stevioside and Fibrosis

Stevioside is a natural diterpenoid compound that possesses anti-inflammatory, immunomodulatory, anti-diabetic, anti-hypertensive, and renal protective effects, but its effect on lipopolysaccharide (LPS)-induced epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells, an important immune pathological mechanism of renal fibrosis, remains unknown. This study employed the renal proximal tubular cells NRK-52E to investigate the effect of stevioside.. The LPS-stimulated renal NRK-52E cells were treated with 50, 100, or 200 μM stevioside in the presence or absence of peroxisome proliferator-activated receptor γ (PPARγ) antagonist GW9662, the expression levels of intracellular E-cadherin, vimentin, α-smooth muscle actin (α-SMA), PPARγ, nuclear factor kappa B (NF-κB) p65, transforming growth factor-β1 (TGF-β1), signal transducer and activator of transcription 3 (STAT3), p-STAT3, Smad2/3, and p-Smad2/3 proteins were detected by Western blot analysis.. In LPS-stimulated NRK-52E cells, stevioside treatment could reverse the expressions of EMT-related E-cadherin, vimentin, and α-SMA proteins, increase the expression of PPARγ protein, and decrease the expressions of NF-κB p65, TGF-β1, p-STAT3, Smad2/3, and p-Smad2/3 proteins, especially in the 200 μM stevioside-treated group. However, these beneficial effects of stevioside were attenuated or canceled by pretreatment with PPARγ antagonist GW9662.

Topics: Cell Line; Diterpenes, Kaurane; Epithelial Cells; Epithelial-Mesenchymal Transition; Fibrosis; Glucosides; Humans; Lipopolysaccharides; PPAR gamma; Transforming Growth Factor beta1

This study aimed to examine the inhibitory effect of stevioside on unilateral ureteral obstruction (UUO)-induced kidney fibrosis. The UUO mice were daily given 50-100 mg/kg stevioside by gavage for 14 days after the operation. The results showed that stevioside decreased the levels of blood urea nitrogen and renal hydroxyproline, severity of kidney fibrosis, and expressions of renal collagen I/III and α-smooth muscle actin proteins. Importantly, stevioside increased the expressions of renal peroxisome proliferator-activated receptor γ (PPARγ) and Smad7 proteins and level of renal glutathione peroxidase, decreased the expressions of renal nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), p-STAT3, transforming growth factor-β1 (TGF-β1), Smad2/3, and p-Smad2/3 proteins, suggesting that the antifibrotic mechanisms are related to the activation of PPARγ and subsequent downregulations of NF-κB-mediated STAT3 and TGF-β1 expressions and inhibition of Smad-mediated signaling pathway. These findings provide an applied perspective of stevioside for kidney fibrosis. PRACTICAL APPLICATIONS: Stevioside is widely used in food products as a sweetener, and it has many beneficial biological effects, including antidiabetes, antihypertension, and renal protective action. Here, we provide a novel potential application of stevioside in the prevention and treatment of kidney fibrosis.

Topics: Animals; Diterpenes, Kaurane; Fibrosis; Glucosides; Kidney; Mice; PPAR gamma; Ureteral Obstruction

Liver cirrhosis is associated with increased morbidity and mortality with important health and social consequences; however, an effective treatment has not been found yet. Previous reports have shown some beneficial effects of stevioside (SVT) in different diseases, but the ability of SVT to inhibit liver cirrhosis has not been reported. Therefore, we studied the potential of this diterpenoid to inhibit liver cirrhosis induced by thioacetamide, a model that shares many similarities with the human disease, and investigated the possible underlying molecular mechanism using in vivo and in vitro approaches. Cirrhosis was induced in male Wistar rats by chronic thioacetamide administration (200 mg/kg) intraperitoneally three times per week. Rats received saline or SVT (20 mg/kg) two times daily intraperitoneally. In addition, co-cultures were incubated with either lipopolysaccharide or ethanol. Liver fibrosis, hepatic stellate cells activation, metalloproteinases activity, canonical and non-canonical Smads pathway and expression of several profibrogenic genes were evaluated. Thioacetamide activated hepatic stellate cells and distorted the liver parenchyma with the presence of abundant thick bands of collagen. In addition, thioacetamide up-regulated the protein expression of α-smooth muscle actin, transforming growth factor-β1, metalloproteinases-9,-2 and -13 and overstimulate the canonical and non-canonical Smad pathways. SVT administration inhibited all of these changes. In vitro, SVT inhibited the up-regulation of several genes implicated in cirrhosis when cells were exposed to lipopolysaccharides or ethanol. We conclude that SVT inhibited liver damage by blocking hepatic stellate cells activation, down-regulating canonical and non-canonical profibrotic Smad pathways.

Topics: Actins; Animals; Cell Line; Collagen Type I; Collagenases; Deoxycytosine Nucleotides; Diterpenes, Kaurane; Down-Regulation; Fibrosis; Glucosides; Hepatic Stellate Cells; Humans; Liver; Liver Cirrhosis; Lymphokines; Male; MAP Kinase Signaling System; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-myc; Rats; Rats, Wistar; Signal Transduction; Smad Proteins; Thioacetamide; Transforming Growth Factor beta1; Up-Regulation

Stevioside, a natural glycoside compound, has many beneficial biological activities, but its protective effect on myocardial fibrosis has not been reported yet. This study aimed to investigate the effect of stevioside. The isoproterenol-induced model mice were orally given stevioside 75-300 mg kg-1 for 40 days. The results showed that after the administration of stevioside, the myocardial hydroxyproline, collagen accumulation, and protein expressions of collagen I/III, α-smooth muscle actin, transforming growth factor-β1 (TGF-β1), nuclear factor kappa B p65 (NF-κB p65), Smad2/3, and P-Smad2/3 were decreased, while the glutathione peroxidase and superoxide dismutase levels in serum and myocardial tissues and protein expressions of myocardial peroxisome proliferator-activated receptor γ (PPARγ) and Smad7 were increased. After the preincubation of isoproterenol-stimulated cardiac fibroblasts with the PPARγ antagonist GW9662, stevioside-reduced protein expressions were decreased, but stevioside-induced Smad7 was not affected. These findings demonstrated that stevioside could exert a protective effect on mouse myocardial fibrosis, and its mechanisms were associated with the increments of antioxidant ability, PPARγ activation, and Smad7 expression, which caused a synergistic inhibition of the NF-κB/TGF-β1/Smad signaling pathway.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Cardiomyopathies; Cell Line; Diterpenes, Kaurane; Dose-Response Relationship, Drug; Fibrosis; Gene Expression Regulation; Glucosides; Isoproterenol; Male; Mice; NF-kappa B; Smad Proteins; Transforming Growth Factor beta1