Sediment pollutant exposures caused hepatotoxicity and disturbed glycogenesis.

Liver metabolic syndrome, which involves impaired hepatic glycogen synthesis, is persistently increased by exposure to environmental pollutants. Most studies have investigated the pathogenesis of liver damage caused by single metal species or pure organics. However, under normal circumstances, the pollutants that we are exposed to are usually chemical mixtures that accumulate over time. Sediments are long-term repositories for environmental pollutants due to their environmental cycles, which make them good samples for evaluating the effect of environmental pollutants on the liver via bioaccumulation. This study aimed to clarify the effects of sediment pollutants on liver damage. Our results indicate that industrial wastewater sediment (downstream) is more cytotoxic than sediments from other zones. Downstream sediment extract (DSE) causes hepatotoxicity, stimulates reactive oxygen species (ROS) generation, triggers mitochondrial dysfunction, induces cell apoptosis, and results in the release of glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) proteins. Additionally, to elucidate the underlying mechanism by which sediment pollutants disturb hepatic glycogen synthesis, we investigated the effects of different sediment samples from different pollution situations on glycogen synthesis in liver cell lines. It was found that DSE induced multiple severe impairments in liver cells, and disturbed glycogen synthesis more than under other conditions. These impairments include decreased hepatic glycogen synthesis via inhibition and insulin receptor substrate 1 (IRS-1) /AKT /glycogen synthase kinase3ß (GSK3ß)-mediated glycogen synthase (GYS) inactivation. To our knowledge, this study provides the first detailed evidence of in vitro sediment-accumulated toxicity that interferes with liver glycogen synthesis, leading to hepatic cell damage through apoptosis.

Urban sediment pollutants alternate human cell essential behaviour through promoting oxidative damage.

The main objective of this study was to establish a human cell-based platform to assess the effects of sediment toxicity on oxidative damage and cell essential behaviour. Since sediment pollution has increased as a consequence of including but not limited to industrialisation, the contaminants accumulated in sediments have already led to human health concerns. The Hsinchu Science Park is one of the most prominent semiconductor manufacturing centres in the world, and the Ke-Ya River flows through Hsinchu Science Park and the Hsinchu urban district. Because semiconductor wastes potentially contribute to higher-than-normal rates of cancers, birth defects, and serious diseases, the quality assessment of the Ke-Ya River has prompted widespread concerns. While previous studies have shown an association between the degradation of fish populations and sediment pollutants, very little is known about the issues on human health. Herein, the effects of sediment from three sediment sampling sites of the Ke-Ya River on 11 different human cell lines were directly evaluated. The upstream represents the undeveloped zone, the middle-stream represents the household/industrial wastewater zone, and the downstream represents the accumulation zone. Our results indicated that the sediment pollution of the downstream Ke-Ya River was more cytotoxic than that of the middle stream and upstream. Downstream sediment extract (DSE) significantly increased reactive oxygen species (ROS) levels across all cell types. Accordingly, oxidative stress can trigger redox-sensitive pathways and alter essential biological processes such as cell viability, cell adhesion, and cell motility. Importantly, the MTT assay indicated that DSE significantly decreased the viability of brain, oral, lung, breast, liver, pancreatic, cervical, prostate, and colorectal cells. Furthermore, the adhesive ability and wound healing ability of most cells were greatly reduced in the presence of DSE compared to other conditions. Thus, this study shows the results of the first analyses completed on the sediment cytotoxicity in human cells, and stimulated ROS levels are crucial for cellular life. In future research, the detailed cause and effect mechanisms of the abundant ROS generated in DSE will be further investigated. We sincerely hope that our study provides a scientific basis for further investigations with a global perspective on public health challenges.

Characterization of TGF-ß by Induced Oxidative Stress in Human Trabecular Meshwork Cells.

Oxidative stress generated by reactive oxygen species (ROS) plays a critical role in the pathomechanism of glaucoma, which is a multifactorial blinding disease that may cause irreversible damage within human trabecular meshwork cells (HTMCs). It is known that the transforming growth factor-ß (TGF-ß) signaling pathway is an important component of oxidative stress-induced damage related to extracellular matrix (ECM) fibrosis and activates cell antioxidative mechanisms. To elucidate the dual potential roles and regulatory mechanisms of TGF-ß in effects on HTMCs, we established an in vitro oxidative model using hydrogen peroxide (H2O2) and further focused on TGF-ß-related oxidative stress pathways and the related signal transduction. Via a series of cell functional qualitative analyses to detect related protein level alterations and cell fibrosis status, we illustrated the role of TGF-ß1 and TGF-ß2 in oxidative stress-induced injury by shTGF-ß1 and shTGF-ß2 knockdown or added recombinant human TGF-ß1 protein (rhTGF-ß1). The results of protein level showed that p38 MAPK, TGF-ß, and its related SMAD family were activated after H2O2 stimulation. Cell functional assays showed that HTMCs with H2O2 exposure duration had a more irregular actin architecture compared to normal TM cells. Data with rhTGF-ß1 (1 ng/mL) pretreatment reduced the cell apoptosis rate and amount of reactive oxygen species (ROS), while it also enhanced survival. Furthermore, TGF-ß1 and TGF-ß2 in terms of antioxidant signaling were related to the activation of collagen I and laminin, which are fibrosis-response proteins. Succinctly, our study demonstrated that low concentrations of TGF-ß1 (1 ng/mL) preserves HTMCs from free radical-mediated injury by p-p38 MAPK level and p-AKT signaling balance, presenting a signaling transduction mechanism of TGF-ß1 in HTMC oxidative stress-related therapies.

Targeting UDP-glucose dehydrogenase inhibits ovarian cancer growth and metastasis.

More than 70% of patients with ovarian cancer are diagnosed in advanced stages. Therefore, it is urgent to identify a promising prognostic marker and understand the mechanism of ovarian cancer metastasis development. By using proteomics approaches, we found that UDP-glucose dehydrogenase (UGDH) was up-regulated in highly metastatic ovarian cancer TOV21G cells, characterized by high invasiveness (TOV21GHI ), in comparison to its parental control. Previous reports demonstrated that UGDH is involved in cell migration, but its specific role in cancer metastasis remains unclear. By performing immunohistochemical staining with tissue microarray, we found overexpression of UGDH in ovarian cancer tissue, but not in normal adjacent tissue. Silencing using RNA interference (RNAi) was utilized to knockdown UGDH, which resulted in a significant decrease in metastatic ability in transwell migration, transwell invasion and wound healing assays. The knockdown of UGDH caused cell cycle arrest in the G0 /G1 phase and induced a massive decrease of tumour formation rate in vivo. Our data showed that UGDH-depletion led to the down-regulation of epithelial-mesenchymal transition (EMT)-related markers as well as MMP2, and inactivation of the ERK/MAPK pathway. In conclusion, we found that the up-regulation of UGDH is related to ovarian cancer metastasis and the deficiency of UGDH leads to the decrease of cell migration, cell invasion, wound healing and cell proliferation ability. Our findings reveal that UGDH can serve as a prognostic marker and that the inhibition of UGDH is a promising strategy for ovarian cancer treatment.

Proteomic analysis of honokiol-induced cytotoxicity in thyroid cancer cells.

AIMS: Honokiol is a natural product extracted from herbal plants such as the Magnolia species which have been shown to exhibit anti-tumor and anti-metastatic properties. However, the effects of honokiol on thyroid cancers are largely unknown. MATERIALS AND METHODS: To determine whether honokiol might be useful for the treatment of thyroid cancer and to elucidate the mechanism of toxicity of honokiol, we analyzed the impact of honokiol treatment on differential protein expression in human thyroid cancer cell line ARO using lysine-labeling two-dimensional difference gel electrophoresis (2D-DIGE) combined with mass spectrometry (MS). KEY FINDINGS: This study revealed 178 proteins that showed a significant change in expression levels and also revealed that honokiol-induced cytotoxicity in thyroid cancer cells involves dysregulation of cytoskeleton, protein folding, transcription control and glycolysis. SIGNIFICANCE: Our work shows that combined proteomic strategy provides a rapid method to study the molecular mechanisms of honokiol-induced cytotoxicity in thyroid cancer cells. The identified targets may be useful for further evaluation as potential targets in thyroid cancer therapy.

[Interdigitating dendritic cell sarcoma/tumor: a study of 3 cases].

OBJECTIVE: To study the pathologic features, diagnosis and differential diagnosis of interdigitating dendritic cell sarcoma (IDCS). METHODS: The clinical findings, morphologic features and immunophenotype of 3 cases of IDCS were investigated. RESULTS: Gross examination showed that IDCS had a greyish-white to greyish-yellow cut surface. The site of occurrence included lung, spleen (with lymph node metastasis) and lymph node. Histologically, the tumor cells were arranged in nests, fascicles and whorls, with intimate admixture of many lymphocytes and plasma cells. They were oval to spindle in shape and contained pale eosinophilic cytoplasm, oval and sometimes grooved nuclei, small distinct nucleoli and ill-defined cell borders. Immunohistochemical study showed that the tumor cells expressed S-100 protein. CONCLUSIONS: IDCS is a rare type of histiocytic and dendritic cell malignancy with distinctive morphologic findings. It needs to be distinguished from follicular dendritic cell sarcoma, inflammatory pseudotumor, Langerhans' cell histiocytosis, malignant melanoma, undifferentiated carcinoma and anaplastic large cell lymphoma. Immunohistochemical staining for S-100 protein is helpful in confirming the diagnosis.

[Sclerosing angiomatoid nodular transformation of spleen].

OBJECTIVE: To study the clinicopathologic features of sclerosing angiomatoid nodular transformation of spleen and its differential diagnosis. METHODS: The clinicopathologic characteristics and immunophenotype of 4 cases of sclerosing angiomatoid nodular transformation of spleen were studied. RESULTS: Histologically, all cases were characterized by multiple angiomatoid nodules of various sizes in a fibrosclerotic stroma. The nodules were round and sometimes convoluted. They were composed of slit-like, irregular-shaped or slightly dilated vascular spaces lined by plump endothelial cells and interspersed with a population of spindly or ovoid cells. Immunohistochemical study showed a heterogeneous staining pattern, with the lining cells of the small capillaries expressing CD34 and those of the sinusoid-like structures expressing CD8. CD31 highlighted both the lining cells and interspersed cells, resulting in a complex meshwork. The lining cells were also focally positive for CD68. Smooth muscle actin revealed conglomerates of spindly shaped cells around and between the vascular channels. These spindly shaped cells in the intervening stroma were focally positive for actin, but negative for desmin, CD21 and CD35. CONCLUSIONS: Sclerosing angiomatoid nodular transformation is a rarely encountered benign lesion of the spleen, which should be distinguished from other angiomatoid tumors and tumor-like lesions.

[Distribution features of Gleason score and its relationship with clinical stages in 346 prostate cancer patients].

OBJECTIVE: To analyze the distribution features of Gleason score and evaluate the relationship between Gleason score and clinical stages in patients with prostate cancer. METHODS: Surveys were made of the inpatients with prostate cancer diagnosed by pathology from January 1992 to June 2005 in our hospital. Gleason score and clinical stages were determined on the basis of pathological examination and clinical data of the prostate cancer patients. The patients were divided into three groups (1992-1999, 2000-2002 and 2003-2005). The Chi-square test was used to evaluate the distribution and differences of Gleason score among the three groups. Spearman rank correlation was applied to the evaluation of the relationship between Gleason score and clinical stages. RESULTS: We found a statistically significant shift in the distribution of Gleason score (chi2 = 17.703, P < 0.01), and a slight increase in the mean Gleason score. The proportion of moderately differentiated tumor increased (chi2 = 10.736, P < 0.01). There was little change in the proportion of Gleason score 7, 8, 9 and 10 (chi2 = 4.038, P > 0.05). Gleason score had a significant positive correlation with clinical stages in the 346 cases of prostate cancer (r = 0.452, P < 0.01). Significant difference was observed between Gleason score 2-6 and 7 or 8-10 (chi2 = 8.786, P < 0.01, chi2 = 22.956, P < 0.01), but not between the latter 2 groups (chi2 = 0.787, P > 0.05) in prediction of organ-confined disease. CONCLUSIONS: Gleason score 7 shows the similar value to Gleason score 8-10 in predicting the progression of the disease. Gleason score was significantly correlated with clinical stages, which suggests that Gleason score is also an important indicator for the prognosis of prostate cancer.

[Age and pathological features of 481 prostate cancer patients].

OBJECTIVE: To investigate the age and pathological features of prostate cancer patients in recent years. METHODS: An analysis was made of the age and pathological features of 481 cases of prostate cancer pathologically diagnosed from January 1998 to April 2004, 39 cases in 1998, 69 in 1999, 73 in 2000, 68 in 2001, 72 in 2002, 121 in 2003, and 39 in the first four months of 2004. RESULTS: The patients ranged in age from 40 to 91 years, averaging 72, 95% between 55 and 84, and 84.2% over 65 years. Pathologically, 14 cases were well, 29 moderately, and 83 poorly differentiated according to the three-grade system (WHO, the Mostofi system), with 355 cases ungraded. Forty cases (8.3%) were microcarcinoma (< 1 cm), and 20 cases (4.2%) incidental carcinoma. Of the total number, 473 cases (98.1%) were pathologically diagnosed as adenocarcinoma, 1 endometrioid adenocarcinoma, 1 squamous cell carcinoma, 1 signet ring cell carcinoma, 1 adenosquamous cell carcinoma, 1 small cell carcinoma, 1 mucinous adenocarcinoma, 1 adenoid cystic carcinoma, and 1 transitional cell carcinoma. CONCLUSION: Prostate cancer commonly develops in men over 65 years, and adenocarcinoma is the most common histological type. The disease has become a major malignant tumor to endanger elderly males.

[Extranodal Rosai-Dorfman disease].

OBJECTIVE: To investigate the diagnosis and differential diagnosis of extranodal Rosai-Dorfman disease. METHODS: Two cases of extranodal Rosai-Dorfman disease were studied using hematoxylin-eosin, and immunohistochemical staining, along with a literature review. RESULTS: The lesions of RDD were characterized by the presence of large histiocytes with emperipolesis, accompanied by infiltration of lymphocytes, plasma cells and other inflammatory cells. The large histiocytes had an abundant cytoplasm, pale to eosinophilic in appearance, positive for S-100 protein staining, with a vesicular nucleus and a small basophilic nucleolus in each cell. CONCLUSIONS: Extranodal Rosai-Dorfman disease is known as an idiopathic proliferative disease of histiocytes with a distinct morphologic feature and is very rare. Differential diagnosis from other types of fibrohistiocytic proliferation lesions is recommended.

[Juxtaglomerular cell tumor of the kidney: a clinicopathologic analysis of five cases].

OBJECTIVE: To study the morphologic characteristics and immunophenotype of juxtaglomerular cell tumor of the kidney (JGCT), with discussion on its diagnostic clues and possible histogenesis. METHODS: The clinical, pathologic and immunohistochemical features of 5 cases of JGCT were evaluated. In addition, 5 cases of hemangiopericytoma and 5 cases of cutaneous glomus tumor were selected for comparative immunohistochemical analysis. RESULTS: The JGCT cases came from 4 females and 1 male (mean age at diagnosis = 32 years). All of them manifested symptoms of systemic hypertension. Four of the patients received partial nephrectomy and the remaining patient was treated by radial nephrectomy. All of them were followed up for a period of 4 to 66 months (average = 27 months). There was no evidence of local recurrence or distant metastases. On gross examination, these JGCTs were well-circumscribed and situated in the renal cortex and measured 4.4 cm in greatest dimension on average. Histologically, the tumor was characterized by the following three features: (1) solid sheets of relatively uniform polygonal to round cells with lightly eosinophilic cytoplasm, sometimes containing PAS-positive intracytoplasmic granules; (2) absence of or very scanty mitotic figures; (3) interstitium rich in thin-walled capillaries, associated with focal hyaline change and hemangiopericytoma-like architectural pattern. Under electron microscopy, characteristic rhomboid-shaped renin granules were found in the cytoplasm. All JGCTs were immunoreactive for renin, CD34, actin, and calponin. In contrast, all glomus tumors were negative for renin and all hemangiopericytomas were negative for actin. CONCLUSIONS: JGCT is a rare benign renal neoplasm typically found in young adults and manifests as systemic hypertension. The tumor cells may be originated from modified vascular smooth muscle cells. The identification of renin granules by electron microscopy and demonstration of the characteristic immunophenotype is the key to correct pathologic diagnosis.