gestation period.
    Significance: In conclusion, elevated insulin demand in the late period of gestation occurs not only as a result of increased β-cell mass and function but also by a potential reduction in hepatic insulin clearance. Knowing this physiological process may be valuable when considering gestational diabetes mellitus results from a failure in insulin supply during pregnancy.
    MeSH term(s) Animals ; Blood Glucose/metabolism ; Cell Size ; Diabetes, Gestational/physiopathology ; Female ; Glucagon-Secreting Cells/metabolism ; Glucose/metabolism ; Glucose Tolerance Test ; Hyperinsulinism/metabolism ; Insulin/metabolism ; Insulin Resistance/physiology ; Insulin-Secreting Cells/metabolism ; Insulysin/metabolism ; Liver/metabolism ; Liver/pathology ; Male ; Pregnancy ; Rats ; Rats, Wistar
    Chemical Substances Blood Glucose ; Insulin ; Insulysin (EC 3.4.24.56) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2021-04-15
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 3378-9
    ISSN 1879-0631 ; 0024-3205
    ISSN (online) 1879-0631
    ISSN 0024-3205
    DOI 10.1016/j.lfs.2021.119509
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    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.368: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  3. Article: Reduced insulin sensitivity and increased β/α cell mass is associated with reduced hepatic insulin-degrading enzyme activity in pregnant rats

    Taschetto, Ana P.D / Zimath, Priscila L / Silvério, Renata / dos Santos, Cristiane / Boschero, Antonio C / dos Santos, Gustavo J / Rafacho, Alex

    Life sciences. 2021 July 15, v. 277

    2021  

    Abstract: Pregnancy is associated with the development of a transitory insulin resistance that parallels with the upregulation of pancreatic β-cell function and mass. These metabolic adaptations guarantee the higher insulin demand, but there is no evidence of ... ...

    Abstract Pregnancy is associated with the development of a transitory insulin resistance that parallels with the upregulation of pancreatic β-cell function and mass. These metabolic adaptations guarantee the higher insulin demand, but there is no evidence of whether insulin clearance contributes to this process. Thus, we investigated some of the hepatic parameters related to insulin clearance during rat pregnancy. We also investigated some molecular parameters in the hypothalamus.We evaluated the body mass and food intake, insulin sensitivity, β- and α-cell masses, insulin clearance based on an exogenous insulin load, hepatic insulin-degrading enzyme (IDE) activity, and hepatic and hypothalamic protein content of IDE and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) in three periods of gestation in Wistar rats.In the first week of pregnancy, both insulin sensitivity and clearance increased, a pattern that inverted in the third week of gestation (reduced insulin sensitivity and clearance). Diminished insulin clearance was associated with lower hepatic IDE activity and higher pancreatic β- and α-cell masses. No alteration in the hepatic IDE and CEACAM protein content was observed throughout pregnancy, but hypothalamic IDE protein content was significantly reduced in the late gestation period.In conclusion, elevated insulin demand in the late period of gestation occurs not only as a result of increased β-cell mass and function but also by a potential reduction in hepatic insulin clearance. Knowing this physiological process may be valuable when considering gestational diabetes mellitus results from a failure in insulin supply during pregnancy.
    Keywords body weight ; cell adhesion molecules ; enzyme activity ; enzymes ; food intake ; gestational diabetes ; insulin ; insulin resistance ; pregnancy ; protein content ; rats
    Language English
    Dates of publication 2021-0715
    Publishing place Elsevier Inc.
    Document type Article
    Note NAL-AP-2-clean
    ZDB-ID 3378-9
    ISSN 1879-0631 ; 0024-3205
    ISSN (online) 1879-0631
    ISSN 0024-3205
    DOI 10.1016/j.lfs.2021.119509
    Database NAL-Catalogue (AGRICOLA)

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    In stock of ZB MED Bonn / Germany

    Z 73/732: Show issues

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  4. Article ; Online: Interferons are key cytokines acting on pancreatic islets in type 1 diabetes.

    Coomans de Brachène, Alexandra / Alvelos, Maria Ines / Szymczak, Florian / Zimath, Priscila L / Castela, Angela / Marmontel de Souza, Bianca / Roca Rivada, Arturo / Marín-Cañas, Sandra / Yi, Xiaoyan / Op de Beeck, Anne / Morgan, Noel G / Sonntag, Sebastian / Jawurek, Sayro / Title, Alexandra C / Yesildag, Burcak / Pattou, François / Kerr-Conte, Julie / Montanya, Eduard / Nacher, Montserrat /
    Marselli, Lorella / Marchetti, Piero / Richardson, Sarah J / Eizirik, Decio L

    Diabetologia

    2024  Volume 67, Issue 5, Page(s) 908–927

    Abstract: Aims/hypothesis: The proinflammatory cytokines IFN-α, IFN-γ, IL-1β and TNF-α may contribute to innate and adaptive immune responses during insulitis in type 1 diabetes and therefore represent attractive therapeutic targets to protect beta cells. However, ...

    Abstract Aims/hypothesis: The proinflammatory cytokines IFN-α, IFN-γ, IL-1β and TNF-α may contribute to innate and adaptive immune responses during insulitis in type 1 diabetes and therefore represent attractive therapeutic targets to protect beta cells. However, the specific role of each of these cytokines individually on pancreatic beta cells remains unknown.
    Methods: We used deep RNA-seq analysis, followed by extensive confirmation experiments based on reverse transcription-quantitative PCR (RT-qPCR), western blot, histology and use of siRNAs, to characterise the response of human pancreatic beta cells to each cytokine individually and compared the signatures obtained with those present in islets of individuals affected by type 1 diabetes.
    Results: IFN-α and IFN-γ had a greater impact on the beta cell transcriptome when compared with IL-1β and TNF-α. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from individuals with type 1 diabetes, and the level of expression of specific IFN-stimulated genes is positively correlated with proteins present in islets of these individuals, regulating beta cell responses to 'danger signals' such as viral infections. Zinc finger NFX1-type containing 1 (ZNFX1), a double-stranded RNA sensor, was identified as highly induced by IFNs and shown to play a key role in the antiviral response in beta cells.
    Conclusions/interpretation: These data suggest that IFN-α and IFN-γ are key cytokines at the islet level in human type 1 diabetes, contributing to the triggering and amplification of autoimmunity.
    MeSH term(s) Humans ; Cytokines/metabolism ; Diabetes Mellitus, Type 1/metabolism ; Interferons/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Interferon-gamma/metabolism ; Islets of Langerhans/metabolism
    Chemical Substances Cytokines ; Interferons (9008-11-1) ; Tumor Necrosis Factor-alpha ; Interferon-gamma (82115-62-6)
    Language English
    Publishing date 2024-02-26
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1694-9
    ISSN 1432-0428 ; 0012-186X
    ISSN (online) 1432-0428
    ISSN 0012-186X
    DOI 10.1007/s00125-024-06106-7
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    In stock of ZB MED Cologne/Königswinter

    Zs.A 279: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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