Zhenzhen Kong

Prevalence of kidney stones in China: an ultrasonography based cross-sectional study

To investigate the prevalence and associated factors of kidney stones among adults in China.

β-Arrestin2 Contributes to Cell Viability and Proliferation via the Down-Regulation of FOXO1 in Castration-Resistant Prostate Cancer.

β‐Arrestin2 has been identified to act as a corepressor of androgen receptor (AR) signaling by binding to AR and serving as a scaffold to affect the activity and expression of AR in androgen‐dependent prostate cancer cells; however, little is known regarding its role in castration‐resistant prostate cancer (CRPC) progression. Here, our data demonstrated that β‐arrestin2 contributes to the cell viability and proliferation of CRPC via the downregulation of FOXO1 activity and expression. Mechanistically, in addition to its requirement for FOXO1 phosphorylation induced by IGF‐1, β‐arrestin2 could inhibit FOXO1 activity in an Akt‐independent manner and delay FOXO1 dephosphorylation through the inhibition of PP2A phosphatase activity and the attenuation of the interaction between FOXO1 and PP2A. Furthermore, β‐arrestin2 could downregulate FOXO1 expression via ubiquitylation and proteasomal degradation. Together, our results identified a novel role for β‐arrestin2 in the modulation of the CRPC progress through FOXO1. Thus, the characterization of β‐arrestin2 may represent an alternative therapeutic target for CRPC treatment. J. Cell. Physiol. 230: 2371–2381, 2015.

Inhibition of PARP1 by small interfering RNA enhances docetaxel activity against human prostate cancer PC3 cells

Though poly(ADP-ribose) polymerase 1 (PARP1) inhibitors have benefits in combination with radiotherapy in prostate cancers, few is known about the exactly role and underlying mechanism of PARP1 in combination with chemotherapy agents. Here our data revealed that inhibition of PARP1 by small interfering RNA (siRNA) could enhance docetaxels activity against PC3 cells, which is associated with an accelerate repression of EGF/Akt/FOXO1 signaling pathway. Our results provide a novel role of PARP1 in transcription regulation of EGFR/Akt/FOXO1 signaling pathway and indicate that PARP1 siRNA combined with docetaxel can be an innovative treatment strategy to potentially improve outcomes in CRPC patients.

β-arrestin1 promotes epithelial-mesenchymal transition via modulating GSK-3β/β-catenin pathway in prostate cancer cells.

Recently, β-arrestin1 was indicated as a tumor promoter in prostate cancer, but its exact role in cancer metastasis still have not been well clarified. Here, our data revealed that β-arrestin1 could promote the migration and invasion of prostate cancer cells via initiating epithelial-mesenchymal transition (EMT). Mechanically, β-arrestin1 could increase the transcriptional activity and expression of β-catenin, together with Akt activity, whereas decrease the activities of GSK-3β and PP2A. In addition, β-arrestin1 could function as a scaffold protein in modulating the interactions between PP2A, Akt, GSK-3β and β-catenin. These results reveal a novel mechanism of β-arrestin1 in modulating EMT and GSK-3β/β-catenin signaling in prostate cancer, thereby suggest that assessment of β-arrestin1 may provide a potential therapeutic target for prostate cancer.

Autophagy inhibition attenuates hyperoxaluria-induced renal tubular oxidative injury and calcium oxalate crystal depositions in the rat kidney

Hyperoxaluria-induced oxidative injury of renal tubular epithelial cell is a casual and essential factor in kidney calcium oxalate (CaOx) stone formation. Autophagy has been shown to be critical for the regulation of oxidative stress-induced renal tubular injury; however, little is known about its role in kidney CaOx stone formation. In the present study, we found that the autophagy antagonist chloroquine could significantly attenuate oxalate-induced autophagy activation, oxidative injury and mitochondrial damage of renal tubular cells in vitro and in vivo, as well as hyperoxaluria-induced CaOx crystals depositions in rat kidney, whereas the autophagy agonist rapamycin exerted contrasting effects. In addition, oxalate-induced p38 phosphorylation was significantly attenuated by chloroquine pretreatment but was markedly enhanced by rapamycin pretreatment, whereas the protective effect of chloroquine on rat renal tubular cell oxidative injury was partly reversed by a p38 protein kinase activator anisomycin. Furthermore, the knockdown of Beclin1 represented similar effects to chloroquine on oxalate-induced cell oxidative injury and p38 phosphorylation in vitro. Taken together, our results revealed that autophagy inhibition could attenuate oxalate-induced oxidative injury of renal tubular cell and CaOx crystal depositions in the rat kidney via, at least in part, inhibiting the activation of p38 signaling pathway, thus representing a novel role of autophagy in the regulation of oxalate-induced renal oxidative injury and CaOx crystal depositions for the first time.

L-Carnitine Protects Renal Tubular Cells Against Calcium Oxalate Monohydrate Crystals Adhesion Through Preventing Cells From Dedifferentiation

Background/Aims: The interactions between calcium oxalate monohydrate (COM) crystals and renal tubular epithelial cells are important for renal stone formation but still unclear. This study aimed to investigate changes of epithelial cell phenotype after COM attachment and whether L-carnitine could protect cells against subsequent COM crystals adhesion. Methods: Cultured MDCK cells were employed and E-cadherin and Vimentin were used as markers to estimate the differentiate state. AlexaFluor-488-tagged COM crystals were used in crystals adhesion experiment to distinguish from the previous COM attachment, and adhesive crystals were counted under fluorescence microscope, which were also dissolved and the calcium concentration was assessed by flame atomic absorption spectrophotometry. Results: Dedifferentiated MDCK cells induced by transforming growth factor β1 (TGF-β1) shown higher affinity to COM crystals. After exposure to COM for 48 hours, cell dedifferentiation were observed and more subsequent COM crystals could bind onto, mediated by Akt/GSK-3β/Snail signaling. L-carnitine attenuated this signaling, resulted in inhibition of cell dedifferentiation and reduction of subsequent COM crystals adhesion. Conclusions: COM attachment promotes subsequent COM crystals adhesion, by inducing cell dedifferentiation via Akt/GSK-3β/Snail signaling. L-carnitine partially abolishes cell dedifferentiation and resists COM crystals adhesion. L-carnitine, may be used as a potential therapeutic strategy against recurrence of urolithiasis.

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

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.

β-arrestin1-medieated inhibition of FOXO3a contributes to prostate cancer cell growth in vitro and in vivo

Recently, β‐arrestin1 has been indicated as a prostate cancer promoter through promoting cell proliferation and epithelial to mesenchymal transition, but its underlying mechanism remains unclear. Here, our data revealed that β‐arrestin1 could promote cell growth through inhibiting the transcriptional activity and expression of FOXO3a in prostate cancer cells in vitro and in vivo. We found that β‐arrestin1 could promote the cell and tumor growth of prostate cancer, and β‐arrestin1 expression represented a negative correlation with FOXO3a expression but not FOXO1 expression in prostate cancer cell lines and tissues. In addition, forced expression of β‐arrestin1 induced a significant decrease of FOXO3a expression but had no clear effect on FOXO1 expression. Mechanistically, β‐arrestin1 could interact with FOXO3a and MDM2, respectively, and promote the interaction between FOXO3a and MDM2, whereas it had no obvious interaction with FOXO1. Furthermore, β‐arrestin1 could inhibit the transcriptional activity of FOXO3a via Akt and ERK1/2 pathways. Together, our results revealed a novel mechanism for β‐arrestin1 in the regulation of the prostate cancer procession through inhibiting FOXO3a.