Multitargeted bioactive ligands for <scp>PPAR</scp>s discovered in the last decade

Zhang, Jun; Liu, Xin; Xie, Xian-Bin; Cheng, Xian-Chao; Wang, Run‐Ling

doi:10.1111/cbdd.12806

Cited by 26 publications

(18 citation statements)

References 129 publications

(125 reference statements)

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“…Decreased insulin resistance and reduced hyperglycemia have been observed in humans [64,65] and in obese mice [66–68] following treatment with rosiglitazone. The major clinical side effect of rosiglitazone is significant weight gain [69,70]. Rosiglitazone is also associated with weight gain in diabetic obese mice [71,72] including the FATZO mice in this study.…”

Section: Discussionmentioning

confidence: 74%

Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse

Peterson¹,

Jackson²,

Zimmerman³

et al. 2017

PLoS ONE

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The FATZO/Pco mouse is the result of a cross of the C57BL/6J and AKR/J strains. The crossing of these two strains and the selective inbreeding for obesity, insulin resistance and hyperglycemia has resulted in an inbred strain exhibiting obesity in the presumed presence of an intact leptin pathway. Routinely used rodent models for obesity and diabetes research have a monogenic defect in leptin signaling that initiates obesity. Given that obesity and its sequelae in humans are polygenic in nature and not associated with leptin signaling defects, the FATZO mouse may represent a more translatable rodent model for study of obesity and its associated metabolic disturbances. The FATZO mouse develops obesity spontaneously when fed a normal chow diet. Glucose intolerance with increased insulin levels are apparent in FATZO mice as young as 6 weeks of age. These progress to hyperglycemia/pre-diabetes and frank diabetes with decreasing insulin levels as they age. The disease in these mice is multi-faceted, similar to the metabolic syndrome apparent in obese individuals, and thus provides a long pre-diabetic state for determining the preventive value of new interventions. We have assessed the utility of this new model for the pre-clinical screening of agents to stop or slow progression of the metabolic syndrome to severe diabetes. Our assessment included: 1) characterization of the spontaneous development of disease, 2) comparison of metabolic disturbances of FATZO mice to control mice and 3) validation of the model with regard to the effectiveness of current and emerging anti-diabetic agents; rosiglitazone, metformin and semaglutide. Conclusion: Male FATZO mice spontaneously develop significant metabolic disease when compared to normal controls while maintaining hyperglycemia in the presence of high leptin levels and hyperinsulinemia. The disease condition responds to commonly used antidiabetic agents.

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Section: Discussionmentioning

confidence: 74%

Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse

Peterson¹,

Jackson²,

Zimmerman³

et al. 2017

PLoS ONE

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“…PPARs agonists show promising effect in improving metabolic disorders including obesity, hypertension, diabetes and cardiovascular diseases and are widely used in practice. Moreover, agonists are developing rapidly from partial agonists to dual agonists, even pan-agonists [23, 24]. However, the more effective the drugs were, the more possibilities they would brought to the activation of viral replication in HBV infected patients.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferators Activated Receptor (PPAR) agonists activate hepatitis B virus replication in vivo

Liu

et al. 2017

Virol J

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BackgroundPPAR agonists are often used in HBV infected patients with metabolic disorders. However, as liver-enriched transcriptional factors, PPARs would activate HBV replication. Risks exsit in such patients. This study aimed to assess the influence of commonly used synthetic PPAR agonists on hepatitis B virus (HBV) transcription, replication and expression through HBV replicative mouse models, providing information for physicians to make necessary monitoring and therapeutic adjustment when HBV infected patients receive PPAR agonists treatment.MethodsThe HBV replicative mouse model was established by hydrodynamic injection of HBV replicative plasmid and the mice were divided into four groups and treated daily for 3 days with saline, PPAR pan-agonist (bezafibrate), PPARα agonist (fenofibrate) and PPARγ agonist (rosiglitazone) respectively. Their serum samples were collected for ECLIA analysis of HBsAg and HBeAg and real-time PCR analysis of Serum HBV DNA. The liver samples were collected for DNA (Southern) filter hybridization of HBV replication intermediates, real-time PCR analysis of HBV mRNA and immunohistochemistry (IHC) analysis of hepatic HBcAg. The alternation of viral transcription, replication and expression were compared in these groups.ResultSerum HBsAg, HBeAg and HBV DNA were significantly elevated after PPAR agonist treatment. So did the viral replication intermediates in mouse livers. HBV mRNA was also significantly increased by these PPAR agonists, implying that PPAR agonists activate HBV replication at transcription level. Moreover, hepatic HBcAg expression in mouse livers with PPAR agonist treatment was elevated as well.ConclusionOur in vivo study proved that synthetic PPAR agonists bezafibrate, fenofibrate and rosiglitazone would increase HBV replication. It suggested that when HBV infected patients were treated with PPARs agonists because of metabolic diseases, HBV viral load should be monitored and regimens may need to be adjusted, an antiviral therapy may be added.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-017-0765-x) contains supplementary material, which is available to authorized users.

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“…Among the natural ligands, there are fatty acids, prostaglandins, and leukotrienes [ 12 , 13 ]. Several high affinity and subtype-specific PPARß/ δ agonists have been developed and submitted for clinical trials for the treatment of metabolic diseases [ 1 , 14 ]; however no ligand has been made available for clinical use.…”

Section: Introductionmentioning

confidence: 99%

Cellular and Biophysical Pipeline for the Screening of Peroxisome Proliferator-Activated Receptor Beta/Delta Agonists: Avoiding False Positives

et al. 2018

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Peroxisome proliferator-activated receptor beta/delta (PPARß/δ) is considered a therapeutic target for metabolic disorders, cancer, and cardiovascular diseases. Here, we developed one pipeline for the screening of PPARß/δ agonists, which reduces the cost, time, and false-positive hits. The first step is an optimized 3-day long cellular transactivation assay based on reporter-gene technology, which is supported by automated liquid-handlers. This primary screening is followed by a confirmatory transactivation assay and by two biophysical validation methods (thermal shift assay (TSA) and (ANS) fluorescence quenching), which allow the calculation of the affinity constant, giving more information about the selected hits. All of the assays were validated using well-known commercial agonists providing trustworthy data. Furthermore, to validate and test this pipeline, we screened a natural extract library (560 extracts), and we found one plant extract that might be interesting for PPARß/δ modulation. In conclusion, our results suggested that we developed a cheaper and more robust pipeline that goes beyond the single activation screening, as it also evaluates PPARß/δ tertiary structure stabilization and the ligand affinity constant, selecting only molecules that directly bind to the receptor. Moreover, this approach might improve the effectiveness of the screening for agonists that target PPARß/δ for drug development.

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Multitargeted bioactive ligands for PPARs discovered in the last decade

Cited by 26 publications

References 129 publications

Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse

Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse

Peroxisome Proliferators Activated Receptor (PPAR) agonists activate hepatitis B virus replication in vivo

Cellular and Biophysical Pipeline for the Screening of Peroxisome Proliferator-Activated Receptor Beta/Delta Agonists: Avoiding False Positives

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