scholarly journals Dual Targeting of PTP1B and Aldose Reductase with Marine Drug Phosphoeleganin: A Promising Strategy for Treatment of Type 2 Diabetes

Marine Drugs ◽  
2021 ◽  
Vol 19 (10) ◽  
pp. 535
Author(s):  
Massimo Genovese ◽  
Concetta Imperatore ◽  
Marcello Casertano ◽  
Anna Aiello ◽  
Francesco Balestri ◽  
...  
Keyword(s):  
Aldose Reductase ◽  
Insulin Signalling ◽  
Marine Invertebrate ◽  
Tyrosine Phosphatase ◽  
Competitive Inhibitor ◽  
Dual Inhibitor ◽  
In Silico Docking ◽  
Insulin Signalling Pathway ◽  
Depth Study ◽  
Multiple Ligands

An in-depth study on the inhibitory mechanism on protein tyrosine phosphatase 1B (PTP1B) and aldose reductase (AR) enzymes, including analysis of the insulin signalling pathway, of phosphoeleganin, a marine-derived phosphorylated polyketide, was achieved. Phosphoeleganin was demonstrated to inhibit both enzymes, acting respectively as a pure non-competitive inhibitor of PTP1B and a mixed-type inhibitor of AR. In addition, in silico docking analyses to evaluate the interaction mode of phosphoeleganin with both enzymes were performed. Interestingly, this study showed that phosphoeleganin is the first example of a dual inhibitor polyketide extracted from a marine invertebrate, and it could be used as a versatile scaffold structure for the synthesis of new designed multiple ligands.

scholarly journals In Search for Multi-Target Ligands as Potential Agents for Diabetes Mellitus and Its Complications—A Structure-Activity Relationship Study on Inhibitors of Aldose Reductase and Protein Tyrosine Phosphatase 1B

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 330
Author(s):  
Rosaria Ottanà ◽  
Paolo Paoli ◽  
Mario Cappiello ◽  
Trung Ngoc Nguyen ◽  
Ilenia Adornato ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Aldose Reductase ◽  
Protein Tyrosine Phosphatase ◽  
Complex Disease ◽  
Tyrosine Phosphatase ◽  
C2c12 Cell ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
In Silico Docking ◽  
Multiple Ligands

Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates.

scholarly journals PTPIP51: A New Interaction Partner of the Insulin Receptor and PKA in Adipose Tissue

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
M. A. Bobrich ◽  
S. A. Schwabe ◽  
A. Brobeil ◽  
M. Viard ◽  
M. Kamm ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Receptor ◽  
Endurance Training ◽  
High Fat Diet ◽  
Insulin Signalling ◽  
Tyrosine Phosphatase ◽  
Proximity Ligation Assay ◽  
Standard Diet ◽  
High Fat ◽  
Insulin Signalling Pathway

Aims. Our previous experiments revealed an association of PTPIP51 (protein tyrosine phosphatase interacting protein 51) with the insulin signalling pathway through PTP1B and 14-3-3beta. We aimed to clarify the role of PTPIP51 in adipocyte metabolism.Methods. Four groups of ten C57Bl/6 mice each were used. Two groups were fed a standard diet; two groups were fed a high-fat diet. Two groups (one high-fat diet and one standard diet) were submitted to endurance training, while the remaining two groups served as untrained control groups. After ten weeks, we measured glucose tolerance of the mice. Adipose tissue samples were analyzed by immunofluorescence and Duolink proximity ligation assay to quantify interactions of PTPIP51 with either insulin receptor (IR) or PKA.Results. PTPIP51 and the IR and PTPIP51 and PKA, respectively, were colocalized in all groups. Standard diet animals that were submitted to endurance training showed low PTPIP51-IR and PTPIP51-PKA interactions. The interaction levels of both the IR and PKA differed between the feeding and training groups.Conclusion. PTPIP51 might serve as a linking protein in adipocyte metabolism by connecting the IR-triggered lipogenesis with the PKA-dependent lipolysis. PTPIP51 interacts with both proteins, therefore being a potential gateway for the cooperation of both pathways.

scholarly journals Long-Chain Acylcarnitines Decrease the Phosphorylation of the Insulin Receptor at Tyr1151 Through a PTP1B-Dependent Mechanism

2021 ◽  
Vol 22 (12) ◽  
pp. 6470
Author(s):  
Karlis Vilks ◽  
Melita Videja ◽  
Marina Makrecka-Kuka ◽  
Martins Katkevics ◽  
Eduards Sevostjanovs ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Insulin Receptor ◽  
Cellular Response ◽  
Insulin Signalling ◽  
Tyrosine Phosphatase ◽  
Insulin Sensitizer ◽  
Akt Phosphorylation ◽  
Insulin Signalling Pathway ◽  
Phosphatase 2A ◽  
Long Chain

The accumulation of lipid intermediates may interfere with energy metabolism pathways and regulate cellular energy supplies. As increased levels of long-chain acylcarnitines have been linked to insulin resistance, we investigated the effects of long-chain acylcarnitines on key components of the insulin signalling pathway. We discovered that palmitoylcarnitine induces dephosphorylation of the insulin receptor (InsR) through increased activity of protein tyrosine phosphatase 1B (PTP1B). Palmitoylcarnitine suppresses protein kinase B (Akt) phosphorylation at Ser473, and this effect is not alleviated by the inhibition of PTP1B by the insulin sensitizer bis-(maltolato)-oxovanadium (IV). This result indicates that palmitoylcarnitine affects Akt activity independently of the InsR phosphorylation level. Inhibition of protein kinase C and protein phosphatase 2A does not affect the palmitoylcarnitine-mediated inhibition of Akt Ser473 phosphorylation. Additionally, palmitoylcarnitine markedly stimulates insulin release by suppressing Akt Ser473 phosphorylation in insulin-secreting RIN5F cells. In conclusion, long-chain acylcarnitines activate PTP1B and decrease InsR Tyr1151 phosphorylation and Akt Ser473 phosphorylation, thus limiting the cellular response to insulin stimulation.

scholarly journals Curcumin regulates insulin pathways and glucose metabolism in the brains of APPswe/PS1dE9 mice

2017 ◽  
Vol 30 (1) ◽  
pp. 25-43 ◽  
Author(s):  
Pengwen Wang ◽  
Caixin Su ◽  
Huili Feng ◽  
Xiaopei Chen ◽  
Yunfang Dong ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Learning And Memory ◽  
Therapeutic Potential ◽  
Insulin Signalling ◽  
Signalling Pathways ◽  
Spatial Learning And Memory ◽  
Positron Emission ◽  
Insulin Signalling Pathway ◽  
Depth Study ◽  
Improved Learning

Recent studies have shown the therapeutic potential of curcumin in Alzheimer’s disease (AD). In 2014, our lab found that curcumin reduced Aβ40, Aβ42 and Aβ-derived diffusible ligands in the mouse hippocampus, and improved learning and memory. However, the mechanisms underlying this biological effect are only partially known. There is considerable evidence in brain metabolism studies indicating that AD might be a brain-specific type of diabetes with progressive impairment of glucose utilisation and insulin signalling. We hypothesised that curcumin might target both the glucose metabolism and insulin signalling pathways. In this study, we monitored brain glucose metabolism in living APPswe/PS1dE9 double transgenic mice using a micro-positron emission tomography (PET) technique. The study showed an improvement in cerebral glucose uptake in AD mice. For a more in-depth study, we used immunohistochemical (IHC) staining and western blot techniques to examine key factors in both glucose metabolism and brain insulin signalling pathways. The results showed that curcumin ameliorated the defective insulin signalling pathway by upregulating insulin-like growth factor (IGF)-1R, IRS-2, PI3K, p-PI3K, Akt and p-Akt protein expression while downregulating IR and IRS-1. Our study found that curcumin improved spatial learning and memory, at least in part, by increasing glucose metabolism and ameliorating the impaired insulin signalling pathways in the brain.

scholarly journals The insulin signalling pathway

2002 ◽  
Vol 12 (7) ◽  
pp. R236-R238 ◽  
Author(s):  
Jose M. Lizcano ◽  
Dario R. Alessi
Keyword(s):  
Insulin Signalling ◽  
Signalling Pathway ◽  
Insulin Signalling Pathway

Discovery of potential aldose reductase inhibitors using in silico docking studies

2012 ◽  
Vol 12 (2) ◽  
pp. 157-161 ◽  
Author(s):  
Arumugam Madeswaran ◽  
Muthuswamy Umamaheswari ◽  
Kuppusamy Asokkumar ◽  
Thirumalaisamy Sivashanmugam ◽  
Varadharajan Subhadradevi ◽  
...  
Keyword(s):  
Aldose Reductase ◽  
In Silico ◽  
Docking Studies ◽  
In Silico Docking ◽  
Aldose Reductase Inhibitors ◽  
Reductase Inhibitors

scholarly journals Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer

2020 ◽  
Vol 38 (6) ◽  
pp. 1836-1845
Author(s):  
Shunsuke Kondo ◽  
Masaomi Tajimi ◽  
Tomohiko Funai ◽  
Koichi Inoue ◽  
Hiroya Asou ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Mammalian Target Of Rapamycin ◽  
Japanese Patients ◽  
Competitive Inhibitor ◽  
Primary Objective ◽  
Dose Escalation Study ◽  
Dual Inhibitor ◽  
Advanced Malignancies ◽  
Grade 3

Summary LY3023414 is an oral, selective adenosine triphosphate-competitive inhibitor of class I phosphatidylinositol 3-kinase isoforms, mammalian target of rapamycin, and DNA-protein kinase in clinical development. We report results of a 3 + 3 dose-escalation Phase 1 study for twice-daily (BID) dosing of LY3023414 monotherapy in Japanese patients with advanced malignancies. The primary objective was to evaluate tolerability and safety of LY3023414. Secondary objectives were to evaluate pharmacokinetics and to explore antitumor activity. A total of 12 patients were enrolled and received 150 mg (n = 3) or 200 mg (n = 9) LY3023414 BID. Dose-limiting toxicities were only reported at 200 mg LY3023414 for 2 patients with Grade 3 stomatitis. Common treatment-related adverse events (AEs) across both the dose levels included stomatitis (75.0%), nausea (66.7%), decreased appetite (58.3%), diarrhea, and decreased platelet count (41.7%), and they were mostly mild or moderate in severity. Related AEs Grade ≥ 3 reported for ≥1 patient included anemia, stomatitis, hypophosphatemia, and hyperglycemia (n = 2, 16.7%). Two patients discontinued due to AEs (interstitial lung disease and stomatitis). No fatal events were reported. The pharmacokinetic profile of LY3023414 was characterized by rapid absorption and elimination. Five patients had a best overall response of stable disease (150 mg, n = 3; 200 mg, n = 2) for a 55.6% disease control rate. LY3023414 up to 200 mg BID is tolerable and safe in Japanese patients with advanced malignancies.

Effect of food restriction on the insulin signalling pathway in rat skeletal muscle and adipose tissue

2005 ◽  
Vol 16 (10) ◽  
pp. 602-609 ◽  
Author(s):  
Ana Alonso ◽  
Yolanda Fernández ◽  
Rebeca Fernández ◽  
Patricia Ordóñez ◽  
María Moreno ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Food Restriction ◽  
Insulin Signalling ◽  
Signalling Pathway ◽  
Rat Skeletal Muscle ◽  
Insulin Signalling Pathway ◽  
Effect Of Food

scholarly journals GPR21 Inhibition Increases Glucose-Uptake in HepG2 Cells

2021 ◽  
Vol 22 (19) ◽  
pp. 10784
Author(s):  
Gemma K. Kinsella ◽  
Stefania Cannito ◽  
Valentina Bordano ◽  
John C. Stephens ◽  
Arianna C. Rosa ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Hepg2 Cells ◽  
Insulin Signalling ◽  
Hepatic Insulin Resistance ◽  
In Vivo Studies ◽  
Negative Effects ◽  
Cellular Models ◽  
Insulin Signalling Pathway ◽  
Novel Strategy

GPR21 is a constitutively active, orphan, G-protein-coupled receptor, with in vivo studies suggesting its involvement in the modulation of insulin sensitivity. However, its precise contribution is not fully understood. As the liver is both a major target of insulin signalling and critically involved in glucose metabolism, the aim of this study was to examine the role of GPR21 in the regulation of glucose uptake and production in human hepatocytes. In particular, HepG2 cells, which express GPR21, were adopted as cellular models. Compared with untreated cells, a significant increase in glucose uptake was measured in cells treated with siRNA to downregulate GPR21 expression or with the GPR21-inverse agonist, GRA2. Consistently, a significantly higher membrane translocation of GLUT-2 was measured under these conditions. These effects were accompanied by an increased ratio of phAKT(Ser473)/tot-AKT and phGSK-3β(Ser9)/tot-GSK-3β, thus indicating a marked activation of the insulin signalling pathway. Moreover, a significant reduction in ERK activation was observed with GPR21 inhibition. Collectively, these results indicate that GPR21 mediates the negative effects on glucose uptake by the liver cells. In addition, they suggest that the pharmacological inhibition of GPR21 could be a novel strategy to improve glucose homeostasis and counteract hepatic insulin resistance.

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