A novel dual PPAR-γ agonist/sEH inhibitor treats diabetic complications in a rat model of type 2 diabetes

Khan, Abdul Hye; Kolb, Lauren L.; Skibba, Melissa; Hartmann, Markus; Blöcher, René; Proschak, Ewgenij; Imig, John D.

doi:10.1007/s00125-018-4685-0

Cited by 39 publications

(41 citation statements)

References 65 publications

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“…The complicated pathophysiology of type 2 diabetes means that a treatment needs to involve multiple therapies to regulate glucose and lipid homeostasis, as well as IR. However, a multitherapy treatment may result in drug effectiveness decreasing or toxicity enhancing and lead to drug interactions or compromised patient compliance [14, 15]. Hence, the development of novel antidiabetic drugs is emerging, such as dual-action drugs [15].…”

Section: Introductionmentioning

confidence: 99%

“…However, a multitherapy treatment may result in drug effectiveness decreasing or toxicity enhancing and lead to drug interactions or compromised patient compliance [14, 15]. Hence, the development of novel antidiabetic drugs is emerging, such as dual-action drugs [15]. However, traditional Chinese medicine formula shows a unique advantage in the complex diseases, because the formula with multicomponents may work on multitargets.…”

Section: Introductionmentioning

confidence: 99%

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Tangduqing Granules Attenuate Insulin Resistance and Abnormal Lipid Metabolism through the Coordinated Regulation of PPARγ and DGAT2 in Type 2 Diabetic Rats

Zhang

Huang

et al. 2019

Journal of Diabetes Research

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Insulin resistance (IR) is a vital hallmark of type 2 diabetes mellitus, which is characterized by an impaired ability of insulin to promote glucose uptake and utilization. Lipid deposition is closely associated with impaired insulin sensitivity. PPARγ plays an important role in glucose homeostasis, adipocyte differentiation, and insulin sensitivity. Likewise, DGAT2 also exerts a crucial role in integrating carbohydrate and lipid metabolism in the liver. The present study is aimed at evaluating a Chinese medicinal formula, Tangduqing granules (TDQ), with multifaceted actions against lipid and glucose metabolism disorder and IR of type 2 diabetes. An animal model of type 2 diabetes was developed by high-fat diet feeding plus low-dose streptozotocin injection. After oral administration of TDQ for 5 weeks, the effects on glucose and lipid metabolism and the underlying mechanism were evaluated by biochemical, histological, RT-PCR, and western blotting methods. The results showed that TDQ decreased fasting blood glucose, ameliorated glucose tolerance, and improved IR. Besides, TDQ regulated hyperlipidemia symptoms, decreased serum lipid levels and liver TG, and reduced hepatic steatosis in a type 2 diabetic rat model. Furthermore, TDQ reversed diabetes-induced decrease in the mRNA and protein expression of PPARγ and elevation in the mRNA and protein levels of DGAT2 in the liver. In addition, we showed that interference of TDQ ameliorated palmitate-induced glucose and lipid metabolic abnormalities in HepG2 cells. TDQ are, therefore, a potential Chinese medicinal formula that relieves IR and lipid metabolism disorder might be through promotion of PPARγ and decrease of DGAT2 expression.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tangduqing Granules Attenuate Insulin Resistance and Abnormal Lipid Metabolism through the Coordinated Regulation of PPARγ and DGAT2 in Type 2 Diabetic Rats

Zhang

Huang

et al. 2019

Journal of Diabetes Research

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“…PSR stained slides were examined for interstitial collagen at 200x magnification and the collagen positive fibrotic kidney area was calculated as an index of renal fibrosis using NIS Elements AR version 3.0 imaging software (Nikon instruments Inc., Melville, NY, United States). Renal fibrosis was scored in a blinded fashion by two observers as published previously (Hye Khan et al, 2016, 2018), and the scores were presented as a percentage area-fraction relative to the total area analyzed.…”

Section: Methodsmentioning

confidence: 99%

Epoxyeicosatrienoic Acid Analog EET-A Blunts Development of Lupus Nephritis in Mice

et al. 2019

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Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder that causes life threatening renal disease and current therapies are limited with serious side-effects. CYP epoxygenase metabolites of arachidonic acid epoxyeicosatrienoic acids (EETs) demonstrate strong anti-inflammatory and kidney protective actions. We investigated the ability of an orally active EET analog, EET-A to prevent kidney injury in a mouse SLE model. Twenty-weeks old female NZBWF1 (SLE) and age-matched NZW/LacJ (Non SLE) were treated with vehicle or EET-A (10 mg/kg/d, p.o.) for 14 weeks and urine and kidney tissues were collected at the end of the protocol. SLE mice demonstrated marked renal chemotaxis with 30–60% higher renal mRNA expression of CXC chemokine receptors (CXCR) and CXC chemokines (CXCL) compared to Non SLE mice. In SLE mice, the elevated chemotaxis is associated with 5-15-fold increase in cytokine mRNA expression and elevated inflammatory cell infiltration in the kidney. SLE mice also had elevated BUN, serum creatinine, proteinuria, and renal fibrosis. Interestingly, EET-A treatment markedly diminished renal CXCR and CXCL renal mRNA expression in SLE mice. EET-A treatment also reduced renal TNF-α, IL-6, IL-1β, and IFN-γ mRNA expression by 70–80% in SLE mice. Along with reductions in renal chemokine and cytokine mRNA expression, EET-A reduced renal immune cell infiltration, BUN, serum creatinine, proteinuria and renal fibrosis in SLE mice. Overall, we demonstrate that an orally active EET analog, EET-A prevents renal injury in a mouse model of SLE by reducing inflammation.

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“…Hepatic steatosis was assessed using frozen liver sections (10 μm) stained with Oil Red O dye using the Oil Red O staining (Abcam, Cambridge, MA, USA). To assess the extent of steatosis, the percent of liver tissue area covered by oil-red positive lipid droplets was calculated as described previously [28]. The percentage area positive for lipid (red color) was calculated from the mean of 20 fields (200×) for each animal using Nikon NIS Elements Software (Nikon Instruments Inc., Melville, NY, USA).…”

Section: Histological Analysismentioning

confidence: 99%

A dual farnesoid X receptor/soluble epoxide hydrolase modulator treats non-alcoholic steatohepatitis in mice

Khan

Schmidt

Stavniichuk

et al. 2019

Biochemical Pharmacology

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Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are the most prevalent metabolic liver disorders and a serious global health burden. NAFLD/NASH pathogenesis and progression are highly multi-factorial and likely demand a combination of multiple mechanisms to provide a more effective treatment. We have developed a dual farnesoid X receptor agonist (FXRA)/soluble epoxide hydrolase inhibitor (sEHi) to simultaneously address two validated and complementary modes of action in NASH treatment. Here we report the in vivo profiling for this FXRA/sEHi in toxin-and diet-induced rodent NASH models. In streptozotocininduced NASH as a proof-of-concept study, the experimental FXRA/sEHi drug robustly prevented hepatic steatosis and fibrosis, and improved lipid homeostasis as well as biochemical markers of liver health. In methionine-choline-deficient high-fat diet-induced NASH, FXRA/sEHi treatment reduced hepatic steatosis and fibrosis to levels similar to healthy animals and demonstrated antiinflammatory activity confirming that dual FXRA/sEHi modulation produces a triad of complementary anti-NASH effects. Our results validate dual FXRA/sEHi modulation as an effective therapeutic strategy to treat NASH and advocates for a combinational drug therapeutic approach for multifactorial liver diseases.

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A novel dual PPAR-γ agonist/sEH inhibitor treats diabetic complications in a rat model of type 2 diabetes

Abstract: These findings demonstrate that a novel sHE inhibitor/PPAR-γ agonist molecule targets multiple risk factors of the metabolic syndrome and is a glucose-lowering agent with a strong ability to treat diabetic complications.

Cited by 39 publications

References 65 publications

Tangduqing Granules Attenuate Insulin Resistance and Abnormal Lipid Metabolism through the Coordinated Regulation of PPARγ and DGAT2 in Type 2 Diabetic Rats

Tangduqing Granules Attenuate Insulin Resistance and Abnormal Lipid Metabolism through the Coordinated Regulation of PPARγ and DGAT2 in Type 2 Diabetic Rats

Epoxyeicosatrienoic Acid Analog EET-A Blunts Development of Lupus Nephritis in Mice

A dual farnesoid X receptor/soluble epoxide hydrolase modulator treats non-alcoholic steatohepatitis in mice

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