Inhibition of GLI Transcriptional Activity and Prostate Cancer Cell Growth and Proliferation by DAX1.

The Hedgehog (Hh) signaling pathway plays an essential role in the initiation and progression of prostate cancer. This is mediated by transcriptional factors belonging to the GLI (glioma-associated oncogene) family, which regulate downstream targets to drive prostate cancer progression. The activity of GLI proteins is tightly controlled by a range of mechanisms, including molecular interactions and post-translational modifications. In particular, mitogenic and oncogenic signaling pathways have been shown to regulate GLI protein activity independently of upstream Hh pathway signaling. Identifying GLI protein regulators is critical for the development of targeted therapies that can improve patient outcomes. This study aimed to identify a novel protein that directly regulates the activity of GLI transcription factors in prostate cancer. We performed gene expression, cellular analyses, and reporter assays to demonstrate that DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) interacts with GLI1 and GLI2, the master regulators of Hh signaling. Interestingly, DAX1 overexpression significantly inhibited Hh signaling by reducing GLI1 and GLI2 activity, prostate cancer cell proliferation, and viability. Our results shed light on a novel regulatory mechanism of Hh signaling in prostate cancer cells. The interaction between DAX1 and GLI transcription factors provides insight into the complex regulation of Hh signaling in prostate cancer. Given the importance of Hh signaling in prostate cancer progression, targeting DAX1-GLI interactions may represent a promising therapeutic approach against prostate cancer. Overall, this study provides new insights into the regulation of the Hh pathway and its role in prostate cancer progression. The findings suggest that DAX1 could serve as a potential therapeutic target for the treatment of prostate cancer.

Effects of Mesenchymal Stem Cells Treatment on Radiation-Induced Proctitis in Rats.

PURPOSE: There are no effective treatment methods with which to control complications of radiation proctitis with fistula or recurrent bleeding following radiation treatment for prostate, cervical, or rectal cancer. Mesenchymal stem cells (MSCs) can induce immune modification, resulting in tissue repair and regeneration. Therefore, we used a rat model of radiation-induced proctitis and observed the effects of using human placenta-derived (PD) and adipose tissue-derived (AD) MSCs. MATERIALS AND METHODS: Female Sprague Dawley rats were irradiated at the pelvic area with 25 Gy. We injected 1×106 cells of human PD-MSCs, human AD-MSCs, human foreskin fibroblasts, and control media into the rectal submucosa following irradiation. We sacrificed rats for pathologic evaluation. RESULTS: Fibrosis on the rectum was reduced in both MSC groups, compared to the control group. Mucosal Ki-67 indices of both MSC injected groups were higher than those in the control group. Although caspase-3 positive cells in the mucosa gradually increased and decreased in the control group, those in both MSC injected groups increased rapidly and decreased thereafter. CONCLUSION: We demonstrated the effects of regional MSC injection treatment for radiation-induced proctitis in rats. MSC injection reduced fibrosis and increased proliferation in rat mucosa. Human AD-MSCs and PD-MSCs had similar effectiveness.

A modified endoscopic full thickness resection for gastric subepithelial tumors from muscularis propria layer: Novel method.

BACKGROUND AND AIM: The removal of subepithelial tumors (SETs) is challenging, particularly in tumors originating from the muscularis propria (MP) in the upper gastrointestinal (GI) tract, owing to the high risk of perforation. We developed mechanical spray lumpectomy (MSL), which is a novel method to safely and easily remove the tumor. This study aimed to evaluate the feasibility and safety of MSL as a novel endoscopic treatment for gastric subepithelial lesions. METHODS: We performed MSL in a total of 13 patients with upper GI SETs originating from the MP layer. First, mucosectomy was performed using a conventional snare. Repeated injections were performed towards the subserosal layer. After injection, the lesion was mechanically pushed to separate the MP layer using an endoscopic cap. Finally, the mucosa, submucosa, and MP layer with SETs were completely dissected using the spray coagulation mode, and the remaining defect was closed with clipping. RESULTS: All tumors were completely resected. The mean procedure time was 84.38 ± 41.73 min. There were four leiomyomas, six GI stromal tumors, one mucosa-associated lymphoid tissue lymphoma, and two ectopic pancreases. Although small perforation occurred in only one case, the defect was successfully closed using hemostatic clipping. Moreover, no serious complications related to MSL were encountered during or after the procedure. No residual lesion or recurrence was observed during the follow-up period. CONCLUSIONS: Mechanical spray lumpectomy can be a novel method that provides a safe and minimally invasive endoscopic treatment for upper GI SETs originating from the MP layer.

Anti-reflux mucosectomy using a cap-assisted endoscopic mucosal resection method for refractory gastroesophageal disease: a prospective feasibility study.

BACKGROUND AND AIMS: Endoscopic therapy of gastroesophageal reflux disease (GERD) overcomes the "treatment gap" for patients with refractory GERD, who are not willing to go into surgery. We propose an easy and efficient technique that is referred to as anti-reflux mucosectomy (ARMS) using cap-assisted endoscopic mucosal resection (EMR-C) which could be called ARMS-C. This study aimed to investigate the short-term outcomes of ARMS-C in GERD patients. METHODS: From December 2016 to February 2018, we performed ARMS-C in 33 patients with pathologic reflux disease and esophageal hypersensitivity. ARMS-C involved endoscopic mucosal resection at the circumference of the esophagogastric junction (EGJ), resulting in narrowing of the hiatal opening after healing. The GERD symptoms, 24-h pH monitoring results, manometry, endoscopy, and EGJ distensibility were compared before and after the procedure. RESULTS: Six months after ARMS-C, 63% of patients discontinued the use of pump inhibitors (PPIs), while 30% patients reduced their PPI dose. The GERD questionnaire scores significantly decreased after ARMS-C, from 11.0 to 6.0 (P < 0.001). The median DeMeester score and acid exposure time based on pH monitoring also improved after ARMS-C. Furthermore, the median flap valve grade and EGJ distensibility decreased from 3.0 to 1.0 (P < 0.001) and from 19.0 to 13.9 (P < 0.001), respectively. Two patients were treated with balloon dilation due to stricture, but no other serious adverse events were encountered. CONCLUSION: ARMS-C may be an effective and safe treatment method for GERD in terms of short-term outcomes.

Utility of EUS elastography in the diagnosis of gastric subepithelial tumors: a pilot study (with video).

BACKGROUND AND AIMS: EUS elastography is a real-time imaging technique that analyzes tissue elasticity. The aim of this study was to investigate the applicability of quantitative EUS elastography in the differential diagnosis of gastric subepithelial tumors (SETs). METHODS: We prospectively registered 41 consecutive patients with gastric SETs and measured their strain ratios with EUS elastography. The strain ratios of gastric SETs were compared with the histopathologic diagnosis. RESULTS: Thirty-one patients (mean age, 51.4 ± 12.6 years) were included in the analysis. The mean size of the SETs was 2.3 ± 0.7 cm. Lipomas had the lowest strain ratio of 1.6 (1.1-2.0), followed by leiomyomas 6.0 (2.0-29.0), ectopic pancreas 11.8 (1.7-29.3), gastrointestinal stromal tumors (GISTs) 51.1 (29.0-67.0), and schwannomas 62.0. With a cut-off value of 22.7, EUS elastography could differentiate GISTs from leiomyomas with sensitivity and specificity of 100% and 94.1%, respectively (P = .001; 95% confidence interval, 0.979-1.000). CONCLUSIONS: EUS elastography could be a promising diagnostic adjunct for the assessment of gastric SETs, especially in differentiating GISTs from leiomyomas.

Umbilical cord/placenta-derived mesenchymal stem cells inhibit fibrogenic activation in human intestinal myofibroblasts via inhibition of myocardin-related transcription factor A.

BACKGROUND: The lack of anti-fibrotic agents targeting intestinal fibrosis is a large unmet need in inflammatory bowel diseases, including Crohn's disease and ulcerative colitis. Previous studies have found that perinatal tissue (umbilical cord, UC; placenta, PL)-derived mesenchymal stem cells (MSCs) reduce fibrosis in several organs. However, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of MSCs derived from UC and PL (UC/PL-MSCs) on human primary intestinal myofibroblasts (HIMFs). METHODS: The HIMFs were treated with TGF-ß1 and co-cultured with UC/PL-MSCs. We used a small molecular inhibitor CCG-100602 to examine whether serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factor A (MRTF-A) are involved in TGF-ß1-induced fibrogenic activation in HIMFs. The anti-fibrogenic mechanism of UC/PL-MSCs on HIMFs was analyzed by detecting the expression of RhoA, MRTF-A, and SRF in HIMFs. RESULTS: UC/PL-MSCs reduced TGF-ß1-induced procollagen1A1, fibronectin, and α-smooth muscle actin expression in HIMFs. This anti-fibrogenic effect was more apparent in the UC-MSCs. TGF-ß1 stimulation increased the expressions of RhoA, MRTF-A, and SRF in the HIMFs. TGF-ß1 induced the synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin through a MRTF-A/SRF-dependent mechanism. Co-culture with the UC/PL-MSCs downregulated fibrogenesis by inhibition of RhoA, MRTF-A, and SRF expression. CONCLUSIONS: UC/PL-MSCs suppress TGF-ß1-induced fibrogenic activation in HIMFs by blocking the Rho/MRTF/SRF pathway and could be considered as a novel candidate for stem cell-based therapy of intestinal fibrosis.

Periodontitis is associated with an increased risk for proximal colorectal neoplasms.

Interval colorectal cancers detected after colonoscopy are known to be highly associated with proximal colorectal neoplasms (CRNs). This cross-sectional study investigated whether periodontitis could be a risk factor for proximal CRNs in healthy individuals. A total of 2504 subjects who received a colonoscopy and dental exam were enrolled in this study. We divided the subjects into the periodontitis group (n = 216) and the control group (n = 2288). The periodontitis group was defined as subjects who had one or more teeth with a probing pocket depth (PPD) ≥4 mm. The prevalence of proximal CRNs was significantly higher in the periodontitis group (25.0%) than in the control group (12.3%) (P < 0.001). Independent risk factors for proximal CRNs in the multivariate analysis were periodontitis, smoking, age, waist circumference, and triglycerides, and those for proximal advanced CRNs were periodontitis, age, and family history of CRC. However, periodontitis was not a risk factor for overall CRNs and advanced CRNs. Periodontitis was associated with an increased risk of proximal CRNs (odds ratio [OR], 1.525; 95% confidence intervals [95% CI], 1.071-2.172) and proximal advanced CRNs (OR, 2.671; 95% CI, 1.088-6.560). Periodontitis might be associated with proximal CRNs and proximal advanced CRNs.

Effectiveness of Autologous Platelet-Rich Plasma for the Healing of Ulcers after Endoscopic Submucosal Dissection.

BACKGROUND/AIMS: Platelet-rich plasma (PRP) has been used for wound healing in various medical fields. The aim of this study was to evaluate the clinical efficacy and safety of local PRP injections after endoscopic submucosal dissection (ESD). METHODS: Patients were non-randomly divided into the following two groups: (1) control group in which patients were administered only an intravenous proton pump inhibitor (PPI), and (2) a study group in which patients were administered an intravenous PPI and a topical PRP injection. We assessed the reduction in the ulcer area and stage of the ulcer after the procedure (24 hours, 48 hours, and 28 days after endoscopic surgery). RESULTS: We enrolled 7 study and 7 control patients. In the study group, the rate of ulcer reduction was 59% compared to 52% in the control group (p=0.372), 28 days after ESD. There were 5 patients in the S stage and 2 patients in the H stage in the study group compared to no patient in the S stage and 7 patients in the H stage in the control group (p=0.05), 28 days after ESD. There were no serious complications in either group. CONCLUSION: The local injection of PRP is a safe and effective procedure for ulcer healing after ESD.

Performance of disposable endoscopic forceps according to the manufacturing techniques.

BACKGROUND/AIMS: Recently, to lower the production costs and risk of infection, new disposable biopsy forceps made using simple manufacturing techniques have been introduced. However, the effects of the manufacturing techniques are unclear. The aim of this study was to evaluate which types of biopsy forceps could obtain good-quality specimens according to the manufacturing techniques. METHODS: By using an in vitro nitrile glove popping model, we compared the popping ability among eight different disposable biopsy forceps (one pair of biopsy forceps with cups made by a cutting method [cutting forceps], four pairs of biopsy forceps with cups made by a pressing method [pressing forceps], and three pairs of biopsy forceps with cups made using a injection molding method [molding forceps]). Using an in vivo swine model, we compared the penetration depth and quality of specimen among the biopsy forceps. RESULTS: In the in vitro model, the molding forceps provided a significantly higher popping rate than the other forceps (cutting forceps, 25.0%; pressing forceps, 17.5%; and molding forceps, 41.7%; p = 0.006). In the in vivo model, the cutting and pressing forceps did not provide larger specimens, deeper biopsy specimen, and higher specimen adequacy than those obtained using the molding forceps (p = 0.2631, p = 0.5875, and p = 0.2147, respectively). However, the molding forceps showed significantly more common crush artifact than the others (cutting forceps, 0%; pressing forceps, 5.0%; and molding forceps, 43.3%; p = 0.0007). CONCLUSION: The molding forceps provided lower performance than the cutting and pressing forceps in terms of crush artifact.

Assessment of Clinical Outcomes after Peroral Endoscopic Myotomy via Esophageal Distensibility Measurements with the Endoluminal Functional Lumen Imaging Probe.

Background/Aims: Endoluminal functional lumen imaging probe (EndoFLIP) is a modality that enables clinicians to measure volume-controlled distension of the esophagus. This study aimed to assess the utility of EndoFLIP in patients who had achalasia treated with peroral endoscopic myotomy (POEM). We hypothesized that improvement in the distensibility index (DI) is correlated with the postoperative clinical outcome of POEM. Methods: Patients who underwent POEM for achalasia at Cha Bundang Medical Center were included. Physiological measurements of the lower esophageal sphincter (LES) pressure before and after POEM were assessed using EndoFLIP. Patients' symptoms were recorded using the Eckardt score. Results: A total of 52 patients with achalasia were included in this study. Patients with a post-POEM DI below 7 (30 or 40 mL) had a significantly higher rate of incomplete response after POEM (p=0.001). Changes in LES pressure or integrated relaxation pressure after POEM were also significantly associated with an incomplete response (p=0.026 and p=0.016, respectively). Multivariate analysis showed that post-POEM DI ＜7 was the most important predictor of an incomplete response after POEM (p=0.004). Conclusions: Lower post-POEM DI values were associated with an incomplete post-POEM response. Therefore, post-POEM DI at the esophagogastric junction using EndoFLIP is a useful index for predicting the clinical outcome of POEM in patients with achalasia.

A double blind, placebo-controlled, randomized clinical trial that breast milk derived-Lactobacillus gasseri BNR17 mitigated diarrhea-dominant irritable bowel syndrome.

The exact pathogenesis of diarrhea-dominant irritable bowel syndrome (IBS) is not known, but the abnormal microbiota of the gastrointestinal tract is considered to be one of the important contributing factors as in other gastrointestinal diseases such as inflammatory bowel disease, antibiotic-associated diarrhea, and colorectal cancer as well as systemic diseases. Though diverse trials of probiotics had been continued in the treatment of diarrhea-IBS, only a few proved by randomized clinical trial. To prove the efficacy of Lactobacillus gasseri BNR17 isolated from breast milk in patients with diarrhea-IBS, prospective, randomized, placebo controlled clinical trial was done including health related-quality of life analysis, colon transit time, and the changes of fecal microbiota. BNR17 significantly improved the symptoms of diarrhea compared to control group. Health related-QOL analysis showed significant improvement of abdominal pain, distension, disturbed daily life, and mean defecation frequency with BNR17. On comparative CTT before and after BNR17, 6 out of 24 subjects showed significant correction of rapid colon transit pattern, while only 2 out of 24 in placebo (p<0.01). Upon fecal microbiota analysis, BNR17 significantly increased B. fecalis, E. rectale, C. aerofaciens, F. prausnitzil and B. steroris. Conclusively, Lactobacillus gasseri BNR17 can be a potential probiotics to ameliorate diarrhea-IBS.

Feasibility of intraperitoneal placental-derived mesenchymal stem cell injection in stomachs of diabetic mice.

BACKGROUND AND AIM: Diabetic gastropathy is associated with loss of interstitial cells of Cajal and autonomic neuropathy. Effective management for diabetic gastropathy is still unavailable. This study was aimed to confirm the pathogenetic changes in diabetic gastropathy and to examine the effect of treatment with placental-derived mesenchymal stem cells (PDMSCs) in stomachs of animal models. METHODS: Fourteen non-obese diabetic/ShiLtJ mice of 8 weeks were bled until week 30. Diabetes mellitus developed in 10 out of 14 mice, which all survived with insulin. The mice were grouped into three groups: nondiabetic group (n = 4), diabetic sham group (n = 5), and diabetic PDMSC group (n = 5) all of which were treated with intraperitoneal PDMSCs injection at week 30. All mice were killed at week 34, and the stomachs were examined by immunohistochemical stain with c-kit and neuronal nitric oxide synthase antibodies. RESULTS: The number of c-kit positive cells in stomach decreased significantly in the diabetic sham group compared with that in the nondiabetic group (21.2 ± 6.7 vs 88.0 ± 29.3, P = 0.006) but increased with PDMSC treatment (21.2 ± 6.7 vs 64.0 ± 15.1, P = 0.02). The positive rate of neuronal nitric oxide synthase in neural plexus was also significantly lower in the diabetic sham group than in the nondiabetic group (22.3% ± 18.5% vs 48.0% ± 22.7%, P = 0.003) but increased with PDMSC treatment (22.3% ± 18.5% vs 43.3% ± 20.5%, P = 0.03). CONCLUSIONS: Interstitial cells of Cajal and neural plexus decreased in stomachs of mice with diabetes mellitus but were significantly repaired with intraperitoneal injection of PDMSC.

Experimental study on the friction effect of plastic stents for biliary stone fragmentation (with video).

BACKGROUND AND AIM: In patients with irretrievable or intractable bile duct stone, temporary insertion of a plastic stent (PS) followed by further endoscopic retrograde cholangiopancreatography (ERCP) or surgery has been recommended as a 'bridge' therapy. However, the exact mechanism of stone fragmentation has not been discovered. The aim of the present study was to evaluate whether PS shape can facilitate stone fragmentation. METHODS: Using a new in vitro bile flow phantom model, we compared the friction effect among three different PS groups (straight PS group, double pigtail-shaped PS group, and screw-shaped PS group) and a control group. Each group had 10 silicon tube blocks that separately contained one stone and two PS. The control group had 10 blocks each with only a stone and no PS. We carried out analysis of the friction effect by stone weight and volume changes among the groups, excluding fragmented stones. RESULTS: After 8 weeks, complete fragmentation was noted in one out of 34 cholesterol stones (2.9%) and in four out of six pigmented stones (66.7%). Fragmentation tended to be more prominent in the screw-shaped PS group than in the straight PS group, double pigtail-shaped group, and control group (volume change: -11.33%, 7.94%, 4.43%, and 2.05%, respectively, P = 0.1390; weight change: -9.30%, 0.71%, -0.10%, and -1.23%, respectively, P = 0.3553). CONCLUSION: Stone fragmentation may be induced by PS friction effect. Also, screw-shaped plastic stents may improve friction effect. These results may help guide future PS development and clinical decisions.

Comparison of the Outcomes of Peroral Endoscopic Myotomy for Achalasia According to Manometric Subtype.

BACKGROUND/AIMS: We evaluated whether manometric subtype is associated with treatment outcome in patients with achalasia treated by peroral endoscopic myotomy (POEM). METHODS: High-resolution manometry data and Eckardt scores were collected from 83 cases at two tertiary referral centers where POEM is performed. Manometric tracings were classified according to the three Chicago subtypes. RESULTS: Among the 83 cases, 48 type I, 24 type II, and 11 type III achalasia cases were identified. No difference was found in pre-POEM Eckardt score, basal lower esophageal sphincter (LES) pressure, or integrated relaxation pressure (IRP) among the type I, type II, and type III groups. All three patient groups showed a significant improvement in post-POEM Eckardt score (6.1±2.1 to 1.5±1.5, p=0.001; 6.8±2.2 to 1.2±0.9, p=0.001; 6.6±2.0 to 1.6±1.4, p=0.011), LES pressure (26.1±13.8 to 15.4±6.8, p=0.018; 32.3±19.0 to 19.2±10.4, p=0.003; 36.8±19.2 to 17.5±9.7, p=0.041), and 4s IRP (21.5±11.7 to 12.0±8.7, p=0.007; 24.5±14.8 to 12.0±7.6, p=0.002; 24.0±15.7 to 11.8±7.1, p=0.019) at a median follow-up of 16 months. CONCLUSIONS: POEM resulted in a good clinical outcome for all manometric subtypes.

Discovery of a novel pan-RAF inhibitor with potent anti-tumor activity in preclinical models of BRAFV600E mutant cancer.

AIMS: BRAF mutations, especially BRAF V600E, are a frequent occurrence in malignant melanomas. The BRAF inhibitors are used as the care standard for BRAF-mutant metastatic melanomas. However, melanomas rapidly develop resistance to BRAF inhibitors after a median response duration of 6months, and the subsequent rapid development of cutaneous toxicity is enhanced by the paradoxical activation of CRAF. In this study, we discovered a potent and selective pan-RAF inhibitor: INU-152. The goal of this study was to investigate whether the inhibition of pan-RAF with INU-152 completely disrupts the MAPK pathway in cancer cells bearing BRAF or RAS mutations. MAIN METHODS: Using a structure-based molecular modeling, we discovered INU-152, which is a potent and selective pan-RAF inhibitor. In kinase assays against RAF proteins, INU-152 exhibited a potent effect against RAF isoforms. INU-152 was tested for its inhibitory effect on the growth of human cancer cells bearing BRAFV600E. To study in vivo effects, INU-152 was administered using human melanoma and colorectal cancer xenograft models. To explore INU-152's potential as a prospective drug candidate, pharmacokinetic studies and toxicity tests were performed using mice. KEY FINDINGS: To inhibit and suppress paradoxical activation in mutant RAS cancer cells completely, it is important for RAF inhibitors to exhibit potent inhibitory activities against RAF isoforms. SIGNIFICANCE: INU-152 inhibits all RAF isoforms and inhibits MAPK pathways in mutant BRAF cells. More importantly, INU-152 exhibits minimal paradoxical pathway activation in melanoma cells with mutant RAS. INU-152 exhibits anti-tumor activities in xenograft models carrying BRAF mutations.

Anti-fibrogenic effect of PPAR-γ agonists in human intestinal myofibroblasts.

BACKGROUND: Intestinal fibrosis is a serious complication of inflammatory bowel disease, including Crohn's disease and ulcerative colitis. There is no specific treatment for intestinal fibrosis. Studies have indicated that peroxisome proliferator-activated receptor- γ (PPAR-γ) agonists have anti-fibrogenic properties in organs besides the gut; however, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of PPAR-γ agonists on human primary intestinal myofibroblasts (HIFs). METHODS: HIFs were isolated from normal colonic tissue of patients undergoing resection due to colorectal cancer. HIFs were treated with TGF-ß1 and co-incubated with or without one of two synthetic PPAR-γ agonists, troglitazone or rosiglitazone. mRNA and protein expression of procollagen1A1, fibronectin, and α-smooth muscle actin were determined by semiquantitative reverse transcription-polymerase chain reaction and Western blot. LY294002 (Akt inhibitor) was used to examine whether Akt phosphorylation was a downstream mechanism of TGF-ß1 induced expression of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs. The irreversible PPAR-γ antagonist GW9662 was used to investigate whether the effect of PPAR-γ agonists was PPAR-γ dependent. RESULTS: Both PPAR-γ agonists reduced the TGF-ß1-induced expression of α-smooth muscle actin which was integrated into stress fibers in HIFs, as determined by actin microfilaments fluorescent staining and α-smooth muscle actin-specific immunocytochemistry. PPAR-γ agonists also inhibited TGF-ß1-induced mRNA and protein expressions of procollagen1A1, fibronectin, and α-smooth muscle actin. TGF-ß1 stimulation increased phosphorylation of downstream signaling molecules Smad2, Akt, and ERK. TGF-ß1 induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin through a phosphatidylinositol 3-kinase/Akt-dependent mechanism. PPAR-γ agonists down regulated fibrogenesis, as shown by inhibition of Akt and Smad2 phosphorylation. This anti-fibrogenic effect was PPAR-γ independent. CONCLUSIONS: Troglitazone and rosiglitazone suppress TGF-ß1-induced synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin in HIFs and may be useful in treating intestinal fibrosis.