Jie Song

Pirfenidone inhibits proliferation, arrests the cell cycle, and downregulates heat shock protein‑47 and collagen type I in rat hepatic stellate cells in vitro

Pirfenidone (esbiret) is an established anti-fibrotic and anti-inflammatory drug used to treat idiopathic pulmonary fibrosis. In the present study, the dose-dependent effects of pirfenidone on the cell cycle, proliferation and expression of heat shock protein (HSP)-47 and collagen type I in a cultured rat hepatic stellate cell line (HSC-T6) were investigated. Following pirfenidone treatment, cell proliferation was determined using the cell counting kit-8 assay and the cell cycle was measured using flow cytometry. HSP-47 expression was estimated using western blot analysis and collagen type I mRNA was assessed using reverse transcription quantitative polymerase chain reaction. Pirfenidone induced significant dose-dependent inhibition of proliferation in HSC-T6 cells. Cell viability was unaffected by treatment with pirfenidone (0, 10 or 100 µM) for 24 and 72 h. However, after 24 h, HSC-T6 cells exhibited dose-dependent decreases in HSP-47 protein and collagen I mRNA levels. In conclusion, pirfenidone inhibited HSC-T6 cell proliferation, arrested the cell cycle and reduced the expression of HSP-47 and collagen type I, indicating that pirfenidone may be a promising drug in the treatment of liver fibrosis.

Inositol-requiring enzyme 1-mediated endoplasmic reticulum stress triggers apoptosis and fibrosis formation in liver cirrhosis rat models

Long‑term and advanced cirrhosis is usually irreversible and often coincides with variceal hemorrhage or development of hepatocellular carcinoma; therefore, liver cirrhosis is a major cause of morbidity and mortality globally. The aim of the present study was to investigate the specific mechanism behind the formation of fibrosis or cirrhosis using rat models of hepatic fibrosis. The cirrhosis model was established by intraperitoneally administering dimethylnitrosamine to the rats. Hematoxylin and eosin staining was performed on the hepatic tissues of the rats to observe the fibrosis or cirrhosis, and western blot analysis was employed to detect α‑smooth muscle actin and desmin protein expression. Flow cytometric analysis was used to examine early and late apoptosis, and the protein and mRNA expression of endoplasmic reticulum (ER) stress-associated unfolded protein response (UPR) pathway proteins and apoptotic proteins [C/EBP homologous protein (CHOP) and caspase‑12] was detected by western blotting and the reverse-transcription polymerase chain reaction, respectively. The results indicated that the cirrhosis model was established successfully and that fibrosis was significantly increased in the cirrhosis model group compared with that in the normal control group. Flow cytometric analysis showed that early and late apoptosis in the cirrhosis model was significantly higher compared with that in the control group. The expression of the UPR pathway protein inositol-requiring enzyme (IRE) 1, as well as the expression of CHOP, was increased significantly in the cirrhotic rat tissues compared with that in the control group tissues (P<0.05). In conclusion, apoptosis was clearly observed in the hepatic tissue of cirrhotic rats, and the apoptosis was caused by activation of the ER stress-mediated IRE1 and CHOP.

Protective effects of ellagic acid against tetrachloride‑induced cirrhosis in mice through the inhibition of reactive oxygen species formation and angiogenesis

Ellagic acid has been proven to have anticancer, antimutation, antimicrobial and antiviral functions. The present study investigated whether treatment with ellagic acid was able to prevent tetrachloride (CCl4)-induced cirrhosis through the inhibition of reactive oxygen species (ROS) formation and angiogenesis. CCl4 diluted in olive oil at a final concentration of 10% was used to induce a cirrhosis model. A total of 40 mice were random allocated into four groups, as follows: Control, cirrhosis model, 7.5 mg/kg ellagic acid and 15 mg/kg ellagic acid groups. In the control group, mice were given normal saline. The results indicated that ellagic acid exerted a protective effect, evidently preventing CCl4-induced cirrhosis. In addition, treatment with ellagic acid significantly inhibited collagen I and inducible nitric oxide synthase protein expression levels in CCl4-induced cirrhosis mice. Oxidative stress and ROS formation were also significantly reduced by ellagic acid treatment. The protein expression levels of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2), and the caspase-3 activity were significantly inhibited by treatment with ellagic acid. In conclusions, these results suggest that ellagic acid exerted protective effects against CCl4-induced cirrhosis through the inhibition of ROS formation and angiogenesis.

Interferon-γ +874A/T polymorphism and hepatocellular carcinoma risk: a meta-analysis.

Background Studies have evaluated the association between interferon-γ (IFN-γ) +874A/T polymorphism and hepatocellular carcinoma (HCC) risk, but the results are controversial. We performed this meta-analysis to further investigate this association. Material/Methods Relevant studies were searched by using the PubMed, Web of Science, and Embase databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Subgroup analysis and sensitivity analysis were conducted. Results Seven case-control studies (859 HCC patients and 1482 healthy controls) were identified to assess the association between IFN-γ +874A/T polymorphism and risk of HCC. IFN-γ +874A/T polymorphism was significantly associated with an increased risk of HCC (OR=1.38; 95% CI 1.12–1.70; P=0.002). In the subgroup analysis by ethnicity, IFN-γ +874A/T polymorphism was significantly associated with HCC risk in Asians (OR=1.42; 95% CI 1.08–1.87; P=0.01), but no significant association was found in Caucasians (OR=1.21; 95% CI 0.86–1.70; P=0.28). IFN-γ +874A/T polymorphism also increased HBV-induced HCC risk (OR=1.42; 95% CI 1.08–1.87; P=0.01). In the subgroup analysis by control source, IFN-γ +874A/T polymorphism was associated with HCC risk in hospital-based studies (OR=1.45; 95% CI 1.09–1.53; P=0.01). A marginal association was found in population-based studies (OR=1.33; 95% CI 0.97–1.83; P=0.08). Conclusions This meta-analysis indicates that the IFN-γ +874A/T polymorphism might contribute to HCC risk.

Comparisons of cognitive function and serum S-100B level between diabetic and non-diabetic patients after the implantation of carotid artery stent (CAS).

To investigate cognitive function improvement in diabetic and non-diabetic patients after the implantation of Carotid Artery Stent (CAS), 128 patients suffering severe carotid stenosis were successfully enrolled in this study. Tests including, the Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Alzheimers Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Clock Drawing Test (CDT), Hasegawas Dementia Scale-Revised (HDS-R) and the serum levels of S-100B, were all measured at baseline for 3 months after the implantation of CAS. The baseline characteristics were similar between the patients with and without diabetes. 3 months after the implantation, significant improvements in MMSE (24.8 ± 2.2 vs. 25.2 ± 2.1, p=0.003), MoCA (25.6 ± 2.0 vs. 26.1 ± 1.9, p=0.000), ADAS-Cog (6.5 ± 1.3 vs. 6.1 ± 1.3, p=0.000), and CDT (3.3 ± 0.7 vs. 3.5 ± 0.7, p=0.034) were observed in the non-diabetic group. In contrast, there was no significant improvement in any of the cognitive test for the diabetic group. Another interesting discovery was the CAS procedure significantly decreased the S-100B level in the non-diabetic group (0.11 ± 0.04 ng/mL vs. 0.10 ± 0.04 ng/mL, p=0.000), but similar phenomena were not discovered in the diabetic group. In this light, the change of the S-100B level was negatively correlated with the results in the MMSE (p<0.01) and the MoCA (p<0.01) tests, and positively correlated with the result in ADAS-Cog (p<0.05) test. Our findings suggest that the CAS-induced beneficial effects on cognitive function might have a correlation relationship with the serum level of S-100B.

Embolization of arterial gastrointestinal hemorrhage with Fuaile medical adhesive

Background: To investigate the safety and effectiveness of Fuaile medical adhesive (FAL) with superselective catheterization in endovascular embolotherapy for the treatment of gastrointestinal hemorrhage (GIH) that was unresponsive to internal medicine treatment and gastroscopy management. Methods: A total of 25 patients with GIH, confirmed using angiography but with failed results after internal medicine treatment or gastroscopy were retrospectively analyzed. A mixture of lipiodol and FAL (1:1) was used to embolize the bleeding vessels. In the follow‐up, the operation time, FAL amount, technical success rate, clinical success rate, postoperative complications, and survival conditions were compared and analyzed. Results: Among the 25 patients with GIH, FAL was applied alone in 23 patients and microcoil combined with FAL was applied in two patients. Hemostasis was successfully achieved in all patients. Two patients treated with embolotherapy experienced relapse of bleeding within 30 days but achieved successful hemostasis with FAL. Four patients died during follow‐up: three patients died of advanced cancer and one patient died of severe infection induced by necrotizing pancreatitis. Three patients developed postoperative intestinal ischemic symptoms, which resolved spontaneously in two patients. In one patient, abdominal pain progressively aggravated. This patient underwent surgical resection, which confirmed the presence of colonic neoplasms. The intraoperative view revealed obvious ischemia of the local normal bowel near the tumor; however, the patient finally recovered and was discharged after surgery. The remaining patients exhibited good survival during the postoperative follow‐up. Conclusion: FAL embolotherapy has a high success rate for arterial GIH that was unresponsive to internal medicine treatment and gastroscopy management, with low postoperative rates of bleeding and complications; thus, this method has a high cost‐efficacy.

Massive Gastrointestinal Bleeding Secondary to Superior Mesenteric Arteriovenous Fistula

consider FMT, only 12 % indicated that the procedure should be reimbursed. Among the survey respondents who were reluctant to consider FMT, availability of published guidelines from gastrointestinal / ID societies was an important requirement in potential acceptance of this therapeutic modality in the future ( Table 1 ). Additionally, all the respondents who indicated “ never thought about the therapy ” were willing to accept FMT if published guidelines were available. Th e recent published guidelines on the management of patients with CDI have now addressed this requirement ( 1 ). However, the principal reason for not considering FMT in our survey participants was the lack of knowledge about the FMT protocol ( Table 1 ). Th e majority of the respondents reluctant to consider FMT were willing to accept it if training for the procedure is promoted and workshops are held (54 % ). A recent review article methodically explains the FMT procedure; however, practical knowledge acquired by procedure-specifi c physician training may promote wider use of this therapy ( 3 ). Contrary to a popular belief, only one respondent considered the unpleasant nature of FMT as the reason for not considering this therapy ( Table 1 ). Th e results of this survey reveal that physicians are mostly interested in considering FMT for their patients with recurrent CDI. Our results are in stark contrast to the results obtained by Kelly et al. ( 4 ) in 2009, in which only 48 % of physicians were willing to try FMT . Th e results of our survey are not surprising. Th ere has been signifi cant addition of published studies supporting the effi cacy and safety of FMT for CDI over the past 4 years ( 2 ). Additionally, there has also been an increasing incidence of recurrent CDI over the past years ( 5 ). Th erefore, in the absence of a potent alternative therapy and consistently increasing evidence of the safety and effi cacy of FMT, physicians seem to be more receptive of this therapeutic option in patients with CDI. However, a recent directive by the US Food and Drug Administration (FDA) requiring Investigational New Drug application for the use of FMT will impede the widespread use of this therapy for CDI. A recent survey by Zipursky et al. ( 6 ) showed patient receptiveness of FMT for treatment of recurrent CDI. Furthermore, our survey reveals that physicians are set to accept this novel therapy for patients with CDI. Currently with the availability of guidelines ( 1 ) and published procedural details ( 3 ), providing practical training to physicians (preferably at the scientifi c meetings) will stimulate wider use of FMT for recurrent CDI.