240 results on '"Ppar-alpha"'
Search Results
2. Effectiveness of One-Year Pemafibrate Therapy on Non-Alcoholic Fatty Liver Disease Refractory to Long-Term Sodium Glucose Cotransporter-2 Inhibitor Therapy: A Pilot Study.
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Shinozaki, Satoshi, Tahara, Toshiyuki, Miura, Kouichi, Lefor, Alan Kawarai, and Yamamoto, Hironori
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SODIUM-glucose cotransporters , *NON-alcoholic fatty liver disease , *TYPE 2 diabetes , *GLUCOSE , *SODIUM , *SODIUM-glucose cotransporter 2 inhibitors - Abstract
Background: Both pemafibrate and sodium glucose cotransporter-2 (SGLT2) inhibitor can decrease serum transaminase levels in patients with non-alcoholic fatty liver disease (NAFLD) complicated with dyslipidemia and type 2 diabetes mellitus (T2DM), respectively. However, the effectiveness of combined therapy has been rarely reported. Methods: This is a two-center retrospective observational study. NAFLD patients complicated with T2DM treated with pemafibrate for >1 year were included, in whom prior treatment with SGLT2 inhibitor > 1 year failed to normalize serum alanine aminotransferase (ALT) levels. Hepatic inflammation, function, and fibrosis were assessed by ALT, albumin-bilirubin (ALBI) score, and Mac-2 binding protein glycosylation isomer (M2BPGi) levels, respectively. Results: Seven patients were included. The median duration of prior treatment with SGLT2 inhibitors was 2.3 years. During the one year before starting pemafibrate therapy, the therapy did not significantly change hepatic enzymes. All patients received pemafibrate 0.1 mg twice daily without dose escalations. During one year of pemafibrate therapy, triglyceride, aspartate aminotransferase, ALT, γ-glutamyl transpeptidase, ALBI score, and M2BPGi levels significantly improved (p < 0.05), although weight or hemoglobin A1c did not significantly change. Conclusions: One year of pemafibrate therapy improves markers of hepatic inflammation, function, and fibrosis in NAFLD patients in whom long-term SGLT2 inhibitor therapy failed to normalize serum ALT. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Biomarkers and treatments for mood disorders encompassing the neurosteroid and endocannabinoid systems.
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Pinna, Graziano
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AFFECTIVE disorders , *MENTAL depression , *SEROTONIN uptake inhibitors , *POSTPARTUM depression , *POST-traumatic stress disorder , *BIPOLAR disorder , *PREMATURE ejaculation - Abstract
Mood disorders, including major depressive disorder, postpartum depression, post‐traumatic stress disorder and suicidality are highly prevalent, associated with a significant economic burden, and remain poorly diagnosed and poorly treated psychiatric conditions. In part, this may result from the lack of biomarkers that can guide precision medicine with individualized treatments for millions of individuals who suffer these debilitating conditions worldwide. While several biomarker candidates have been proposed for mood disorders, none has been implemented in clinical practice and the treatment still relies in the prescription of selective serotonin reuptake inhibitors that shows mixed efficacy and significant side effects. Both neurosteroid biosynthesis and the endocannabinoid system have recently provided evidence for pharmacological targets to improve mood symptoms and the neuroactive steroid allopregnanolone has recently been approved by the USA Food and Drug Administration for the treatment of post‐partum depression. Clinical studies also show efficacy for the management of major depression and more studies are being conducted to study efficacy in post‐traumatic stress disorder. Likewise, the endocannabinoid‐like modulator, N‐palmioyl ethanolamide (PEA) has shown efficacy in the treatment of major depression and bipolar disorder. While these new agents are coming forward in the field of neuropsychopharmacology as a new generation of fast‐acting antidepressants, the hypothesis of whether their deficits underlying mood disorders could constitute valid predictive biomarkers to facilitate diagnosis and treatment of these conditions is under consideration. [ABSTRACT FROM AUTHOR]
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- 2023
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4. Effects of naringin and valproate interaction on liver steatosis and dyslipidaemia parameters in male C57BL6 mice
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Jutrić David, Đikić Domagoj, Boroš Almoš, Odeh Dyna, Drozdek Sandra Domjanić, Gračan Romana, Dragičević Petar, Crnić Irena, and Jurčević Irena Landeka
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acox1 ,cholesterol ,dyslipidaemia ,lipid regulating transcription factors ,nrf2 ,oxidative stress ,ppar-alpha ,pgc-1 alpha ,kolesterol ,dislipidemija ,ppar-alfa ,pgc-1 alfa ,oksidacijski stres ,transkripcijski faktori za regulaciju lipida ,Toxicology. Poisons ,RA1190-1270 - Abstract
Valproate is a common antiepileptic drug whose adverse effects include liver steatosis and dyslipidaemia. The aim of our study was to see how natural flavonoid antioxidant naringin would interact with valproate and attenuate these adverse effects. For this reason we treated male C57BL6 mice with a combination of 150 mg/kg of valproate and 25 mg/kg naringin every day for 10 days and compared their serum triglycerides, cholesterol, LDL, HDL, VLDL, and liver PPAR-alpha, PGC-1 alpha, ACOX1, Nrf2, SOD, CAT, GSH, and histological signs of steatosis. Valproate increased lipid peroxidation parameters and caused pronounced microvesicular steatosis throughout the hepatic lobule in all acinar zones, but naringin co-administration limited steatosis to the lobule periphery. In addition, it nearly restored total serum cholesterol, LDL, and triglycerides and liver ACOX1 and MDA to control levels. and upregulated PPAR-alpha and PGC-1 alpha, otherwise severely downregulated by valproate. It also increased SOD activity. All these findings suggest that naringin modulates key lipid metabolism regulators and should further be investigated in this model, either alone or combined with other lipid regulating drugs or molecules.
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- 2022
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5. Inhibition of ATGL alleviates MASH via impaired PPARα signalling that favours hydrophilic bile acid composition in mice.
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Dixon ED, Claudel T, Nardo AD, Riva A, Fuchs C, Mlitz V, Busslinger G, Schnarnagl H, Stojakovic T, Senéca J, Hinteregger H, Grabner GF, Kratky D, Verkade H, Zimmermann R, Haemmerle G, and Trauner M
- Abstract
Background and Aims: Adipose triglyceride lipase (ATGL) is an attractive therapeutic target in insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD). This study investigated the effects of pharmacological ATGL inhibition on the development of metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis in mice., Methods: Streptozotocin-injected male mice were fed an HFD to induce MASH. Mice receiving the ATGL inhibitor, Atglistatin (ATGLi), were compared to controls using liver histology, lipidomics, metabolomics, 16s rRNA, and RNA sequencing. Human ileal organoids, HepG2 cells, and Caco2 cells treated with the human ATGL inhibitor NG-497, HepG2 ATGL knockdown cells, gel-shift, and luciferase assays were analysed for mechanistic insights. We validated its benefits on steatohepatitis and fibrosis in a low-methionine choline-deficient mouse model., Results: ATGLi improved serum liver enzymes, hepatic lipid content, and histological liver injury. Mechanistically, ATGLi attenuated PPARα signalling, favouring hydrophilic bile acid (BA) synthesis with increased Cyp7a1, Cyp27a1, Cyp2c70, and reduced Cyp8b1 expression. Additionally, reduced intestinal Cd36 and Abca1, along with increased Abcg5 expression, were consistent with reduced levels of hepatic TAG-species containing PUFAs like linoleic acids as well as reduced cholesterol levels in the liver and plasma. Similar changes in gene expression associated with PPARα signaling and intestinal lipid transport were observed in ileal organoids treated with NG-497. Furthermore, HepG2 ATGL knockdown cells revealed reduced expression of PPARα target genes and upregulation of genes involved in hydrophilic BA synthesis, consistent with reduced PPARα binding and luciferase activity in the presence of the ATGL inhibitors., Conclusions: Inhibition of ATGL attenuates PPARα signalling, translating into hydrophilic BAs, interfering with dietary lipid absorption, and improving metabolic disturbances. The validation with NG-497 opens a new therapeutic perspective for MASLD., Impact and Implications: The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is a crucial public health concern. Since adherence to behavioural interventions is limited, pharmacological strategies are necessary, as highlighted by the recent FDA approval of resmetirom. However, since our current mechanistic understanding and pathophysiology-oriented therapeutic options for MASLD are still limited, novel mechanistic insights are urgently needed. Our present work uncovers that pharmacological inhibition of ATGL, the key enzyme in lipid hydrolysis using Atglistatin (ATGLi), improves metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and associated key features of metabolic dysfunction in a mouse model of MASH and MCD-induced liver fibrosis. Mechanistically, we demonstrated that attenuation of PPARα signalling in the liver and gut favours hydrophilic bile acid composition, ultimately interfering with dietary lipid absorption. One of the drawbacks of ATGLi is its lack of efficacy against human ATGL, thus limiting its clinical applicability. Against this backdrop, we could show that ATGL inhibition using the human inhibitor NG-497 in human primary ileum-derived organoids, Caco2 cells, and HepG2 cells translated into therapeutic mechanisms similar to ATGLi. Collectively, these findings open a new avenue for MASLD treatment development by inhibiting human ATGL activity., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
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- 2024
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6. LDT409 (pan-PPAR partial agonist) mitigates metabolic dysfunction-associated steatotic liver disease in high-fructose-fed mice.
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Fernandes-da-Silva A, Santana-Oliveira DA, Oliveira AS, Ferreira TAM, Monteiro NC, Silva-Veiga FM, Martins FF, Cummins CL, Romeiro LAS, and Souza-Mello V
- Abstract
Aim: This study sought to evaluate the effects of LDT409, a pan-PPAR partial agonist obtained from the main industrial waste from cashew nut processing, on hepatic remodeling, highlighting energy metabolism and endoplasmic reticulum (ER) stress in high-fructose-fed mice., Methods: Male C57BL/6 mice received a control diet (C) or a high-fructose diet (HFRU) for ten weeks. Then, a five-week treatment started: C, C-LDT409, HFRU, and HFRU-LDT409. The LDT409 (40 mg/kg of body weight) was mixed with the diets., Results: The HFRU diet caused insulin resistance and endoplasmic reticulum (ER) stress. High Pparg and decreased Ppara expression increased steatosis and pro-fibrogenic gene expression in livers of HFRU-fed mice. Suppressed lipogenic factors, orchestrated by PPAR-gamma, and mitigated ER stress concomitant with the increase in beta-oxidation driven by PPAR-alpha mediated the LDT409 beneficial effects., Conclusions: LDT409 may represent a potential low-cost approach to treat metabolic dysfunction-associated steatotic liver disease, which does not currently have a specific treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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7. Effectiveness of One-Year Pemafibrate Therapy on Non-Alcoholic Fatty Liver Disease Refractory to Long-Term Sodium Glucose Cotransporter-2 Inhibitor Therapy: A Pilot Study
- Author
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Satoshi Shinozaki, Toshiyuki Tahara, Kouichi Miura, Alan Kawarai Lefor, and Hironori Yamamoto
- Subjects
non-alcoholic fatty liver disease ,non-alcoholic steatohepatitis ,pemafibrate ,dyslipidemias ,PPAR-alpha ,sodium glucose transporter-2 inhibitors ,Science - Abstract
Background: Both pemafibrate and sodium glucose cotransporter-2 (SGLT2) inhibitor can decrease serum transaminase levels in patients with non-alcoholic fatty liver disease (NAFLD) complicated with dyslipidemia and type 2 diabetes mellitus (T2DM), respectively. However, the effectiveness of combined therapy has been rarely reported. Methods: This is a two-center retrospective observational study. NAFLD patients complicated with T2DM treated with pemafibrate for >1 year were included, in whom prior treatment with SGLT2 inhibitor > 1 year failed to normalize serum alanine aminotransferase (ALT) levels. Hepatic inflammation, function, and fibrosis were assessed by ALT, albumin-bilirubin (ALBI) score, and Mac-2 binding protein glycosylation isomer (M2BPGi) levels, respectively. Results: Seven patients were included. The median duration of prior treatment with SGLT2 inhibitors was 2.3 years. During the one year before starting pemafibrate therapy, the therapy did not significantly change hepatic enzymes. All patients received pemafibrate 0.1 mg twice daily without dose escalations. During one year of pemafibrate therapy, triglyceride, aspartate aminotransferase, ALT, γ-glutamyl transpeptidase, ALBI score, and M2BPGi levels significantly improved (p < 0.05), although weight or hemoglobin A1c did not significantly change. Conclusions: One year of pemafibrate therapy improves markers of hepatic inflammation, function, and fibrosis in NAFLD patients in whom long-term SGLT2 inhibitor therapy failed to normalize serum ALT.
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- 2023
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8. Untargeted metabolomics identifies the potential role of monocarboxylate transporter 6 (MCT6/SLC16A5) in lipid and amino acid metabolism pathways.
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Ren, Tianjing, Jones, Robert S., and Morris, Marilyn E.
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MONOCARBOXYLATE transporters , *AMINO acid metabolism , *LIPID metabolism , *METABOLOMICS , *SMALL molecules , *CARRIER proteins , *LIPIDS , *PROTEIN expression - Abstract
Monocarboxylate transporter 6 (MCT6; SLC16A5) is an orphan transporter protein with expression in multiple tissues. The endogenous function of MCT6 related to human health and disease remains unknown. Our previous transcriptomic and proteomic analyses in Mct6 knockout (KO) mice suggested that MCT6 may play a role in lipid and glucose homeostasis, but additional evidence is required. Thus, the objective of this study was to further explore the impact of MCT6 on metabolic function using untargeted metabolomic analysis in Mct6 KO mice. The plasma from male and female mice and livers from male mice were submitted for global metabolomics analysis to assess the relative changes in endogenous small molecules across the liver and systemic circulation associated with absence of Mct6. More than 782 compounds were detected with 101 and 51 metabolites significantly changed in plasma of male and female mice, respectively, and 100 metabolites significantly changed in the livers of male mice (p < .05). Significant perturbations in lipid metabolism were annotated in the plasma and liver metabolome, with additional alterations in the amino acid metabolism pathway in plasma samples from male and female mice. Elevated lipid diacylglycerol and altered fatty acid metabolite concentrations were found in liver and plasma samples of male Mct6 KO mice. Significant reduction of N-terminal acetylated amino acids was found in plasma samples of male and female Mct6 KO mice. In summary, the present study confirmed the significant role of MCT6 in lipid and amino acid homeostasis, suggesting its contribution in metabolic diseases. [ABSTRACT FROM AUTHOR]
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- 2022
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9. A PPAR-alpha agonist and DPP-4 inhibitor mitigate adipocyte dysfunction in obese mice.
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Araujo Santana-Oliveira, Daiana, Fernandes-da-Silva, Aline, Santos Miranda, Carolline, Ferreira Martins, Fabiane, Alberto Mandarim-de-Lacerda, Carlos, and Souza-Mello, Vanessa
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BROWN adipose tissue , *HIGH-fat diet , *BODY temperature , *GLUCOSE intolerance , *OBESITY , *FAT cells - Abstract
Obesity causes white and brown adipocyte dysfunction, reducing browning and stimulating whitening. Drugs that tackle adipocyte dysfunction through thermogenesis stimulation could be used to treat obesity. This study sought to address whether a combination of the PPAR-alpha agonist (WY14643) and DPP4i (linagliptin) potentiates browning and mitigates adipose tissue dysfunction, emphasizing the pathways related to browning induction and the underlying thermogenesis in high-fat-fed mice. Adult male C57BL/6 mice were randomly assigned to receive a control diet (C, 10% lipids) or a high-fat diet (HF, 50% lipids) for 12 weeks. Experiment 1 aimed to evaluate whether 5 weeks of combined therapy was able to potentiate browning using a five-group design: C, HF, HFW (monotherapy with WY14643, 2.5 mg/kg body mass), HFL (monotherapy with linagliptin, 15 mg/kg body mass), and HFC (a combination of both drugs). Experiment 2 further addressed the pathways involved in browning maximization using a four-group study design: C, CC (C diet plus the drug combination), HF, and HFC (HF diet plus the drug combination). The HF group showed overweight, oral glucose intolerance, sWAT adipocyte hypertrophy, and reduced numerical density of nuclei per area of BAT confirming whitening. Only the combined treatment normalized these parameters in addition to body temperature increase, browning induction, and whitening rescue. The high expression of thermogenic marker genes parallel to reduced expression of inflammatory and endoplasmic reticulum stress genes mediated the beneficial findings. Hence, the PPAR-alpha agonist and DPP-4i combination is a promising target for obesity control by inducing functional brown adipocytes, browning of sWAT, and enhanced adaptive thermogenesis. [ABSTRACT FROM AUTHOR]
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- 2022
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10. Untargeted metabolomics identifies the potential role of monocarboxylate transporter 6 (MCT6/SLC16A5) in lipid and amino acid metabolism pathways
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Tianjing Ren, Robert S. Jones, and Marilyn E. Morris
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amino acid homeostasis ,lipid metabolism ,MCT6 ,metabolomics ,PPAR‐alpha ,SLC16A5 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract Monocarboxylate transporter 6 (MCT6; SLC16A5) is an orphan transporter protein with expression in multiple tissues. The endogenous function of MCT6 related to human health and disease remains unknown. Our previous transcriptomic and proteomic analyses in Mct6 knockout (KO) mice suggested that MCT6 may play a role in lipid and glucose homeostasis, but additional evidence is required. Thus, the objective of this study was to further explore the impact of MCT6 on metabolic function using untargeted metabolomic analysis in Mct6 KO mice. The plasma from male and female mice and livers from male mice were submitted for global metabolomics analysis to assess the relative changes in endogenous small molecules across the liver and systemic circulation associated with absence of Mct6. More than 782 compounds were detected with 101 and 51 metabolites significantly changed in plasma of male and female mice, respectively, and 100 metabolites significantly changed in the livers of male mice (p
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- 2022
- Full Text
- View/download PDF
11. Effects of naringin and valproate interaction on liver steatosis and dyslipidaemia parameters in male C57BL6 mice.
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Jutrić, David, Đikić, Domagoj, Boroš, Almoš, Odeh, Dyna, Drozdek, Sandra Domjanić, Gračan, Romana, Dragičević, Petar, Crnić, Irena, and Jurčević, Irena Landeka
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NARINGIN ,VALPROIC acid ,ANTILIPEMIC agents ,DYSLIPIDEMIA ,FATTY degeneration ,BLOOD cholesterol ,HIGH density lipoproteins - Abstract
Copyright of Archives of Industrial Hygiene & Toxicology / Arhiv za Higijenu Rada I Toksikologiju is the property of Sciendo and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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- 2022
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12. Role of the satiety factor oleoylethanolamide in alcoholism
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Bilbao, Ainhoa, Serrano, Antonia, Cippitelli, Andrea, Pavón, Francisco J, Giuffrida, Andrea, Suárez, Juan, García-Marchena, Nuria, Baixeras, Elena, Gómez de Heras, Raquel, Orio, Laura, Alén, Francisco, Ciccocioppo, Roberto, Cravatt, Benjamin F, Parsons, Loren H, Piomelli, Daniele, and Rodríguez de Fonseca, Fernando
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Biological Psychology ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Psychology ,Alcoholism ,Alcohol Use and Health ,Behavioral and Social Science ,Basic Behavioral and Social Science ,Brain Disorders ,Neurosciences ,Substance Misuse ,Stroke ,Cardiovascular ,Cancer ,Oral and gastrointestinal ,Good Health and Well Being ,Alcohol Drinking ,Alcoholism ,Animals ,Disease Models ,Animal ,Endocannabinoids ,Male ,Mice ,Oleic Acids ,PPAR alpha ,Rats ,Wistar ,Satiety Response ,Signal Transduction ,Alcohol self-administration ,alcoholism ,oleoylethanolamide ,PPAR-alpha ,relapse ,PPAR-α ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Substance Abuse ,Biomedical and clinical sciences ,Health sciences - Abstract
Oleoylethanolamide (OEA) is a satiety factor that controls motivational responses to dietary fat. Here we show that alcohol administration causes the release of OEA in rodents, which in turn reduces alcohol consumption by engaging peroxisome proliferator-activated receptor-alpha (PPAR-α). This effect appears to rely on peripheral signaling mechanisms as alcohol self-administration is unaltered by intracerebral PPAR-α agonist administration, and the lesion of sensory afferent fibers (by capsaicin) abrogates the effect of systemically administered OEA on alcohol intake. Additionally, OEA is shown to block cue-induced reinstatement of alcohol-seeking behavior (an animal model of relapse) and reduce the severity of somatic withdrawal symptoms in alcohol-dependent animals. Collectively, these findings demonstrate a homeostatic role for OEA signaling in the behavioral effects of alcohol exposure and highlight OEA as a novel therapeutic target for alcohol use disorders and alcoholism.
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- 2016
13. Medications Activating Tubular Fatty Acid Oxidation Enhance the Protective Effects of Roux-en-Y Gastric Bypass Surgery in a Rat Model of Early Diabetic Kidney Disease.
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Martin, William P., Chuah, Yeong H. D., Abdelaal, Mahmoud, Pedersen, Anders, Malmodin, Daniel, Abrahamsson, Sanna, Hutter, Michaela, Godson, Catherine, Brennan, Eoin P., Fändriks, Lars, le Roux, Carel W., and Docherty, Neil G.
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DIABETIC nephropathies ,GASTRIC bypass ,FATTY acid oxidation ,ANIMAL disease models ,DRUGS ,TRICARBOXYLIC acids - Abstract
Background: Roux-en-Y gastric bypass surgery (RYGB) improves biochemical and histological parameters of diabetic kidney disease (DKD). Targeted adjunct medical therapy may enhance renoprotection following RYGB. Methods: The effects of RYGB and RYGB plus fenofibrate, metformin, ramipril, and rosuvastatin (RYGB-FMRR) on metabolic control and histological and ultrastructural indices of glomerular and proximal tubular injury were compared in the Zucker Diabetic Sprague Dawley (ZDSD) rat model of DKD. Renal cortical transcriptomic (RNA-sequencing) and urinary metabolomic (
1 H-NMR spectroscopy) responses were profiled and integrated. Transcripts were assigned to kidney cell types through in silico deconvolution in kidney single-nucleus RNA-sequencing and microdissected tubular epithelial cell proteomics datasets. Medication-specific transcriptomic responses following RYGB-FMRR were explored using a network pharmacology approach. Omic correlates of improvements in structural and ultrastructural indices of renal injury were defined using a molecular morphometric approach. Results: RYGB-FMRR was superior to RYGB alone with respect to metabolic control, albuminuria, and histological and ultrastructural indices of glomerular injury. RYGB-FMRR reversed DKD-associated changes in mitochondrial morphology in the proximal tubule to a greater extent than RYGB. Attenuation of transcriptomic pathway level activation of pro-fibrotic responses was greater after RYGB-FMRR than RYGB. Fenofibrate was found to be the principal medication effector of gene expression changes following RYGB-FMRR, which led to the transcriptional induction of PPARα-regulated genes that are predominantly expressed in the proximal tubule and which regulate peroxisomal and mitochondrial fatty acid oxidation (FAO). After omics integration, expression of these FAO transcripts positively correlated with urinary levels of PPARα-regulated nicotinamide metabolites and negatively correlated with urinary tricarboxylic acid (TCA) cycle intermediates. Changes in FAO transcripts and nicotinamide and TCA cycle metabolites following RYGB-FMRR correlated strongly with improvements in glomerular and proximal tubular injury. Conclusions: Integrative multi-omic analyses point to PPARα-stimulated FAO in the proximal tubule as a dominant effector of treatment response to combined surgical and medical therapy in experimental DKD. Synergism between RYGB and pharmacological stimulation of FAO represents a promising combinatorial approach to the treatment of DKD in the setting of obesity. [ABSTRACT FROM AUTHOR]- Published
- 2022
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14. Tenofovir–disoproxil–fumarate modulates lipid metabolism via hepatic CD36/PPAR-alpha activation in hepatitis B virus infection.
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Suzuki, Kazuharu, Suda, Goki, Yamamoto, Yoshiya, Furuya, Ken, Baba, Masaru, Nakamura, Akinobu, Miyoshi, Hideaki, Kimura, Megumi, Maehara, Osamu, Yamada, Ren, Kitagataya, Takashi, Yamamoto, Koji, Shigesawa, Taku, Nakamura, Akihisa, Ohara, Masatsugu, Kawagishi, Naoki, Nakai, Masato, Sho, Takuya, Natsuizaka, Mitsuteru, and Morikawa, Kenichi
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LIPID metabolism , *HEPATITIS B virus , *VIRUS diseases , *BLOOD cholesterol , *DYSLIPIDEMIA , *PROPENSITY score matching , *CHRONIC hepatitis B - Abstract
Background: Entecavir and tenofovir–disoproxil–fumarate are first-line nucleos(t)ide analogs (NA) for treatment of hepatitis B virus (HBV) infections; however, their long-term administration can impact extrahepatic organs. Herein, we sought to examine the effect of NA on lipid metabolism while also characterizing the associated mechanism. Methods: A retrospective study was performed on HBV patients administered entecavir or tenofovir–disoproxil–fumarate. Patient clinical information, as well as their preserved serum samples obtained at baseline and 6–12 months after treatment initiation, were analyzed. A 1:1 propensity score matching was applied to the assignment of tenofovir–disoproxil–fumarate or entecavir treatment. Changes in serum cholesterol, including oxidized-LDL, were analyzed. Subsequently, in vitro analysis elucidated the mechanism associated with the effect of NAs on lipid metabolism. Results: Administration of tenofovir–disoproxil–fumarate, not entecavir, to chronic HBV patients, decreased serum cholesterol levels, including non-HDL and oxidized-LDL, which are strongly associated with arteriosclerosis. In vitro analysis revealed that tenofovir–disoproxil–fumarate reduced supernatant cholesterol, and upregulated the scavenger receptor, CD36, in hepatocytes. Meanwhile, silencing of hepatic CD36 increased supernatant cholesterol and negated the cholesterol-reducing effect of tenofovir–disoproxil–fumarate in HepG2-cells. Reporter, microarray, and RT-PCR analyses further revealed that tenofovir–disoproxil–fumarate treatment activates PPAR-α-mediated signaling, and upregulates PPAR-α target genes, including CPT1 and CD36. Alternatively, silencing of PPAR-α reversed the effects of tenofovir–disoproxil–fumarate on CD36. Conclusions: Tenofovir–disoproxil–fumarate modulates lipid metabolism by upregulating hepatic CD36 via PPAR-α activation. Since dyslipidemia could be associated with arteriosclerosis and hepatocarcinogenesis, these discoveries provide novel insights into anti-HBV therapies, as well as the associated extrahepatic effects of NA. [ABSTRACT FROM AUTHOR]
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- 2021
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15. Blockade of Nicotine Reward and Reinstatement by Activation of Alpha-Type Peroxisome Proliferator-Activated Receptors
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Mascia, Paola, Pistis, Marco, Justinova, Zuzana, Panlilio, Leigh V, Luchicchi, Antonio, Lecca, Salvatore, Scherma, Maria, Fratta, Walter, Fadda, Paola, Barnes, Chanel, Redhi, Godfrey H, Yasar, Sevil, Le Foll, Bernard, Tanda, Gianluigi, Piomelli, Daniele, and Goldberg, Steven R
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Basic Behavioral and Social Science ,Tobacco ,Drug Abuse (NIDA only) ,Tobacco Smoke and Health ,Substance Misuse ,Behavioral and Social Science ,Neurosciences ,Good Health and Well Being ,Action Potentials ,Animals ,Behavior ,Animal ,Conditioning ,Operant ,Dopamine ,Dose-Response Relationship ,Drug ,Drug Interactions ,Enzyme Inhibitors ,Indoles ,Male ,Microdialysis ,Neurons ,Nicotine ,Nicotinic Agonists ,Nucleus Accumbens ,Oligosaccharides ,PPAR alpha ,Peroxisome Proliferators ,Pyrimidines ,Rats ,Rats ,Sprague-Dawley ,Reinforcement ,Psychology ,Reward ,Saimiri ,Self Administration ,Ventral Tegmental Area ,FAAH ,nicotine ,OEA ,PEA ,PPAR-alpha ,reinstatement ,reward ,Biological Sciences ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Psychiatry - Abstract
BackgroundRecent findings indicate that inhibitors of fatty acid amide hydrolase (FAAH) counteract the rewarding effects of nicotine in rats. Inhibition of FAAH increases levels of several endogenous substances in the brain, including the endocannabinoid anandamide and the noncannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide, which are ligands for alpha-type peroxisome proliferator-activated nuclear receptors (PPAR-α). Here, we evaluated whether directly acting PPAR-α agonists can modulate reward-related effects of nicotine.MethodsWe combined behavioral, neurochemical, and electrophysiological approaches to evaluate effects of the PPAR-α agonists [[4-Chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]acetic acid (WY14643) and methyl oleoylethanolamide (methOEA; a long-lasting form of OEA) on 1) nicotine self-administration in rats and squirrel monkeys; 2) reinstatement of nicotine-seeking behavior in rats and monkeys; 3) nicotine discrimination in rats; 4) nicotine-induced electrophysiological activity of ventral tegmental area dopamine neurons in anesthetized rats; and 5) nicotine-induced elevation of dopamine levels in the nucleus accumbens shell of freely moving rats.ResultsThe PPAR-α agonists dose-dependently decreased nicotine self-administration and nicotine-induced reinstatement in rats and monkeys but did not alter food- or cocaine-reinforced operant behavior or the interoceptive effects of nicotine. The PPAR-α agonists also dose-dependently decreased nicotine-induced excitation of dopamine neurons in the ventral tegmental area and nicotine-induced elevations of dopamine levels in the nucleus accumbens shell of rats. The ability of WY14643 and methOEA to counteract the behavioral, electrophysiological, and neurochemical effects of nicotine was reversed by the PPAR-α antagonist 1-[(4-Chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-a,a-dimethyl-5-(1-methylethyl)-1H-Indole-2-propanoic acid (MK886).ConclusionsThese findings indicate that PPAR-α might provide a valuable new target for antismoking medications.
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- 2011
16. Acute administration of beta-caryophyllene prevents endocannabinoid system activation during transient common carotid artery occlusion and reperfusion
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Laura Poddighe, Gianfranca Carta, Maria Pina Serra, Tiziana Melis, Marianna Boi, Sara Lisai, Elisabetta Murru, Laura Muredda, Maria Collu, Sebastiano Banni, and Marina Quartu
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Bilateral common carotid artery occlusion ,Endocannabinoid system ,PPAR-alpha ,Beta-caryophyllene ,Cerebral cortex ,Plasma ,Nutritional diseases. Deficiency diseases ,RC620-627 - Abstract
Abstract Background The transient global cerebral hypoperfusion/reperfusion achieved by induction of Bilateral Common Carotid Artery Occlusion followed by Reperfusion (BCCAO/R) has been shown to stimulate early molecular changes that can be easily traced in brain tissue and plasma, and that are indicative of the tissue physiological response to the reperfusion-induced oxidative stress and inflammation. The aim of the present study is to probe the possibility to prevent the molecular changes induced by the BCCAO/R with dietary natural compounds known to possess anti-inflammatory activity, such as the phytocannabinoid beta-caryophyllene (BCP). Methods Two groups of adult Wistar rats were used, sham-operated and submitted to BCCAO/R. In both groups, 6 h before surgery, half of the rats were gavage-fed with a single dose of BCP (40 mg/per rat in 300 μl of sunflower oil as vehicle), while the second half were pre-treated with the vehicle alone. HPLC, Western Blot and immunohistochemistry were used to analyze cerebral cortex and plasma. Results After BCCAO/R, BCP prevented the increase of lipoperoxides occurring in the vehicle-treated rats in both cerebral cortex and plasma. In the frontal cortex, BCP further prevented activation of the endocannabinoid system (ECS), spared the docosahexaenoic acid (DHA), appeared to prevent the increase of cyclooxygenase-2 and increased the peroxisome-proliferator activated receptor-alpha (PPAR-alpha) protein levels, while, in plasma, BCP induced the reduction of arachidonoylethanolamide (AEA) levels as compared to vehicle-treated rats. Conclusions Collectively, the pre-treatment with BCP, likely acting as agonist for CB2 and PPAR-alpha receptors, modulates in a beneficial way the ECS activation and the lipoperoxidation, taken as indicative of oxidative stress. Furthermore, our results support the evidence that BCP may be used as a dietary supplement to control the physiological response to the hypoperfusion/reperfusion-induced oxidative stress.
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- 2018
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17. Gut-liver axis modulation in fructose-fed mice: a role for PPAR-alpha and linagliptin.
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Maria Silva-Veiga, Flávia, Santos Miranda, Carolline, Ferreira Martins, Fabiane, Beltrame Daleprane, Julio, Alberto Mandarim-de-Lacerda, Carlos, and Souza-Mello, Vanessa
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GLUCOSE intolerance , *GUT microbiome , *HEPATITIS , *MICE , *ENDOTOXEMIA - Abstract
Fructose dietary intake affects the composition of the intestinal microbiota and influences the development of hepatic steatosis. Endotoxins produced by gram-negative bacteria alter intestinal permeability and cause bacterial translocation. This study evaluated the effects of gut microbiota modulation by a purified PPAR-alpha agonist (WY14643), a DPP-4 inhibitor (linagliptin), or their association on intestinal barrier integrity, endotoxemia, and hepatic energy metabolism in high-fructose-fed C57BL/6 mice. Fifty mice were divided to receive the control diet (C group) or the high-fruct ose diet (HFRU) for 12 weeks. Subsequently, the HFRU group was divided to initiate the treatment with PPARalpha agonist (3.5 mg/kg/BM) and DPP-4 inhibitor (15 mg/kg/BM). The HFRU group had glucose intolerance, endotoxemia, and dysbiosis (with increased Proteobacteria) without changes in body mass in comparison with the C group. HFRU group showed damaged intestinal ultrastructure, which led to liver inflammation and marked hepatic steatosis in the HFRU group when compared to the C group. PPAR-alpha acti vation and DPP-4 inhibition countered glucose intolerance, endotoxemia, and dysbiosis, ameliorating the ultrastructure of the intestinal barrier and reducing Tlr4 expression in the liver of treated animals. These beneficial effects suppressed lipogenesis and mitigated hepatic steatosis. In conclusion, the results herein propose a role for PPAR-alpha activation, DPP-4 inhibition, and their association in attenuating hepatic steatosis by gut-liver axis modulation in high-fructose mice model. These observations suggest these treatments as potential targets to treat hepatic steatosis and avoid its progression. [ABSTRACT FROM AUTHOR]
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- 2020
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18. Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation
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Solorzano, Carlos, Zhu, Chenggang, Battista, Natalia, Astarita, Giuseppe, Lodola, Alessio, Rivara, Silvia, Mor, Marco, Russo, Roberto, Maccarrone, Mauro, Antonietti, Francesca, Duranti, Andrea, Tontini, Andrea, Cuzzocrea, Salvatore, Tarzia, Giorgio, and Piomelli, Daniele
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Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Amides ,Amidohydrolases ,Animals ,Anti-Inflammatory Agents ,Butyrates ,Carrageenan ,Catalytic Domain ,Cell Movement ,Drug Discovery ,Endocannabinoids ,Enzyme Inhibitors ,Ethanolamines ,Inflammation ,Mice ,Mice ,Inbred C57BL ,Neutrophils ,PPAR alpha ,Palmitic Acids ,Phenylpropionates ,Phenylurea Compounds ,Spinal Cord Injuries ,NAAA ,oleoylethanolamide ,PPAR-alpha - Abstract
Identifying points of control in inflammation is essential to discovering safe and effective antiinflammatory medicines. Palmitoylethanolamide (PEA) is a naturally occurring lipid amide that, when administered as a drug, inhibits inflammatory responses by engaging peroxisome proliferator-activated receptor-alpha (PPAR-alpha). PEA is preferentially hydrolyzed by the cysteine amidase N-acylethanolamine-hydrolyzing acid amidase (NAAA), which is highly expressed in macrophages. Here we report the discovery of a potent and selective NAAA inhibitor, N-[(3S)-2-oxo-3-oxetanyl]-3-phenylpropanamide [(S)-OOPP], and show that this inhibitor increases PEA levels in activated leukocytes and blunts responses induced by inflammatory stimuli both in vitro and in vivo. These effects are stereoselective, mimicked by exogenous PEA, and abolished by PPAR-alpha deletion. (S)-OOPP also attenuates inflammation and tissue damage and improves recovery of motor function in mice subjected to spinal cord trauma. The results suggest that PEA activation of PPAR-alpha in leukocytes serves as an early stop signal that contrasts the progress of inflammation. The PEA-hydrolyzing amidase NAAA may provide a previously undescribed target for antiinflammatory medicines.
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- 2009
19. Fat-induced satiety factor oleoylethanolamide enhances memory consolidation
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Campolongo, Patrizia, Roozendaal, Benno, Trezza, Viviana, Cuomo, Vincenzo, Astarita, Giuseppe, Fu, Jin, McGaugh, James L, and Piomelli, Daniele
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Behavioral and Social Science ,Basic Behavioral and Social Science ,Neurosciences ,1.1 Normal biological development and functioning ,Underpinning research ,Amygdala ,Animals ,Brain ,Dietary Fats ,Emotions ,Endocannabinoids ,Learning ,Lipids ,Maze Learning ,Memory ,Mice ,Mice ,Inbred C57BL ,Neurons ,Afferent ,Oleic Acids ,PPAR alpha ,Propranolol ,Rats ,Rats ,Sprague-Dawley ,Rats ,Wistar ,fatty acid ethanolamide ,lipid ,PPAR-alpha - Abstract
The ability to remember contexts associated with aversive and rewarding experiences provides a clear adaptive advantage to animals foraging in the wild. The present experiments investigated whether hormonal signals released during feeding might enhance memory of recently experienced contextual information. Oleoylethanolamide (OEA) is an endogenous lipid mediator that is released when dietary fat enters the small intestine. OEA mediates fat-induced satiety by engaging type-alpha peroxisome proliferator-activated receptors (PPAR-alpha) in the gut and recruiting local afferents of the vagus nerve. Here we show that post-training administration of OEA in rats improves retention in the inhibitory avoidance and Morris water maze tasks. These effects are blocked by infusions of lidocaine into the nucleus tractus solitarii (NTS) and by propranolol infused into the basolateral complex of the amygdala (BLA). These findings suggest that the memory-enhancing signal generated by OEA activates the brain via afferent autonomic fibers and stimulates noradrenergic transmission in the BLA. The actions of OEA are mimicked by PPAR-alpha agonists and abolished in mutant mice lacking PPAR-alpha. The results indicate that OEA, acting as a PPAR-alpha agonist, facilitates memory consolidation through noradrenergic activation of the BLA, a mechanism that is also critically involved in memory enhancement induced by emotional arousal.
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- 2009
20. Sleep deprivation increases oleoylethanolamide in human cerebrospinal fluid
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Koethe, Dagmar, Schreiber, Daniela, Giuffrida, Andrea, Mauss, Christian, Faulhaber, Johannes, Heydenreich, Bernd, Hellmich, Martin, Graf, Rudolf, Klosterkötter, Joachim, Piomelli, Daniele, and Leweke, F Markus
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Sleep Research ,Neurosciences ,Adult ,Arachidonic Acids ,Cannabinoid Receptor Modulators ,Chromatography ,High Pressure Liquid ,Endocannabinoids ,Female ,Humans ,Lipid Metabolism ,Male ,Mass Spectrometry ,Middle Aged ,Neuroprotective Agents ,Oleic Acids ,PPAR alpha ,Polyunsaturated Alkamides ,Sleep Deprivation ,Young Adult ,Oleoylethanolamide ,PPAR-alpha ,Sleep deprivation ,Neuroprotection ,Oxidative stress ,Psychology ,Neurology & Neurosurgery - Abstract
This study investigated the role of two fatty acid ethanolamides, the endogenous cannabinoid anandamide and its structural analog oleoylethanolamide in sleep deprivation of human volunteers. Serum and cerebrospinal fluid (CSF) samples were obtained from 20 healthy volunteers before and after a night of sleep deprivation with an interval of about 12 months. We found increased levels of oleoylethanolamide in CSF (P = 0.011) but not in serum (P = 0.068) after 24 h of sleep deprivation. Oleoylethanolamide is an endogenous lipid messenger that is released after neural injury and activates peroxisome proliferator-activated receptor-alpha (PPAR-alpha) with nanomolar potency. Exogenous PPAR-alpha agonists, such as hypolipidemic fibrates and oleoylethanolamide, exert both neuroprotective and neurotrophic effects. Thus, our results suggest that oleoylethanolamide release may represent an endogenous neuroprotective signal during sleep deprivation.
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- 2009
21. Genetic Differences in Peroxisome Proliferator-Activated Receptor Alpha Gene in Endurance Athletes (Long Distance Runners) and Power/Endurance Athletes (Wrestlers, Football Players)
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Gökdemir, Kadir, Kesici, Tahsin, Günay, Mehmet, Kurtulus, Melahat, Keskin, Kadir, Gökdemir, Kadir, Kesici, Tahsin, Günay, Mehmet, Kurtulus, Melahat, and Keskin, Kadir
- Abstract
Purpose: Peroxisome proliferator-activated receptor alpha gene plays an important role in the expression of genes involved in fatty acid, glucose, and energy metabolism. PPARa intron 7 G/C polymorphism (rs4253778) is one of the genes associated with athletic performance. This study aimed to investigate the genotype distribution and allele frequencies of PPARa G/C of endurance-oriented athletes (long-distance runners) and power/endurance-oriented athletes (wrestlers and football players) and non-athletic individuals.Material and Methods: The elite Turkish wrestlers (n=53), football players (n=71), long-distance runners (n=34), and non-athletic individuals (n=56) were involved in the study. The PPARa G/C polymorphism in intron 7 was analyzed using polymerase chain reaction (PCR) primers and restriction fragment length polymorphism method (RFLP). Genomic DNA was extracted by the phenol/chloroform method. Genotyping for the intron 7 G/C variant was performed by PCR and restriction enzyme digestion. The amplified fragment of 266 bp digested by TaqI restriction enzyme generated 216 bp and 50 bp in the presence of the CC genotype, and only 266 bp in the presence of the GG genotype.Results: Genotypes and allele frequencies of PPARa intron 7 G/C were compared between endurance-oriented athletes (long-distance runners) and power/endurance-oriented athletes (wrestlers, and football players) categorized according to their sport disciplines. In addition, athletes were compared to non-athletic individuals. The genotype and allele frequencies of PPARa intron 7 G/C were similar in the groups of athletes and non-athletic individuals (p>0.05). There was no statistically significant association in genotype distribution and allele frequencies of the PPARa gene among endurance-oriented athletes, power/endurance-oriented athletes, and non-athletic individuals (p>0.05).Conclusion: The PPARa gene polymorphism may not be considered as a distinctive genetic marker in endurance and mixed spor, Gazi University Scientific Research Projects Coordination Unit [02/2010-33], Funding: This study has been supported by Gazi University Scientific Research Projects Coordination Unit under grant number 02/2010-33.
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- 2023
22. Synergistic antinociception by the cannabinoid receptor agonist anandamide and the PPAR-α receptor agonist GW7647
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Russo, Roberto, LoVerme, Jesse, La Rana, Giovanna, D'Agostino, Giuseppe, Sasso, Oscar, Calignano, Antonio, and Piomelli, Daniele
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Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Neurosciences ,Substance Misuse ,Pain Research ,Drug Abuse (NIDA only) ,Chronic Pain ,Analgesics ,Animals ,Arachidonic Acids ,Behavior ,Animal ,Butyrates ,Cannabinoid Receptor Agonists ,Drug Synergism ,Endocannabinoids ,Formaldehyde ,Male ,Mice ,PPAR alpha ,Pain ,Phenylurea Compounds ,Polyunsaturated Alkamides ,PPAR-alpha ,cannabinoid ,pain ,palmitoylethanolamide ,isopimaric acid ,formalin ,Artificial Intelligence and Image Processing ,Psychology ,Cognitive Sciences ,Behavioral Science & Comparative Psychology ,Pharmacology & Pharmacy ,Zoology ,Pharmacology and pharmaceutical sciences ,Cognitive and computational psychology ,Social and personality psychology - Abstract
The analgesic properties of cannabinoid receptor agonists are well characterized. However, numerous side effects limit the therapeutic potential of these agents. Here we report a synergistic antinociceptive interaction between the endogenous cannabinoid receptor agonist anandamide and the synthetic peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist 2-(4-(2-(1-Cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid (GW7647) in a model of acute chemical-induced pain. Moreover, we show that anandamide synergistically interacts with the large-conductance potassium channel (KCa1.1, BK) activator isopimaric acid. These findings reveal a synergistic interaction between the endocannabinoid and PPAR-alpha systems that might be exploited clinically and identify a new pharmacological effect of the BK channel activator isopimaric acid.
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- 2007
23. Synergistic antinociception by the cannabinoid receptor agonist anandamide and the PPAR-alpha receptor agonist GW7647.
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Russo, Roberto, LoVerme, Jesse, La Rana, Giovanna, D'Agostino, Giuseppe, Sasso, Oscar, Calignano, Antonio, and Piomelli, Daniele
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Animals ,Mice ,Pain ,Formaldehyde ,Butyrates ,Phenylurea Compounds ,Arachidonic Acids ,PPAR alpha ,Analgesics ,Endocannabinoids ,Behavior ,Animal ,Drug Synergism ,Male ,Polyunsaturated Alkamides ,Cannabinoid Receptor Agonists ,PPAR-alpha ,cannabinoid ,pain ,palmitoylethanolamide ,isopimaric acid ,formalin ,Behavior ,Animal ,Behavioral Science & Comparative Psychology ,Pharmacology & Pharmacy ,Artificial Intelligence and Image Processing ,Psychology ,Cognitive Sciences ,Pharmacology and Pharmaceutical Sciences - Abstract
The analgesic properties of cannabinoid receptor agonists are well characterized. However, numerous side effects limit the therapeutic potential of these agents. Here we report a synergistic antinociceptive interaction between the endogenous cannabinoid receptor agonist anandamide and the synthetic peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist 2-(4-(2-(1-Cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid (GW7647) in a model of acute chemical-induced pain. Moreover, we show that anandamide synergistically interacts with the large-conductance potassium channel (KCa1.1, BK) activator isopimaric acid. These findings reveal a synergistic interaction between the endocannabinoid and PPAR-alpha systems that might be exploited clinically and identify a new pharmacological effect of the BK channel activator isopimaric acid.
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- 2007
24. Effectiveness of One-Year Pemafibrate Therapy on Non-Alcoholic Fatty Liver Disease Refractory to Long-Term Sodium Glucose Cotransporter-2 Inhibitor Therapy: A Pilot Study
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Yamamoto, Satoshi Shinozaki, Toshiyuki Tahara, Kouichi Miura, Alan Kawarai Lefor, and Hironori
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non-alcoholic fatty liver disease ,non-alcoholic steatohepatitis ,pemafibrate ,dyslipidemias ,PPAR-alpha ,sodium glucose transporter-2 inhibitors - Abstract
Background: Both pemafibrate and sodium glucose cotransporter-2 (SGLT2) inhibitor can decrease serum transaminase levels in patients with non-alcoholic fatty liver disease (NAFLD) complicated with dyslipidemia and type 2 diabetes mellitus (T2DM), respectively. However, the effectiveness of combined therapy has been rarely reported. Methods: This is a two-center retrospective observational study. NAFLD patients complicated with T2DM treated with pemafibrate for >1 year were included, in whom prior treatment with SGLT2 inhibitor > 1 year failed to normalize serum alanine aminotransferase (ALT) levels. Hepatic inflammation, function, and fibrosis were assessed by ALT, albumin-bilirubin (ALBI) score, and Mac-2 binding protein glycosylation isomer (M2BPGi) levels, respectively. Results: Seven patients were included. The median duration of prior treatment with SGLT2 inhibitors was 2.3 years. During the one year before starting pemafibrate therapy, the therapy did not significantly change hepatic enzymes. All patients received pemafibrate 0.1 mg twice daily without dose escalations. During one year of pemafibrate therapy, triglyceride, aspartate aminotransferase, ALT, γ-glutamyl transpeptidase, ALBI score, and M2BPGi levels significantly improved (p < 0.05), although weight or hemoglobin A1c did not significantly change. Conclusions: One year of pemafibrate therapy improves markers of hepatic inflammation, function, and fibrosis in NAFLD patients in whom long-term SGLT2 inhibitor therapy failed to normalize serum ALT.
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- 2023
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25. Benefits of Fenofibrate in prenatal valproic acid-induced autism spectrum disorder related phenotype in rats.
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Mirza, Roohi and Sharma, Bhupesh
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MAZE tests , *AUTISM spectrum disorders , *COMMUNICATIVE disorders - Abstract
Highlights • Pre-VPA rat showed social deficits, hyperlocomotion, anxiety & repetitive behavior. • Pre-VPA increased TBARS, IL-6, TNF-α & reduced GSH, IL-10 in various brain regions. • Fenofibrate attenuated autism related behavioral phenotypes in pre-VPA rats. • Fenofibrate reduced pre-VPA induced brain oxidative stress & inflammation. • PPAR-α modulator should be explored further in ASD related phenotypes. Abstract Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with two major behavioral symptoms i.e. repetitive behavior and social-communication impairment. The unknown etiology of ASD is responsible for the difficulty in identifying the possible therapeutic modulators for ASD. Valproic acid (VPA) is an anticonvulsant drug in both human and rodents with teratogenic effects during pregnancy. Therefore, prenatal exposure of VPA induced autism spectrum disorder like phenotypes in both human and rodents. Peroxisome proliferator-activated receptor-alpha (PPAR-α) is widely localized in the brain. This research investigates the utility of fenofibrate, a selective agonist of PPAR-α in prenatal VPA-induced experimental ASD in Wistar rats. The prenatal VPA has induced social impairment (three chambers social behavior apparatus), repetitive behavior (Y-maze), hyperlocomotion (actophotometer), anxiety (elevated plus maze) and low exploratory activity (hole board test). Also, prenatal VPA treated rats have shown higher levels of oxidative stress (increased in thiobarbituric acid reactive species and decreased in reduced glutathione level) and inflammation (increased in interleukin-6, tumor necrosis factor-α and decreased in interleukin-10) in the cerebellum, brainstem and prefrontal cortex. Treatment with fenofibrate significantly attenuated prenatal VPA-induced social impairment, repetitive behavior, hyperactivity, anxiety, and low exploratory activity. Furthermore, fenofibrate also decreased the prenatal VPA-induced oxidative stress and inflammation in brain regions. Hence, it may be concluded that fenofibrate may provide neurobehavioral and biochemical benefits in prenatal VPA-induced autism phenotypes in rats. [ABSTRACT FROM AUTHOR]
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- 2019
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26. Cooperativity as quantification and optimization paradigm for nuclear receptor modulators
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Pim J. de Vink, Auke A. Koops, Giulia D'Arrigo, Gabriele Cruciani, Francesca Spyrakis, Luc Brunsveld, and Chemical Biology
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ACTIVATION ,MODEL ,STABILIZATION ,COMPLEX ,IDENTIFICATION ,genetic structures ,PPAR-ALPHA ,SLIGAND-BINDING ,General Chemistry ,STRUCTURAL BASI ,PROTEIN INTERACTIONS ,AFFINITY - Abstract
Nuclear Receptors (NRs) are highly relevant drug targets, for which small molecule modulation goes beyond a simple ligand/receptor interaction. NR–ligands modulate Protein–Protein Interactions (PPIs) with coregulator proteins. Here we bring forward a cooperativity mechanism for small molecule modulation of NR PPIs, using the Peroxisome Proliferator Activated Receptor γ (PPARγ), which describes NR–ligands as allosteric molecular glues. The cooperativity framework uses a thermodynamic model based on three-body binding events, to dissect and quantify reciprocal effects of NR–coregulator binding (KID) and NR–ligand binding (KIID), jointly recapitulated in the cooperativity factor (α) for each specific ternary ligand·NR·coregulator complex formation. These fundamental thermodynamic parameters allow for a conceptually new way of thinking about structure–activity-relationships for NR–ligands and can steer NR modulator discovery and optimization via a completely novel approach.
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- 2022
27. Peroxisome proliferator-activated receptor alpha accelerates neuronal differentiation and this might involve the mitogen-activated protein kinase pathway.
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Lin, Chingju, Chen, Pei-Yi, Chan, Hsu-Chin, Huang, Yi-Ping, and Chang, Nai Wen
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EMBRYONIC stem cells , *CELL differentiation , *NEURONS , *PEROXISOMES , *CELL proliferation , *NEURONAL differentiation , *PROTEIN kinases - Abstract
Highlights • PPARα plays an important role in the differentiation of embryonic stem cells towards neurons. • PPARα activation induced an increase in the level of neuronal markers and Cdk5. • ERK and p38 signaling pathways might be involved in PPARα-induced neuronal differentiation. Abstract Activation of peroxisome proliferator-activated receptor alpha (PPARα) has been reported to modulate cell proliferation, migration, and differentiation in astrocytes. In this study, we used a retinoic acid (RA)-induced differentiation model of NTERA-2/clone D1 (NT2) cells to explore the functional significance of PPARα in neuronal differentiation. We found that activating PPARα by Wy14643 accelerated neuronal differentiation via regulating the expression of neuronal markers. RT-PCR assays showed a significant increase in NeuroD expression and a decrease in nestin expression in cells treated concomitantly with RA and Wy14643 for 2 days compared to the levels in cells treated with RA alone. Expression of MAP2 protein, a mature neuronal marker, was markedly upregulated at day 10 of Wy14643 treatment, which was maintained after 21 days of neuronal formation. Corresponding to the changes in MAP2 expression, the expression of Cdk5 was upregulated with Wy14643 exposure from day 10 to day 21. Moreover, cells treated with Wy14643 displayed higher expression levels of phospho-ERK and phospho-p38 in the differentiation process than cell treated with RA alone. These results indicated that activation of PPARα accelerated neuronal differentiation through upregulating the expression of NeuroD, MAP2, and Cdk5 and downregulating the expression of nestin. MAPK signals, ERK and p38, might contribute to the accelerated differentiation process. These findings suggest that PPARα plays a role in regulating neuronal differentiation and may be beneficial for functional recovery from neurological disorders. [ABSTRACT FROM AUTHOR]
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- 2018
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28. Selective modulator of peroxisome proliferator-activated receptor-α protects propionic acid induced autism-like phenotypes in rats.
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Mirza, Roohi and Sharma, Bhupesh
- Subjects
- *
PEROXISOME proliferator-activated receptors , *PROPIONIC acid , *HUMAN phenotype , *NEUROPHARMACOLOGY , *LABORATORY rats - Abstract
Abstract Aims The present study investigated the neuropharmacological role of PPAR-α modulator, fenofibrate in postnatal-propionic acid induced symptomatology related with autism spectrum disorders (ASD) in Wistar rats. Main methods The propionic acid (250 mg/kg, p.o.) was administered to rats from postnatal 21st day to 23rd day to induce autism-related neurobehavioral and neurobiochemical alterations in rats. Then, rats were treated with fenofibrate (100 mg/kg and 200 mg/kg, orally) from postnatal 24th day till 48th day. The social behavior (three chambers social testing apparatus), repetitive behavior (Y-maze), locomotor activity (actophotometer), anxiety (elevated plus maze) and exploratory behavior (hole board test) were assessed. Biochemically, oxidative stress (thiobarbituric acid reactive species and reduced glutathione level) and neuroinflammation (interleukin-6, tumor necrosis factor-α and interleukin-10) were evaluated in the cerebellum, brainstem and prefrontal cortex of rats. Key findings Propionic acid-treated rats showed social impairment, repetitive behavior, hyperlocomotion, anxiety and low exploratory activity. Also, these animals showed higher levels of oxidative stress (increased in thiobarbituric acid reactive species and decreased in reduced glutathione level) as well as inflammation (increased in interleukin-6, tumor necrosis factor-α and decreased in interleukin-10) and inflammation in aforementioned brain-regions. Treatment with fenofibrate significantly attenuated the propionic acid induced-social impairment, repetitive behavior, hyperactivity, anxiety and low exploratory activity. Furthermore, fenofibrate also reduced the oxidative stress and neuroinflammation in propionic acid-treated rats. Significance A selective PPAR-α agonist, fenofibrate provides neurobehavioral and neurobiochemical benefits in postnatal-propionic acid induced autism-related phenotype in rats. Thus, fenofibrate may further be studied for its possible benefits in ASD symptoms. [ABSTRACT FROM AUTHOR]
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- 2018
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29. Hepatocyte-specific deletion of adipose triglyceride lipase (adipose triglyceride lipase/patatin-like phospholipase domain containing 2) ameliorates dietary induced steatohepatitis in mice
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Merima Herac, Gerald Timelthaler, Claudia D. Fuchs, Michael Trauner, Tatjana Stojakovic, Richard Radun, Emina Halilbasic, Johan W. Jonker, Guenter Haemmerle, Matteo Tardelli, Emmanuel D Dixon, Veronika Mlitz, Henkjan J. Verkade, Onne A H O Ronda, Robert Zimmermann, Hubert Scharnagl, and Center for Liver, Digestive and Metabolic Diseases (CLDM)
- Subjects
Adult ,Male ,medicine.medical_specialty ,Lipolysis ,Adipose tissue ,UNITED-STATES ,Fatty Acids, Nonesterified ,GW0742 ,Diet, High-Fat ,Proinflammatory cytokine ,MITOCHONDRIAL-FUNCTION ,Mice ,LIPID-METABOLISM ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,PPAR-ALPHA ,medicine ,Animals ,Humans ,DELTA AGONIST ,HEPATIC STEATOSIS ,FATTY LIVER-DISEASE ,GENE-EXPRESSION ,Mice, Knockout ,Science & Technology ,Hepatology ,Gastroenterology & Hepatology ,Chemistry ,NONALCOHOLIC STEATOHEPATITIS ,Hep G2 Cells ,Lipase ,Middle Aged ,medicine.disease ,Disease Models, Animal ,Endocrinology ,medicine.anatomical_structure ,Liver ,Hepatocyte ,Adipose triglyceride lipase ,LIGAND-BINDING-DOMAIN ,Female ,Steatosis ,Steatohepatitis ,Diet, Carbohydrate Loading ,Life Sciences & Biomedicine - Abstract
BACKGROUND AND AIMS: Increased fatty acid (FA) flux from adipose tissue to the liver contributes to the development of NAFLD. Because free FAs are key lipotoxic triggers accelerating disease progression, inhibiting adipose triglyceride lipase (ATGL)/patatin-like phospholipase domain containing 2 (PNPLA2), the main enzyme driving lipolysis, may attenuate steatohepatitis. APPROACH AND RESULTS: Hepatocyte-specific ATGL knockout (ATGL LKO) mice were challenged with methionine-choline-deficient (MCD) or high-fat high-carbohydrate (HFHC) diet. Serum biochemistry, hepatic lipid content and liver histology were assessed. Mechanistically, hepatic gene and protein expression of lipid metabolism, inflammation, fibrosis, apoptosis, and endoplasmic reticulum (ER) stress markers were investigated. DNA binding activity for peroxisome proliferator-activated receptor (PPAR) α and PPARδ was measured. After short hairpin RNA-mediated ATGL knockdown, HepG2 cells were treated with lipopolysaccharide (LPS) or oleic acid:palmitic acid 2:1 (OP21) to explore the direct role of ATGL in inflammation in vitro. On MCD and HFHC challenge, ATGL LKO mice showed reduced PPARα and increased PPARδ DNA binding activity when compared with challenged wild-type (WT) mice. Despite histologically and biochemically pronounced hepatic steatosis, dietary-challenged ATGL LKO mice showed lower hepatic inflammation, reflected by the reduced number of Galectin3/MAC-2 and myeloperoxidase-positive cells and low mRNA expression levels of inflammatory markers (such as IL-1β and F4/80) when compared with WT mice. In line with this, protein levels of the ER stress markers protein kinase R-like endoplasmic reticulum kinase and inositol-requiring enzyme 1α were reduced in ATGL LKO mice fed with MCD diet. Accordingly, pretreatment of LPS-treated HepG2 cells with the PPARδ agonist GW0742 suppressed mRNA expression of inflammatory markers. Additionally, ATGL knockdown in HepG2 cells attenuated LPS/OP21-induced expression of proinflammatory cytokines and chemokines such as chemokine (C-X-C motif) ligand 5, chemokine (C-C motif) ligand (Ccl) 2, and Ccl5. CONCLUSIONS: Low hepatic lipolysis and increased PPARδ activity in ATGL/PNPLA2 deficiency may counteract hepatic inflammation and ER stress despite increased steatosis. Therefore, lowering hepatocyte lipolysis through ATGL inhibition represents a promising therapeutic strategy for the treatment of steatohepatitis. ispartof: HEPATOLOGY vol:75 issue:1 pages:125-139 ispartof: location:United States status: published
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- 2022
30. PPAR-α Deletion Attenuates Cisplatin Nephrotoxicity by Modulating Renal Organic Transporters MATE-1 and OCT-2
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Leandro Ceotto Freitas-Lima, Alexandre Budu, Adriano Cleis Arruda, Mauro Sérgio Perilhão, Jonatan Barrera-Chimal, Ronaldo Carvalho Araujo, and Gabriel Rufino Estrela
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cisplatin nephrotoxicity ,PPAR-alpha ,organic transporters ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Cisplatin is a chemotherapy drug widely used in the treatment of solid tumors. However, nephrotoxicity has been reported in about one-third of patients undergoing cisplatin therapy. Proximal tubules are the main target of cisplatin toxicity and cellular uptake; elimination of this drug can modulate renal damage. Organic transporters play an important role in the transport of cisplatin into the kidney and organic cations transporter 2 (OCT-2) has been shown to be one of the most important transporters to play this role. On the other hand, multidrug and toxin extrusion 1 (MATE-1) transporter is the main protein that mediates the extrusion of cisplatin into the urine. Cisplatin nephrotoxicity has been shown to be enhanced by increased OCT-2 and/or reduced MATE-1 activity. Peroxisome proliferator-activated receptor alpha (PPAR-α) is the transcription factor which controls lipid metabolism and glucose homeostasis; it is highly expressed in the kidneys and interacts with both MATE-1 and OCT-2. Considering the above, we treated wild-type and PPAR-α knockout mice with cisplatin in order to evaluate the severity of nephrotoxicity. Cisplatin induced renal dysfunction, renal inflammation, apoptosis and tubular injury in wild-type mice, whereas PPAR-α deletion protected against these alterations. Moreover, we observed that cisplatin induced down-regulation of organic transporters MATE-1 and OCT-2 and that PPAR-α deletion restored the expression of these transporters. In addition, PPAR-α knockout mice at basal state showed increased MATE-1 expression and reduced OCT-2 levels. Here, we show for the first time that PPAR-α deletion protects against cisplatin nephrotoxicity and that this protection is via modulation of the organic transporters MATE-1 and OCT-2.
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- 2020
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31. Gemfibrozil Induces Anemia, Leukopenia and Reduces Hematopoietic Stem Cells via PPAR-α in Mice
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Gabriel Rufino Estrela, Adriano Cleis Arruda, Heron Fernandes Vieira Torquato, Leandro Ceotto Freitas-Lima, Mauro Sérgio Perilhão, Frederick Wasinski, Alexandre Budu, Ricardo Ambrósio Fock, Edgar Julian Paredes-Gamero, and Ronaldo Carvalho Araujo
- Subjects
gemfibrozil ,anemia ,leukopenia ,PPAR-alpha ,hematopoietic stem cells ,erythropoiesis ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Hypercholesterolemia, also called high cholesterol, is a form of hyperlipidemia, which may be a consequence of diet, obesity or diabetes. In addition, increased levels of low-density lipoprotein (LDL) and reduced levels of high-density lipoprotein (HDL) cholesterol are associated with a higher risk of atherosclerosis and coronary heart disease. Thus, controlling cholesterol levels is commonly necessary, and fibrates have been used as lipid-lowering drugs. Gemfibrozil is a fibrate that acts via peroxisome proliferator-activated receptor alpha to promote changes in lipid metabolism and decrease serum triglyceride levels. However, anemia and leukopenia are known side effects of gemfibrozil. Considering that gemfibrozil may lead to anemia and that gemfibrozil acts via peroxisome proliferator-activated receptor alpha, we treated wild-type and peroxisome proliferator-activated receptor alpha-knockout mice with gemfibrozil for four consecutive days. Gemfibrozil treatment led to anemia seven days after the first administration of the drug; we found reduced levels of hemoglobin, as well as red blood cells, white blood cells and a reduced percentage of hematocrits. PPAR-alpha-knockout mice were capable of reversing all of those reduced parameters induced by gemfibrozil treatment. Erythropoietin levels were increased in the serum of gemfibrozil-treated animals, and we also observed an increased expression of hypoxia-inducible factor-2 alpha (HIF-2α) and erythropoietin in renal tissue, while PPAR-alpha knockout mice treated with gemfibrozil did not present increased levels of serum erythropoietin or tissue HIF-2α and erythropoietin mRNA levels in the kidneys. We analyzed bone marrow and found that gemfibrozil reduced erythrocytes and hematopoietic stem cells in wild-type mice but not in PPAR-alpha-knockout mice, while increased colony-forming units were observed only in wild-type mice treated with gemfibrozil. Here, we show for the first time that gemfibrozil treatment leads to anemia and leukopenia via peroxisome proliferator-activated receptor alpha in mice.
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- 2020
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32. Renal cortical RNA-seq and urinary 1H-NMR data following dietary restriction plus medical therapy in two rat models of diabetic kidney disease
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Martin, William, le Roux, Carel, and Docherty, Neil
- Subjects
liraglutide ,ramipril ,fenofibrate ,diabetic kidney disease ,medical therapy ,mitochondria ,diet-induced weight loss ,metabolome ,peroxisome ,PPAR-alpha ,weight loss ,metformin ,rosuvastatin ,transcriptome ,fatty acid oxidation - Abstract
This repository contains renal cortical RNA-seq (ZDF and ZDSD rat models) and urinary 1H-NMR data (ZDSD rat model) following a diet-induced weight loss plus medical therapy intervention in rat models of diabetic kidney disease.
- Published
- 2022
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33. Renal cortical RNA-seq and urinary 1H-NMR data following Roux-en-Y gastric bypass (RYGB) and RYGB + fenofibrate, metformin, ramipril, and rosuvastatin in experimental diabetic kidney disease
- Author
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Martin, William
- Subjects
mitochondria ,bariatric surgery ,metabolome ,peroxisome ,PPAR-alpha ,transcriptome ,diabetic kidney disease ,fatty acid oxidation - Abstract
This repository contains renal cortical RNA-seq and urinary 1H-NMR data for the research manuscript entitled “Medications Activating Tubular Fatty Acid Oxidation Enhance the Protective Effects of Roux-en-Y Gastric Bypass Surgery in a Rat Model of Early Diabetic Kidney Disease”.
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- 2022
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34. Emerging nanomaterials for targeting peroxisomes
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Universitat Rovira i Virgili, Bachhuka, Akash; Yadav, Tara Chand; Santos, Abel; Marsal, Lluis F.; Ergun, Sueleyman; Karnati, Srikanth, Universitat Rovira i Virgili, and Bachhuka, Akash; Yadav, Tara Chand; Santos, Abel; Marsal, Lluis F.; Ergun, Sueleyman; Karnati, Srikanth
- Abstract
Peroxisomes are single membrane-bound metabolic organelles whose dysfunction can lead to several metabolic disorders. In addition, they have been associated with the pathology of several diseases such as cancer, autoimmune diseases, diabetes, stroke, etc. In the last few decades, research has been focused on detecting peroxisomes in the physiological environment. However, the detection of these peroxisomes was based on fluorescent probes, which had limited success due to their toxicity, photobleaching, poor selectivity, and spontaneous oxidation. Moreover, research has been focused on mimicking the functionality of peroxisomes by fabricating artificial peroxisomes using synthetic materials, which have been limited due to poor stability and biocompatibility. Therefore, a new class of materials, "nanomaterials" has shown promise in overcoming the limitations underlying traditional techniques by providing better optical properties, stability and biocompatibility. Despite the advancement, the field remains in its infancy. Only a handful of studies have reported nanomaterials such as quantum dots, zeolites, liposomes, dendrimers, and nanoparticles to detect and fabricate peroxisomes. This review will provide a general description of peroxisomes and their role in different metabolic activities. The later part will focus on the challenges and progress related to nanomaterials-based peroxisome detection, fabrication, and delivery. This review will also provide insights into the critical research gaps and advances on different strategies utilized to explore peroxisomes, opening new avenues for future research in this field.(c) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.
- Published
- 2022
35. Vanin 1: Its Physiological Function and Role in Diseases
- Author
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Roberta Bartucci, Anna Salvati, Peter Olinga, and Ykelien L. Boersma
- Subjects
vanin 1 ,oxidative stress ,PPAR-alpha ,PPAR-gamma ,urinary biomarker ,pro-inflammatory role ,protective role ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The enzyme vascular non-inflammatory molecule-1 (vanin 1) is highly expressed at gene and protein level in many organs, such as the liver, intestine, and kidney. Its major function is related to its pantetheinase activity; vanin 1 breaks down pantetheine in cysteamine and pantothenic acid, a precursor of coenzyme A. Indeed, its physiological role seems strictly related to coenzyme A metabolism, lipid metabolism, and energy production. In recent years, many studies have elucidated the role of vanin 1 under physiological conditions in relation to oxidative stress and inflammation. Vanin’s enzymatic activity was found to be of key importance in certain diseases, either for its protective effect or as a sensitizer, depending on the diseased organ. In this review, we discuss the role of vanin 1 in the liver, kidney, intestine, and lung under physiological as well as pathophysiological conditions. Thus, we provide a more complete understanding and overview of its complex function and contribution to some specific pathologies.
- Published
- 2019
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36. Ppar-Alpha in Lipid and Lipoprotein Metabolism, Vascular Inflammation and Atherosclerosis
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Fruchart, Jean-Charles, Staels, Bart, Duriez, Patrick, Dhalla, Naranjan S., editor, Pierce, Grant N., editor, Nagano, Makoto, editor, and Zahradka, Peter, editor
- Published
- 2003
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37. Mice with a deficiency in Peroxisomal Membrane Protein 4 (PXMP4) display mild changes in hepatic lipid metabolism
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Maaike Blankestijn, Vincent W. Bloks, Dicky Struik, Nicolette Huijkman, Niels Kloosterhuis, Justina C. Wolters, Ronald J. A. Wanders, Frédéric M. Vaz, Markus Islinger, Folkert Kuipers, Bart van de Sluis, Albert K. Groen, Henkjan J. Verkade, Johan W. Jonker, Center for Liver, Digestive and Metabolic Diseases (CLDM), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
- Subjects
BILE-ACID SYNTHESIS ,PHYTANIC ACID ,Multidisciplinary ,PHYTOL ,METHYLACYL-COA RACEMASE ,MOUSE MODELS ,PPAR-ALPHA ,CHAIN FATTY-ACID ,GENE ,ACTIVATED RECEPTOR-ALPHA ,PRISTANIC ACID - Abstract
Peroxisomes play an important role in the metabolism of a variety of biomolecules, including lipids and bile acids. Peroxisomal Membrane Protein 4 (PXMP4) is a ubiquitously expressed peroxisomal membrane protein that is transcriptionally regulated by peroxisome proliferator-activated receptor α (PPARα), but its function is still unknown. To investigate the physiological function of PXMP4, we generated a Pxmp4 knockout (Pxmp4−/−) mouse model using CRISPR/Cas9-mediated gene editing. Peroxisome function was studied under standard chow-fed conditions and after stimulation of peroxisomal activity using the PPARα ligand fenofibrate or by using phytol, a metabolite of chlorophyll that undergoes peroxisomal oxidation. Pxmp4−/− mice were viable, fertile, and displayed no changes in peroxisome numbers or morphology under standard conditions. Also, no differences were observed in the plasma levels of products from major peroxisomal pathways, including very long-chain fatty acids (VLCFAs), bile acids (BAs), and BA intermediates di- and trihydroxycholestanoic acid. Although elevated levels of the phytol metabolites phytanic and pristanic acid in Pxmp4−/− mice pointed towards an impairment in peroxisomal α-oxidation capacity, treatment of Pxmp4−/− mice with a phytol-enriched diet did not further increase phytanic/pristanic acid levels. Finally, lipidomic analysis revealed that loss of Pxmp4 decreased hepatic levels of the alkyldiacylglycerol class of neutral ether lipids, particularly those containing polyunsaturated fatty acids. Together, our data show that while PXMP4 is not critical for overall peroxisome function under the conditions tested, it may have a role in the metabolism of (ether)lipids.
- Published
- 2022
38. Ligands of peroxisome proliferator-activated receptor-alpha promote glutamate transporter-1 endocytosis in astrocytes.
- Author
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Huang, Hui-Ting, Liao, Chih-Kai, Chiu, Wen-Tai, and Tzeng, Shun-Fen
- Subjects
- *
GLUTAMATE transporters , *ASTROCYTES , *ENDOCYTOSIS , *PROTEIN kinase C , *PEROXISOME proliferator-activated receptors - Abstract
Astrocytes, a stellate-shape glial population in the central nervous system (CNS), maintain glutamate homeostasis in adult CNS by undergoing glutamate uptake at the synapse through their glutamate transporter-1 (GLT-1). Peroxisome proliferator-activated receptor-α (PPARα) can be activated by endogenous saturated fatty acids to regulate astrocytic lipid metabolism and functions. However, it is unclear if PPARα can exert the regulatory action on GLT-1 expression in astrocytes. This study showed that treatment with palmitic acid (PA) and the other two PPARα agonists (GW 7647 and WY 14,643) caused no change in the morphology of astrocytes, whereas membranous GLT-1 protein levels in astrocytes were significantly decreased by PA and PPARα agonists. Through lentivirus-mediated overexpression of GLT-1 tagged with red fluorescent protein (GLT-1-RFP), we also observed that GLT-1-RFP puncta in the processes of astrocytes were inhibited by the PPARα agonists. This reduction was prevented by the addition of the PPARα antagonist, GW6471. GLT-1-RFP was co-localized to the early endosome marker–EEA1 in astrocytes treated with the PPARα agonists. Moreover, PPARα-induced inhibition in membranous GLT-1 expression was abolished by the addition of dynamin inhibitor (dynasore). Furthermore, the co-treatment of astrocytes with PPARα agonists and dynasore, or with PPARα agonists and protein kinase C (PKC) inhibitor bis-indolylmaleimide 1 (BIS1), prevented the endocytosis of GLT-1-RFP. Based on the results, we conclude that the PPARα agonists increased GLT-1 endocytosis in astrocytes possibly through the PKC signaling pathway. In addition, our findings provide important information of PPARα involvement in the downregulation of astrocytic glutamate uptake via the promoted GLT-1 endocytosis. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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39. Caloric Restriction Is More Efficient than Physical Exercise to Protect from Cisplatin Nephrotoxicity via PPAR-Alpha Activation.
- Author
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Estrela, Gabriel R., Wasinski, Frederick, Batista, Rogério O., Hiyane, Meire I., Felizardo, Raphael J. F., Cunha, Flavia, de Almeida, Danilo C., Malheiros, Denise M. A. C., Câmara, Niels O. S., Barros, Carlos C., Bader, Michael, and Araujo, Ronaldo C.
- Subjects
LOW-calorie diet ,NEPHROTOXICOLOGY ,CISPLATIN ,EXERCISE therapy ,MEDICAL protocols ,PREVENTION - Abstract
The antineoplastic drug cisplatin promotes renal injury, which limits its use. Protocols that reduce renal cisplatin toxicity will allow higher doses to be used in cisplatin treatment. Here, we compare physical exercise and caloric restriction (CR) as protocols to reduce cisplatin renal injury in mice. Male C57BL/6 were divided into four groups: Control, cisplatin, exercise + cisplatin, and 30% CR + cisplatin. Animals were injected with a single dose of cisplatin (20mg/kg i.p.) and sacrificed 96 h after injection. Quantitative real time PCR, histological analyses, immunohistochemistry, and biochemical measurements were performed to investigate renal injury, necrosis, apoptosis, and inflammatory mechanisms. Both protocols protected against cisplatin renal injury, but CR was more effective in reducing uraemia and renal necrosis. The CR + Cisplatin group exhibited reduced serum IL-1β and TNF-α levels. No differences were noted in the renal mRNA expression of cytokines. Both interventions reduced apoptosis, but only the CR + Cisplatin group decreased TNFR2 protein expression. PPAR-α was activated in mice after CR. An antagonist of PPAR-α blocked the protective effect of CR. Both interventions attenuated the nephrotoxicity caused by cisplatin injection, but CR + Cisplatin showed a better response by modulating TNFR2. Moreover, part of the CR benefit depends on PPAR-α activation. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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40. Gastric Bypass Surgery Recruits a Gut PPAR-α-Striatal D1R Pathway to Reduce Fat Appetite in Obese Rats.
- Author
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Hankir, Mohammed K., Seyfried, Florian, Hintschich, Constantin A., Diep, Thi-Ai, Kleberg, Karen, Kranz, Mathias, Deuther-Conrad, Winnie, Tellez, Luis A., Rullmann, Michael, Patt, Marianne, Teichert, Jens, Hesse, Swen, Sabri, Osama, Brust, Peter, Hansen, Harald S., de Araujo, Ivan E., Krügel, Ute, and Fenske, Wiebke K.
- Abstract
Summary Bariatric surgery remains the single most effective long-term treatment modality for morbid obesity, achieved mainly by lowering caloric intake through as yet ill-defined mechanisms. Here we show in rats that Roux-en-Y gastric bypass (RYGB)-like rerouting of ingested fat mobilizes lower small intestine production of the fat-satiety molecule oleoylethanolamide (OEA). This was associated with vagus nerve-driven increases in dorsal striatal dopamine release. We also demonstrate that RYGB upregulates striatal dopamine 1 receptor (D1R) expression specifically under high-fat diet feeding conditions. Mechanistically, interfering with local OEA, vagal, and dorsal striatal D1R signaling negated the beneficial effects of RYGB on fat intake and preferences. These findings delineate a molecular/systems pathway through which bariatric surgery improves feeding behavior and may aid in the development of novel weight loss strategies that similarly modify brain reward circuits compromised in obesity. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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41. Alport syndrome: Proteomic analysis identifies early molecular pathway alterations in Col4a3 knock out mice
- Author
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Kyriacos Kyriacou, Andreas Kousios, Kyriakos Ioannou, Louiza Potamiti, Theo M. Luider, Orthodoxia Nicolaou, Christoph Stingl, Revekka Papacharalampous, Andreas Hadjisavvas, George Neophytou, Lola Koniali, Kleitos Sokratous, Maria Zanti, and Neurology
- Subjects
Collagen Type IV ,Male ,Proteomics ,RENAL-FAILURE ,030232 urology & nephrology ,ENERGY-METABOLISM ,Peroxisome proliferator-activated receptor ,Nephritis, Hereditary ,030204 cardiovascular system & hematology ,Col4a3 knockout mice ,PPARα ,Autoantigens ,End stage renal disease ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,PPAR-ALPHA ,medicine ,FIBROSIS ,Animals ,PPAR alpha ,Alport syndrome ,mass spectrometry ,chemistry.chemical_classification ,Mice, Knockout ,Kidney ,Science & Technology ,business.industry ,Col4a3knockout mice ,1103 Clinical Sciences ,General Medicine ,PPAR Pathway ,Original Articles ,Urology & Nephrology ,medicine.disease ,RECEPTORS ,Disease Models, Animal ,medicine.anatomical_structure ,Basic Research ,chemistry ,Nephrology ,Cancer research ,Original Article ,business ,Life Sciences & Biomedicine ,Kidney disease - Abstract
Aim Alport syndrome (AS) is the second most common hereditary kidney disease caused by mutations in collagen IV genes. Patients present with microhaematuria that progressively leads to proteinuria and end stage renal disease. Currently, no specific treatment exists for AS. Using mass spectrometry based proteomics, we aimed to detect early alterations in molecular pathways implicated in AS before the stage of overt proteinuria, which could be amenable to therapeutic intervention. Methods Kidneys were harvested from male Col4a3 −/− knock out and sex and age‐matched Col4a3 +/+ wild‐type mice at 4 weeks of age. Purified peptides were separated by liquid chromatography and analysed by high resolution mass spectrometry. The Cytoscape bioinformatics tool was used for function enrichment and pathway analysis. PPARα expression levels were evaluated by immunofluorescence and immunoblotting. Results Proteomic analysis identified 415 significantly differentially expressed proteins, which were mainly involved in metabolic and cellular processes, the extracellular matrix, binding and catalytic activity. Pathway enrichment analysis revealed among others, downregulation of the proteasome and PPAR pathways. PPARα protein expression levels were observed to be downregulated in Alport mice, supporting further the results of the discovery proteomics. Conclusion This study provides additional evidence that alterations in proteins which participate in cellular metabolism and mitochondrial homeostasis in kidney cells are early events in the development of chronic kidney disease in AS. Of note is the dysregulation of the PPAR pathway, which is amenable to therapeutic intervention and provides a new potential target for therapy in AS., SUMMARY AT A GLANCE Alterations in proteins which participate in cellular metabolism and mitochondrial homeostasis in kidney cells, are early events in the development of CKD in Alport syndrome. In addition, pathway enrichment analysis revealed among others, dysregulation of the proteasome, protein digestion and absorption pathways as well as PPAR pathway in AS compared to control mice. Targeting the PPAR pathway could be a potential therapeutic approach in AS.
- Published
- 2020
42. Potential genomic biomarkers of obesity and its comorbidities for phthalates and bisphenol A mixture: In silico toxicogenomic approach
- Author
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Danijela Đukić-Ćosić, Katarina Živančević, Evica Antonijević Miljaković, Aleksandra Buha Djordjevic, Danyel Jennen, Dragica BoŽIĆ, Katarina Baralić, RS: GROW - R1 - Prevention, and Toxicogenomics
- Subjects
Bisphenol A ,endocrine system ,Bioinformatics ,TOXICOLOGY ,In silico ,Computational biology ,Toxicology ,ENDOCRINE DISRUPTORS ,ACTIVATION ,chemistry.chemical_compound ,INFLAMMATION ,PPAR-ALPHA ,Medicine ,Endocrine disruptors ,Data mining ,URINARY PHTHALATE ,INSULIN-RESISTANCE ,business.industry ,General Medicine ,ASSOCIATION ,Genomic biomarkers ,3. Good health ,chemistry ,RISK-ASSESSMENT ,HEALTH ,business - Abstract
This in silico toxicogenomic study aims to explore the relationship between phthalates and bisphenol A (BPA) co-exposure and obesity, as well as its comorbid conditions, in order to construct a possible set of genomic biomarkers. The Comparative Toxicogenomics Database (CTD; http://ctd.mdibl.org ) was used as the main data mining tool, along with GeneMania (https://genemania.org), ToppGene Suite (https://toppgene.cchmc.org ) and DisGeNET (http://www. disgenet.org). Among the phthalates, bis(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) were chosen as the most frequently curated phthalates in CTD, which also share similar mechanisms of toxicity. DEHP, DBP and BPA interacted with 84, 90 and 194 obesity-related genes/proteins, involved in 67, 65 and 116 pathways, respectively. Among these, 53 genes/proteins and 42 pathways were common to all three substances. 31 genes/proteins had matching interactions for all three investigated substances, while more than half of these genes/proteins (56.49%) were in co-expression. 7 of the common genes/proteins (6 relevant to humans: CCL2, IL6, LPL, PPARG, SERPINE1, and TNF) were identified in all the investigated obesity comorbidities, while PPARG and LPL were most closely linked to obesity. These genes/proteins could serve as a target for further in vitro and in vivo studies of molecular mechanisms of DEHP, DBP and BPA mixture obesogenic properties. Analysis reported here should be applicable to any mixture of environmental chemicals and any disease present in CTD.
- Published
- 2022
43. Changes in Cardiac Metabolism in Prediabetes
- Subjects
INSULIN-RESISTANCE ,prediabetes ,DIASTOLIC DYSFUNCTION ,HEART-DISEASE ,cardiac metabolism ,mitochondrial function ,PPAR-ALPHA ,DIABETIC CARDIOMYOPATHY ,MAGNETIC-RESONANCE ,CORONARY-ARTERY-DISEASE ,MYOCARDIAL TRIGLYCERIDES ,cardiac function ,EPICARDIAL ADIPOSE-TISSUE ,PERICARDIAL FAT - Abstract
In type 2 diabetes mellitus (T2DM), there is an increased prevalence of cardiovascular disease (CVD), even when corrected for atherosclerosis and other CVD risk factors. Diastolic dysfunction is one of the early changes in cardiac function that precedes the onset of cardiac failure, and it occurs already in the prediabetic state. It is clear that these changes are closely linked to alterations in cardiac metabolism; however, the exact etiology is unknown. In this narrative review, we provide an overview of the early cardiac changes in fatty acid and glucose metabolism in prediabetes and its consequences on cardiac function. A better understanding of the relationship between metabolism, mitochondrial function, and cardiac function will lead to insights into the etiology of the declined cardiac function in prediabetes.
- Published
- 2021
44. Changes in Cardiac Metabolism in Prediabetes
- Author
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Tineke van de Weijer and Vera H. W. de Wit-Verheggen
- Subjects
Cardiac function curve ,medicine.medical_specialty ,Diastole ,Cardiac metabolism ,Disease ,Review ,HEART-DISEASE ,prediabetes ,Carbohydrate metabolism ,Biochemistry ,Microbiology ,Prediabetic State ,cardiac metabolism ,mitochondrial function ,Internal medicine ,PPAR-ALPHA ,DIABETIC CARDIOMYOPATHY ,MAGNETIC-RESONANCE ,Medicine ,Humans ,Prediabetes ,Molecular Biology ,PERICARDIAL FAT ,INSULIN-RESISTANCE ,business.industry ,Type 2 Diabetes Mellitus ,DIASTOLIC DYSFUNCTION ,medicine.disease ,QR1-502 ,Diabetes Mellitus, Type 2 ,Cardiovascular Diseases ,Etiology ,Cardiology ,cardiovascular system ,CORONARY-ARTERY-DISEASE ,MYOCARDIAL TRIGLYCERIDES ,cardiac function ,business ,EPICARDIAL ADIPOSE-TISSUE - Abstract
In type 2 diabetes mellitus (T2DM), there is an increased prevalence of cardiovascular disease (CVD), even when corrected for atherosclerosis and other CVD risk factors. Diastolic dysfunction is one of the early changes in cardiac function that precedes the onset of cardiac failure, and it occurs already in the prediabetic state. It is clear that these changes are closely linked to alterations in cardiac metabolism; however, the exact etiology is unknown. In this narrative review, we provide an overview of the early cardiac changes in fatty acid and glucose metabolism in prediabetes and its consequences on cardiac function. A better understanding of the relationship between metabolism, mitochondrial function, and cardiac function will lead to insights into the etiology of the declined cardiac function in prediabetes.
- Published
- 2021
45. Administration of Fresh Juice of Tinospora cordifolia Decreases Levels of Urinary Markers of Peroxisome Proliferator-Activated Receptors in Hyperlipidemic Patients.
- Author
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Shirolkar, Amey R. and Dabur, Rajesh
- Subjects
TINOSPORA cordifolia ,HYPERLIPIDEMIA treatment ,URINE ,LIPID metabolism ,PEROXISOME proliferator-activated receptors ,OXIDATIVE stress ,PHYSIOLOGY ,THERAPEUTICS - Abstract
Objective: Tinospora cordifolia (Willd.) Miers juice (TCJ) is known for its anti-hyperlipidemic properties. This study was aimed to validate the efficacy of TCJ to activate PPARα in vivo in hyperlipidemic (HPL) patients. Materials and Methods: HPL (n=20) and healthy (n=22) volunteers were enrolled in the study. HPL patients were treated with TCJ for 14 days. The fasting urine and blood samples were collected on 0 and 14
th day for analysis. The blood samples were used for biochemical analysis. Urine samples were subjected to LC-ESI-QTOFMS for the analysis of PPAR-α markers. Results: Treatment with TCJ depleted cholesterol (TC-24%), triglycerides (TG-28%) and low density lipoprotein (LDL-14%) levels and increased high density lipoprotein (HDL) (p<0.05) levels in HPL. The QTOFMS data revealed increased urinary excretions of pantothenic acid (5.99 fold), hippuric acid (<15.0 fold), acylcarnitines (<2.0 folds) and branched chain amino acids (BCAA) in HPL patients which significantly depleted (p<0.01) after TCJ treatment. Two new acylcarnitines, L-hexanoylcarnitine and 4-hydroxyisovaleric acid observed in HPL patients were depleted (>2.0 fold) after treatment with TCJ. The other biomarkers of HPL, ursodeoxycholic acid and chenodeoxycholic acid were also depleted (>4.0 fold) after TCJ treatment. Conclusion: The present data clearly depicted the regulatory effects of TCJ on the lipid metabolism. It emphasize that TCJ activates PPAR-α in vivo that decreased the urinary levels of PPARα biomarkers. [ABSTRACT FROM AUTHOR]- Published
- 2016
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46. Anti-obesity potential of enzymatic fragments of hyaluronan on high-fat diet-induced obesity in C57BL/6 mice.
- Author
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Park, Byong-Gon, Park, Yoon-Sun, Park, Joo Woong, Shin, Eunji, and Shin, Woon-Seob
- Subjects
- *
ANTIOBESITY agents , *HYALURONIC acid , *HIGH-fat diet , *FATTY liver , *FATTY acid synthases , *PEROXISOME proliferator-activated receptors , *LABORATORY mice - Abstract
Hyaluronan has diverse biological activities depending on its molecular size. The hyaluronan fragments (50 kDa) can decrease adipogenic differentiation in vitro. However, in vivo anti-obesitic effects of hyaluronan fragments have not been elucidated. Therefore, we examined the anti-obesity effects of hyaluronan fragments on high-fat diet induced obesity in C57BL/6 mice. Oral administration of hyaluronan fragments (200 mg/kg for 8 weeks) decreased body weight, adipose tissues, serum lipid (low-density lipoprotein cholesterol, triglyceride), and leptin level. Hyaluronan fragments decreased the hypertrophy of adipose tissue and ameliorated liver steatosis. The mRNA expression of leptin was reduced in adipocyte by treatment with hyaluronan fragments. Additionally, hyaluronan fragments enhanced the mRNA expression of PPAR-α and its target genes UCP-2 and decreased mRNA expression of PPAR- γ and fatty acid synthase in liver. In conclusions, hyaluronan fragments had marked effects on inhibiting the development of obesity in obese mice fed the high-fat diet. It suggested that enhancing PPAR-α and suppressing PPAR-γ expression are two possible mechanisms for the anti-obesitic effect of hyaluronan fragments. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
47. The effects of short-chain fatty acids on the transcription and secretion of apolipoprotein A-I in human hepatocytes in vitro
- Author
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Kim H. R. Mulders, Jehad Z. Tayyeb, Ronald P. Mensink, Herman E. Popeijus, Jogchum Plat, Maurice C. J. M. Konings, Promovendi NTM, Nutrition and Movement Sciences, and RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health
- Subjects
Hepatoblastoma ,0301 basic medicine ,Apolipoprotein B ,Peroxisome proliferator-activated receptor ,PPARα ,Biochemistry ,antibiotics ,SUPPLEMENTATION ,Transactivation ,0302 clinical medicine ,Transcription (biology) ,PPAR-ALPHA ,Gene expression ,Tumor Cells, Cultured ,polycyclic compounds ,Research Articles ,GENE-EXPRESSION ,ApoA‐I ,chemistry.chemical_classification ,Kelch-Like ECH-Associated Protein 1 ,biology ,Chemistry ,Liver Neoplasms ,ApoA-I ,GUT MICROBIOTA ,Anti-Bacterial Agents ,Gene Expression Regulation, Neoplastic ,Real-time polymerase chain reaction ,030220 oncology & carcinogenesis ,lipids (amino acids, peptides, and proteins) ,HEALTH ,transcription ,ACTIVATED RECEPTOR-ALPHA ,Research Article ,medicine.medical_specialty ,In Vitro Techniques ,MECHANISMS ,03 medical and health sciences ,BETA-LACTAM ,Internal medicine ,medicine ,Humans ,PPAR alpha ,Molecular Biology ,Messenger RNA ,Apolipoprotein A-I ,Carnitine O-Palmitoyltransferase ,nutritional and metabolic diseases ,Cell Biology ,Fatty Acids, Volatile ,BET ,SCFA ,030104 developmental biology ,Endocrinology ,biology.protein ,AMOXICILLIN ,Lipoprotein - Abstract
Background Apolipoprotein-I (ApoA-I), the major component of high-density lipoprotein (HDL) particles, mediates cholesterol efflux by which it facilitates the removal of excess cholesterol from peripheral tissues. Therefore, elevating ApoA-I production leading to the production of new pre-beta-HDL particles is thought to be beneficial in the prevention of cardiovascular diseases. Recently, we observed that amoxicillin treatment led to decreased HDL concentrations in healthy human volunteers. We questioned whether this antibiotic effect was directly or indirectly, via changed short-chain fatty acids (SCFA) concentrations through an altered gut microflora. Therefore, we here evaluated the effects of amoxicillin and various SCFA on hepatic ApoA-I expression, secretion, and the putative underlying pathways. Methods and Results Human hepatocytes (HepG2) were exposed to increasing dose of amoxicillin or SCFA for 48 hours. ApoA-I messenger RNA (mRNA) transcription and secreted protein were analyzed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. To study underlying mechanisms, changes in mRNA expression of KEAP1, CPT1, and PPAR alpha, as well as a PPAR alpha transactivation assay, were analyzed. Amoxicillin dose-dependently decreased ApoA-I mRNA transcription as well as ApoA-I protein secretion. SCFA treatment resulted in a dose-dependent stimulation of ApoA-I mRNA transcription, however, the ApoA-I protein secretion was decreased. Furthermore, SCFA treatment increased PPAR alpha transactivation, PPAR alpha and CPT1 mRNA transcription, whereas KEAP1 mRNA transcription was decreased. Conclusion Direct treatment of HepG2 cells with amoxicillin has either direct effects on lowering ApoA-I transcription and secretion or indirect effects via modified SCFA concentrations because SCFA were found to stimulate hepatic ApoA-I expression. Furthermore, BET inhibition and PPAR alpha activation were identified as possible mechanisms behind the observed effects on ApoA-I transcription.
- Published
- 2019
48. OLHA (Nα-oleoylhistamine) modulates activity of mouse brain histaminergic neurons.
- Author
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Sergeeva, Olga A., Mazur, Karolina, Reiner-Link, David, Lutsenko, Kiril, Haas, Helmut L., Alfonso-Prieto, Mercedes, and Stark, Holger
- Subjects
- *
HISTAMINE receptors , *TRPV cation channels , *CANNABINOID receptors , *ACTION potentials , *NEURONS , *HYPOTHALAMUS , *INTRACELLULAR calcium - Abstract
Histaminergic (HA) neurons are located in the tuberomamillary nucleus (TMN) of the posterior hypothalamus, from where they project throughout the whole brain to control wakefulness. We examined the effects of N α-oleoylhistamine (OLHA), a non-enzymatic condensation product of oleic acid (OLA) and histamine, on activity of mouse HA neurons in brain slices. OLHA bidirectionally modulated the firing of HA neurons. At 10 nM OLHA inhibited or had no action, whereas at 1 μM it evoked excitatory and inhibitory responses. Inhibition was not seen in presence of the histamine receptor H3 (H 3 R) antagonist clobenpropit and in calcium-free medium. Pre-incubation with a histamine-reuptake blocker prevented the decrease in firing by OLHA. OLHA-evoked increase in firing (EC 50 ∼44 nM) was insensitive to blockers of cannabinoid 1 and 2 receptors and of the capsaicin receptor, but was significantly impaired by the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) antagonist MK886, which suppressed also the rise in intracellular calcium level caused by OLHA. The OLHA-evoked excitation was mimicked by synthetic PPAR-alpha agonists (gemfibrozil and GW7647) and was abolished by the PKA inhibitor H-89. The H 3 R affinity (Ki) for histamine, measured in HEK293 cells with stable expression of human H 3 R, was higher than for OLHA (Ki: 42 vs 310 nM, respectively). Expression of PPAR-alpha was not different between TMN regions of males and females, responses to OLHA did not differ. Molecular modelling of PPAR-alpha bound to either OLHA or OEA showed similar binding energies. These findings shed light on a novel biotransformation product of histamine which may play a role in health and disease. • OLHA bidirectionally modulates histaminergic neuron firing. • Histamine 3 receptor and PPAR-alpha are involved in inhibition and excitation respectively. • OLHA interacts with histamine reuptake and may modulate histaminergic transmission under pathological conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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- View/download PDF
49. In vitro evaluation of the effects of perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) on IL-2 production in human T-cells.
- Author
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Midgett, Kristin, Peden‐Adams, Margie M., Gilkeson, Gary S., and Kamen, Diane L.
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PERFLUOROOCTANE sulfonate ,PERFLUOROOCTANOIC acid ,T cells ,INTERLEUKIN-2 ,AUTOIMMUNE diseases ,SYSTEMIC lupus erythematosus - Abstract
Perfluorinated compounds, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), have been shown to alter various immune functions suggesting they are immunotoxic. This study assessed the effects of PFOS and PFOA on interleukin (IL)-2 production in the human Jurkat T-cell line and PFOS in healthy human primary T cells. Jurkat cells were stimulated with phytohemagglutinin (PHA)/phorbol myristate acetate (PMA), anti CD-3/anti CD-28, or anti CD-3, and dosed with 0, 0.05, 0.1, 0.5, 1, 5, 10, 50, 75, or 100 µg ml
−1 PFOS or 0, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, or 10 µg ml−1 PFOA. Jurkat cells stimulated with PHA/PMA or anti CD-3 exhibited decreased IL-2 production beginning at 50 µg PFOS ml−1 and 5 µg PFOS ml−1 respectively, but stimulation with anti-CD3/anti-CD28 resulted in no changes compared with the control. Addition of the PPAR-alpha antagonist GW6471 to PFOS-dosed cells stimulated with PHA/PMA resulted in decreases in IL-2 production starting at 50 µg PFOS ml−1 , which suggests PFOS affected T-cell IL-2 production via PPAR-alpha-independent mechanisms. Exposure to PFOA, PFOA + GW6471, or PFOS + PFOA in Jurkat cells resulted in no significant differences in IL-2 production. In vitro dosing studies using healthy primary human CD4+ T cells were consistent with the Jurkat results. These data demonstrated that PFOA did not impact IL-2 production, but PFOS suppressed IL-2 production in both a human cell line and human primary cells at dose levels within the high end of the human exposure range. A decrease in IL-2 production is characteristic of autoimmune diseases such as systemic lupus erythematosus and should be further investigated. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]- Published
- 2015
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- View/download PDF
50. Placental fibroblast growth factor 21 is not altered in late-onset preeclampsia.
- Author
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Nitert, Marloes Dekker, Scholz-Romero, Katherin, Kubala, Marta H., McIntyre, H. David, Callaway, Leonie K., and Barrett, Helen L.
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RISK factors of preeclampsia , *DISEASE incidence , *FIBROBLAST growth factors , *MESSENGER RNA , *GENE expression , *DIAGNOSTIC use of polymerase chain reaction , *WESTERN immunoblotting - Abstract
Background: Preeclampsia (PE) is associated with alterations of placental function. The incidence of PE is higher in insulin resistant states. Women with PE have high circulating levels of the metabolic regulator fibroblast growth factor 21 (FGF21). FGF21 is synthesized in the placenta. The aim of this study was to compare the expression of FGF21, its receptors, downstream targets and transcriptional regulators in placental tissue from pregnancies with and without late-onset PE. Circulating FGF21 in maternal and cord blood was also studied. Methods: mRNA expression was determined by semi-quantitative real-time PCR and normalized for cellular composition in 17 women with and 20 without PE. Protein expression was quantified by Western Blot. FGF21 levels were measured by ELISA in maternal and cord serum of ten mother-baby dyads per condition. Results: Placental FGF21 mRNA and protein expression were similar in PE compared with control. Placental mRNA expression of the FGF receptors (1-4) and the co-receptor beta-Klotho was not different between the groups. There was no difference in the expression of the glucose transporters GLUT1, 3 or 4. PPAR-alpha but not PPAR-gamma expression was decreased in PE. Maternal FGF21 serum levels were not significantly different in PE. FGF21 was detected in cord blood of 6 infants (4 PE, 2 controls) but was undetectable in 14 infants. Conclusions: Late-onset PE is not associated with major changes to the expression of FGF21, its receptors or metabolic targets. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
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