The association between endocrine disrupting chemicals and nonalcoholic fatty liver disease: A systematic review and meta-analysis.

Nonalcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver disease worldwide. Epidemiological studies have reported that exposure of the population to environmental endocrine-disrupting chemicals (EDCs) is associated with NAFLD. However, EDCs are of different types, and there are inconsistencies in the relevant evidence and descriptions, which have not been systematically summarized so far. Therefore, this study aimed to determine the association between population exposure to EDCs and NAFLD. Three databases, including PubMed, Web of science, and Embase were searched, and 27 articles were included in this study. Methodological quality, heterogeneity, and publication bias of the included studies were assessed using the Newcastle-Ottawa scale, I2 statistics, Begg's test, and Egger's test. The estimated effect sizes of the included studies were pooled and evaluated using the random-effects model (I2 > 50 %) and the fixed-effects model ( I2 < 50 %). The pooled-estimate effect sizes showed that population exposure to Phthalates (PAEs) (OR = 1.18, 95 % CI:1.03-1.34), cadmium (Cd) (OR = 1.37, 95 % CI:1.09-1.72), and bisphenol A (OR = 1.43, 95 % CI:1.24-1.65) were positively correlated with the risk of NAFLD. Exposure to mercury (OR =1.46, 95 % CI:1.17-1.84) and Cd increased the risk of "elevated alanine aminotransferase". On the contrary, no significant association was identified between perfluoroalkyl substances (OR =0.99, 95 % CI:0.93-1.06) and NAFLD. However, female exposure to perfluorooctanoic acid (OR =1.82, 95 % CI:1.01-3.26) led to a higher risk of NAFLD than male exposure. In conclusion, this study revealed that EDCs were risk factors for NAFLD. Nonetheless, the sensitivity analysis results of some of the meta-analyses were not stable and demonstrated high heterogeneity. The evidence for these associations is limited, and more large-scale population-based studies are required to confirm these findings.

Knockdown of vitellogenin receptor based on minute insect RNA interference methods affects the initial mature egg load in the pest natural enemy Trichogramma dendrolimi.

Vitellogenin receptor (VgR) plays a crucial role in oogenesis by mediating endocytosis of vitellogenin and a portion of the yolk proteins in many insect species. However, the function of VgR in minute parasitoid wasps is largely unknown. Here, we applied Trichogramma dendrolimi, a minute egg parasitoid, as a study model to investigate the function of VgR in parasitoids. We developed RNA interference (RNAi) methods based on microinjection of prepupae in T. dendrolimi. RNAi employs nanomaterial branched amphipathic peptide capsules (BAPC) as a carrier for double-stranded RNA (dsRNA), significantly enhancing delivery efficiency. Also, artificial hosts without medium were used to culture the injected prepupae in vitro. Utilizing these methods, we found that ovarian growth was disrupted after knockdown of TdVgR, as manifested by the suppressed development of the ovariole and the inhibition of nurse cell internalization by oocytes. Also, the initial mature egg load in the ovary was significantly reduced. Notably, the parasitic capacity of the female adult with ovarian dysplasia was significantly decreased, possibly resulting from the low availability of mature eggs. Moreover, ovarian dysplasia in T. dendrolimi caused by VgR deficiency are conserved despite feeding on different hosts. The results confirmed a critical role of TdVgR in the reproductive ability of T. dendrolimi and provided a reference for gene functional studies in minute insects.

Regulatory mechanism of perinatal nonylphenol exposure on cardiac mitochondrial autophagy and the PINK1/Parkin signaling pathway in male offspring rats.

OBJECTIVE: This study investigated whether perinatal exposure to nonylphenol (NP) induces mitochondrial autophagy (i.e., mitophagy) damage in neonatal rat cardiomyocytes (NRCMs) and whether the PINK1/Parkin signaling pathway is involved in NP-induced primary cardiomyocyte injury. METHODS AND RESULTS: In vivo: Perinatal NP exposure increased apoptosis and mitochondrial damage in NRCMs. Mitochondrial swelling and autophagosome-like structures with multiple concentric membranes were observed in the 100 mg/kg NP group, with an increase in the number of autophagosomes. Disorganized fiber arrangement and elevated serum myocardial enzyme levels were observed with increasing NP dosage. Additionally, NP exposure led to increased MDA levels and decreased SOD activity and ATP levels in myocardial tissue. The mRNA expression levels of autophagy-related genes, including Beclin-1, p62, and LC3B, as well as the expression of mitochondrial autophagy-related proteins (PINK1, p-Parkin, Parkin, Beclin-1, p62, LC3-I, LC3-II, and LC3-II/I) and apoptosis-related proteins (Bax and caspase-3), increased, whereas the expression levels of the mitochondrial membrane protein TOMM20 and the anti-apoptotic protein Bcl-2 decreased. In vitro: NP increased ROS levels, LDH release, and decreased ATP levels in NRCMs. CsA treatment significantly inhibited the expression of autophagy-related proteins (Beclin-1, LC3-II/I, and p62) and apoptosis-related proteins (caspase-3 and Bax), increased the expression levels of TOMM20 and Bcl-2 proteins, increased cellular ATP levels, and inhibited LDH release. The inhibition of the PINK1/Parkin signaling pathway suppressed the expression of mitochondrial autophagy-related proteins (PINK1, p-Parkin, Parkin, Beclin-1, LC3-II/I, and p62) and apoptosis-related proteins (caspase-3 and Bax), increased TOMM20 and Bcl-2 protein expression, increased ATP levels, and decreased LDH levels in NRCMs. CONCLUSIONS: This study is novel in reporting that perinatal NP exposure induced myocardial injury in male neonatal rats, thereby inducing mitophagy. The PINK1/Parkin signaling pathway was involved in this injury by regulating mitophagy.

Amelioration of nonylphenol-induced anxiety/depression-like behaviors in male rats using green tea and Zn-Se tea interventions.

Objective: This study aimed to investigate the effects of exposure to nonylphenol (NP) on anxiety/depression-like behaviors in rats and alleviation of those effects via green tea and zinc selenium (Zn-Se) tea interventions. Material and Methods: Totally, 40 male specific-pathogen free (SPF) Sprague-Dawley (SD) male rats were randomly divided into four groups (n = 10 rats per group): control group (5 ml/kg corn oil), NP group (40 mg/kg NP), NP + GT group (40 mg/kg NP + 1 g/kg/day green tea), and NP + Zn-Se tea group (40 mg/kg NP + 1 g/kg/day ZST). All dose-based groups received oral gavage of either corn oil or drugs over a 6-month period: NP at a dosage of 40 mg/kg/day was administered to rats for the initial 3 months, followed by a combination of NP with green tea and NP with Zn-Se tea for the subsequent 3 months. Results: Tea intervention resulted in weight loss in rats. The hippocampal tissue NP level in the tea group was slightly lower than that in the NP group. Following tea intervention, compared with the NP group, the residence time in the light-dark box test was shortened PGT = 0.048, P < 0.001), and the number of entries into the closed arm in the elevated plus maze test in the tea-treated group was significantly reduced. In addition, the immobility time in the central square in the open field test decreased. The sucrose preference index score in the sucrose preference test increased, and the immobility time in the forced swimming test was reduced (PGT = 0.049, PZST < 0.001). The effects of Zn-S e tea were superior to green tea. The damage to the hippocampal tissues in the group treated with tea was less than that in the NP group. The cellular arrangement was tighter with degeneration, deepstaining, and pyknotic nerve cells were visible. The nuclei in the NP group were atrophied, and the cells were sparsely arranged. Compared with the control group, serum brain-derived neurotrophic factor (BDNF) level was lower in the NP group. The serum corticosterone level in the NP group was elevated. Compared with the NP group, serum corticosterone level was reduced in the NP + Zn-Se tea group. Conclusion: Chronic NP exposure induced anxiety/depression-like behaviors in rats. Green tea effectively reduced the damage to the hippocampus and prefrontal cortex induced by NP. The effects of Zn-Se tea were slightly more noticeable than those of conventional green tea. Highlights: 1) Chronic NP exposure induced anxiety/depression-like behaviors in rats.2) Zn-Se tea reduced the damage of hippocampal and prefrontal cortex induced by NP.3) NP-induced depression accompanied by the changes of BDNF, CORT and neuropathology.

Relationship between parasitism and morphology of Trichogramma (Hymenoptera: Trichogrammatidae) on Spodoptera frugiperda (Lepidoptera: Noctuidae).

In this study, 5 species of Trichogramma Westwood were evaluated for the biological control of Spodoptera frugiperda (JE Smith), concerning the physical characteristics of female Trichogramma. The results showed that Trichogramma chilonis Ishii, Trichogramma dendrolimi Matsumura, and Trichogramma ostriniae Pang et Chen exhibited high parasitism rates, emergence rates, and offspring numbers, with the highest values observed for T. ostriniae. The ovipositor length of Trichogramma japonicum Ashmead and T. dendrolimi were longer than those of other species, and the hind tibia length was the shortest in Trichogramma cacoeciae Marchal. We further evaluated relationships between the parasitism ability of Trichogramma and various morphological indexes based on Spearman's rank correlation coefficients. A positive correlation was found between the parasitism rate and hind tibia length of T. cacoeciae. In T. dendrolimi, the parasitism rate was negatively correlated with ovipositor width and positively correlated with the length-width ratio of the ovipositor. A significant positive correlation was observed between the proportion of female offspring and the mother's ovipositor length in T. japonicum. However, there were no significant correlations between morphological indexes and indexes of parasitism in T. ostriniae. Overall, the parasitic abilities of T. chilonis on S. frugiperda eggs were significantly correlated with the morphology of the female ovipositors.

Prognostic and biological function value of OSBPL3 in colorectal cancer analyzed by multi-omic data analysis.

BACKGROUND: Colorectal cancer (CRC) is one of the most common malignancies in the world. This study proposes to reveal prognostic biomarkers for the prognosis and treatment of CRC patients. METHODS: Differential analysis of OSBPL3 was performed in pan-cancer, and the correlation between clinical stage and OSBPL3 was analyzed. Multiple omics analysis was used to compare the relationship between survival of patients and copy number variation, single nucleotide variant, and methylation status. Survival differences between high and low OSBPL3 expression groups were analyzed. Differentially expressed genes (DEGs) between high and low OSBPL3 expression groups were obtained, and functional enrichment analysis was implemented. Correlations between immune cells and OSBPL3 was analyzed. Drug sensitivity between the two OSBPL3 expression groups was compared. Moreover, the expression of OSBPL3 was verified by immunohistochemistry and real-time quantitative PCR. RESULTS: OSBPL3 was differentially expressed in 13 tumors and had some correlations with T and N stages. OSBPL3 expression was regulated by methylation and higher OSBPL3 expression was associated with poorer prognosis in CRC. 128 DEGs were obtained and they were mainly involved in signaling receptor activator activity, aspartate and glutamate metabolism. T cell gamma delta and T cell follicular helper were significantly different in the high and low OSBPL3 expression groups. Moreover, OSBPL3 showed negative correlations with multiple drugs. OSBPL3 was significantly upregulated in CRC samples compared to normal samples. CONCLUSIONS: A comprehensive analysis demonstrated that OSBPL3 had potential prognostic value, and guiding significance for CRC chemotherapeutic.

Identification and verification of the prognostic value of CUL7 in colon adenocarcinoma.

CUL7, a gene composed of 26 exons associated with cullin 7 protein, is also an E3 ligase that is closely related to cell senescence, apoptosis, and cell transformation and also plays an important role in human cancer. However, there is no systematic pan-cancer analysis has been performed to explore its role in prognosis and immune prediction. In this study, the expression of CUL7 in colon adenocarcinoma (COAD) was investigated to determine its prognosis value. First, based on the Cancer Genome Atlas (TCGA), Genotypic-Tissue Expression Project(GTEx), Cancer Cell Line Encyclopedias(CCLE), and TISIDB database, the potential role of CUL7 in different tumors was explored. Subsequently, the expression of CUL7 in COAD was explored and verified by Immunohistochemistry (IHC). Furthermore, the mutation frequency of CUL7 in COAD was analyzed, and the prognostic value of CUL7 in COAD was discussed. In addition, the nomogram was constructed, and its prognostic value was verified by follow-up data from Jiangmen Central Hospital. Finally, PPI network analysis explored the potential biological function of CUL7 in COAD. The results show that CUL7 is upregulated in most tumors, which is significantly associated with poor survival. At the same time, CUL7 is correlated with the clinical stage and immune landscape of various tumors. In colorectal cancer, CUL7 was overexpressed in tumor tissues by IHC with a mutation frequency of about 4%. CUL7 is an independent prognostic factor for colorectal cancer. The nomogram constructed has effective predictive performance, and external databases proved the prognostic value of CUL7. In addition, PPI network analysis showed that CUL7 was closely related to FBXW8, and further pathway enrichment analysis showed that CUL7 was mainly involved in ubiquitin-mediated proteolysis. Therefore, our study provides a comprehensive understanding of the potential role of CUL7 in different tumors, and CUL7 might be a prognostic marker for COAD.

Hsa-miR-1248 suppressed the proliferation, invasion and migration of colorectal cancer cells via inhibiting PSMD10.

BACKGROUND: Lymph node metastasis (LNM) is a critical event during the colorectal cancer (CRC) development and is indicative of poor prognosis. Identification of molecular markers of LNM may facilitate better therapeutic decision-making. METHODS: Six pairs of CRC tissues and corresponding adjacent tissues [3 pairs diagnosed as pT1N0M0 (M_Low group) and 3 pairs diagnosed as pT4N2M0 (M_High group)] collected from CRC patients who underwent surgical resection were used. MicroRNA sequencing was performed to screen differential microRNAs involved in CRC LNM. The selected microRNAs were validated in CRC tissues and cell lines using qRT-PCR. The functions of candidate hsa-miR-1248 were evaluated by CCK-8, colony formation, and Transwell assay. The binding of hsa-miR-1248 with its target PSMD10 was confirmed by luciferase activity assay, and the expression of PSMD10 in tissues was detected by droplet digital polymerase chain reaction. RESULTS: Ninety-five miRNAs were downregulated in carcinoma tissues (M_Low and M_high groups) compared with the normal group. Their expression in M_High group was significantly lower compared with M_Low group. The top 3 were hsa-miR-635, hsa-miR-1248, and hsa-miR-668-3p. After validation in tissues/cell lines, only hsa- hsa-miR-1248 was decreased in high metastatic tissues or SW620 cells compared to low metastatic tissues or SW480 cells. Hsa-miR-1248 was found to inhibit CRC cell viability, proliferation, invasion, and migration. The tumor suppressor effect of has-miR-1248 in CRC cells was attenuated or enhanced by up-regulating or down-regulating PSMD10, respectively. CONCLUSION: Hsa-miR-1248 may act as a tumor suppressor gene in CRC by targeting and inhibiting PSMD10, which provides a clue for CRC treatment.

Gankyrin as Potential Biomarker for Colorectal Cancer With Occult Liver Metastases.

The majority of occult liver metastases cannot be detected by computed tomography (CT), magnetic resonance imaging (MRI) or other traditionally morphological imaging approaches since the lesions are too small or they have not yet formed cancer nodules. Gankyrin is a small molecular protein composed of seven ankyrin domains. In this study, the expression of Gankyrin in colorectal cancer (CRC) patients with liver metastases was investigated to determine its prognosis value. Gankyrin expression in CRC patients was initially analyzed using data from The Cancer Genome Atlas (TCGA) database and bioinformatics tools. RT-qPCR, western blotting, immunohistochemistry (IHC) and transwell migration and invasion assays were then performed to verify the expression and function of Gankyrin in CRC cell line, CRC tissues and matched non-tumor tissues of clinical patients. General clinicopathological information including TNM stage as well as preoperative and postoperative imaging results were collected. The main outcome indicator was overall survival (OS), referring to the length of time from surgery to either death or the last visit. Statistical analyses included chi-squared tests, Cox analyses, progression free survival (PFS) rates and OS rates. Elevated Gankyrin expression was confirmed in CRC patients. The upregulated Gankyrin expression was positively correlated with the progression of disease and liver metastasis in CRC patients. OS analysis revealed that prognosis was worse in CRC patients with high Gankyrin expression compared to those with low expression. CRC patients with higher Gankyrin expression also had a higher risk of occult liver metastases and a lower PFS rate. Therefore, Gankyrin can be used as a potential biomarker for early diagnosis of CRC with occult liver metastasis.

A Signature of Autophagy-Related Long Non-coding RNA to Predict the Prognosis of Breast Cancer.

Background: A surge in newly diagnosed breast cancer has overwhelmed the public health system worldwide. Joint effort had beed made to discover the genetic mechanism of these disease globally. Accumulated research has revealed autophagy may act as a vital part in the pathogenesis of breast cancer. Objective: Aim to construct a prognostic model based on autophagy-related lncRNAs and investigate their potential mechanisms in breast cancer. Methods: The transcriptome data and clinical information of patients with breast cancer were obtained from The Cancer Genome Atlas (TCGA) database. Autophagy-related genes were obtained from the Human Autophagy Database (HADb). Long non-coding RNAs (lncRNAs) related to autophagy were acquired through the Pearson correlation analysis. Univariate Cox regression analysis as well as the least absolute shrinkage and selection operator (LASSO) regression analysis were used to identify autophagy-related lncRNAs with prognostic value. We constructed a risk scoring model to assess the prognostic significance of the autophagy-related lncRNAs signatures. The nomogram was then established based on the risk score and clinical indicators. Through the calibration curve, the concordance index (C-index) and receiver operating characteristic (ROC) curve analysis were evaluated to obtain the model's predictive performance. Subgroup analysis was performed to evaluate the differential ability of the model. Subsequently, gene set enrichment analysis was conducted to investigate the potential functions of these lncRNAs. Results: We attained 1,164 breast cancer samples from the TCGA database and 231 autophagy-related genes from the HAD database. Through correlation analysis, 179 autophagy-related lncRNAs were finally identified. Univariate Cox regression analysis and LASSO regression analysis further screened 18 prognosis-associated lncRNAs. The risk scoring model was constructed to divide patients into high-risk and low-risk groups. It was found that the low-risk group had better overall survival (OS) than those of the high-risk group. Then, the nomogram model including age, tumor stage, TNM stage and risk score was established. The evaluation index (C-index: 0.78, 3-year OS AUC: 0.813 and 5-year OS AUC: 0.785) showed that the nomogram had excellent predictive power. Subgroup analysis showed there were difference in OS between high-risk and low-risk patients in different subgroups (stage I-II, ER positive, Her-2 negative and non-TNBC subgroups; all P < 0.05). According to the results of gene set enrichment analysis, these lncRNAs were involved in the regulation of multicellular organismal macromolecule metabolic process in multicellular organisms, nucleotide excision repair, oxidative phosphorylation, and TGF-ß signaling pathway. Conclusions: We identified 18 autophagy-related lncRNAs with prognostic value in breast cancer, which may regulate tumor growth and progression in multiple ways.

Prognostic model of invasive ductal carcinoma of the breast based on differentially expressed glycolysis-related genes.

BACKGROUND: Invasive ductal carcinoma (IDC) is a common pathological type of breast cancer that is characterized by high malignancy and rapid progression. Upregulation of glycolysis is a hallmark of tumor growth, and correlates with the progression of breast cancer. We aimed to establish a model to predict the prognosis of patients with breast IDC based on differentially expressed glycolysis-related genes (DEGRGs). METHODS: Transcriptome data and clinical data of patients with breast IDC were from The Cancer Genome Atlas (TCGA). Glycolysis-related gene sets and pathways were from the Molecular Signatures Database (MSigDB). DEGRGs were identified by comparison of tumor tissues and adjacent normal tissues. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression were used to screen for DEGRGs with prognostic value. A risk-scoring model based on DEGRGs related to prognosis was constructed. Receiver operating characteristic (ROC) analysis and calculation of the area under the curve (AUC) were used to evaluate the performance of the model. The model was verified in different clinical subgroups using an external dataset (GSE131769). A nomogram that included clinical indicators and risk scores was established. Gene function enrichment analysis was performed, and a protein-protein interaction network was developed. RESULTS: We analyzed data from 772 tumors and 88 adjacent normal tissues from the TCGA database and identified 286 glycolysis-related genes from the MSigDB. There were 185 DEGRGs. Univariate Cox regression and LASSO regression indicated that 13 of these genes were related to prognosis. A risk-scoring model based on these 13 DEGRGs allowed classification of patients as high-risk or low-risk according to median score. The duration of overall survival (OS) was longer in the low-risk group (P < 0.001), and the AUC was 0.755 for 3-year OS and 0.726 for 5-year OS. The results were similar when using the GEO data set for external validation (AUC for 3-year OS: 0.731, AUC for 5-year OS: 0.728). Subgroup analysis showed there were significant differences in OS among high-risk and low-risk patients in different subgroups (T1-2, T3-4, N0, N1-3, M0, TNBC, non-TNBC; all P < 0.01). The C-index was 0.824, and the AUC was 0.842 for 3-year OS and 0.808 for 5-year OS from the nomogram. Functional enrichment analysis demonstrated the DEGRGs were mainly involved in regulating biological functions. CONCLUSIONS: Our prognostic model, based on 13 DEGRGs, had excellent performance in predicting the survival of patients with IDC of the breast. These DEGRGs appear to have important biological functions in the progression of this cancer.

Insights into the venom protein components of the egg parasitoid Anastatus japonicus (Hymenoptera: Eupelmidae).

BACKGROUND: Parasitoid venom is composed of a complex mixture of various active substances with different biological functions and is injected in the host during the parasitoid oviposition. Anastatus japonicus (Hymenoptera: Eupelmidae) is an egg parasite of Tessaratoma papillosa (Hemiptera: Tessaratomidae). Although the venom of this egg parasitoid plays an important role in the parasitic process, relatively little work has been done to address the mechanism. RESULTS: In the present study, proteomic analysis was performed to identify the proteins that play an important role in the parasitic process of A. japonicus. A total of 2084 proteins were identified, including 81 putative venom proteins, most of which were identified as Hexamerin, Chitinase 2, Calreticulin, Heat shock protein 83-like, Serine protease, Arginine kinase, Phosphoserine aminotransferase and Actin protein. Together the before (Be) and after (Af) parasitization venom contains 1628 proteins, including 212 DEPs with 181 and 31 significantly up-regulated and down-regulated respectively. In addition, 10 differentially expressed proteins (DEPs) with fold change ≥8.71 were subjected to RT-qPCR to validate the proteomic data. The differential expression analysis revealed that nine proteins were specifically present in the pre-parasitic venom, whereas 26 proteins were specific to the post-parasitic treatments. Results of RT-qPCR analysis showed high expression of the selected DEPs which further validated our proteomics data. CONCLUSION: These new proteomic data greatly enrich our current knowledge about key venom proteins associated with parasitic process in A. japonicus and contribute to better understanding of the parasitic mechanisms leading to the development of new biological control strategies. © 2020 Society of Chemical Industry.

Gambogic acid reverses oxaliplatin resistance in colorectal cancer by increasing intracellular platinum levels.

Resistance to oxaliplatin (L-OHP) is a major obstacle to successful chemotherapy in colorectal cancer (CRC). In the present study, the ability of gambogic acid (GA) to reverse L-OHP resistance in CRC LoVo cells was investigated. L-OHP-resistant LoVo/L-OHP cells were established by exposing them to increasing concentrations of L-OHP. GA-reversed L-OHP-sensitive LoVo/L-OHP/GA cells were established by exposure to 0.5 µmol/l GA for 2 weeks. A Cell Counting Kit-8 assay was used to assess levels of proliferation. Flow cytometry was applied to detect apoptosis rates. Transwell assays were used to analyse invasion. Inductively coupled plasma mass spectrometry was used to determine intracellular platinum (Pt) content. Western blot analysis was used to reveal the protein levels of Human copper transporter 1 (hCTR1), Copper-transporting p-type adenosine triphosphatases 1 (ATP7A) and Copper-transporting p-type adenosine triphosphatases 2 (ATP7B). LoVo/L-OHP and LoVo/L-OHP/GA cell lines were successfully established, and it was identified that L-OHP inhibited the proliferation of LoVo, LoVo/L-OHP and LoVo/L-OHP/GA cells in a dose-dependent manner. Compared with the parent LoVo cells, the anti-apoptosis and invasion properties of LoVo/L-OHP cells were enhanced, and were reversed by GA treatment. Intracellular Pt content was highest in the LoVo cells, followed by LoVo/L-OHP/GA cells, and then lowest in the LoVo/L-OHP cells. Downregulated hCTP1 and upregulated ATP7A and ATP7B were associated with L-OHP resistance, and GA reversed the resistance by increasing levels of hCTR1 and decreasing levels of ATP7A and ATP7B. In conclusion, GA has the potential ability to reverse L-OHP resistance in CRC cells by increasing intracellular Pt content, which it achieves by increasing hCTR1 levels and decreasing ATP7A and ATP7B levels. GA may represent a promising treatment agent for L-OHP resistance.

Gambogic acid potentiates the chemosensitivity of colorectal cancer cells to 5-fluorouracil by inhibiting proliferation and inducing apoptosis.

Chemotherapy using 5-fluorouracil (5-FU) for colorectal cancer (CRC) has low specificity and response rates, leading to severe side effects. Gambogic acid (GA), a traditional Chinese medicine, has multi-targeted anticancer effects, including growth inhibition and apoptosis induction. However, it is unclear whether a combination of 5-FU and GA has synergistic anticancer effects in CRC cells. In this study, SW480 and HCT116 human CRC cells and human intestinal epithelial cells (IECs) were treated with different concentrations of 5-FU, GA or 5-FU+GA. A Cell Counting kit-8 assay was conducted to quantify cell proliferation. The combination index (CI) was calculated and the median-effect principle was applied to analyze the interaction between 5-FU and GA. Flow cytometry was used to determine the percentage of cells undergoing apoptosis. Reverse transcription-quantitative polymerase chain reaction and western blotting were applied to measure P53, survivin and thymidylate synthase (TS) mRNA and protein levels. It was found that 5-FU+GA more pronouncedly inhibited cell growth and induced apoptosis, compared with either monotherapy. CI values <1 indicated the synergistic effects of the drugs. 5-FU+GA further decreased P53, survivin and TS mRNA and protein levels in the two CRC cell lines compared with single drugs, whereas increased P53 protein levels were observed in HCT116 cells. Moreover, 5-FU+GA did not increase cytotoxicity to IECs. These results demonstrate that GA enhances the anticancer effects of 5-FU on CRC cells. Combined treatment with 5-FU and GA is effective and safe for CRC cells, and may become a promising chemotherapy treatment.

Gankyrin sustains PI3K/GSK-3ß/ß-catenin signal activation and promotes colorectal cancer aggressiveness and progression.

High levels of angiogenesis, metastasis and chemoresistance are major clinical features of colorectal cancer (CRC), a lethal disease with a high incidence worldwide. Aberrant activation of Wnt/ß-catenin pathway contributes to CRC progression. However, little is known about regulatory mechanisms of the ß-catenin activity in cancer progression. Here we report that Gankyrin was markedly upregulated in primary tumor tissues from CRC patients and was associated with poor survival. Moreover, we demonstrated that overexpressing Gankyrin promoted, while knockdown of Gankyrin impaired, the aggressive phenotype of proliferation, angiogenesis, chemoresistance and metastasis of CRC cells both in vitro and in vivo. Importantly, we found a unique molecular mechanism of Gankyrin in CRC cells signaling transduction, that regulated the cross-talk between PI3K/Akt and Wnt/ß-catenin signaling pathways, sustaining PI3K/GSK-3ß/ß-catenin signal activation in CRC. Therefore, these findings not only reveal a mechanism that promotes aggressiveness and progression in CRC, but also provide insight into novel molecular targets for antitumor therapy in CRCs.

Tuning the charge states of CrW2O9 clusters deposited on perfect and defective MgO(001) surfaces with different color centers: A comprehensive DFT study.

The structures and electronic properties of bimetallic oxide CrW2O9 clusters supported on the perfect and defective MgO(001) surfaces with three different color centers, FS (0), FS (+), and FS (2+) centers, respectively, have been investigated by density functional theory calculations. Our results show that the configurations, adsorption energies, charge transfers, and bonding modes of dispersed CrW2O9 clusters are sensitive to the charge states of the FS centers. Compared with the gas-phase configuration, the CrW2O9 clusters supported on the defective surfaces are distorted dramatically, which exhibit different chain structures. On the perfect MgO surface, the depositions of clusters do not involve obvious charge transfer, while the situation is quite different on the defective MgO(001) surfaces in which significant electron transfer occurs from the surface to the cluster. Interestingly, this effect becomes more remarkable for electron-rich oxygen vacancies (FS (0) center) than that for electron-poor oxygen vacancies (FS (+) and FS (2+) centers). Furthermore, our work reveals a progressive Brønsted acid sites where spin density preferentially localized around the Cr atoms not the W atoms for all kinds of FS-centers, indicating the better catalytic activities can be expected for CrW2O9 cluster on defective MgO(001) surfaces with respect to the W3O9 cluster.

[Association of gankyrin protein expression in human colorectal cancer with postoperative prognosis].

OBJECTIVE: To investigate the association of gankyrin protein expression in colorectal cancer (CRC) with its prognosis. METHODS: Clinical data and resection samples of 100 colorectal cancer patients identified by pathology undergoing resection in our department from June 2008 to June 2009 were collected. The gankyrin expression in CRC tissues and matched adjacent noncancerous tissues collected during the operation of 100 CRC cases was detected by immunohistochemical staining and Western blotting. The associations of gankyrin expression level with overall survival, clinicopathologic features were analyzed by Chi square test, Cox regression analysis, Kaplan-Meier analysis and log rank test. RESULTS: Immunohistochemical staining showed that the positive brown granules were mainly distributed in the cytoplasm, and nuclear immunostaining was observed in tissue samples of 29 cases, of whom 16 cases had distal metastasis [55.2% (16/29)]. The positive rate of gankyrin and the relative gray value of Western blotting in CRC tissues were 67% (67/100) and 0.69±0.23, respectively, which were significantly higher than those of 2 cm adjacent noncancerous tissues [6% (6/100) and 0.31±0.16] and 10 cm adjacent noncancerous tissues [1%(1/100) and 0.16±0.11] (all P<0.001). Patients with positive expression of gankyrin had worse survival than those with negative ones (41.8% vs. 72.7%, P=0.008). The gankyrin expression was associated to lymph node metastasis (P=0.005), tumor stage (P=0.001) and distal metastasis (P=0.002). Cox regression analysis showed that distal metastasis (P=0.004) and high expression of gankyrin (P=0.038) were independent risk factors for poor prognosis of patients with CRC. CONCLUSION: Up-regulated expression of gankyrin is related to invasion and metastasis of human CRC, and gankyrin may be valuable in predicting prognosis.

[Study on the traditional lime mortar from the memorial archway in the southern Anhui province].

The traditional lime mortar was investigated by means of scanning electron microscope (SEM), X-ray diffractometry and Fourier transform infrared spectrometry (FTIR). The results show that the mortar from the memorial archway in the southern Anhui province was the organic-inorganic composite materials composed of lime with tung oil or sticky rice. It was found that the excellent performance of the tung oil-lime mortar can be explained by the compact lamellar organic-inorganic composite structure that was produced by carbonization reaction of lime, cross-linking reactions of tung oil and oxygen and complexing reaction of Ca2+ and -COO-. The compact micro-structure of sticky rice-lime mortar, which was produced due to carbonation process of lime controlled by amylopectin, should be the cause of the good performance of this kind of organic-inorganic mortar.

S100A8/A9 (calprotectin) negatively regulates G2/M cell cycle progression and growth of squamous cell carcinoma.

Malignant transformation results in abnormal cell cycle regulation and uncontrolled growth in head and neck squamous cell carcinoma (HNSCC) and other cancers. S100A8/A9 (calprotectin) is a calcium-binding heterodimeric protein complex implicated in cell cycle regulation, but the specific mechanism and role in cell cycle control and carcinoma growth are not well understood. In HNSCC, S100A8/A9 is downregulated at both mRNA and protein levels. We now report that downregulation of S100A8/A9 correlates strongly with a loss of cell cycle control and increased growth of carcinoma cells. To show its role in carcinogenesis in an in vitro model, S100A8/A9 was stably expressed in an S100A8/A9-negative human carcinoma cell line (KB cells, HeLa-like). S100A8/A9 expression increases PP2A phosphatase activity and p-Chk1 (Ser345) phosphorylation, which appears to signal inhibitory phosphorylation of mitotic p-Cdc25C (Ser216) and p-Cdc2 (Thr14/Tyr15) to inactivate the G2/M Cdc2/cyclin B1 complex. Cyclin B1 expression then downregulates and the cell cycle arrests at the G2/M checkpoint, reducing cell division. As expected, S100A8/A9-expressing cells show both decreased anchorage-dependent and -independent growth and mitotic progression. Using shRNA, silencing of S100A8/A9 expression in the TR146 human HNSCC cell line increases growth and survival and reduces Cdc2 inhibitory phosphorylation at Thr14/Tyr15. The level of S100A8/A9 endogenous expression correlates strongly with the reduced p-Cdc2 (Thr14/Tyr14) level in HNSCC cell lines, SCC-58, OSCC-3 and UMSCC-17B. S100A8/A9-mediated control of the G2/M cell cycle checkpoint is, therefore, a likely suppressive mechanism in human squamous cell carcinomas and may suggest new therapeutic approaches.

Surgical management of primary and secondary tumors in the pterygopalatine fossa.

OBJECTIVE: This article describes a surgical approach that has been applied to managing primary tumors in the pterygopalatine fossa and secondary tumors involving the pterygopalatine fossa. PATIENTS AND METHODS: The Barbosa approach was modified by adding a lateral incision in the mandibular gingivobuccal fold from the canine tooth to the retromolar area. This technique was applied to nine patients with primary and secondary tumors in the pterygopalatine fossa. All patients had been observed by clinical examinations, MRI, and CT examinations. RESULTS: This technique allowed a large, inferiorly based flap to be raised, which includes the parotid gland. The masseter and temporalis muscles were divided horizontally, and the ascending ramus of the mandible was osteotomied between the mandibular angle and the sigmoid notch and reflected to expose the tumor in the pterygopalatine fossa and maxillary sinus. We have applied this technique in 9 patients. Of the 9 patients in our study, 5 (55%) were male and 4 (45%) were female. The median age of the patients at the time of operation for primary and secondary tumors in the pterygopalatine fossa was 49.5 years (range, 19-66 years). Four of the 9 patients had primary tumors in the pterygopalatine fossa. One patient had a tumor in the pterygoaplatine fossa extending into the maxillary sinus, 2 patients had tumors occurring in the maxilla involving the pterygopalatine fossa, 2 patients had tumors from the deep lobe of the parotid gland to the pterygopalatine fossa, and 1 patient had extracranial meningioma. Nine patients have been followed up from 3 months to 9 years and 6 months, and 1 patient had recurrence 2 years and 2 months postoperatively. CONCLUSION: This technique is especially useful to tumors in the pterygopalatine fossa and tumors in the pterygopalatine fossa extending into the maxillary sinus.