scholarly journals Discovery of Novel Insulin Sensitizers: Promising Approaches and Targets

PPAR Research ◽  
2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Yadan Chen ◽  
Haiming Ma ◽  
Dasheng Zhu ◽  
Guowei Zhao ◽  
Lili Wang ◽  
...  
Keyword(s):  
Adenosine Monophosphate ◽  
Future Research ◽  
Diabetic Patients ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Downstream Effectors ◽  
Insulin Sensitizers ◽  
Mitochondrial Target ◽  
Unmet Demand ◽  
New Generation

Insulin resistance is the undisputed root cause of type 2 diabetes mellitus (T2DM). There is currently an unmet demand for safe and effective insulin sensitizers, owing to the restricted prescription or removal from market of certain approved insulin sensitizers, such as thiazolidinediones (TZDs), because of safety concerns. Effective insulin sensitizers without TZD-like side effects will therefore be invaluable to diabetic patients. The specific focus on peroxisome proliferator-activated receptorγ- (PPARγ-) based agents in the past decades may have impeded the search for novel and safer insulin sensitizers. This review discusses possible directions and promising strategies for future research and development of novel insulin sensitizers and describes the potential targets of these agents. Direct PPARγagonists, selective PPARγmodulators (sPPARγMs), PPARγ-sparing compounds (including ligands of the mitochondrial target of TZDs), agents that target the downstream effectors of PPARγ, along with agents, such as heat shock protein (HSP) inducers, 5′-adenosine monophosphate-activated protein kinase (AMPK) activators, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) selective inhibitors, biguanides, and chloroquines, which may be safer than traditional TZDs, have been described. This minireview thus aims to provide fresh perspectives for the development of a new generation of safe insulin sensitizers.

scholarly journals Abdominal Fat SIRT6 Expression and Its Relationship with Inflammatory and Metabolic Pathways in Pre-Diabetic Overweight Patients

2019 ◽  
Vol 20 (5) ◽  
pp. 1153 ◽  
Author(s):  
Nunzia D’Onofrio ◽  
Gorizio Pieretti ◽  
Feliciano Ciccarelli ◽  
Antonio Gambardella ◽  
Nicola Passariello ◽  
...  
Keyword(s):  
Regulatory Element ◽  
Abdominal Fat ◽  
Control Group ◽  
Diabetic Patients ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metformin Therapy ◽  
Ppar Γ ◽  
Visceral Abdominal Fat ◽  
Factor Α

: The role of sirtuin 6 (SIRT6) in adipose abdominal tissue of pre-diabetic (pre-DM) patients is poorly known. Here, we evaluated SIRT6 expression in visceral abdominal fat of obese pre-diabetic patients and the potential effects of metformin therapy. Results indicated that obese pre-DM subjects showed low SIRT6 protein expression and high expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), peroxisome proliferator-activated receptor gamma (PPAR-γ), and sterol regulatory element-binding transcription factor 1 (SREBP-1). Obese pre-DM patients showed high values of glucose, insulin resistance (HOMA-IR), C reactive protein (CRP), nitrotyrosine, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), and low values of insulin (p < 0.05). Of note, abdominal fat tissue of obese pre-DM patients treated with metformin therapy presented higher SIRT6 expression and lower NF-κB, PPAR-γ, and SREBP-1 expression levels compared to pre-DM control group. Collectively, results show that SIRT6 is involved in the inflammatory pathway of subcutaneous abdominal fat of obese pre-DM patients and its expression responds to metformin therapy.

scholarly journals The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

2017 ◽  
Vol 1 (6) ◽  
pp. 524-537 ◽  
Author(s):  
Guillaume Wettstein ◽  
Jean-Michel Luccarini ◽  
Laurence Poekes ◽  
Patrick Faye ◽  
Francine Kupkowski ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Metabolic Disorders ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
New Generation

scholarly journals Anti-Adipogenic Effects of Delphinidin-3-O-β-Glucoside in 3T3-L1 Preadipocytes and Primary White Adipocytes

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1848 ◽  
Author(s):  
Miey Park ◽  
Anshul Sharma ◽  
Hae-Jeung Lee
Keyword(s):  
Fatty Acid Synthase ◽  
Regulatory Element ◽  
Adenosine Monophosphate ◽  
Immunoblot Analysis ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
White Adipocytes ◽  
Health Promoting ◽  
Treatment Of Obesity

Delphinidin-3-O-β-glucoside (D3G) is a health-promoting anthocyanin whose anti-obesity activity has not yet been thoroughly investigated. We examined the effects of D3G on adipogenesis and lipogenesis in 3T3-L1 adipocytes and primary white adipocytes using real-time RT-PCR and immunoblot analysis. D3G significantly inhibited the accumulation of lipids in a dose-dependent manner without displaying cytotoxicity. In the 3T3-L1 adipocytes, D3G downregulated the expression of key adipogenic and lipogenic markers, which are known as peroxisome proliferator-activated receptor gamma (PPARγ), sterol regulatory element-binding transcription factor 1 (SREBP1), CCAAT/enhancer-binding protein alpha (C/EBPα), and fatty acid synthase (FAS). Moreover, the relative protein expression of silent mating type information regulation 2 homolog 1 (SIRT1) and carnitine palmitoyltransferase-1 (CPT-1) were increased, alongside reduced lipid levels and the presence of several small lipid droplets. Furthermore, D3G increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC), which suggests that D3G may play a role in AMPK and ACC activation in adipocytes. Our data indicate that D3G attenuates adipogenesis and promotes lipid metabolism by activating AMPK-mediated signaling, and, hence, could have a therapeutic role in the management and treatment of obesity.

scholarly journals Effects of Caloric Intake on Learning and Memory Function in Juvenile C57BL/6J Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Bao-Lei Xu ◽  
Rong Wang ◽  
Li-Na Ma ◽  
Wen Dong ◽  
Zhi-Wei Zhao ◽  
...  
Keyword(s):  
Learning And Memory ◽  
Memory Function ◽  
Caloric Intake ◽  
Camp Response Element Binding ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Downstream Effectors ◽  
Element Binding Protein

Dietary composition may influence neuronal function as well as processes underlying synaptic plasticity. In this study, we aimed to determine the effect of high and low caloric diets on a mouse model of learning and memory and to explore mechanisms underlying this process. Mice were divided into three different dietary groups: normal control(n=12), high-caloric (HC) diet(n=12), and low-caloric (LC) diet(n=12). After 6 months, mice were evaluated on the Morris water maze to assess spatial memory ability. We found that HC diet impaired learning and memory function relative to both control and LC diet. The levels of SIRT1 as well as its downstream effectors p53, p16, and peroxisome proliferator-activated receptorγ(PPARγ) were decreased in brain tissues obtained from HC mice. LC upregulated SIRT1 but downregulated p53, p16, and PPARγ. The expressions of PI3K and Akt were not altered after HC or LC diet treatment, but both LC and HC elevated the levels of phosphorylated-cAMP response element-binding protein (p-CREB) and IGF-1 in hippocampal CA1 region. Therefore, HC diet-induced dysfunction in learning and memory may be prevented by caloric restriction via regulation of the SIRT1-p53 or IGF-1 signaling pathways and phosphorylation of CREB.

Mass spectrometry of doping preparations of a new generation: Peroxisome proliferator-activated receptor agonists

2010 ◽  
Vol 65 (13) ◽  
pp. 1411-1419
Author(s):  
M. A. Dikunets ◽  
E. D. Virus ◽  
E. N. Semenistaya ◽  
T. G. Sobolevsky ◽  
G. M. Rodchenkov
Keyword(s):  
Mass Spectrometry ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Agonists ◽  
New Generation

Beneficial Effect of Flavone Derivatives on Aβ-Induced Memory Deficit Is Mediated by Peroxisome Proliferator-Activated Receptor γ Coactivator 1α

2015 ◽  
Vol 34 (3) ◽  
pp. 274-283 ◽  
Author(s):  
Farshad Arsalandeh ◽  
Shahin Ahmadian ◽  
Forough Foolad ◽  
Fariba Khodagholi ◽  
Mahdi M. Farimani ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Neuroprotective Effect ◽  
Memory Function ◽  
Adenosine Monophosphate ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nuclear Respiratory Factor ◽  
Mitochondrial Transcription Factor ◽  
Nuclear Respiratory Factor 1

In the present study, the neuroprotective effect of 5-hydroxy-6,7,4′-trimethoxyflavone (flavone 1), a natural flavone, was investigated in comparison with another flavone, 5,7,4′-trihydroxyflavone (flavone 2) on the hippocampus of amyloid beta (Aβ)-injected rats. Rats were treated with the 2 flavones (1 mg/kg/d) for 1 week before Aβ injection. Seven days after Aβ administration, memory function of rats was assessed in a passive avoidance test (PAT). Changes in the levels of mitochondrial transcription factor A (TFAM), peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α), phospho-adenosine monophosphate (AMP)-activated protein kinase (pAMPK), AMPK, phospho-cAMP-responsive element-binding protein (CREB), CREB, and nuclear respiratory factor 1 (NRF-1) proteins were determined by Western blot analysis. Our results showed an improvement in memory in rats pretreated with flavonoids. At the molecular level, phosphorylation of CREB, known as the master modulator of memory processes, increased. On the other hand, the level of mitochondrial biogenesis factors, PGC-1α and its downstream molecules NRF-1 and TFAM significantly increased by dietary administration of 2 flavones. In addition, flavone 1 and flavone 2 prevented mitochondrial swelling and mitochondrial membrane potential reduction. Our results provided evidence that flavone 1 is more effective than flavone 2 presumably due to its O-methylated groups. In conclusion, it seems that in addition to classical antioxidant effect, flavones exert part of their protective effects through mitochondrial biogenesis.

scholarly journals Voluntary Wheel Running Exercise Improves Aging-Induced Sarcopenia via Activation of Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α/Fibronectin Type III Domain-Containing Protein 5/Adenosine Monophosphate-Activated Protein Kinase Signaling Pathway

2021 ◽  
Vol 25 (Suppl 1) ◽  
pp. S27-34 ◽  
Author(s):  
Young Jun Ko ◽  
Il-Gyu Ko
Keyword(s):  
Signaling Pathway ◽  
Wheel Running ◽  
Adenosine Monophosphate ◽  
Peroxisome Proliferator ◽  
Voluntary Wheel Running ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ampk Signaling ◽  
Running Exercise ◽  
Fibronectin Type Iii Domain ◽  
Voluntary Wheel

Purpose: In this study, the protective effect of voluntary wheel running exercise on muscle loss and muscle weakness in gastrocnemius of old rats was investigated. The association of voluntary wheel exercise with the peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)/fibronectin type III domain-containing protein 5 (FNDC5)/adenosine monophosphate- activated protein kinase (AMPK) signaling pathway and vascular endothelial growth factor (VEGF) expression was also evaluated.Methods: Six-month-old and 22-month-old male rats were used for this experiment. The rats in voluntary wheel running exercise groups were performed wheel running for 2 months. Weight bearing test for walking strength, rotarod test for motor coordination and balance, hematoxylin and eosin (H&E) staining for histological changes in the muscle tissues, Western blot analysis for PGC-1α, FNDC5, AMPK, immunofluorescence for VEGF were conducted.Results: Decreased muscle mass, strength, and coordination due to aging were associated with a decrease in the PGC-1α/ FNDC5/AMPK signaling pathway in the gastrocnemius. Voluntary wheel running exercise enhanced VEGF expression by activating the PGC-1α/FNDC5/AMPK signaling pathway, then increased muscle mass, strength, and coordination.Conclusions: It has been suggested that voluntary wheel running exercise alleviates symptoms of urological diseases that are difficult to treat. Wheel running exercise is a good therapeutic strategy to prevent or treat aging-related sarcopenia.

scholarly journals Proteomic Analysis Reveals the Protective Effects of Yiqi Fumai Lyophilized Injection on Chronic Heart Failure by Improving Myocardial Energy Metabolism

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoying Han ◽  
Yi Zhang ◽  
Ou Qiao ◽  
Haixia Ji ◽  
Xinyu Zhang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Energy Metabolism ◽  
Chronic Heart Failure ◽  
Heart Tissue ◽  
Protective Mechanism ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Alpha ◽  
Downstream Effectors

Yiqi Fumai lyophilized injection (YQFM) is the recombination of Sheng mai san (SMS).YQFM has been applied clinically to efficaciously and safely treat chronic heart failure (CHF). However, the mechanism of YQFM is still not fully elucidated. The purpose of our study was to investigate the protective mechanism of YQFM against abdominal aortic coarctation (AAC) in rats by proteomic methods. After YQFM treatment, the cardiac function were obviously meliorated. One hundred and fifty-seven important differentially expressed proteins (DEPs) were identified, including 109 in model rat compared with that in control rat (M:C) and 48 in YQFM-treated rat compared with that in model rat (T:M) by iTRAQ technology to analyze the proteomic characteristics of heart tissue. Bioinformatics analysis showed that DEPs was mainly involved in the body’s energy metabolism and was closely related to oxidative phosphorylation. YQFM had also displayed efficient mitochondrial dysfunction alleviation properties in hydrogen peroxide (H2O2)-induced cardiomyocyte damage by Transmission Electron Microscope (TEM), Metabolic assay, and Mitotracker staining. What’s more, the levels of total cardiomyocyte apoptosis were markedly reduced following YQFM treatment. Furthermore, Western blot analysis showed that the expressions of peroxisome proliferator activated receptor co-activator-1α(PGC-1α) (p &lt; 0.01 or p &lt; 0.001), perixisome proliferation-activated receptor alpha (PPAR-α) (p &lt; 0.001)and retinoid X receptor alpha (RXR-α) were upregulated (p &lt; 0.001), PGC-1α as well as its downstream effectors were also found to be upregulated in cardiomyocytes after YQFM treatment(p &lt; 0.001).These results provided evidence that YQFM could enhance mitochondrial function of cardiomyocytes to play a role in the treatment of CHF by regulating mitochondrial biogenesis-related proteins.

scholarly journals Synthesis, Characterization and Biological Evaluation of Thiazolidinedione Derivative as Novel Antidiabetic Agents

2021 ◽  
pp. 123-133
Author(s):  
Shivkant Patel ◽  
Ashim Kumar Sen ◽  
Dillip Kumar Dash ◽  
Piyushkumar Sadhu ◽  
Mamta Kumari ◽  
...  
Keyword(s):  
Biological Evaluation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Chemical Structures ◽  
Insulin Sensitizers ◽  
Diabetes Model ◽  
Glucose Synthesis ◽  
Sucrose Loading ◽  
Derivatives Of

Thiazolidinedione derivative have Antihyperglycemic activity, they are agonists for the peroxisome proliferator-activated receptor (PPAR), which controls glucose synthesis, transport, and utilization via regulating the transcription of insulin-responsive genes. A number of novel insulin sensitizers are currently being researched. Several of these are derivatives of Thiazolidinedione, but others have different chemical structures. In this work, we created some new Thiazolidinedione derivative based on structure–activity relationship as closely as feasible. The Thiazolidine-2,4-Dione derivatives were manually developed and synthesized using the proper synthetic techniques, then tested in vitro for antihyperglycemic action using the Sucrose loading model (SLM) and the Alloxan induced diabetes model (AIDM). The newly synthesized Thiazolidine-2,4-Dione derivative was characterized using infrared (IR) and proton (H) nuclear magnetic resonance. In this study we found that Compound M-4 has a lot of antihyperglycemic action, thus it's a good idea to think about using it as a lead material for the creation of anti-diabetic drugs.

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