Nintedanib induces apoptosis in human pterygium cells through the FGFR2-ERK signalling pathway

AIM:To investigate whether nintedanib can inhibit pterygium cells through the fibroblast growth factor receptor 2(FGFR2)/extracellular-signal-regulated kinase(ERK)pathway.METHODS:Human primary pterygium cells were cultured in vitro.After treatment with nintedanib,the cell morphology was observed under microscopy,the morphological changes of the nucleus were observed after DAPI staining,apoptosis was analyzed by Annexin-V FITC/PI double staining,and the changes of apoptosis-associated proteins were detected by Western blot.The binding ability of nintedanib to FGFR2 was predicted by molecular docking.Finally,by silencing FGFR2,we explored whether nintedanib inhibited FGFR2/ERK pathway.RESULTS:The results showed that nintedanib inhibited the growth of pterygium cells and caused nuclear pyknosis.The results of Annexin-VFITC/PI double staining showed that nintedanib was able to induce early and late apoptosis of pterygium cells,significantly increasing the expression of apoptosis-associated proteins Bax and cleaved-Caspase3(P<0.05),and reducing the expression of Bcl-2(P<0.05).In addition,nintedanib significantly inhibited ERK1/2 phosphorylation through FGFR2(P<0.05).After silencing the expression of FGFR2,there was no significant difference in the inhibition of ERK1/2 phosphorylation by nintedanib(P>0.05).CONCLUSION:Nintedanib induces apoptosis of pterygium cells by inhibiting FGFR2/ERK pathway.

Artificial intelligence assisted pterygium diagnosis:current status and perspectives

Pterygium is a prevalent ocular disease that can cause discomfort and vision impairment.Early and accurate diagnosis is essential for effective management.Recently,artificial intelligence(AI)has shown promising potential in assisting clinicians with pterygium diagnosis.This paper provides an overview of AI-assisted pterygium diagnosis,including the AI techniques used such as machine learning,deep learning,and computer vision.Furthermore,recent studies that have evaluated the diagnostic performance of AI-based systems for pterygium detection,classification and segmentation were summarized.The advantages and limitations of AI-assisted pterygium diagnosis and discuss potential future developments in this field were also analyzed.The review aims to provide insights into the current state-of-the-art of AI and its potential applications in pterygium diagnosis,which may facilitate the development of more efficient and accurate diagnostic tools for this common ocular disease.

Clinical analysis of risk factors contributing to recurrence of pterygium after excision and graft surgery

AIM: To find the risk factors related to the reproliferation of the pterygial tissue after excision and graft surgery.METHODS: Charts of 130 eyes of 130 patients who had pterygial excision from March 2006 to April 2011 were reviewed. Preoperative pterygium morphology, surgical methods, and adjunctive treatments were statistically analyzed for their relationship with recurrence.RESULTS: During the follow-up period, recurrence was observed in 20 eyes(15.4%). None of the preoperative morphologic features were affected the rate of the recurrence. However, an age <40y [P =0.085, odds ratio(OR) 3.609, 95% confidence interval(CI) 0.838-15.540]and amniotic membrane graft instead of conjunctival autograft(P =0.002, OR 9.093, 95% CI 2.316-35.698) were statistically significant risk factors for recurrence.Multivariate analysis revealed that intraoperative mitomycin C(MMC)(P =0.072, OR 0.298, 95% CI 0.080-1.115)decreased the rate of recurrence. CONCLUSION: Younger age is a risk factor for reproliferation of pterygial tissue after excision and amniotic membrane transplantation(AMT) are less effective in preventing recurrence of pterygium after excision based on the comparison between conjunctival autograft and AMT. Intraoperative MMC application and conjunctival autograft reduce recurrence.

Aberrant expression of genes and proteins in pterygium and their implications in the pathogenesis

Pterygium is a common ocular surface disease induced by a variety of factors. The exact pathogenesis of pterygium remains unclear. Numbers of genes and proteins are discovered in pterygium and they function differently in the occurrence and development of this disease. We searched the Web of Science and Pub Med throughout history for literatures about the subject. The keywords we used contain pterygium, gene, protein, angiogenesis, fibrosis, proliferation, inflammation, pathogenesis and therapy. In this review, we summarize the aberrant expression of a range of genes and proteins in pterygium compared with normal conjunctiva or cornea, including growth factors, matrix metalloproteinases and tissue inhibitors of metalloproteinases, interleukins, tumor suppressor genes, proliferation related proteins, apoptosis related proteins, cell adhesion molecules, extracellular matrix proteins, heat shock proteins and tight junction proteins. We illustrate their possible mechanisms in the pathogenesis of pterygium as well as the related intervention based on them for pterygium therapy.

Novel sutureless transplantation for primary pterygium associated with cysts

AIM: To evaluate the efficacy and safety of a novel sutureless AMT (amniotic membrane transplantation) or CAT (conjunctivolimbal autograft transplantation) using fibrin glue for reconstructing corneoconjunctival surfaces for primary pterygium associated with cysts.METHODS: A prospective descriptive study was made of the period 1 January 2006-1 May 2009.Nine patients with primary pterygium associated with cysts underwent pterygium and cyst excision followed by sutureless AMT or CAT using fibrin glue.RESULTS: During a mean follow-up of 8.00±0.67 months,all eyes maintained a smooth and stable corneal epithelial surface without recurrent erosion or persistent epithelial defect.The limbal donor site showed the presence of mild depressions without the formation of pseudopterygium.All eyes have good tear secretion function,tear film stability and ocular motility.CONCLUSION: Sutureless transplantation using fibrin glue is safe and effective for restoring a stable corneoconjunctival epithelium in primary pterygium associated with cysts.

Clinical outcome of combined conjunctival autograft transplantation and amniotic membrane transplantation in pterygium surgery

AIM: To compare long-term outcome of primary and recurrent pterygium surgery with three different techniques: combined conjunctival autograft and overlay amniotic membrane transplantation(CAT with AMT), conjunctival autograft transplantation(CAT) alone and amniotic membrane transplantation(AMT) alone.METHODS: In this retrospective study, 142 eyes of 142 pterygium patients(104 primary, 38 recurrent) who underwent CAT(group A), AMT(group B) or CAT with AMT(group C) respectively following surgical excision were reviewed and compared based on the recurrences and post-operative complications.RESULTS: The number of recurrence post-surgery were 17(9 from primary, 8 from recurrent; the same description below), 18(10, 8) and 2(1, 1) in groups A, B, and C respectively; dry eyes were 22(16, 6), 27(18, 9) and 7(3, 4); conjunctival inflammations were 30(17, 13), 27(16, 11) and 11(6, 5). Patients in group C(either primary or recurrent or both) mainly showed significantly better results than those in group A or B(P<0.05) regarding above-mentioned clinical effects.CONCLUSION: Combined CAT and overly AMT have significantly lower rates of recurrence and postoperative complications for primary and recurrent pterygium surgery than CAT or AMT alone.

Bare sclera resection followed by mitomycin C and/or autograft limbus conjunctiva in the surgery for pterygium:a Meta-analysis

AIM: To evaluate the recurrence and complications after bare sclera resection(BSR) combined with mitomycin C(MMC) treatment and/or autograft limbus conjunctiva(ALC) in the surgery for pterygium.·METHODS: Meta-analysis was used to evaluate the differences in patient outcomes between BSR of pterygium with or without MMC and/or ALC. All included studies were randomized trials of patients with pterygium who received BSR followed by MMC and/or ALC in the surgery. The recurrence of pterygium and other complications resulting from different treatments were extracted for analysis.·RESULTS: Thirteen studies met the inclusion criteria.The recurrence of pterygium with intraoperative(IO) MMC was higher than that with ALC(OR=2.38,95% confidence interval 1.45-3.91, I2=29%). Postoperative MMC resulted in an incidence of recurrence similar to that of ALC(OR=0.66, 95% confidence interval 0.30-1.42, I2=0%), and IO MMC treatment in combination with ALC produced similar patient outcomes to ALC alone(OR =0.41, 95%confidence interval 0.16-1.01, I2=16%). Other complications such as punctate epitheliopathy, scleral thinning and ischemia, irritation and persistent epithelium defect, were more common in patients in the MMC group as compared to those treated with ALC.·CONCLUSION: The recurrence of pterygium with BSR followed by ALC is lower than that of BSR followed by MMC, and the incidence of other complications is lower.While ALC is a more effective strategy for treating pterygium, the quality of the ALC transplant should be considered when the patient has a history of glaucoma.

Mitomycin C in pterygium treatment

Pterygium is a benign lesion usually growing from the nasal side of the conjunctiva onto the cornea.Most cases of pterygium does not cause problem or requires specific treatment.The exact cause of pterygium is not clear yet,but some factors are pointed as causes,being the most important the long-term ultraviolet ray exposure.Pterygium surgery is usually considered when there are symptoms that do not respond to conservative treatment.Recurrence is the main complication of the surgery,and much has been done to avoid it.Mitomycin C(MMC) has been used as a fibroblast proliferation inhibitor during the surgery to reduce the chance of recurrence of the pterygium.This review describes the use of MMC as an adjunctive,the optimal dosage,the duration of administration of MMC and possible complications,when used during,after and before the surgery.Most studies suggest that increased exposure(dose or duration) of MMC is associated with a lower recurrence,but with higher risks of complications.

Semaphorin 7a participants in pterygium by regulating vascular endothelial growth factor

AIM: To investigate the relationship between semaphorin 7a expression and cell proliferation and migration in pterygium fibroblasts. METHODS: Twenty-six patients with surgically diagnosed pterygium were enrolled, including 15 cases of primary pterygium and 11 cases of recurrent pterygium. In addition, 12 cases of normal conjunctival tissue were collected. The expression of semaphorin 7a in normal conjunctival tissue, primary pterygium and recurrent pterygium was detected by real-time polymerase chain reaction. Recurrent pterygium fibroblasts were isolated and cultured, and the expression of semaphorin 7a was silenced by small interfering RNA(siRNA) interference technique. Furthermore, the effects of si-semaphorin 7a interference on the mRNA and protein levels of β1-integrin, vascular endothelial growth factor A(VEGFA) and vascular endothelial growth factor receptor(VEGFR), and on fibroblast proliferation were analyzed. Transwell assay was used to detect the effect of semaphorin 7a interference on fibroblast migration. RESULTS: Semaphorin 7a was highly expressed in the primary pterygium and recurrent pterygium samples than that of the normal conjunctival tissue. Compared with the primary pterygium, the expression of semaphoring 7a in the recurrent pterygium samples was significantly increased(P<0.05). The mRNA and protein expression levels of β1-integrin, VEGFA and VEGFR were decreased after si-semaphorin 7a transfection, and as well as the cell proliferation and migration. CONCLUSION: Semaphorin 7a might play important roles in the pathogenesis of pterygium by affecting the expression of β1-integrin, VEGFA and VEGFR.

Survivin and p53 expression in primary and recurrent pterygium in Chinese patients

AIM: To assess the expression of anti-apoptotic protein survivin and tumor suppressor p53 protein in primary and recurrent pterygium and to investigate the relationship between them. METHODS: Survivin was assessed immunohistochemically using rabbit polyclonal antibody and p53 using mouse monoclonal antibody in a study sample of 20 cases of primary pterygium, 10 cases of recurrent pterygium and 10 cases of normal conjunctiva. RESULTS: In our study, 35% of primary (7 of 20) and 40% of recurrent (4 of 10) pterygium specimens were positive for survivin staining; 45% of primary (9 of 20) and 50% of recurrent (5 of 10) pterygium specimens were positive for p53 expression; and all normal conjunctiva showed no staining of either survivin or p53. The p53 and survivin immunoreactivity in primary and recurrent pterygium groups was greater than those in normal conjunctiva group (P <0.05). There were no differences in p53 and survivin immunoreactivity between groups of primary and recurrent pterygium (P >0.05). The expression of survivin clearly segregated with p53-positive pterygium as compared with p53-negative cases [8 of 14 cases (57.1%) vs ersus 3 of 16 cases (15.2%)] . The Fisher's exact test analysis confirmed a highly statistically significant correlation between survivin and p53 expression (P <0.05). CONCLUSION: The survivin and p53 are overexpressed with correlation between them in primary and recurrent pterygium.

The role of heredity in pterygium development

Several risk factors,which include heredity,ultra-violet (UV) light and chronic inflammation,contribute to pterygium development.However,there is no report integrating these factors in the pathogenesis of pterygium.The aim of this review is to describe the connection between heredity,UV,and inflammation in pterygium development.Existing reports indicate that sunlight exposure is the main factor in pterygium occurrence by inducing growth factor production or chronic inflammation or DNA damage.Heredity may be a factor.Our studies on factors in pterygium occurrence and recurrence identify that heredity is crucial for pterygium to develop,and that sunlight is only a trigger,and that chronic inflammation promotes pterygium enlargement.We propose that genetic factors may interfere with the control of fibrovascular proliferation while UV light or(sunlight)most likely only triggers pterygium development by inducing growth factors which promote vibrant fibrovascular proliferation in predisposed individuals.It also just triggers inflammation and collagenolysis,which may be promoters of the enlargement of the fibrovascular mass.Pterygium probably occurs in the presence of exuberant collagen production and profuse neovascularisation.

Pterygium epithelium abnormal differentiation related to activation of extracellular signal-regulated kinase signaling pathway in vitro

AIM: To investigate whether the abnormal differentiation of the pterygium epithelium is related to the extracellular signal-regulated kinase(ERK) signaling pathway in vitro.·METHODS: The expression levels of phosphorylated ERK(P-ERK), keratin family members including K19 and K10 and the ocular master control gene Pax-6 were measured in 16 surgically excised pterygium tissues and 12 eye bank conjunctiva. In colony-forming cell assays,the differences in clone morphology and in K10, K19, PERK and Pax-6 expression between the head and body were investigated. When cocultured with the ERK signaling pathway inhibitor PD98059, the changes in clone morphology, colony-forming efficiency,differentiated marker K10, K19 and Pax-6 expression and P-ERK protein expression level were examined by immunoreactivity and Western blot analysis.· RESULTS: The expression of K19 and Pax-6 decreased in the pterygium, especially in the head. No staining of K10 was found in the normal conjunctiva epithelium, but it was found to be expressed in the superficial cells in the head of the pterygium.Characteristic upregulation of P-ERK was observed by immunohistochemistry. The clone from the head with more differentiated cells in the center expressed more K10, and the clone from the body expressed more K19.The P-ERK protein level increased in the pterygium epithelium compared with conjunctiva and decreased when cocultured with PD98059. The same medium with the ERK inhibitor PD98059 was more effective in promoting clonal growth than conventional medium with3T3 murine feeder layers. It was observed that the epithelium clone co-cultured with the inhibitor had decreased K10 expression and increased K19 and Pax-6 expression.· CONCLUSION: We suggest ERK signaling pathway activation might play a role in the pterygium epithelium abnormal differentiation.

Inhibitory Effect of Curcumin on Proliferation of Human Pterygium Fibroblasts

In order to investigate the effect of curcumin on proliferation and apoptosis of human pterygium fibroblasts (HPF) in culture and search for a new method to prevent the recurrence after pterygium surgery, HPF was incubated with 0-160 μmol/L curcumin for 24-96 h. The MTT method was used to assay the biologic activities of curcumin at different time points and different doses. The expression of proliferating cell nuclear antigen (PCNA) in each group was detected by immunohistochemistry. The cell cycle distribution was detected by flow cytometry (FCM). Admini- stration of 20-80 μmol/L curcumin for 24-72 h could significantly inhibit HPF proliferation in a dose- and time-dependent manner (P<0.05). After treatment with curcumin at different concentrations of 20, 40, 80 and 160 μmol/L for 24 h, FCM revealed there was a significant sub-G1 peak at each concentration. The number of HPF in G0/G1 phase was increased, while in S phase, it was decreased (P<0.05). At the concentration of 20-80 μmol/L, curcumin, in a dose-dependent manner (P<0.05), could inhibit the expression of PCNA in HPF. It was suggesterd that curcumin could significantly in- hibit the proliferation of HPF, make HPF arrest in G0/G1 phase and induce the apoptosis of HPF in a dose- and time-dependent manner.

Current approaches and future directions in the management of pterygium

Pterygium,a common ocular surface disorder,has a complex pathophysiology that may mimic tumorigenesis.There is altered expression of cell cycle/proliferation-related factors in pterygium tissues.Therefore,similar to cancer treatments,the management of pterygium ought to be multifactorial based on the patient’s condition.Current therapeutic methods for pterygium are focused on surgical resection in conjunction with antimetabolite use,in addition tissue graft is usually performed in the context of the avoidance of bare sclera.However,future directions in the management of pterygia will likely focus on genetic approaches.This perspective views the pathogenesis of pterygium,its existing therapies as well as current and future challenges in its treatment.

Expression of micro RNAs in fibroblast of pterygium

AIM:To screen microRNAs(miRNAs) and set up target miRNAs in pterygium.METHODS:Primary fibroblasts were isolated from pterygium and Tenon's capsule and cultured.Immunocytochemical analysis and Western blotting were performed to confirm the culture of fibroblasts.In all,1733 miRNAs were screened in the first step by using GeneChip^(?) miRNA3.0 Array.Specific miRNAs involved in the pathogenesis of pterygium were subsequently determined using the following criteria:1) high reproducibility in a repetitive test;2) base log value of >7.0 for both control and pterygial fibroblasts;and 3) log ratio of >1.0 between pterygial fibroblasts and control fibroblasts.RESULTS:Primary screening showed that 887/1733 miRNAs were up-regulated and 846/1733 miRNAs were down-regulated in pterygial fibroblasts compared with those in control fibroblasts.Of the 1733 miRNAs screened,4 miRNAs,namely,miRNA-143a-3p,miRNA-181a-2-3p,miRNA-377-5p and miRNA-411a-5p,met the above-mentioned criteria.Primary screening showed that these 4 miRNAs were up-regulated in pterygial fibroblasts compared with control fibroblasts and that miRNA-143a-3p had the highest mean ratio compared with the miRNAs in control fibroblasts.CONCLUSION:miRNA-143a-3p,miRNA-181a-2-3p,miRNA-377-5p and miRNA-411a-5p are up-regulated in pterygial fibroblasts compared with control fibroblasts,suggesting their involvement in the pathogenesis of pterygium.

Identification of pathogenic genes of pterygium based on the Gene Expression Omnibus database

AIM: To identify the pathogenic genes in pterygium.METHODS: We obtained m RNA expression profiles from the Gene Expression Omnibus database(GEO) to identify differentially expressed genes(DEGs) between pterygium tissues and normal conjunctiva tissues. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway analysis, protein-protein interaction(PPI) network and transcription factors(TFs)-target gene regulatory network was performed to understand the function of DEGs. The expression of selected DEGs were validated by the quantitative real-time polymerase chain reaction(qRT-PCR).RESULTS: A total of 557 DEGs were identified between pterygium and normal individual. In PPI network, several genes were with high degrees such as FN1, KPNB1, DDB1, NF2 and BUB3. SSH1, PRSS23, LRP5L, MEOX1, RBM14, ABCA1, JOSD1, KRT6 A and UPK1B were the most downstream genes regulated by TFs. q RT-PCR results showed that FN1, PRSS23, ABCA1, KRT6A, ECT2 and SPARC were significantly up-regulated in pterygium and MEOX1 and MMP3 were also up-regulated with no significance, which was consistent with the our integrated analysis. CONCLUSION: The deregulated genes might be involved in the pathology of pterygium and could be used as treatment targets for pterygium.

Does topical bevacizumab prevent postoperative recurrence after pterygium surgery with conjunctival autografting?

AIM:To assess the effect of topical bevacizumab use on postoperative pterygium recurrence in eyes who underwent pterygium excision with limbal-conjunctival autograft transplantation(LCAT).METHODS:eighty-eight eyes of 88 patients with primary pterygium were included.Pterygia were graded preoperatively from type 1 to type 3(type 1 atrophic,type3 inflamed)according to the inflammatory status.The eyes were preoperatively randomized to receive topical steroid and antibiotic treatment(group 1,46 eyes)and additional topical bevacizumab(5 mg/mL;group 2,42eyes)in the postoperative period.All eyes underwent pterygium excision and LCAT.Medications were tapered and discontinued at one month.Postoperative complications and recurrence rates were recorded.RESULTS:The mean follow-up duration was 29.3±4.2mo(24-52mo)and 28.5±3.4(24-48mo)in group 1 and2,respectively(P>0.05).There were no statistically significant differences regarding the age or gender between groups(P>0.05).Also,the difference between groups with respect to pterygium type was not significant.During the follow-up period,recurrence developed in 2 eyes(4.3%)in group 1,whereas in one eye(2.4%)in group 2.No statistically significant difference between groups was found in recurrence rates(P>0.05).No re-operation for recurrence was necessary during the follow-up period in both groups.CONCLUSION:Topical bevacizumab seems to have no additonal effect on pterygium recurrence after LCAT.

Anti-fibrotic effect of rosmarinic acid on inhibition of pterygium epithelial cells

AIM: To investigate the anti-fibrosis effect of rosmarinic acid(RA) in pterygium epithelial cells(PECs) to determine if RA is a potent agent for treating pterygium.METHODS: The PECs(1×10~4 cells/mL) were treated with 100 μmol/L of RA for 1, 3 and 6h. After RA treatment, the cell viability was determined by staining with acridine orange/DAPI and analysis via a NucleoC ounter NC-3000. The protein expression levels of type I collagen, transforming growth factor beta-1(TGF-β1), TGF-β type Ⅱ receptor(TGF-βRⅡ), p-Smad1/5, p-Smad2, p-Smad3, and Smad4 of the cell lysates were measured by Western blot analysis.RESULTS: The cell viability of PECs was significantly decreased after RA treatment(P<0.01). As the result, RA reduced the protein expression of typeⅠcollagen and TGF-β1 of PECs. Additionally, RA also inhibited TGF-β1/Smad signaling by decreasing the protein expressions of TGF-βRII, p-Smad1/5, p-Smad2, p-Smad3, and Smad4.CONCLUSION: This study demonstrate that RA could inhibit fibrosis of PECs by down-regulating type I collagen expression and TGF-β1/Smad signaling. Therefore, RA is a potent therapeutic agent for the treatment of pterygium.

Bevacizumab as adjuvant therapy in the management of pterygium: a systematic review and Meta-analysis

AIM: To evaluate the clinical effect of bevacizumab in pterygium treatment.METHODS: A systematic review and quantitative Metaanalysis was performed. Pub Med, EMBASE, Web of Science and Cochrane database were searched for eligible literatures published in English until June 2016. The endpoint was recurrence rate and pooled risk ratio(RR) was calculated.RESULTS: Nine eligible studies were included and Metaanalysis results showed no significantly difference in patients treated with bevacizumab in short term followup [3mo: RR=0.70(0.34, 1.45); 6mo: RR=0.55(0.23, 1.32)] compared with control groups. No significant effects were observed in favor of bevacizumab in subgroup analyses: patients with subconjunctival injection of bevacizumab [3mo: RR=0.95(0.70, 1.29); 6mo: RR=0.83(0.55, 1.28)], primary pterygium [3mo: RR=0.59(0.23, 1.54; 6mo: RR=0.59(0.23, 1.53)], simple pterygium excision [3mo: 0.32(0.05, 2.04), P=0.23; 6mo: 0.27(0.05, 1.53)] and excision with conjunctival autograft [3mo: 1.51(0.25, 9.15); 6mo: 1.11(0.06, 21.69)].CONCLUSION: In this Meta-analysis, we did not found the significant effect of bevacizumab in pterygium treatment, at least in short term follow-up(3mo and 6mo).

Inhibitory Effect of PPARγ Agonist on the Proliferation of Human Pterygium Fibroblasts

The effects of DK2,a peroxisome proliferator-activated receptor γ agonist,on cultured human pterygium fibroblasts (HPFs) in virto were studied.The HPFs were incubated with 0-200 μmol/L DK2 for 12-72 h.The MTT method was used to assay the bio-activity of DK2 at different doses and time.The cytotoxic effect of DK2 was measured by LDH release assay.The cell cycle distribution and apoptosis were flow cytometrically detected.The expression of proliferating cell nuclear antigen (PCNA) in each group was detected by real-time PCR (RT-PCR) and Western blotting.The results showed that administration of 1-75 μmol/L DK2 for 12-72 h could significantly inhibit HPF proliferation in a dose-and time-dependent manner.DK2-treated cells did not release significant amount of LDH as compared with rosiglitazone-treated cells.After treatment with DK2 at concentrations of 15,25 μmol/L for 24 h,the number of HPFs in G 0 /G 1 phase was significantly increased while that in S phase was significantly decreased (P<0.05),leading to arrest at G 0 /G 1 phase.The apoptosis rates of HPF cells in drug-treated groups were significantly higher than the rate of control group (P<0.05).At the dosage range between 15-25 μmol/L,DK2 could inhibit the expression of PCNA mRNA and protein in HPFs in a dose-dependent fashion (P<0.05).It was concluded that PPARγ agonist can significantly inhibit HPF proliferation,resulting in the arrest at G 0 /G 1 phase,induce the apoptosis of HPFs,and suppress the synthesis of PCNA,in dose-and time-dependent manners.