Phillyrin ameliorates diabetic nephropathy through the PI3K/Akt/GSK-3β signalling pathway in streptozotocin-induced diabetic mice

2021 ◽  
pp. 096032712110515
Author(s):  
Tianyang Wang ◽  
Xuejiao Wen ◽  
Ziwen Zhang ◽  
Minjuan Xie ◽  
Jie Zhou
Keyword(s):  
Diabetic Nephropathy ◽  
Glycogen Synthase ◽  
Fasting Blood Glucose ◽  
Underlying Mechanism ◽  
Signalling Pathway ◽  
Chinese Herbs ◽  
Diabetic Patients ◽  
Haemoglobin A1c ◽  
Serum Blood Urea Nitrogen ◽  
Gsk 3Β

Diabetic nephropathy is a progressive kidney disease resulting from long-term hyperglycaemia in diabetic patients, and the underlying mechanism is complex and lacks effective treatments. Various active ingredients in Chinese herbs have been shown to alleviate renal injury and improve DN in recent years. Phillyrin, a natural medicinal active compound extracted from the Oleaceae family, has various pharmacological effects, including antioxidative, antiapoptotic and antiobesity effects. However, the role of phillyrin and its underlying mechanism in DN have not yet been explored. To investigate the effects of phillyrin on DN and its potential mechanisms of action, we performed experiments using streptozotocin (STZ)-induced DN mice as models. Phillyrin significantly reduced the levels of fasting blood glucose (FBG) and glycosylated haemoglobin A1c (HbA1c), downregulated the levels of serum blood urea nitrogen (BUN), serum creatinine (Scr), serum and urine β2-microglobulins (β2-MG) and improved the pathological changes of the kidney in a DN mouse model. Phillyrin also increased the level of antioxidants and attenuated oxidative damage in DN model mice. In addition, phillyrin inhibited Glycogen synthase kinase-3β (GSK-3β) activity by activating the PI3K/Akt signalling pathway, increased the Bcl-2/Bax ratio, reduced the release of cytochrome c from the mitochondria to the cytoplasm, subsequently inhibited the activation of caspase-3 and ultimately suppressed renal cell apoptosis. These findings suggested that phillyrin could be a new promising therapeutic strategy for DN, and this protective effect might be related to suppressing oxidative stress and apoptosis via the PI3K/Akt/GSK-3β pathway.

scholarly journals Protective Effects of Grape Seed Proanthocyanidins on the Kidneys of Diabetic Rats through the Nrf2 Signalling Pathway

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yusong Ding ◽  
Haiyan Li ◽  
Yang Li ◽  
Dandan Liu ◽  
Liyuan Zhang ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Fasting Blood Glucose ◽  
Underlying Mechanism ◽  
Antioxidant Response ◽  
Grape Seed ◽  
Signalling Pathway ◽  
Related Factor ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Quinone Oxidoreductase

Background. Diabetic nephropathy (DN) is the most common cause of end-stage renal failure. Grape seed proanthocyanidin extract (GSPE) is a powerful antioxidant that is believed to protect the kidney through antioxidant action. However, the underlying mechanism of GSPE protection against DN remains unclear. Objective. To explore if GSPE can improve DN by activating nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant response element signalling and to clarify its possible mechanism. Materials and methods. Ten healthy Sprague-Dawley rats were randomly selected as controls. Rats with streptozotocin-induced diabetes were randomly divided into three groups (10 animals/group): type 2 diabetes mellitus (T2DM) group (untreated), L-GSPE group (treated with 125-mg/kg/day GSPE for 8 weeks), and H-GSPE group (treated with 250 mg/kg/day GSPE for 8 weeks). Results. Renal histopathological results indicated limited pathological damage in GSPE-treated groups. Compared with the T2DM group, the H-GSPE group had significantly reduced kidney weight and renal index. Similarly, the levels of fasting blood glucose, serum creatinine, blood urea nitrogen, uric acid, urinary albumin, and renal malondialdehyde ( p < 0.05 ) were also significantly decreased. In addition, GSPE significantly increased the levels of superoxide dismutase, total antioxidative capability, and glutathione ( p < 0.05 ) as well as the protein levels of Nrf2, HO-1, glutathione S-transferase, and NAD (P)H quinone oxidoreductase 1 ( p < 0.05 ). Conclusion. The results indicate that GSPE reduced renal damage in rats with diabetes by activating the Nrf2 signalling pathway, which consequently increased the antioxidant capacity of the tissue. Therefore, GSPE is a potential natural agent for the treatment of diabetic nephropathy.

scholarly journals Glycemic Status, Lipid Profile and Proteinuria in Diabetic nephropathy

2010 ◽  
Vol 49 (178) ◽  
Author(s):  
P Jha ◽  
BKL Das ◽  
S Shrestha ◽  
S Majhi ◽  
L Chandra ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Nephropathy ◽  
Lipid Profile ◽  
Glycated Hemoglobin ◽  
Fasting Blood Glucose ◽  
Diabetic Patients ◽  
Age Group ◽  
Arterial Blood ◽  
Cardiovascular Morbidity And Mortality ◽  
Glycated Hemoglobin Level

INTRODUCTION: Diabetic nephropathy is one of the major complications of Diabetes Mellitus characterized by persistent albuminuria, elevated arterial blood pressure, a relentless decline in glomerular filtration rate (GFR) and a high risk of cardiovascular morbidity and mortality. METHODS: In this study, urinary micro-albumin estimation was done in 177 diabetic patients. This study aims to ascertain association of glycemicstatus, lipid profile and proteinuria in Type 2 Diabetes Mellitus with nephropathy. RESULTS: Among 177 patients, 26 had frank proteinuria, 79 had micro-albuminuria and 72 were without proteinuria. Increased frequency ofproteinuria was seen in male than female. Micro-albuminuria and frank proteinuria was seen more in older age group. The multiple comparisons showed the significantly increased levels of urea, creatinine, fasting blood glucose in micro-albuminuria and overt proteinuria patients in comparison to without proteinuria. Glycated hemoglobin level was increased with the increasing age group particularly in overt proteinuric patients. CONCLUSIONS: The glycemic control, monitoring of lipid profile and early urinary protein estimation with better management may delay diabetic nephropathy or its further complications in diabetes mellitus.  KEYWORDS: diabetes mellitus, diabetic nephropathy, frank proteinuria, glycated hemoglobin, micro-albuminuria.

scholarly journals Insulin Has Multiple Antiamyloidogenic Effects on Human Neuronal Cells

Endocrinology ◽  
2013 ◽  
Vol 154 (1) ◽  
pp. 375-387 ◽  
Author(s):  
Giuseppe Pandini ◽  
Vincenza Pace ◽  
Agata Copani ◽  
Sebastiano Squatrito ◽  
Danilo Milardi ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Neuronal Cells ◽  
Neuronal Cell ◽  
Diabetic Patients ◽  
Cell Fractionation ◽  
Intracellular Accumulation ◽  
Insulin Degrading Enzyme ◽  
App Processing ◽  
Gsk 3Β ◽  
Human Neuronal Cells

Alzheimer’s disease is increased in diabetic patients. A defective insulin activity on the brain has been hypothesized to contribute to the neuronal cell dysregulation leading to AD, but the mechanism is not clear. We analyzed the effect of insulin on several molecular steps of amyloid precursor protein (APP) processing and β-amyloid (Aβ) intracellular accumulation in a panel of human neuronal cells and in human embryonic kidney 293 cells overexpressing APP-695. The data indicate that insulin, via its own receptor and the phosphatidylinositol-3-kinase/AKT pathway, influences APP phosphorylation at different sites. This rapid-onset, dose-dependent effect lasts many hours and mainly concerns dephosphorylation at the APP-T668 site. This effect of insulin was confirmed also in a human cortical neuronal cell line and in rat primary neurons. Cell fractionation and immunofluorescence studies indicated that insulin-induced APP-T668 dephosphorylation prevents the translocation of the APP intracellular domain fragment into the nucleus. As a consequence, insulin increases the transcription of antiamyloidogenic proteins such as the insulin-degrading enzyme, involved in Aβ degradation, and α-secretase. In contrast, the transcripts of pro-amyloidogenic proteins such as APP, β-secretase, and glycogen synthase kinase (Gsk)-3β are decreased. Moreover, cell exposure to insulin favors the nonamyloidogenic, α-secretase-dependent APP-processing pathway and reduces Aβ40 and Aβ42 intracellular accumulation, promoting their release in the extracellular compartment. The latter effects of insulin are independent of both Gsk-3β phosphorylation and APP-T668 dephosphorylation, as indicated by experiments with Gsk-3β inhibitors and with cells transfected with the nonphosphorylatable mutated APP-T668A analog. In human neuronal cells, therefore, insulin may prevent Aβ formation and accumulation by multiple mechanisms, both Gsk-3β dependent and independent.

Virtual Screening in Chinese Herbs with Multi-Target Effect on Alzheimer's Disease

2013 ◽  
Vol 765-767 ◽  
pp. 256-260
Author(s):  
Yan Ling Zhang ◽  
Yuan Ming Wang ◽  
Yan Jiang Qiao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Virtual Screening ◽  
Glycogen Synthase ◽  
Chinese Herbs ◽  
Multiple Targets ◽  
Active Compounds ◽  
Ache Inhibitors ◽  
Gsk 3Β ◽  
Pharmacophore Models

Multiple targets which closely related to Alzheimer's disease (AD) pathogenesis were selected for pharmacophore models generation and virtual screening in Chinese herbs. The targets comprised Acetylcholinesterase (AchE), muscarinic receptor 1 (M1), γ-secretase and glycogen synthase kinase 3β (GSK-3β). The pharmacophore models, which of AchE inhibitors, M1 agonists, γ-secretase inhibitors and GSK-3β inhibitors, were constructed by distance comparison method. Four testing databases for the evaluation of pharmacophore models were constructed with the active compounds with clearly marked activity on each target. The metric CAI (Comprehensive Appraisal Index) was then used to evaluate and obtain the best pharmacophore models of each target, which were then applied to screen the Traditional Chinese Medicine Database for potential active compounds in Chinese herbs. Four common used herbs were obtained, which contain the active compounds and can act on multiple targets, and were expected to have multiple activity of anti-AD disease.

scholarly journals Altered Wnt signalling in the teenage suicide brain: focus on glycogen synthase kinase-3β and β-catenin

2013 ◽  
Vol 16 (5) ◽  
pp. 945-955 ◽  
Author(s):  
Xinguo Ren ◽  
Hooriyah S. Rizavi ◽  
Mansoor A. Khan ◽  
Yogesh Dwivedi ◽  
Ghanshyam N. Pandey
Keyword(s):  
Protein Expression ◽  
Glycogen Synthase ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Glycogen Synthase Kinase ◽  
Mrna Levels ◽  
Protein Levels ◽  
Wnt Signalling Pathway ◽  
Gsk 3Β ◽  
Teenage Suicide

Abstract Glycogen synthase kinase (GSK)-3β and β-catenin are important components of the Wnt signalling pathway, which is involved in numerous physiological functions such as cognition, brain development and cell survival. Their abnormalities have been implicated in mood disorders and schizophrenia. Teenage suicide is a major public health concern; however, very little is known about its neurobiology. In order to examine if abnormalities of GSK-3β and β-catenin are associated with teenage suicide, we determined the gene and protein expression of GSK-3β and β-catenin in the prefrontal cortex (PFC) and hippocampus obtained from 24 teenage suicide victims and 24 normal control subjects. Protein expression was determined using Western blot with specific antibodies and gene expression (mRNA levels) was determined using the real-time polymerase chain reaction method. No significant change was observed in the GSK-3β protein levels either in the PFC or hippocampus of suicide victims compared to controls. However, protein levels of pGSK-3β-ser9 were significantly decreased in the PFC and hippocampus of suicide victims compared to normal controls. We also found that GSK-3β mRNA levels were significantly decreased in the PFC but not in the hippocampus of teenage suicide victims compared to controls. Mean protein and mRNA levels of β-catenin were significantly decreased in both the PFC and hippocampus of teenage suicide group compared to controls. The observation that there is a decrease in β-catenin and pGSK-3β-ser9 in the PFC and hippocampus of teenage suicide victims does indicate a disturbance in the Wnt signalling pathway in teenage suicide.

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 Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

2020 ◽  
Vol 21 (4) ◽  
pp. 1289
Author(s):  
Amit Koren-Iton ◽  
Shiran Salomon-Zimri ◽  
Alex Smolar ◽  
Efrat Shavit-Stein ◽  
Amir Dori ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Control Diet ◽  
Fasting Blood Glucose ◽  
Apoe Genotype ◽  
Dependent Manner ◽  
Fiber Density ◽  
Akt Activation ◽  
Glucose Levels ◽  
Insulin Tolerance ◽  
Gsk 3Β

Apolipoprotein E (APOE) ε4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer’s disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we employed a model of APOE-targeted replacement mice and high-fat diet (HFD)-induced insulin resistance to investigate diabetic mechanisms associated with apoE4 pathology and the extent to which they are driven by peripheral and central processes. Results obtained revealed an intriguing pattern, in which under basal conditions, apoE4 mice display impaired glucose and insulin tolerance and decreased insulin secretion, as well as cognitive and sensorimotor characteristics relative to apoE3 mice, while the HFD impairs apoE3 mice without significantly affecting apoE4 mice. Measurements of weight and fasting blood glucose levels increased in a time-dependent manner following the HFD, though no effect of genotype was observed. Interestingly, sciatic electrophysiological and skin intra-epidermal nerve fiber density (IENFD) peripheral measurements were not affected by the APOE genotype or HFD, suggesting that the observed sensorimotor and cognitive phenotypes are related to central nervous system processes. Indeed, measurements of hippocampal insulin receptor and glycogen synthase kinase-3β (GSK-3β) activation revealed a pattern similar to that obtained in the behavioral measurements while Akt activation presented a dominant effect of diet. HFD manipulation induced genotype-independent hyperlipidation of apoE, and reduced levels of brain apoE in apoE3 mice, rendering them similar to apoE4 mice, whose brain apoE levels were not affected by the diet. No such effect was observed in the peripheral plasma levels of apoE, suggesting that the pathological effects of apoE4 under the control diet and apoE3 under HFD conditions are related to the decreased levels of brain apoE. Taken together, our data suggests that diabetic mechanisms play an important role in mediating the pathological effects of apoE4 and that consequently, diabetic-related therapy may be useful in treating apoE4 pathology in AD.

Retrograde signalling at the synapse: a role for Wnt proteins

2005 ◽  
Vol 33 (6) ◽  
pp. 1295-1298 ◽  
Author(s):  
P.C. Salinas
Keyword(s):  
Synapse Formation ◽  
Glycogen Synthase ◽  
Signalling Pathway ◽  
Axon Extension ◽  
Wnt Proteins ◽  
Retrograde Signalling ◽  
Synaptic Differentiation ◽  
The Central Nervous System ◽  
Gsk 3Β

The formation of functional synapses requires a proper dialogue between incoming axons and their future synaptic targets. As axons approach their target, they are instructed to slow down and remodel to form proper presynaptic terminals. Although significant progress has been made in the identification of the mechanisms that control axon guidance, little is known about the mechanisms that regulate the conversion of actively growing axon into a presynaptic terminal. We found that Wnt secreted proteins are retrograde signals that regulate the terminal arborization of axons and synaptic differentiation. Wnts released from postsynaptic neurons induce extensive remodelling on incoming axons. This remodelling is manifested by a decrease in axon extension with a concomitant increase in growth-cone size. This morphological change is correlated with changes in the dynamics and organization of microtubules. Studies of a vertebrate synapse and the Drosophila neuromuscular junction suggest that a conserved Wnt signalling pathway modulates presynaptic microtubules as axons remodel during synapse formation. In this paper I discuss the role of the Wnt–Dvl (Dishevelled protein)–GSK-3β (glycogen synthase kinase-3β) signalling pathway in axon remodelling during synapse formation in the central nervous system.

scholarly journals The Anticancer Properties of Cordycepin and Their Underlying Mechanisms

2018 ◽  
Vol 19 (10) ◽  
pp. 3027 ◽  
Author(s):  
So Yoon ◽  
Soo Park ◽  
Yoon Park
Keyword(s):  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Growth Factor Receptor ◽  
Underlying Mechanism ◽  
Herbal Remedies ◽  
Anticancer Properties ◽  
Mitogen Activated Protein ◽  
Bioactive Ingredients ◽  
Underlying Mechanisms ◽  
Gsk 3Β

Cordyceps is a genus of ascomycete fungi that has been used for traditional herbal remedies. It contains various bioactive ingredients including cordycepin. Cordycepin, also known as 3-deoxyadenosine, is a major compound and has been suggested to have anticancer potential. The treatment of various cancer cells with cordycepin in effectively induces cell death and retards their cancerous properties. However, the underlying mechanism is not fully understood. Recent evidence has shed light on the molecular pathways involving cysteine-aspartic proteases (caspases), mitogen-activated protein kinases (MAPKs), and glycogen synthase kinase 3 beta (GSK-3β). Furthermore, the pathways are mediated by putative receptors, such as adenosine receptors (ADORAs), death receptors (DRs), and the epidermal growth factor receptor (EGFR). This review provides the molecular mechanisms by which cordycepin functions as a singular or combinational anticancer therapeutic agent.

scholarly journals Inhibition of TRIM32 Attenuates the Apoptosis, Oxidative Stress and Inflammatory Injury of Podocytes Induced by High Glucose by Affecting the Akt/GSK-3β/Nrf2 Pathway

2021 ◽  
Author(s):  
Zhao Chen ◽  
Lifang Tian ◽  
Li Wang ◽  
Xiaotao Ma ◽  
Fuqian Lei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
Inflammatory Response ◽  
High Glucose ◽  
Glycogen Synthase ◽  
Related Factor ◽  
Protective Effects ◽  
Gsk 3Β ◽  
Induced Apoptosis

Abstract Hyperglycemia-induced oxidative stress of podocytes exerts a major role in the pathological process of diabetic nephropathy. Tripartite motif-containing protein 32 (TRIM32) has been reported as a key protein in the modulation of cellular apoptosis and oxidative stress under various pathological processes. However, whether TRIM32 participates in the regulation of high glucose (HG)-induced injury in podocytes has not been investigated. The aims of this work were to assess the possible role of TRIM32 in mediating HG-induced apoptosis, oxidative stress and inflammatory response in podocytes in vitro. Herein, our results showed a marked increase in TRIM32 expression in HG-exposed podocytes. Loss-of-function experiments showed that the knockdown of TRIM32 improved the viability of HG-stimulated podocytes, and suppressed HG-induced apoptosis, oxidative stress and inflammatory response in podocytes. Further investigation revealed that the inhibition of TRIM32 enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling associated with modulation of the Akt/glycogen synthase kinase-3β (GSK-3β) axis in podocytes following HG exposure. However, the suppression of Akt abrogated the TRIM32-knockdown-mediated activation of Nrf2 in HG-exposed podocytes. In addition, the knockdown of Nrf2 markedly abolished the TRIM32-inhibition-induced protective effects in HG-exposed podocytes. In summary, the results of this work show that the inhibition of TRIM32 protects podocytes from HG-induced injury by potentiating Nrf2 signaling via the modulation of Akt/GSK-3β signaling. This study indicates a potential role of TRIM32 in mediating podocyte injury during the progression of diabetic nephropathy.

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