Prostaglandin F2α synthase promotes oxaliplatin resistance in colorectal cancer through prostaglandin F2α-dependent and F2α-independent mechanism.

BACKGROUND: Oxaliplatin (Oxa) is the first-line chemotherapy drug for colorectal cancer (CRC), and Oxa resistance is crucial for treatment failure. Prostaglandin F2α synthase (PGF2α) (PGFS), an enzyme that catalyzes the production of PGF2α, is involved in the proliferation and growth of a variety of tumors. However, the role of PGFS in Oxa resistance in CRC remains unclear. AIM: To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC. METHODS: The PGFS expression level was examined in 37 pairs of CRC tissues and paracancerous tissues at both the mRNA and protein levels. Overexpression or knockdown of PGFS was performed in CRC cell lines with acquired Oxa resistance (HCT116-OxR and HCT8-OxR) and their parental cell lines (HCT116 and HCT8) to assess its influence on cell proliferation, chemoresistance, apoptosis, and DNA damage. For determination of the underlying mechanisms, CRC cells were examined for platinum-DNA adducts and reactive oxygen species (ROS) levels in the presence of a PGFS inhibitor or its products. RESULTS: Both the protein and mRNA levels of PGFS were increased in the 37 examined CRC tissues compared to the adjacent normal tissues. Oxa induced PGFS expression in the parental HCT116 and HCT8 cells in a dose-dependent manner. Furthermore, overexpression of PGFS in parental CRC cells significantly attenuated Oxa-induced proliferative suppression, apoptosis, and DNA damage. In contrast, knockdown of PGFS in Oxa-resistant HCT116 and HCT8 cells (HCT116-OxR and HCT8-OxR) accentuated the effect of Oxa treatment in vitro and in vivo. The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa. Treatment with the PGFS-catalyzed product PGF2α reversed the effect of PGFS knockdown on Oxa sensitivity. Interestingly, PGFS inhibited the formation of platinum-DNA adducts in a PGF2α-independent manner. PGF2α exerts its protective effect against DNA damage by reducing ROS levels. CONCLUSION: PGFS promotes resistance to Oxa in CRC via both PGF2α-dependent and PGF2α-independent mechanisms.

Exploration of walnut components and their association with health effects.

Traditionally, walnuts have occupied an imperative position in the functional food market with consistently recognized nutritious and functional properties. In the past years, the lipid profile of walnuts has brought much scientific attention via linking a cascade of biological attributes and health-promoting effects. Over time, researchers have focused on diversified composition (polyphenols and vitamins) of different parts of walnut (flower, pellicle, and kernel) and emphasized their physiological significance. Consequently, a plethora of reports has emerged on the potential role of walnut consumption against a series of diseases including cancer, gut dysbiosis, cardiovascular, and neurodegenerative diseases. Therefore, we accumulated the updated data on composition and classification, extraction methods, and utilization of different parts of walnuts as well as associated beneficial effects under in vivo and clinical studies. Altogether, this review summarized the ameliorative effects of a walnut-enriched diet in chronic diseases which can be designated to the synergistic or individual effects of walnut components mainly through anti-oxidative and anti-inflammatory role.

Y-box binding protein 1 augments sorafenib resistance via the PI3K/Akt signaling pathway in hepatocellular carcinoma.

BACKGROUND: Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Y-box binding protein 1 (YB-1) is closely correlated with tumors and drug resistance. However, the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown. AIM: To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC. METHODS: The protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues. Next, we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib. Then, we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling, flow cytometry and Western blotting assays. We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo. Moreover, we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing (DGE-seq). RESULTS: YB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues. YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis. Consistently, the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down. Furthermore, KEGG pathway enrichment analysis of DGE-seq demonstrated that the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway was essential for the sorafenib resistance induced by YB-1. Subsequently, YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway (Akt1 and PIK3R1) as shown by searching the BioGRID and HitPredict websites. Finally, YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib, and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance. CONCLUSION: Overall, we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene, which is of great significance for the application of sorafenib in advanced-stage HCC.

Effect of grape seed power on the structural and physicochemical properties of wheat gluten in noodle preparation system.

Noodles were prepared using wheat flour supplemented with 1%, 3%, and 5% grape seed power (GSP). The farinograph properties of wheat flour, the textural properties of the dough, and thermal properties of the gluten were determined. The microstructure was analyzed by scanning electron and atomic force microscopy, and the effects of the addition of GSP on the physicochemical and structural properties (free sulfhydryl content, surface hydrophobic region, and secondary structure) of wheat gluten protein were analyzed. 1% GSP promoted the aggregation of gluten proteins by promoting hydrophobic interactions and hydrogen bonding, thus enhanced the noodle quality. Whereas, 3% and 5% GSP addition disrupted the disulfide bonds between gluten protein molecules and formed macromolecular aggregates linked to gluten proteins through non-covalent bonds and hydrophobic interactions, which prevented the formation of the gluten protein reticulation structure. Our study emphasized the interaction between wheat proteins and GSP in noodle making dough.

Comparison of phenolic compounds extracted from Diaphragma juglandis fructus, walnut pellicle, and flowers of Juglans regia using methanol, ultrasonic wave, and enzyme assisted-extraction.

The phenols in Diaphragma juglandis fructus (DJF), walnut pellicle (WP), and flowers of Juglans regia (FJR) from walnut were extracted using three methods (methanolic condensation reflux extraction, ultrasonic wave extraction, and enzyme assisted-extraction), and phenolics and antioxidant capacities of different extractions were compared. Overall, 50 phenolics were identified by HPLC-MS/MS with 41 compounds in DJF, 32 in WP, and 29 in FJR. It was observed that tannins in WP was higher than those in DJF and FJR. As for PCA, more than 70% of the variance was explained with the obvious comparison between the phenolic constituents. The phenolics in walnut contributed to remarkable antioxidant effect, with the highest effect observed in WP. This study presents the analysis and comparison of the phenols can be further extended for the development of functional walnut instant foods.

[Effects of CDH1 gene promoter methylation on expression of E-cadherin and beta-catenin and its clinicopathological significance in colon carcinoma].

OBJECTIVE: To investigate the relationship between methylation of the CDH1 gene promoter on the expression of E-cadherin and ß-catenin, and to evaluate the correlation with clinicopathological characteristics of the colonic carcinoma. METHODS: Methylation specific PCR (MSP) was used to detect CDH1 gene promoter methylation in the cancer tissue, adjacent tissues and normal tissues in 68 patients. The expression of E-cadherin and ß-catenin was determined by immunohistochemistry staining. RESULTS: The positive rate of CDH1 gene promoter methylation was 32.4% in adjacent tissues and 57.4% in cancer tissue, while no detectable methylation was found in all the normal tissues. The difference was statistically significant. The positive rate of E-cadherin was 92.6% in the normal tissues, 66.2% in the adjacent tissues and 44.1% in the cancer tissues. In all normal tissues, ß-catenin was expressed only at the cellular membrane but not in the cytosol or nucleus, while the expression of ß-catenin was present in the cytosol or nucleus in 29.4% of the adjacent tissues and 50.0% of the cancer tissues. The positive rate of CDH1 gene promoter methylation was negatively correlated with E-cadherin expression(r=-0.312, P=0.01) and positively correlated with ß-catenin cytosolic/nucleus expression(r=0.309, P=0.018). The differentiation and metastasis of colonic carcinoma were associated with the aberrant expression of E-cadherin, ß-catenin, and methylation of CDH1 promoter (P<0.05). CONCLUSION: CDH1 gene promoter methylation may lead to aberrant expression of E-cadherin and ß-catenin in colonic carcinoma, and may play an important role in promoting the invasion of tumor.