Connective tissue growth factor and fibronectin secretion in renal tubular epithelial cells induced by TGF-beta1: suppressive effects of troglitazone

Although some studies have suggested that troglitazone could retard the progression of glomerulosclerosis, its effects on renal tubulointerstitial fibrosis have not been completely clarified. The aim of this study was to investigate the effects of troglitazone on the secretion of connective tissue growth factor (CTGF) and fibronectin (FN) in human renal proximal tubular epithelial (HK-2) cells induced by transforming growth factor-beta1 (TGF-beta1). The mRNA of CTGF and FN were measured by semi-quantitative RT-PCR. CTGF and FN protein were detected by Western blot and ELISA, respectively. Our results revealed that troglitazone could inhibit CTGF and FN expression in a dose-dependent manner in human renal proximal tubular epithelial cells induced by TGF-beta1, which may be one of the mechanisms of troglitazone contributing to retard the progression of renal tubulointerstitial fibrosis.     

Synergistic effects of pravastatin and pioglitazone in renal tubular epithelial cells induced by transforming growth factor-beta1

Recent studies suggest that treatment with PPAR-gamma agonists and statins have beneficial effects on renal disease. However, the combined effects of PPAR-gamma agonists and statins in human renal epithelial cells are unknown. Our present study revealed that there were synergistic effects of pravastatin and pioglitazone in the expression of alpha-smooth muscle actin (alpha-SMA), connective tissue growth factor (CTGF), fibronectin (FN), plasminogen activator inhibitor-1 (PAI-1) and collagen 1 in human renal proximal tubular epithelial cells induced by transforming growth factor-beta 1 (TGF-beta1). The beneficial effects of combined therapy against renal tubular epithelial cell injury are attributed, at least in part, to the inhibition of transdifferentiation, extracellular matrix deposition and cytokine production.     

Transforming growth factor-β signaling: Tumorigenesis and targeting for cancer therapy

Transforming growth factor (TGF)-β is a multitasking cytokine such that its aberrant expression is related to cancer progression and metastasis. TGF-β is produced by a variety of cells within the tumor microenvironment (TME), and it is responsible for regulation of the activity of cells within this milieu. TGF-β is a main inducer of epithelial–mesenchymal transition (EMT), immune evasion, and metastasis during cancer progression. TGF-β exerts most of its functions by acting on TβRI and TβRII receptors in canonical (Smad-dependent) or noncanonical (Smad-independent) pathways. Members of mitogen-activated protein kinase, phosphatidylinositol 3-kinase/protein kinase B, and nuclear factor κβ are involved in the non-Smad TGF-β pathway. TGF-β acts by complex signaling, and deletion in one of the effectors in this pathway may influence the outcome in a diverse way by taking even an antitumor role. The stage and the type of tumor (contextual cues from cancer cells and/or the TME) and the concentration of TGF-β are other important factors determining the fate of cancer (progression or repression). There are a number of ways for targeting TGF-β signaling in cancer, among them the special focus is on TβRII suppression.     

Peroxisome proliferator-activated receptor γ modulates renal crystal retention associated with high oxalate concentration by regulating tubular epithelial cellular transdifferentiation

The differentiated phenotype of renal tubular epithelial cell exerts significant effect on crystal adherence. Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to be critical for the regulation of cell transdifferentiation in many physiological and pathological conditions; however, little is known about its role in kidney stone formation. In the current study, we found that temporarily high oxalate concentration significantly decreased PPARγ expression, induced Madin Darby Canine Kidney cell dedifferentiation, and prompted subsequent calcium oxalate (CaOx) crystal adhesion in vitro. Furthermore, cell redifferentiation after the removal of the high oxalate concentration, along with a decreasing affinity to crystals, was an endogenic PPARγ-dependent process. In addition, the PPARγ antagonist GW9662, which can depress total-PPARγ expression and activity, enhanced cell dedifferentiation induced by high oxalate concentration and inhibited cell redifferentiation after removal of the high oxalate concentration. These effects were partially reversed by the PPARγ agonist 15d-PGJ2. Similar results were observed in animals that suffered from temporary hyperoxaluria followed by a recovery period. The active crystal-clearing process occurs through the transphenotypical morphology of renal tubular epithelial cells, reflecting cell transdifferentiation during the recovery period. However, GW9662 delayed cell redifferentiation and increased the secondary temporary crystalluria-induced crystal retention. This detrimental effect was partially reversed by 15d-PGJ2. Taken together, our results revealed that endogenic PPARγ activity plays a vital regulatory role in crystal clearance, subsequent crystal adherence, and CaOx stone formation via manipulating the transdifferentiation of renal tubular epithelial cells.     

Long non‐coding RNA H19 is responsible for the progression of lung adenocarcinoma by mediating methylation‐dependent repression of CDH1 promoter

Lung adenocarcinoma is a common histologic type of lung cancer with a high death rate globally. Increasing evidence shows that long non‐coding RNA H19 (lncRNA H19) and CDH1 methylation are involved in multiple tumours. Here, we tried to investigate whether lncRNA H19 or CDH1 methylation could affect the development of lung adenocarcinoma. First, lung adenocarcinoma tissues were collected to detect CDH1 methylation. Then, the regulatory mechanisms of lncRNA H19 were detected mainly in concert with the treatment of overexpression of lncRNA H19, siRNA against lncRNA H19, overexpression of CDH1 and demethylating agent A‐5az in lung adenocarcinoma A549 cell. The expression of lncRNA H19 and epithelial‐mesenchymal transition (EMT)‐related factors as well as cell proliferation, sphere‐forming ability, apoptosis, migration and invasion were detected. Finally, we observed xenograft tumour in nude mice so as to ascertain tumorigenicity of lung adenocarcinoma cells. LncRNA H19 and methylation of CDH1 were highly expressed in lung adenocarcinoma tissues. A549 cells with silencing of lncRNA H19, overexpression of CDH1 or reduced CDH1 methylation by demethylating agent 5‐Az had suppressed cell proliferation, sphere‐forming ability, apoptosis, migration and invasion, in addition to inhibited EMT process. Silencing lncRNA H19 could reduce methylation level of CDH1. In vivo, A549 cells with silencing lncRNA H19, overexpression of CDH1 or reduced CDH1 methylation exhibited low tumorigenicity, reflected by the smaller tumour size and lighter tumour weight. Taken together, this study demonstrates that silencing of lncRNA H19 inhibits EMT and proliferation while promoting apoptosis of lung adenocarcinoma cells by inhibiting methylation of CDH1 promoter.     

EZH2 promotes invasion and tumour glycolysis by regulating STAT3 and FoxO1 signalling in human OSCC cells

The enhancer of zeste homolog 2 (EZH2), known as a member of the polycomb group (PcG) proteins, is an oncogene overexpressed in a variety of human cancers. Here, we found that EZH2 correlated with poor survival of oral squamous cell carcinoma (OSCC) patients using immunohistochemistry staining. EZH2 overexpression led to a significant induction in tumour glycolysis, Epithelial‐mesenchymal transition (EMT), migration and invasion of OSCC cells. Conversely, silencing of EZH2 inhibited tumour glycolysis, EMT, migration and invasion in OSCC cells. Ectopic overexpression of EZH2 increased phosphorylation of STAT3 at pY705 and decreased FoxO1 expression, and FoxO1 expression was enhanced when inhibiting STAT3. In addition, EZH2 overexpression led to a significant decrease in FoxO1 mRNA levels in nude mice xenograft. These results indicated that regulation of EZH2 might have the potential to be targeted for OSCC treatment.     

MicroRNA‐224, negatively regulated by c‐jun,inhibits growth and epithelial‐to‐mesenchymal transition phenotype via targeting ADAM17 in oral squamous cell carcinoma

Abnormal expression of miR‐224 has been reported to promote cancer progression. However, the role of miR‐224 is seldom reported in oral squamous cell carcinoma (OSCC). We reported that miR‐224 expression was significantly down‐regulated in OSCC tissues and cell lines. Restoration of miR‐224 decreased OSCC cell growth and invasion. In addition, luciferase and Western blot assays revealed that ADAM17 protein was a downstream target of miR‐224. The overexpression of ADAM17 dismissed miR‐224’s effect on cell growth and invasion. We concluded that miR‐224 inhibited OSCC cell growth and invasion through regulating ADAM17 expression. Subsequently, we revealed that c‐jun directly bind to miR‐224 promoter and decreased miR‐224 expression. Taken together, these findings demonstrated that miR‐224 may function as a tumour‐suppressive microRNA in OSCC and suggested that miR‐224 may be a potential therapeutic target for OSCC patients.     

Review: The roles and functions of glutamine on intestinal health and performance of weaning pigs

The gut is composed of a single layer of intestinal epithelial cells and plays important roles in the digestion and absorption of nutrients, immune and barrier functions and amino acid metabolism. Weaning stress impairs piglet intestinal epithelium structural and functional integrities, which results in reduced feed intake, growth rates and increased morbidity and mortality. Several measures are needed to maintain swine gut development and growth performance after weaning stress. A large body of evidence indicates that, in weaning piglets, glutamine, a functional amino acid, may improve growth performance and intestinal morphology, reduce oxidative damage, stimulate enterocyte proliferation, modulate cell survival and death and enhance intestinal paracellular permeability. This review focuses on the effects of glutamine on intestinal health in piglets. The aim is to provide evidentiary support for using glutamine as a feed additive to alleviate weaning stress.