scholarly journals Ginsenoside Rg1 Alleviates Podocyte EMT Passage by Regulating AKT/GSK3 β/β-Catenin Pathway by Restoring Autophagic Activity

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Yimin Shi ◽  
Yanbin Gao ◽  
Tao Wang ◽  
Xiaolei Wang ◽  
Jiaxin He ◽  
...  
Keyword(s):  
High Glucose ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Diabetic Rats ◽  
Ginsenoside Rg1 ◽  
Glomerular Diseases ◽  
Mesenchymal Transition ◽  
Glucose Levels ◽  
Autophagic Activity

Background. Diabetic nephropathy (DN), a complication of diabetes, is the result of high glucose-induced pathological changes in podocytes, such as epithelial-mesenchymal transition (EMT). Autophagy is an important mechanism of podocyte repair. Ginsenoside Rg1, the active ingredient of ginseng extract, has antifibrotic and proautophagic effects. Therefore, we hypothesized that ginsenoside Rg1 can reverse podocyte EMT via autophagy and alleviate DN. Aim. This study aimed to investigate the effect of ginsenoside Rg1 on DN rats and high glucose-induced podocyte EMT by regulating the AKT/GSK3β/β-catenin pathway by restoring autophagy activity. Methods. Diabetic rats induced by STZ injection were treated with 50 mg/kg ginsenoside Rg1 for 8 weeks, and the renal functional, metabolic, and histopathological indices were evaluated. DN was simulated in vitro by exposing podocytes to high glucose levels and treated with ginsenoside Rg1. The expression of EMT and autophagy-related markers was analyzed in vivo and in vitro by immunofluorescence, western blotting, and real-time PCR. Results. Ginsenoside Rg1 significantly alleviated renal fibrosis and podocyte EMT in diabetic rats, and podocytes exposed to high glucose levels, which was abolished by the autophagy inhibitor 3-MA. Furthermore, ginsenoside Rg1 regulated the AKT/GSK3 β/β-catenin pathway by restoring autophagic activity. Conclusion. Ginsenoside Rg1 alleviated podocyte EMT by enhancing AKT/GSK3β/β-catenin pathway-mediated autophagy, indicating its therapeutic potential for DN and other glomerular diseases.

scholarly journals Emodin Ameliorates High Glucose Induced-Podocyte Epithelial-Mesenchymal Transition In-Vitro and In-Vivo

2015 ◽  
Vol 35 (4) ◽  
pp. 1425-1436 ◽  
Author(s):  
Tingfang Chen ◽  
Li Yang Zheng ◽  
Wenzhen Xiao ◽  
Dingkun Gui ◽  
Xiaoxia Wang ◽  
...  
Keyword(s):  
High Glucose ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Option ◽  
Diabetic Rats ◽  
Protective Effects ◽  
Mesenchymal Transition ◽  
Epithelial Marker

Background: Epithelial-to-mesenchymal transition (EMT) is a potential pathway leading to podocyte depletion and proteinuria in diabetic kidney disease (DKD). Here, we investigated the protective effects of Emodin (EMO) on high glucose (HG) induced-podocyte EMT in-vitro and in-vivo. Methods: Conditionally immortalized mouse podocytes were exposed to HG with 30μg /ml of EMO and 1μmol/ml of integrin-linked kinase (ILK) inhibitor QLT0267 for 24 h. Streptozotocin (STZ)-induced diabetic rats were treated with EMO at 20 mg· kg-1· d-1 and QLT0267 at 10 mg· kg-1· w-1 p.o., for 12 weeks. Albuminuria and blood glucose level were measured. Immunohistochemistry, immunofluorescence, western blotting and real-time PCR were used to detect expression of ILK, the epithelial marker of nephrin and the mesenchymal marker of desmin in-vitro and in-vivo. Results: HG increased podocyte ILK and desmin expression while decreased nephrin expression. However, EMO significantly inhibited ILK and desmin expression and partially restored nephrin expression in HG-stimulated podocytes. These in-vitro observations were further confirmed in-vivo. Treatment with EMO for 12 weeks attenuated albuminuria, renal histopathology and podocyte foot process effacement in diabetic rats. EMO also repressed renal ILK and desmin expression, preserved nephrin expression, as well as ameliorated albuminuria in STZ-induced diabetic rats. Conclusion: EMO ameliorated glucose-induced EMT and subsequent podocyte dysfunction partly through ILK and desmin inhibition as well as nephrin upregulatiotion, which might provide a potential novel therapeutic option for DKD.

Mechanism of chronic aristolochic acid nephropathy: role of Smad3

2010 ◽  
Vol 298 (4) ◽  
pp. F1006-F1017 ◽  
Author(s):  
Li Zhou ◽  
Ping Fu ◽  
Xiao Ru Huang ◽  
Fei Liu ◽  
Arthur C. K. Chung ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Aristolochic Acid ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Chronic Administration ◽  
Mesenchymal Transition ◽  
Aristolochic Acid Nephropathy

Aristolochic acid nephropathy (AAN) has become a worldwide disease and is the most severe complication related to the use of traditional Chinese medicine. However, the pathogenic mechanisms of AAN remain unclear and therapies are limited. The present study tested the hypothesis that transforming growth factor (TGF)-β/Smad3 may be a key pathway leading to chronic AAN. This was examined in vivo in Smad3 wild-type/knockout (WT/KO) mice and in vitro in tubular epithelial cells with knockdown of Smad2 or Smad3. Results revealed that chronic administration of aristolochic acid (AA) resulted in a severe AAN characterized by progressive renal dysfunction and tubulointerstitial fibrosis including epithelial-mesenchymal transition (EMT) in Smad3 WT mice, but not in Smad3 KO mice, suggesting a critical role for Smad3 in the development of AAN. This was further tested in vitro. We found that AA was able to activate Smad signaling to mediate EMT and renal fibrosis via both TGF-β-dependent and JNK/MAP kinase-dependent mechanisms because blockade of JNK and specific knockdown of Smad3, but not Smad2, were able to attenuate AA-stimulated collagen matrix expression and EMT. In conclusion, TGF-β/Smad3 may be an essential mediator for chronic AAN. Results from this study indicate that specific blockade of the TGF-β/Smad3 signaling pathway may have therapeutic potential for chronic AAN.

scholarly journals Decrease of Klotho in the Kidney of Streptozotocin-Induced Diabetic Rats

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Meng-Fu Cheng ◽  
Li-Jen Chen ◽  
Juei-Tang Cheng
Keyword(s):  
Oxidative Stress ◽  
High Glucose ◽  
Diabetic Rats ◽  
Glucose Levels ◽  
Renal Functions ◽  
Blood Glucose Levels ◽  
Convoluted Tubules ◽  
The Brain ◽  
Darby Canine Kidney

Theklothogene is expressed in a limited number of tissues, most notably in distal convoluted tubules in the kidney and choroid plexus in the brain. A previous study suggested that Klotho increases resistance to oxidative stress. However, changes of Klotho expression in high glucose-induced oxidative stress remain unclear. In the present study, we used streptozotocin-induced diabetic rats (STZ rats) to examine the effects of insulin, phloridzin or antioxidant, tiron on diabetic nephropathy. Both insulin and phloridzin reversed the lower Klotho expression levels in kidneys of STZ rats by the correction of hyperglycemia. Also, renal functions were improved by these treatments. In addition to the improvement of renal functions, the decrease of Klotho expression in kidney of STZ rats was also reversed by tiron without changing blood glucose levels. The reduction of oxidative stress induced by high glucose can be considered for this action of tiron. This view was further confirmed in vitro using high glucose-exposed Madin-Darby canine kidney (MDCK) epithelial cells. Thus, we suggest that decrease of oxidative stress is not only responsible for the improvement of renal function but also for the recovery of Klotho expression in kidney of STZ rats.

scholarly journals Adiponectin Modified BMSCs Alleviate Heart Fibrosis via Inhibition TGF-beta1/Smad in Diabetic Rats

2021 ◽  
Vol 9 ◽  
Author(s):  
Ke Meng ◽  
Huabo Cai ◽  
Simin Cai ◽  
Yucai Hong ◽  
Xiaoming Zhang
Keyword(s):  
Myocardial Fibrosis ◽  
High Glucose ◽  
Cardiac Fibrosis ◽  
Therapeutic Potential ◽  
Heart Diseases ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
H9c2 Cells

Background: Accumulating evidence suggested that bone marrow mesenchymal stem cells (BMSCs) have therapeutic potential for diabetes and heart diseases. However, the effects of BMSC on reducing myocardial fibrosis need to be optimized. This study aimed to investigate the mechanism of adiponectin (APN) modified BMSCs on myocardial fibrosis in diabetic model in vivo and in vitro.Methods: The high-fat diet combined with streptozotocin (STZ) injection were used to induced diabetic rat model. H9c2 cells were cultured under a high glucose medium as in vitro model. The BMSCs were modified by APN plasmid or APN small interfering RNA (siRNA), then transplanted to the diabetic rats by a single tail-vein injection, or co-cultured with H9c2 cells.Results: We demonstrated that diabetic rats showed typical diabetic symptoms, such as decreased cardiac function, accumulation of pathological lesions and collagen expression. However, these impairments were significantly prevented by the APN modified BMSCs treatment while no effects on APN siRNA modified BMSCs treated diabetic rats. Moreover, we confirmed that APN modified BMSCs could attenuate the expression of TGF-beta1/smad to suppress the myocardial fibrosis in the diabetic rats and high glucose induced H9c2 cells.Conclusion: The present results for the first time showed that APN modified BMSCs exerted protection on cardiac fibrosis via inhibiting TGF-beta1/smad signal pathway in diabetic rats. Our findings suggested that APN modified BMSCs might be a novel and optimal therapy for the diabetic cardiomyopathy in future.

scholarly journals Bortezomib limits renal allograft interstitial fibrosis by inhibiting NF-κB/TNF-α/Akt/mTOR/P70S6K/Smurf2 pathway via IκBα protein stabilization

2021 ◽  
Vol 135 (1) ◽  
pp. 53-69
Author(s):  
Chuanjian Suo ◽  
Zeping Gui ◽  
Zijie Wang ◽  
Jiajun Zhou ◽  
Ming Zheng ◽  
...  
Keyword(s):  
Renal Allograft ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Interstitial Fibrosis ◽  
Protein Stabilization ◽  
Mesenchymal Transition ◽  
P70s6 Kinase ◽  
Tnf Α

Abstract Chronic allograft dysfunction is a major cause of late graft failure after kidney transplantation. One of the histological changes is interstitial fibrosis, which is associated with epithelial–mesenchymal transition. Bortezomib has been reported to prevent the progression of fibrosis in organs. We used rat renal transplantation model and human kidney 2 cell line treated with tumor necrosis factor-α (TNF-α) to examine their response to bortezomib. To explore the mechanism behind it, we assessed the previously studied TNF-α/protein kinase B (Akt)/Smad ubiquitin regulatory factor 2 (Smurf2) signaling and performed RNA sequencing. Our results suggested that bortezomib could attenuate the TNF-α-induced epithelial–mesenchymal transition and renal allograft interstitial fibrosis in vitro and in vivo. In addition to blocking Akt/mammalian target of rapamycin (mTOR)/p70S6 kinase/Smurf2 signaling, bortezomib’s effect on the epithelial–mesenchymal transition was associated with inhibition of nuclear factor kappa B (NF-κB) pathway by stabilizing inhibitor of NF-κB. The study highlighted the therapeutic potential of bortezomib on renal allograft interstitial fibrosis. Such an effect may result from inhibition of NF-κB/TNF-α/Akt/mTOR/p70S6 kinase/Smurf2 signaling via stabilizing protein of inhibitor of NF-κB.

scholarly journals Core structure of flavonoids precursor as an antihyperglycemic and antihyperlipidemic agent: an in vivo study in rats.

2010 ◽  
Vol 57 (4) ◽  
Author(s):  
Mahmoud Najafian ◽  
Azadeh Ebrahim-Habibi ◽  
Parichehreh Yaghmaei ◽  
Kazem Parivar ◽  
Bagher Larijani
Keyword(s):  
Beneficial Effect ◽  
Therapeutic Potential ◽  
Urine Volume ◽  
Diabetic Rats ◽  
Core Structure ◽  
Alpha Amylase ◽  
Glucose Levels ◽  
Blood Glucose Levels

trans-Chalcone is the core structure of naringenin chalcone, located halfway in the biosynthesis pathway of flavonoids. Flavonoids have been reported as mammalian alpha-amylase inhibitors, a property which could be useful in the management of postprandial hyperglycemia in diabetes and related disorders. As a mammalian alpha-amylase inhibitor in vitro, the putative beneficial effect of trans-chalcone on diabetes was tested in a streptozotocin-induced rat model of diabetes type 1, and the results analyzed with commonly used statistical methods. Significant reduction of blood glucose levels and beneficial effect on dyslipidemia were observed in diabetic rats, as well as reduction of disturbing consequences of diabetes such as high urine volume and water intake. trans-chalcone was observed to have a weight loss-inductive effect, alongside with a reduction in food intake, which is suggestive of a therapeutic potential of this compound in overweight and obese patients.

scholarly journals HOXC10 promotes growth and migration of melanoma by regulating Slug to activate the YAP/TAZ signaling pathway

2021 ◽  
Author(s):  
Yuanxin Miao ◽  
Weina Zhang ◽  
Su Liu ◽  
Xiangfeng Leng ◽  
Chunnan Hu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Melanoma Cells ◽  
Mesenchymal Transition ◽  
Normal Tissues ◽  
Slug Expression ◽  
Melanoma Patients ◽  
And Migration

Abstract Homeobox C10 (HOXC10) has been reported to participate in various cancers. However, the involvement of HOXC10 in melanoma is still remains unknown. Here, we attempted to determine whether HOXC10 can affect the development of melanoma. We separated melanoma tissues and the matched tumor-adjacent normal tissues from melanoma patients, and examined HOXC10 expression in the melanoma cells and tissues. Comparing with the tumor-adjacent normal tissues, HOXC10 was up-regulated in melanoma tissues. Melanoma cells also displayed an up-regulation of HOXC10. Moreover, HOXC10 overexpression promoted cell proliferation, clone formation and inhibited apoptosis of melanoma cells. HOXC10 up-regulation also enhanced migration, invasion and epithelial-mesenchymal transition (EMT) in melanoma cells. Additionally, HOXC10 accelerated Slug expression by interacting with Slug, and activating the promoter of Slug. Slug activated the YAP/TAZ signaling pathway, which was reversed by HOXC10 silencing. The in vitro assays demonstrated that inhibition of HOXC10 significantly repressed tumor growth and lung metastasis of melanoma in mice by inhibiting Slug and YAP/TAZ signaling pathway. In conclusion, this work demonstrated that HOXC10 promoted growth and migration of melanoma by regulating Slug to activate the YAP/TAZ signaling pathway. Therefore, this study suggests that inhibition of HOXC10 has therapeutic potential in melanoma.

scholarly journals Spironolactone improves nephropathy by enhancing glucose-6-phosphate dehydrogenase activity and reducing oxidative stress in diabetic hypertensive rat

2011 ◽  
Vol 13 (1) ◽  
pp. 56-66 ◽  
Author(s):  
Bruno S Pessôa ◽  
Elisa BMI Peixoto ◽  
Alexandros Papadimitriou ◽  
Jacqueline M Lopes de Faria ◽  
José B Lopes de Faria
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
High Glucose ◽  
Diabetic Rats ◽  
G6pd Activity ◽  
Spontaneously Hypertensive ◽  
Glucose Levels ◽  
Glucose 6 Phosphate Dehydrogenase

Spironolactone (SPR), a mineralocorticoid receptor blocker, diminishes hyperglycemia-induced reduction in glucose-6-phosphate dehydrogenase (G6PD) activity, improving oxidative stress damage. This study investigated whether SPR ameliorates nephropathy by increasing G6PD activity and reducing oxidative stress in spontaneously hypertensive diabetic rats (SHRs). The streptozotocin-induced diabetic rats received or not SPR 50 mg/kg per day, for eight weeks. A human mesangial cell line was cultured in normal or high glucose conditions, with or without SPR, for 24 h. Plasma glucose levels and systolic blood pressure were unaltered by diabetes or by SPR treatment. Albuminuria, fibronectin expression, 8-OHdG urinary levels, lipid peroxidation and p47phox expression were higher in the diabetic rats compared with the control and were reduced by SPR. The antioxidant GSH/GSSG ratio was reduced in the diabetic rats and the treatment reestablished it. Diabetes-induced SGK1 up-regulation was inhibited by SPR. Reactive oxygen species (ROS) and superoxide production induced by NADPH oxidase were increased by hyperglycemia and high glucose, in vivo and in vitro, respectively, and were reduced with SPR. Hyperglycemia and high glucose decreased G6PD activity, which was restored with SPR. These results suggest that SPR ameliorates nephropathy in diabetic SHRs by restoring G6PD activity and diminishes oxidative stress without affecting glycaemia and blood pressure.

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