Troglitazone ameliorates high glucose-induced EMT and dysfunction of SGLTs through PI3K/Akt, GSK-3β, Snail1, and β-catenin in renal proximal tubule cells

2010 ◽  
Vol 298 (5) ◽  
pp. F1263-F1275 ◽  
Author(s):  
Yu Jin Lee ◽  
Ho Jae Han
Keyword(s):  
Protein Expression ◽  
Glucose Uptake ◽  
Membrane Transport ◽  
High Glucose ◽  
Transforming Growth Factor ◽  
Glycogen Synthase ◽  
Mesenchymal Transition ◽  
Pparγ Agonist ◽  
Gsk 3Β ◽  
Tgf Β1

Peroxisome proliferator-activated receptor-γ (PPARγ) agonists ameliorate renal fibrotic lesions in diabetic nephropathy. However, the effects of the agonists on the epithelial-mesenchymal transition (EMT) linked to membrane transport dysfunction are unknown. The present study aimed to verify the effects of the PPARγ agonist troglitazone on high glucose (HG)-induced EMT in primary cultured renal proximal tubular epithelial cells (PTCs). HG (25 mM) as well as hydrogen peroxide (H2O2) and transforming growth factor-β1 (TGF-β1) decreased expression of epithelial cell marker E-cadherin and increased the expression of the mesenchymal markers vimentin and α-smooth muscle actin (α-SMA). HG, H2O2, and TGF-β1 decreased Na+/H+ exchangers (NHEs) or Na+-glucose cotransporters (SGLTs) and glucose uptake, showing membrane transport dysfunction. HG stimulated the production of cellular reactive oxygen species (ROS), and antioxidants blocked the HG-induced increase in phosphatidylinositol 3-kinase (PI3K)/Akt activation. Antioxidants and inhibitors of PI3K/Akt reversed HG-induced EMT protein expression. Inhibition of PI3K/Akt also blocked HG-induced glycogen synthase kinase-3β (GSK-3β) phosphorylation. HG and lithium chloride (GSK-3β inhibitor) blocked Snail1 and β-catenin activation. Moreover, transfection with Snail1 or β-catenin small interfering RNA (siRNA) reversed HG-induced EMT protein expression. Importantly, HG decreased PPARγ activation and troglitazone reversed HG-induced expression of PI3K/Akt, GSK-3β, Snail1, and β-catenin as well as EMT proteins. Finally, inhibitors of PI3K/Akt, Snail1/β-catenin siRNA, and troglitazone blocking the HG-induced EMT restored glucose uptake in PTCs. In conclusion, HG induces EMT through ROS, PI3K/Akt, GSK-3β, Snail, and β-catenin. Subsequently, HG-induced EMT may result in SGLT dysfunction that is restored by the PPARγ agonist troglitazone in primary cultured PTCs.

scholarly journals Different Regulation of Glut1 Expression and Glucose Uptake during the Induction and Chronic Stages of TGFβ1-Induced EMT in Breast Cancer Cells

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1621
Author(s):  
Azadeh Nilchian ◽  
Nikolina Giotopoulou ◽  
Wenwen Sun ◽  
Jonas Fuxe
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Glucose Uptake ◽  
Cancer Cells ◽  
Transforming Growth Factor Beta ◽  
Breast Cancer Cells ◽  
Transforming Growth Factor ◽  
Mesenchymal Transition ◽  
Glut1 Expression ◽  
Tgf Β1

Transforming growth factor beta 1 (TGF-β1) is associated with epithelial-mesenchymal transition (EMT), lymph metastasis, and poor prognosis in breast cancer. Paradoxically, TGF-β1 is also a potent inhibitor of cell proliferation. TGF-β1-induced EMT involves activation of several pathways including AKT, which also regulates glucose uptake. Recent data show that prolonged TGF-β1 exposure leads to a more stable EMT phenotype in breast cancer cells. However, whether this is linked to changes in glucose metabolism is not clear. Here, we used a model of TGF-β1-induced EMT in mammary epithelial cells to study the regulation of Glut1 and EMT markers during the induction compared to a prolonged phase of EMT by western blot, immunofluorescence and qPCR analysis. We also measured cell proliferation and uptake of the glucose analogue 2-NDBG. We found that EMT induction was associated with decreased Glut1 expression and glucose uptake. These effects were linked to reduced cell proliferation rather than EMT. Knockdown of Glut1 resulted in growth inhibition and less induction of vimentin during TGF-β1-induced EMT. Intriguingly, Glut1 levels, glucose uptake and cell proliferation were restored during prolonged EMT. The results link Glut1 repression to the anti-proliferative response of TGF-β1 and indicate that re-expression of Glut1 during chronic TGF-β1 exposure allows breast cancer cells to develop stable EMT and proliferate, in parallel.

scholarly journals Nrf2-Heme Oxygenase-1 Attenuates High-Glucose-Induced Epithelial-to-Mesenchymal Transition of Renal Tubule Cells by Inhibiting ROS-Mediated PI3K/Akt/GSK-3β Signaling

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Jong Ho Shin ◽  
Kyeong Min Kim ◽  
Jin Uk Jeong ◽  
Jae Min Shin ◽  
Ju Hyung Kang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
High Glucose ◽  
Epithelial To Mesenchymal Transition ◽  
Glycogen Synthase ◽  
Heme Oxygenase 1 ◽  
Mesenchymal Transition ◽  
Gsk 3Β ◽  
Nrf2 Activator ◽  
Hk2 Cells ◽  
E Cadherin

Background. Epithelial-to-mesenchymal transition (EMT) is thought to play a significant role in the advancement to chronic kidney disease and contributes to the deposition of extracellular matrix proteins and renal fibrosis relating to diabetic nephropathy. Method. We studied the effect of Nrf2-HO-1 signaling on high-glucose- (HG-) induced EMT in normal human tubular epithelial cells, that is, HK2 cells. In short, we treated HK2 cells with HG and sulforaphane (SFN) as an Nrf2 activator. EMT was evaluated by the expression activity of the epithelial marker E-cadherin and mesenchymal markers such as vimentin and fibronectin. Results. Exposure of HK2 cells to HG (60 mM) activated the expression of vimentin and fibronectin but decreased E-cadherin. Treatment of HK2 cells with SFN caused HG-induced attenuation in EMT markers with activated Nrf2-HO-1. We found that SFN decreased HG-induced production of reactive oxygen species (ROS), phosphorylation of PI3K/Akt at serine 473, and inhibitory phosphorylation of serine/threonine kinase glycogen synthase kinase-3β (GSK-3β) at serine 9. Subsequently, these signaling led to the downregulation of the Snail-1 transcriptional factor and the recovery of E-cadherin. Conclusion. The present study suggests that Nrf2-HO-1 signaling has an inhibitory role in the regulation of EMT through the modulation of ROS-mediated PI3K/Akt/GSK-3β activity, highlighting Nrf2-HO-1 and GSK-3β as potential therapeutic targets in diabetic nephropathy.

scholarly journals Transforming growth factor-β2 promotes Snail-mediated endothelial–mesenchymal transition through convergence of Smad-dependent and Smad-independent signalling

2011 ◽  
Vol 437 (3) ◽  
pp. 515-520 ◽  
Author(s):  
Damian Medici ◽  
Scott Potenta ◽  
Raghu Kalluri
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Cardiac Development ◽  
Glycogen Synthase ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Mesenchymal Transition ◽  
Transforming Growth Factor Β2 ◽  
Gsk 3Β ◽  
Endothelial Mesenchymal Transition

EndMT (endothelial–mesenchymal transition) is a critical process of cardiac development and disease progression. However, little is know about the signalling mechanisms that cause endothelial cells to transform into mesenchymal cells. In the present paper we show that TGF-β2 (transforming growth factor-β2) stimulates EndMT through the Smad, MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase], PI3K (phosphinositide 3-kinase) and p38 MAPK signalling pathways. Inhibitors of these pathways prevent TGF-β2-induced EndMT. Furthermore, we show that all of these pathways are essential for increasing expression of the cell-adhesion-suppressing transcription factor Snail. Inhibition of Snail with siRNA (small interfering RNA) prevents TGF-β2-induced EndMT. However, overexpression of Snail is not sufficient to cause EndMT. Chemical inhibition of GSK-3β (glycogen synthase kinase-3β) allows EndMT to be induced by Snail overexpression. Expression of a mutant Snail protein that is resistant to GSK-3β-dependent inactivation also promotes EndMT. These results provide the foundation for understanding the roles of specific signalling pathways in mediating EndMT.

scholarly journals A Switch in Akt Isoforms Is Required for Notch-Induced Snail1 Expression and Protection from Cell Death

2015 ◽  
Vol 36 (6) ◽  
pp. 923-940 ◽  
Author(s):  
Alex Frías ◽  
Guillem Lambies ◽  
Rosa Viñas-Castells ◽  
Catalina Martínez-Guillamon ◽  
Natàlia Dave ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Glycogen Synthase ◽  
Total Activity ◽  
Transforming Growth Factor Β1 ◽  
Protein Stabilization ◽  
Nuclear Retention ◽  
Mesenchymal Transition ◽  
Akt Isoforms ◽  
Gsk 3Β ◽  
Transcriptional Complex

Notch activation in aortic endothelial cells (ECs) takes place at embryonic stages during cardiac valve formation and induces endothelial-to-mesenchymal transition (EndMT). Using aortic ECs, we show here that active Notch expression promotes EndMT, resulting in downregulation of vascular endothelial cadherin (VE-cadherin) and upregulation of mesenchymal genes such as those for fibronectin and Snail1/2. In these cells, transforming growth factor β1 exacerbates Notch effects by increasing Snail1 and fibronectin activation. When Notch-downstream pathways were analyzed, we detected an increase in glycogen synthase kinase 3β (GSK-3β) phosphorylation and inactivation that facilitates Snail1 nuclear retention and protein stabilization. However, the total activity of Akt was downregulated. The discrepancy between Akt activity and GSK-3β phosphorylation is explained by a Notch-induced switch in the Akt isoforms, whereby Akt1, the predominant isoform expressed in ECs, is decreased and Akt2 transcription is upregulated. Mechanistically, Akt2 induction requires the stimulation of the β-catenin/TCF4 transcriptional complex, which activates theAkt2promoter. Active, phosphorylated Akt2 translocates to the nucleus in Notch-expressing cells, resulting in GSK-3β inactivation in this compartment. Akt2, but not Akt1, colocalizes in the nucleus with lamin B in the nuclear envelope. In addition to promoting GSK-3β inactivation, Notch downregulates Forkhead box O1 (FoxO1), another Akt2 nuclear substrate. Moreover, Notch protects ECs from oxidative stress-induced apoptosis through an Akt2- and Snail1-dependent mechanism.

scholarly journals Protein kinase B/Akt activity is involved in renal TGF-β1-driven epithelial-mesenchymal transition in vitro and in vivo

2008 ◽  
Vol 295 (1) ◽  
pp. F215-F225 ◽  
Author(s):  
Jayesh J. Kattla ◽  
Rosemarie M. Carew ◽  
Mediha Heljić ◽  
Catherine Godson ◽  
Derek P. Brazil
Keyword(s):  
Diabetic Nephropathy ◽  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Protein Kinase B ◽  
Critical Role ◽  
Mesenchymal Transition ◽  
Akt Activation ◽  
Smad3 Phosphorylation ◽  
Gsk 3Β ◽  
Tgf Β1

The molecular pathogenesis of diabetic nephropathy (DN), the leading cause of end-stage renal disease worldwide, is complex and not fully understood. Transforming growth factor-β (TGF-β1) plays a critical role in many fibrotic disorders, including DN. In this study, we report protein kinase B (PKB/Akt) activation as a downstream event contributing to the pathophysiology of DN. We investigated the potential of PKB/Akt to mediate the profibrotic bioactions of TGF-β1 in kidney. Treatment of normal rat kidney epithelial cells (NRK52E) with TGF-β1 resulted in activation of phosphatidylinositol 3-kinase (PI3K) and PKB/Akt as evidenced by increased Ser473 phosphorylation and GSK-3β phosphorylation. TGF-β1 also stimulated increased Smad3 phosphorylation in these cells, a response that was insensitive to inhibition of PI3K or PKB/Akt. NRK52E cells displayed a loss of zona occludins 1 and E-cadherin and a gain in vimentin and α-smooth muscle actin expression, consistent with the fibrotic actions of TGF-β1. These effects were blocked with inhibitors of PI3K and PKB/Akt. Furthermore, overexpression of PTEN, the lipid phosphatase regulator of PKB/Akt activation, inhibited TGF-β1-induced PKB/Akt activation. Interestingly, in the Goto-Kakizaki rat model of type 2 diabetes, we also detected increased phosphorylation of PKB/Akt and its downstream target, GSK-3β, in the tubules, relative to that in control Wistar rats. Elevated Smad3 phosphorylation was also detected in kidney extracts from Goto-Kakizaki rats with chronic diabetes. Together, these data suggest that TGF-β1-mediated PKB/Akt activation may be important in renal fibrosis during diabetic nephropathy.

scholarly journals Pulmonary artery smooth muscle hypertrophy: roles of glycogen synthase kinase-3β and p70 ribosomal S6 kinase

2010 ◽  
Vol 298 (6) ◽  
pp. L793-L803 ◽  
Author(s):  
Huan Deng ◽  
Marc B. Hershenson ◽  
Jing Lei ◽  
Anuli C. Anyanwu ◽  
David J. Pinsky ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Protein Expression ◽  
Cell Size ◽  
Translational Control ◽  
Muscle Hypertrophy ◽  
Glycogen Synthase ◽  
Contractile Protein ◽  
Ribosomal S6 Kinase ◽  
Gsk 3Β ◽  
Tgf Β1

Increased medial arterial thickness is a structural change in pulmonary arterial hypertension (PAH). The role of smooth muscle hypertrophy in this process has not been well studied. Bone morphogenetic proteins (BMPs), transforming growth factor (TGF)-β1, serotonin (or 5-hydroxytryptamine; 5-HT), and endothelin (ET)-1 have been implicated in PAH pathogenesis. We examined the effect of these mediators on human pulmonary artery smooth muscle cell size, contractile protein expression, and contractile function, as well on the roles of glycogen synthase kinase (GSK)-3β and p70 ribosomal S6 kinase (p70S6K), two proteins involved in translational control, in this process. Unlike epidermal growth factor, BMP-4, TGF-β1, 5-HT, and ET-1 each increased smooth muscle cell size, contractile protein expression, fractional cell shortening, and GSK-3β phosphorylation. GSK-3β inhibition by lithium or SB-216763 increased cell size, protein synthesis, and contractile protein expression. Expression of a non-phosphorylatable GSK-3β mutant blocked BMP-4-, TGF-β1-, 5-HT-, and ET-1-induced cell size enlargement, suggesting that GSK-3β phosphorylation is required and sufficient for cellular hypertrophy. However, BMP-4, TGF-β1, 5-HT, and ET-1 stimulation was accompanied by an increase in serum response factor transcriptional activation but not eIF2 phosphorylation, suggesting that GSK-3β-mediated hypertrophy occurs via transcriptional, not translational, control. Finally, BMP-4, TGF-β1, 5-HT, and ET-1 treatment induced phosphorylation of p70S6K and ribosomal protein S6, and siRNAs against p70S6K and S6 blocked the hypertrophic response. We conclude that mediators implicated in the pathogenesis of PAH induce pulmonary arterial smooth muscle hypertrophy. Identification of the signaling pathways regulating vascular smooth muscle hypertrophy may define new therapeutic targets for PAH.

scholarly journals MCP-1/CCR2 system is involved in high glucose-induced fibronectin and type IV collagen expression in cultured mesangial cells

2008 ◽  
Vol 295 (3) ◽  
pp. F749-F757 ◽  
Author(s):  
Jehyun Park ◽  
Dong-Ryeol Ryu ◽  
Jin Ji Li ◽  
Dong-Sub Jung ◽  
Seung-Jae Kwak ◽  
...  
Keyword(s):  
Protein Expression ◽  
High Glucose ◽  
Type Iv Collagen ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Monocyte Chemoattractant Protein 1 ◽  
Type Iv ◽  
Ccr2 Expression ◽  
Tgf Β1

Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that plays an important role in the recruitment of macrophages. Although previous studies have demonstrated the importance of MCP-1 in the pathogenesis of diabetic nephropathy (DN) in terms of inflammation, the role of MCP-1 and its receptor (C-C chemokine receptor 2; CCR2) in extracellular matrix (ECM) accumulation under diabetic conditions has been largely unexplored. This study was undertaken to investigate the functional role of the MCP-1/CCR2 system in high glucose-induced ECM (fibronectin and type IV collagen) protein expression in cultured mesangial cells (MCs). Mouse MCs were exposed to medium containing 5.6 mM glucose (NG), NG+24.4 mM mannitol (NG+M), or 30 mM glucose (HG) with or without mutant MCP-1 (mMCP-1), CCR2 small interfering (si)RNA, or CCR2 inhibitor (RS102895). To examine the relationship between MCP-1 and transforming growth factor (TGF)-β1, MCs were also treated with TGF-β1 (2 ng/ml) with or without mMCP-1 or CCR2 siRNA. Transient transfection was performed with Lipofectamine 2000 for 24 h. Cell viability was determined by an MTT assay, mouse and human MCP-1 and TGF-β1 levels by ELISA, and CCR2 and ECM protein expression by Western blotting. Transfections of mMCP-1 and CCR2 siRNA increased human MCP-1 levels and inhibited CCR2 expression, respectively. HG-induced ECM protein expression and TGF-β1 levels were significantly attenuated by mMCP-1, CCR2 siRNA, and RS102895 ( P < 0.05). MCP-1 directly increased ECM protein expression, and this increase was inhibited by an anti-TGF-β1 antibody. In addition, TGF-β1-induced ECM protein expression was significantly abrogated by the inhibition of the MCP-1/CCR2 system ( P < 0.05). These results suggest that an interaction between the MCP-1/CCR2 system and TGF-β1 may contribute to ECM accumulation in DN.

scholarly journals How scars shape the neural landscape: key molecular mediators of TGF-β1’s anti-neuritogenic effects

2020 ◽  
Author(s):  
Kye-Im Jeon ◽  
Krystel R. Huxlin
Keyword(s):  
Neurite Outgrowth ◽  
Sensory Neurons ◽  
Transforming Growth Factor ◽  
Glycogen Synthase ◽  
Neuronal Morphology ◽  
Contrast Imaging ◽  
Neurite Extension ◽  
Gsk 3Β ◽  
Tgf Β1

AbstractFollowing injury to the peripheral and central nervous systems, tissue levels of transforming growth factor (TGF)-β1 often increase, which is key for wound healing and scarring. However, active wound regions and scars appear to inhibit process outgrowth by regenerating neurons. We recently showed that corneal wound myofibroblasts block corneal nerve regeneration in vivo, and sensory neurite outgrowth in vitro in a manner that relies critically on TGF-β1. In turn, delayed, abnormal re-innervation contributes to long-term sensory dysfunctions of the ocular surface. Here, we exposed morphologically and biochemically-differentiated sensory neurons from the ND7/23 cell line to TGF-β1 to identify the intracellular signals regulating these anti-neuritogenic effects, contrasting them with those of Semaphorin(Sema)3A, a known inhibitor of neurite outgrowth. Neuronal morphology was quantified using phase-contrast imaging. Western blotting and specific inhibitors were then used to identify key molecular mediators. Differentiated ND7/23 cells expressed neuron-specific markers, including those involved in neurite extension and polarization. TGF-β1 increased phosphorylation of collapsin response mediator protein-2 (CRMP2), a molecule that is key for neurite extension. We now show that both glycogen synthase kinase (GSK)-3β and Smad3 modulate phosphorylation of CRMP2 after treatment with TGF-β1. GSK-3β appeared to exert a particularly strong effect, which could be explained by its ability to phosphorylate not only CRMP2, but also Smad3. In conclusion, TGF-β1’s inhibition of neurite outgrowth in sensory neurons appears to be regulated through a highly-conserved signaling pathway, which involves the GSK-3β/CRMP-2 loop via both canonical and non-canonical mechanisms. It is hoped that by defining the signaling pathways that control neurite outgrowth in wound environments, it will become possible to identify optimal molecular targets to promote re-innervation following injury.

scholarly journals How scars shape the neural landscape: Key molecular mediators of TGF-β1’s anti-neuritogenic effects

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0234950
Author(s):  
Kye-Im Jeon ◽  
Krystel R. Huxlin
Keyword(s):  
Neurite Outgrowth ◽  
Sensory Neurons ◽  
Transforming Growth Factor ◽  
Glycogen Synthase ◽  
Neuronal Morphology ◽  
Contrast Imaging ◽  
Neurite Extension ◽  
Gsk 3Β ◽  
Tgf Β1

Following injury to the peripheral and central nervous systems, tissue levels of transforming growth factor (TGF)-β1 often increase, which is key for wound healing and scarring. However, active wound regions and scars appear to inhibit process outgrowth by regenerating neurons. We recently showed that corneal wound myofibroblasts block corneal nerve regeneration in vivo, and sensory neurite outgrowth in vitro in a manner that relies critically on TGF-β1. In turn, delayed, abnormal re-innervation contributes to long-term sensory dysfunctions of the ocular surface. Here, we exposed morphologically and biochemically-differentiated sensory neurons from the ND7/23 cell line to TGF-β1 to identify the intracellular signals regulating these anti-neuritogenic effects, contrasting them with those of Semaphorin(Sema)3A, a known inhibitor of neurite outgrowth. Neuronal morphology was quantified using phase-contrast imaging. Western blotting and specific inhibitors were then used to identify key molecular mediators. Differentiated ND7/23 cells expressed neuron-specific markers, including those involved in neurite extension and polarization. TGF-β1 increased phosphorylation of collapsin response mediator protein-2 (CRMP2), a molecule that is key for neurite extension. We now show that both glycogen synthase kinase (GSK)-3β and Smad3 modulate phosphorylation of CRMP2 after treatment with TGF-β1. GSK-3β appeared to exert a particularly strong effect, which could be explained by its ability to phosphorylate not only CRMP2, but also Smad3. In conclusion, TGF-β1’s inhibition of neurite outgrowth in sensory neurons appears to be regulated through a highly-conserved signaling pathway, which involves the GSK-3β/CRMP-2 loop via both canonical and non-canonical mechanisms. It is hoped that by defining the signaling pathways that control neurite outgrowth in wound environments, it will become possible to identify optimal molecular targets to promote re-innervation following injury.

scholarly journals Structural-Based Optimizations of the Marine-Originated Meridianin C as Glucose Uptake Agents by Inhibiting GSK-3β

Marine Drugs ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. 149
Author(s):  
Shuwen Han ◽  
Chunlin Zhuang ◽  
Wei Zhou ◽  
Fener Chen
Keyword(s):  
Glucose Uptake ◽  
Therapeutic Potential ◽  
Glycogen Synthase ◽  
Molecular Target ◽  
Optimization Strategy ◽  
Lead Compounds ◽  
Significant Toxicity ◽  
Treatment Of Diabetes ◽  
Gsk 3Β ◽  
Positive Compound

Glycogen synthase kinase 3β (GSK-3β) is a widely investigated molecular target for numerous diseases, and inhibition of GSK-3β activity has become an attractive approach for the treatment of diabetes. Meridianin C, an indole-based natural product isolated from marine Aplidium meridianum, has been reported as a potent GSK-3β inhibitor. In the present study, applying the structural-based optimization strategy, the pyrimidine group of meridianin C was modified by introducing different substituents based on the 2-aminopyrimidines-substituted pyrazolo pyridazine scaffold. Among them, compounds B29 and B30 showed a much higher glucose uptake than meridianin C (<5%) and the positive compound 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8, 16%), with no significant toxicity against HepG2 cells at the same time. Furthermore, they displayed good GSK-3β inhibitory activities (IC50 = 5.85; 24.4 μM). These results suggest that these meridianin C analogues represent novel lead compounds with therapeutic potential for diabetes.

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