Knockdown of LMX1B Suppressed Cell Apoptosis and Inflammatory Response in IL-1ß-Induced Human Osteoarthritis Chondrocytes through NF-κB and NLRP3 Signal Pathway.

Osteoarthritis (OA), a chronic degenerative joint disease, always occurred in the aging population. There is evidence suggests that chondrocytes' survival, inflammation, and apoptosis play critical roles in OA pathogenesis. LMX1B has been shown to be involved in antiosteogenic function in early patterning of the calvaria. However, the role and mechanism of LMX1B in OA is not unknown. The present study observed that LMX1B was highly expressed in OA patients compared with normal patients. Besides, we found that IL-1ß increased LMX1B mRNA and protein expression in SW1353 and C28/I2 chondrocytes. LMX1B knockdown increased IL-1ß-induced cell viability and proliferation and suppressed cell apoptosis and inflammation response, including IFN-γ, TNF-α, IL-6, prostaglandin E2 (PGE2), and NO both in SW1353 and C28/I2. Furthermore, LMX1B silence inhibited MMP-3 and MMP-13 expression both in SW1353 and C28/I2 cells. Also, the activation of the NF-κB and NLRP3 signaling pathway was suppressed in LMX1B silence cells by decreasing the p-p65 and NLRP3 protein expressions. Additionally, inhibition of NF-κB by PDTC suppressed NLRP3 expression. Moreover, NLRP3 overexpression reversed the effects of LMX1B silence on chondrocytes' survival, proliferation, apoptosis, and inflammation. Finally, we confirmed that LMX1B depletion had protective effects in OA rats in vivo.

The protective effects of naproxen against interleukin-1ß (IL-1ß)- induced damage in human umbilical vein endothelial cells (HUVECs).

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most widely used medications in the world. Naproxen is an NSAID with relatively low selectivity for cyclooxygenase-2 (COX-2), thereby having decreased risk for cardiovascular (CV) events. However, it is unclear whether naproxen might provide protection against atherosclerosis, an underlying cause of numerous cardiovascular diseases (CVDs). In the present study, we exposed human umbilical vein endothelial cells to interleukin-1ß (IL-1ß), a key cytokine involved in atherogenesis, with or without naproxen. Our findings indicate that naproxen could protect against IL-1ß-induced damage by improving cell viability and preventing cell death. Additionally, naproxen suppressed the expression of the cytokines IL-6, IL-12, and tumor necrosis factor-α (TNF-α), and downregulated the expression of vascular endothelial growth factor (VEGF) and tissue factor (TF) induced by IL-1ß. Importantly, naproxen also inhibited the attachment of monocytes to endothelial cells, which was achieved through Krüppel-like factor 6 (KLF6)-mediated reduced expression of intracellular adhesion molecule-1 (ICAM-1) and E-selectin. These findings suggest that naproxen may aid in the prevention of atherosclerosis by exerting cardioprotective effects beyond low COX-2-selectivity.

Fork head box M1 regulates vascular endothelial growth factor-A expression to promote the angiogenesis and tumor cell growth of gallbladder cancer.

BACKGROUND: Gallbladder cancer (GBC) is an aggressive type of biliary tract cancer that lacks effective therapeutic targets. Fork head box M1 (FoxM1) is an emerging molecular target associated with tumor progression in GBC, and accumulating evidence suggests that vascular endothelial growth factor (VEGF) promotes various tumors by inducing neoangiogenesis. AIM: To investigate the role of FoxM1 and the angiogenesis effects of VEGF-A in primary GBC. METHODS: Using immunohistochemistry, we investigated FoxM1 and VEGF-A expression in GBC tissues, paracarcinoma tissues and cholecystitis tissues. Soft agar, cell invasion, migration and apoptosis assays were used to analyze the malignant phenotype influenced by FoxM1 in GBC. Kaplan-Meier survival analysis was performed to evaluate the impact of FoxM1 and VEGF-A expression in GBC patients. We investigated the relationship between FoxM1 and VEGF-A by regulating the level of FoxM1. Next, we performed MTT assays and Transwell invasion assays by knocking out or overexpressing VEGF-A to evaluate its function in GBC cells. The luciferase assay was used to reveal the relationship between FoxM1 and VEGF-A. BALB/c nude mice were used to establish the xenograft tumor model. RESULTS: FoxM1 expression was higher in GBC tissues than in paracarcinoma tissues. Furthermore, the high expression of Foxm1 in GBC was significantly correlated with a malignant phenotype and worse overall survival. Meanwhile, high expression of FoxM1 influenced angiogenesis; high expression of FoxM1 combined with high expression of VEGF-A was related to poor prognosis. Attenuated FoxM1 significantly suppressed cell proliferation, transfer and invasion in vitro. Knockdown of FoxM1 in GBC cells reduced the expression of VEGF-A. Luciferase assay showed that FoxM1 was the transcription factor of VEGF-A, and knockdown VEGF-A in FoxM1 overexpressed cells could partly reverse the malignancy phenotype of GBC cells. In this study, we found that FoxM1 was involved in regulation of VEGF-A expression. CONCLUSION: FoxM1 and VEGF-A overexpression were associated with the prognosis of GBC patients. FoxM1 regulated VEGF-A expression, which played an important role in the progression of GBC.

Casticin protects against IL-1ß-induced inflammation in human osteoarthritis chondrocytes.

Casticin, an active compound isolated from Vitex rotundifolia L., was reported to possess anti-inflammatory activity. However, the effect of casticin on inflammatory response in human osteoarthritis (OA) chondrocytes remains unclear. In the current study, we examined the anti-inflammatory effects of casticin on chondrocytes exposed to interleukin-1ß (IL-1ß). Our results demonstrated that casticin treatment significantly improved cell viability in chondrocytes exposed to IL-1ß. Casticin significantly inhibited IL-1ß-induced NO and PGE2 production, and iNOS and COX-2 expression in human OA chondrocytes. It also suppressed the levels of TNF-α and IL-6, as well as decreased production of MMP-3, MMP-13, ADAMTS-4 and ADAMTS-5 in IL-1ß-stimulated chondrocytes. Furthermore, casticin prevented IL-1ß-induced NF-κB activation in chondrocytes. Taken together, these findings showed that casticin attenuates inflammatory responses in chondrocytes stimulated with IL-1ß, possibly through the NF-κB signaling pathway. Thus, casticin may serve as a potential anti-inflammatory agent in the treatment of OA.

Prognostic significance of preoperative platelet count in patients with gallbladder cancer.

AIM: To investigate the prognostic value of preoperative platelet count (PLT) in patients with primary gallbladder cancer (GBC). METHODS: The clinical data of 223 GBC patients after surgery was retrospectively reviewed. A receiver operating characteristic (ROC) curve was plotted to verify the optimum cutoff point for PLT. Univariate and multivariate survival analyses were performed to identify the factors associated with the prognosis. RESULTS: The ROC curve showed that the optimum cutoff point for PLT was 178 × 10(9)/L, and the entire cohort was stratified into group A with PLT > 178 × 10(9)/L and group B with PLT ≤ 178 × 10(9)/L. Group A had a better survival than group B (P < 0.001). There was an obvious difference between the two groups in terms of the differentiation degree, advanced tumor stage, lymph node metastasis (P < 0.001) and pathological type (P < 0.05). The univariate analysis demonstrated that tumor location, differentiation degree, TNM stage, Nevin stage, lymph node metastasis and PLT were associated with overall survival (P < 0.001). In the multivariate analysis, PLT (P = 0.032), lymph node metastasis (P = 0.007), tumor location (P < 0.001) and TNM stage (P = 0.005) were independent prognostic factors. CONCLUSION: PLT is closely correlated with GBC prognosis and could be used to identify the population with a poorer prognosis after surgery.

[Surgical treatment of hepatocellular carcinoma with tumor thrombus in inferior vena cava].

OBJECTIVE: To review the experience for the management of hepatocellular carcinoma with tumor thrombus in inferior vena cava. METHODS: From July 2003 to May 2005, hepatectomy combined with thrombectomy were performed on 7 cases of hepatocellular carcinoma with tumor thrombus in inferior vena cava. In order to remove the tumor thrombus in inferior vena cava, total hepatic vascular exclusion were adopted on all cases to control the blood flow of IVC. According to the position of extension of tumor thrombus, 5 different procedures were adopted in the cases to control the suprahepatic IVC and extract the tumor thrombus out of IVC and atrium. Procedure 1: Median sternotomy, extracorporeal bypass, cardiac arrest, incision on right atrium and IVC were performed on 1 case for thrombectomy. Procedure 2: Median sternotomy, extracorporeal bypass without cardiac arrest, incision on IVC and (or without) incision on right atrium were performed on 2 cases for thrombectomy. Procedure 3: Abdominal approach to control intrapericardial IVC through an incision on diaphragm was performed on 1 case for thrombectomy. Procedure 4: Abdominal approach to control suprahepatic IVC above diaphragm through a small incision made on vena cava foramen for thrombectomy was performed on 1 case. Procedure 5: Abdominal approaches to control suprahepatic IVC below diaphragm for thrombectomy were performed on 2 cases. RESULTS: All operations were successfully performed. The postoperative complications included pleural effusion in 1 case, subphrenic fluid collection in 1 case and wound infection in 1 case. The average survival time of 7 cases was 9.8 month. The longest survival time was 26 months. CONCLUSION: Hepatectomy and thrombectomy can be safely performed on the case of HCC combined with tumor thrombus in IVC. Surgical treatment can relieve the patient from the risk of sudden death caused by heart failure and pulmonary.

[Surgical treatment of hepatocellular carcinoma originating from caudate lobe].

OBJECTIVE: To explore the significance of surgical treatment of HCC originating from caudate lobe. METHODS: From 1995 to 2003, caudate lobectomy, including 19 cases of isolated lobectomy and 20 cases of combined lobectomy, were performed in 39 patients with HCC originating from caudate lobe, and the factors that might influence postoperative liver function were compared between the two groups. RESULTS: All tumors were resected successfully. One patient died of postoperative renal failure. Hydrothorax occurred in 3 patients, ascites in 4 patients, and bile leakage in 1 patient. The survival rates of 1, 3, 5 year were 53%, 50%, 39% respectively. CONCLUSIONS: Caudate lobectomy is a effective method for HCC originating from caudate lobe.

[Role and significance of extrahepatic control of hepatic vein and inferior vena cava in difficult hepatectomies for patients with liver tumors].

OBJECTIVE: To explore the role of extrahepatic control on blood flow of hepatic vein and inferior vena cava in hepatectomy, and observe its effect on minimizing hemorrhage. METHODS: From 2001 to April 2003, 33 patients who had liver tumors involving segment IV, VII, VIII or half liver underwent major hepatectomies that required exposure of the inferior vena cava and main trunks of hepatic veins, during which the major hepatic veins and inferior vena cava were isolated and taped to control blood flow when necessary. RESULTS: In 33 attempts, 32 were successful and all tumors were resected successfully. The placement of occlusion tape was unsuccessful in 1 case. 7 cases did not need blood transfusion during operation. The amount of blood transfusion for other cases were form 0 to 1 600 ml. there was no operative mortality. CONCLUSIONS: Appropriate control of main truck of hepatic vein and inferior vena cava is effective in reducing blood loss during hepatectomies. It is also very helpful for performing difficult hepatectomies.

Prospective study of scoring system in selective intraoperative cholangiography during laparoscopic cholecystectomy.

AIM: To evaluate of scoring system in predicting choledocholithiasis in selective intraoperative cholangiography (IOC) during laparoscopic cholecystectomy (LC). METHODS: The scoring system of predicting choledocholithiasis was developed during the retrospective study in 264 cases, and was tested in 184 to evaluate its predictive value in choledocholithiasis. RESULTS: The scoring system was developed in a retrospective study of 264 cases, the statistical analyses showed the predictive factors included sex, transaminase levels, alkaline phosphatase level, bilirubin level, and common bile duct diameter on ultrasonography. The scoring system was used in 184 cases prospectively, of which, 3 of 162 (1.9 %) cases scoring <3 had choledocholithiasis, 17 of 22 (77.3 %) cases scores >=3 had choledocholithiasis. A case of scores >=3 or more prospectively should be considered highly intraoperative cholangiography during laparoscopic cholecystectomy. CONCLUSION: The scoring system can predict choledocholithiasis and is helpful in selection patients for intraoperative cholangiography.