[Molecular mechanism of cyclooxygenase-2 inhibitor in inhibition of proliferation of colon cancer cells by modulating Stat5 signal transduction pathway].

OBJECTIVE: To investigate the role of NS398, a selective cyclooxygenase (COX)-2 inhibitor, in proliferation and apoptosis of colorectal cancer, and to reveal the mechanism of inhibiting colon cancer by NS-398 Independent of COX-2. METHODS: Human colon cancer cells of the line SW480 were cultured and then divided into 2 groups: experimental group and control group. NS398 of the concentrations of 12.5, 25, 50, 75, 100, and 125 micromol/L was added into the culture fluid of the experimental group. MTT assay was used to observe the proliferation of the cells, flow cytometry was used to test the cell cycle, RT-PCR analysis was performed to examine COX-2 mRNA expression, and Western blotting analysis was performed to detect the expression of Stat5, peroxisome proliferators-activated receptors (PPARs), cyclin D1 and Bcl-x(L). RESULTS: Expression of COX-2 mRNA was not detected in the SW480 colon cancer cells. 72 hours after the addition of NS398 75 micromol/L the proliferative level of the SW480 cells was decreased; the rate of the cells at the G(1) stage increased from 31.2% to 40.6%, and the rate of cells at the S stage decreased from 52.8% to 41.2%. The expression of Stat5, PPARdelta, cyclin D1 and Bcl-x(L) decreased along with the elongation of time of NS398 action. CONCLUSION: COX-2 inhibitor, such as NS-398 inhibits the colon cancer cell proliferation and induces apoptosis of colon cancer cells with the possible mechanism of inhibiting the proliferation and inducing the apoptosis of colon cancer cells through a pathway independent of COX-2.

Caffeic acid phenethyl ester possesses potent cardioprotective effects in a rabbit model of acute myocardial ischemia-reperfusion injury.

Although great achievements have been made in elucidating the molecular mechanisms contributing to acute myocardial ischemia/reperfusion (I/R) injury, an effective pharmacological therapy to protect cardiac tissues from serious damage associated with acute myocardial infarction, coronary arterial bypass grafting surgery, or acute coronary syndromes has not been developed. We examined the in vivo cardioprotective effects of caffeic acid phenethyl ester (CAPE), a natural product with potent anti-inflammatory, antitumor, and antioxidant activities. CAPE was systemically delivered to rabbits either 60 min before or 30 min after surgically inducing I/R injury. Infarct dimensions in the area at risk were reduced by >2-fold (P < 0.01) with CAPE treatment at either period. Accordingly, serum levels of normally cytosolic enzymes lactate dehydrogenase, creatine kinase (CK), MB isoenzyme of CK, and cardiac-specific troponin I were markedly reduced in both CAPE treatment groups (P < 0.05) compared with the vehicle-treated control group. CAPE-treated tissues displayed significantly less cell death (P < 0.05), which was in part due to inhibition of p38 mitogen-activated protein kinase activation and reduced DNA fragmentation often associated with caspase 3 activation (P < 0.05). In addition, CAPE directly blocked calcium-induced cytochrome c release from mitochondria. Finally, the levels of inflammatory proteins IL-1beta and TNF-alpha expressed in the area at risk were significantly reduced with CAPE treatment (P < 0.05). These data demonstrate that CAPE has potent cardioprotective effects against I/R injury, which are mediated, at least in part, by the inhibition of inflammatory and cell death responses. Importantly, protection is conferred when CAPE is systemically administered after the onset of ischemia, thus demonstrating potential efficacy in the clinical scenario.

Clinical analysis of surgical treatment of portal hypertension.

AIM: To review the experience in surgery for 508 patients with portal hypertension and to explore the selection of reasonable operation under different conditions. METHODS: The data of 508 patients with portal hypertension treated surgically in 1991-2001 in our centers were analyzed. Of the 508 patients, 256 were treated with portaazygous devascularization (PAD), 167 with portasystemic shunt (PSS), 62 with selective shunt (SS), 11 with combined portasystemic shunt and portaazygous devascularization (PSS+PAD), 9 with liver transplantation (LT), 3 with union operation for hepatic carcinoma and portal hypertension (HCC+PH). RESULTS: In the 167 patients treated with PSS, free portal pressure (FPP) was significantly higher in the patients with a longer diameter of the anastomotic stoma than in those with a shorter diameter before the operation (P < 0.01). After the operation, FPP in the former patients markedly decreased compared to the latter ones (P < 0.01). The incidence rate of hemorrhage in patients treated with PAD, PSS, SS, PSS+PAD, and HCC+PH was 21.09% (54/256), 13.77 (23/167), 11.29 (7/62), 36.36% (4/11), and 100% (3/3), respectively. The incidence rate of hepatic encephalopathy was 3.91% (10/256), 9.58% (16/167), 4.84% (3/62), 9.09% (1/11), and 100% (3/3), respectively while the operative mortality was 5.49% (15/256), 4.22% (7/167), 4.84% (3/62), 9.09% (1/11), and 66.67% (2/3) respectively. The operative mortality of liver transplantation was 22.22% (2/9). CONCLUSION: Five kinds of operation in surgical treatment of portal hypertension have their advantages and disadvantages. Therefore, the selection of operation should be based on the actual needs of the patients.

Constitutive activation of Stat3 signaling pathway in human colorectal carcinoma.

AIM: Signal transducers and activators of transcription (STATs) are a family of transcription factors activated in response to cytokines and growth factors. Constitutive activation of Stat3 has been observed in a growing number of tumor-derived cell lines, as well as tumor specimens from human cancers. The purpose of this study was to investigate the expression of p-Stat3, activated form of Stat3, and its downstream mediators including cyclin D1 and Bcl-x(L) in colorectal carcinoma (CRC), and to explore the possible mechanism of Stat3 signaling pathway in the tumorigenesis of colorectal carcinoma. METHODS: Tissue samples from 45 patients of primary colorectal carcinoma were selected for studying Stat3 signaling pathway protein expression. Western blot analysis was used to measure the expression of p-Stat3, cyclin D1, and Bcl-x(L) proteins in colorectal carcinomas. Furthermore, the expression patterns of these proteins were analyzed for their distribution at the cellular level by immunohistochemical staining of the tissues. RESULTS: Protein levels of p-Stat3, cyclin D1, and Bcl-x(L) were increased in colorectal carcinomas compared with adjacent normal mucosae (P<0.05). Elevated levels of p-Stat3 were correlated with the nodal metastasis and the stage (P<0.05). Overexpression of cyclin D1 was associated with the nodal metastasis (P<0.05). There was also a significant correlation between the expressions of p-Stat3 and cyclin D1 (r=0.382, P<0.05). CONCLUSION: Constitutive activation of Stat3 may play an important role in the tumorigenesis of colorectal carcinoma, and the detailed mechanism of Stat3 signaling pathway in CRC deserves further investigation.

[The reason and treatment of portal vein thrombosis in patients with portal hypertension postoperation].

OBJECTIVE: To investigate reason and the management of portal vein thrombosis in patients with portal hypertension postoperatively. METHODS: 329 patients with portal hypertension in liver cirrhosis who had splenectomy was reviewed from 1992 to 2001. In whom 43 (13.1%) patients with portal vein thrombosis postoperative were analyzed. RESULTS: In these patients, except 1 died for portal vein phlebitis, all patients were recovered. There are 138 patients who underwent splenectomy or splenectomy and devascularization, 26 (18.8%) of them had thrombosis. 191 patients underwent splenectomy and portacaval or portasplenic shut, 17 (8.9%) of them had thrombosis. The data of these two groups have significant difference (chi(2) = 8.44, P < 0.01). CONCLUSIONS: Thrombocytosis postsplenectomy as well as the changes of portal hemodynamics is the main reason of portal vein thrombosis. Portal vein thrombosis is also in association with the operative ways. Operation standardization, dynamic examining platelet count, routine color ultrasonography examining and early anticoagulation therapy are the effective methods in preventing and managing portal thrombosis postoperation for portal hypertension.

[Relationship of Stat3 and its target gene products with malignancy in human colorectal carcinoma].

BACKGROUND & OBJECTIVE: Signal transducers and activators of transcription 3 (Stat3) pathway can be activated by cytokines and growth factors, and activation of Stat3 is involved in modulating cell proliferation, differentiation, and apoptosis. Stat3 has been classified as an oncogene because Stat3 can mediate malignant transformation of cultured cells. This study was conducted to investigate the expression of Stat3 and its target gene products including Cyclin D1 and Bcl-x(L) in human colorectal carcinoma (CRC) tissues and cells, and to explore the mechanisms in tumorigenesis of CRC. METHODS: The expression of Stat3, p-Stat3, Cyclin D1, and Bcl-x(L) in 45 cases of cancerous tissues, adjacent normal tissues, and two colon cancer cell lines including SW480 and HCT116 was measured by Western blot analysis. The expression pattern of Stat3 and its activated form p-Stat3 was determined by immunohistochemical staining. The relationship of the expression of p-Stat3, Cyclin D1, and Bcl-x(L) in CRC with various clinicopathological characteristics was analyzed statistically. RESULTS: The protein expression rates of p-Stat3, Cyclin D1, and Bcl-x(L) in colorectal cancer and adjacent normal mucosa were 57.8%, 64.4%, 68.9%, and 42.2%, 35.6%, 31.1%,respectively; and their protein levels (A value) were 114263+/-53598, 58321+/-24872, 71032+/-43425 in colorectal cancer and 55971+/-28762, 22563+/-11160, 37281+/-14622 in adjacent normal mucosa (P< 0.05). Overexpression of p-Stat3 was correlated with clinical stage and nodal metastasis in colorectal cancer (P = 0.026 and P= 0.018, respectively). Elevated levels of Cyclin D1 were associated with nodal metastasis (P= 0.041). It was found that Cyclin D1 was in a positive linear correlation fashion with p-Stat3 in tumor (r = 0.382, P< 0.05). Activated Stat3 was also detected in both colon cancer cell lines SW480 and HCT116. CONCLUSION: Stat3 signaling pathway may play an important role in the tumorigenesis of colorectal carcinoma. Determination of Stat3 and its target gene products can be used to indicate the malignancy degree of colorectal carcinoma.

[Stat3 signal transduction pathway orchestrates G1 to S cell cycle transition in colon cancer cells].

OBJECTIVE: To show that Stat3 plays a key role in the G1 to S phase transition in colon cancer cells. METHODS: Human colon cancer cell lines SW480 and HCT116 were transfected with Stat3 antisense oligonucleotide mediated by liposome, MTT assay was used to measure the proliferation, flow cytometry was applied to analyze the cell cycle, and the expressions of Stat3, phosphorylation-specific Stat3 (tyrosine 705), Cyclin D1, Cyclin E, CDK2, CDK4, CDK6, p21 and p27 were measured by western blot. RESULTS: SW480 and HCT116 colon cancer cell lines expressed constitutively activated Stat3. Targeting of Stat3 using antisense oligonucleotide which directed against the translation site resulted in growth inhibition, downregulation of Stat3, p-Stat3, Cyclins and CDKs, and up-regulation of p21 and p27. CONCLUSION: Our findings suggest that Stat3 plays an important role in the G1 to S phase transition in colon cancer cells, Stat3 orchestrates cell cycle by regulating the balance between CDK/Cyclin complex and CKI.

[Expression and clinical significance of hepatocellular cancer antigen genes in human hepatocellular carcinoma].

OBJECTIVE: To investigate the expression of four hepatocellular cancer antigen (HCA) gene mRNA in hepatocellular carcinoma. METHODS: The expression of HCA90, HCA519, HCA520, HCA587 mRNA was detected using RT-PCR in HCC tissues and the corresponding adjacent non-HCC tissues from 46 HCC patients, cirrhosis tissues from 10 samples and normal liver tissues from 10 samples. The relationship between positive expression rate of HCA gene and clinical and lab data was evaluated. RESULTS: Of 46 HCC tissues, HCA90, HCA519, HCA520 and HCA587 mRNA were detectable in 65.2%, 76.1%, 45.7% and 32.6%, respectively. At least one HCA gene mRNA was positive in 82.6% of HCC tissues. Only weak expression of HCA519 could be detectable in 6.5% of the corresponding adjacent non-HCC tissues. None of 10 samples of cirrhosis and normal liver tissues expressed any HCA gene mRNA. No correlation was found between the expression of HCA and clinical date such as age, sex, tumor size, tumor differentiation, serum alpha-fetoprotein level and hepatitis B virus infection or hepatitis C virus infection (P > 0.05). However, in some patients with normal serum alpha-fetoprotein (< 25 ng/L), specific expression of HCA genes was observed. CONCLUSION: HCA gene mRNA is expressed with a high percentage and specificity in hepatocellular carcinomas and their products are new potential promising targets for immunotherapy of HCC.

[Depressive disorder in patients undergoing general surgical operations].

OBJECTIVE: To investigate the prevalence of depressive disorder in patients undergoing general surgical operations. METHODS: One hundred and four patients who had undergone general surgical operations were investigated. Each patient filled in the self rating depression scale (SDS) as the baseline data. RESULTS: Among these patients 40.4% of them had depressive disorder. The major factors for the prevalence of depression were sex, educational background and malignant diseases. CONCLUSIONS: A certain proportion of patients undergoing general surgical operations have depressive disorder. It is important to recognize and treat for this disorder.

[Expression of mitogen-activated protein kinase and its upstream regulated signal in human hepatocellular carcinoma].

OBJECTIVE: To detect protein expression of ERK(1), ERK(2), JNK(1), p38 and MEK(1), MEK(2) in human hepatocellular carcinoma and adjacent non-neoplastic liver. METHODS: In 16 surgically resected hepatocellular carcinoma and para-carcinoma tissues, Western blotting was used to detect expression of ERK(1), ERK(2), JNK(1), p38 and MEK(1), MEK(2). RESULTS: In all cases, ERK(1), ERK(2), p38 expression in hepatocellular carcinoma was significantly higher than that in para-carcinoma: integral optic density (IOD) of ERK(1) was 300 +/- 98 in carcinoma and 98 +/- 48 in para-carcinoma tissues (t = 2.519, P < 0.01); IOD of ERK(2) was 587 +/- 83 in carcinoma and 232 +/- 96 in para-carcinoma tissues (t = 2.745, P < 0.01); IOD of p38 was 270 +/- 85 in carcinoma and 107 +/- 88 in para-carcinoma tissues (t = 2.491, P < 0.01). JNK(1) expression in hepatocellular carcinoma was significantly lower than that in para-carcinoma; IOD of JNK(1) was 111 +/- 93 in carcinoma and 292 +/- 109 in para-carcinoma tissues (t = 2.473, P < 0.01). Protein levels of MEK(1) and MEK(2) in carcinoma were significantly higher than in para-carcinoma. IOD of MEK(1) was 1 418 +/- 244 in carcinoma and 806 +/- 90 in para-carcinoma tissues (t = 2.546, P < 0.01). IOD of MEK(2) was 1 041 +/- 122 in carcinoma and 468 +/- 40 in para-carcinoma tissues (t = 2.861, P < 0.01). CONCLUSIONS: ERK(1), ERK(2), MEK(1) and MEK(2) in the signal transduction pathway for cell proliferation are significantly overexpressed and the expression of JNK(1) is lower in hepatocellular carcinoma. Their unbalance is one of the important reasons for the over growth and infinite proliferation of the hepatocellular carcinoma cell. The p38 and JNK(1) may be activated by different pathway.