Peritoneal dissemination is a major clinical obstacle in gastrointestinal cancer therapy, and it accounts for the majority of cancer‐related mortality. Calreticulin (CRT) is over‐expressed in gastric tumors and has been linked to poor prognosis. In this study, immunohistochemistry studies revealed that the up‐regulation of CRT was associated with lymph node and distant metastasis in patients with gastric cancer specimens. CRT was significantly down‐regulated in highly metastatic gastric cancer cell lines and metastatic animal by Honokiol‐treated. Small RNA interference blocking CRT by siRNA‐CRT was translocated to the cells in the early immunogenic response to Honokiol. Honokiol activated endoplasmic reticulum (ER) stress and down‐regulated peroxisome proliferator‐activated receptor‐γ (PPARγ) activity resulting in PPARγ and CRT degradation through calpain‐II activity, which could be reversed by siRNA‐calpain‐II. The Calpain‐II/PPARγ/CRT axis and interaction evoked by Honokiol could be blocked by gene silencing or pharmacological agents. Both transforming growth factor (TGF)‐β1 and N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG) induced cell migration, invasion and reciprocal down‐regulation of epithelial marker E‐cadherin, which could be abrogated by siRNA‐CRT. Moreover, Honokiol significantly suppressed MNNG‐induced gastrointestinal tumor growth and over‐expression of CRT in mice. Knockdown CRT in gastric cancer cells was found to effectively reduce growth ability and metastasis in vivo. The present study provides insight into the specific biological behavior of CRT in epithelial‐to‐mesenchymal transition (EMT) and metastasis. Taken together, our results suggest that the therapeutic inhibition of CRT by Honokiol suppresses both gastric tumor growth and peritoneal dissemination by dictating early translocation of CRT in immunogenic cell death, activating ER stress, and blocking EMT.

Honokiol is known to suppress the growth of cancer cells; however, to date, its antiperitoneal dissemination effects have not been studied in an orthotopic mouse model. In the present study, we evaluated the antiperitoneal dissemination potential of Honokiol in an orthotopic mouse model and assessed associations with tumor growth factor-β1 (TGFβ1) and cells stimulated by a carcinogen, N-methyl-N′-nitro-N-nitrosoguanidine (MNNG). Our results demonstrate that tumor growth, peritoneal dissemination and peritoneum or organ metastasis of orthotopically implanted MKN45 cells were significantly decreased in Honokiol-treated mice and that endoplasmic reticulum (ER) stress was induced. Honokiol-treated tumors showed increased epithelial signatures such as E-cadherin, cytokeratin-18 and ER stress marker. In contrast, decreased expression of vimentin, Snail and tumor progression locus 2 (Tpl2) was also noted. TGFβ1 and MNNG-induced downregulation of E-cadherin and upregulation of Tpl2 were abrogated by Honokiol treatment. The effect of Tpl2 inhibition in cancer cells or endothelial cells was associated with inactivation of CCAAT/enhancer binding protein B, nuclear factor kappa-light-chain-enhancer of activated B cell and activator protein-1 and suppression of vascular endothelial growth factor. Inhibition of Tpl2 in gastric cancer cells by small interfering RNA or pharmacological inhibitor was found to effectively reduce growth ability and vessel density in vivo. Honokiol-induced reversal of epithelial-to-mesenchymal transition (EMT) and ER stress-induced apoptosis via Tp12 may involve the paralleling processes. Taken together, our results suggest that the therapeutic inhibition of Tpl2 by Honokiol thwarts both gastric tumor growth and peritoneal dissemination by inducing ER stress and inhibiting EMT.

The aim of the study was to investigate the long-term association between contrast medium exposure during computed tomography (CT) and the subsequent development of end-stage renal disease (ESRD) in patients with chronic kidney disease (CKD). We conducted a population-based cohort study using Taiwan's National Health Insurance Research Database. A total of 7100 patients with nonadvanced CKD who underwent contrast medium-enhanced CT were identified and served as the study cohort. To avoid selection bias, we used the propensity score to match 7100 nonadvanced CKD patients, who underwent noncontrast medium-enhanced CT to serve as the comparison cohort. The age, sex, index year, and frequency of undergoing CTs were also matched between the study and comparison cohorts. Participants were followed until a new diagnosis of ESRD or December 31, 2011. Hazard ratios (HRs) with 95% confidence interval (95% CI) were calculated using the Cox proportional hazards regression. Contrast medium exposure was not identified as a risk factor for developing ESRD in nonadvanced CKD patients after confounders adjustment (adjusted HR = 0.91; 95% CI, 0.66-1.26; P = 0.580). We further divided the patients who underwent CTs with contrast medium use into ≤1 exposure per year on average, >1 and 1 and <2 exposure per year on average and ≥2 exposure per year on average (adjusted HR = 8.13; 95% CI, 5.57-11.87 and adjusted HR = 12.08; 95% CI, 7.39-19.75, respectively) compared with the patients who underwent CTs without contrast medium use. This long-term follow-up study demonstrated that contrast medium exposure was not associated with an increased risk of ESRD development in nonadvanced CKD patients.

Palmyra palm syrup, produced from Borassus flabellifer flowers’ sap, is rich in nutrients and minerals and has unique flavors. This study evaluated the in vitro antioxidant activity, physicochemical characteristics, and Maillard reaction products of palmyra palm syrup prepared by thermal and ultrafiltration processes. Palmyra palm syrup prepared by a thermal process had smaller L*, b* values, and larger a* values than that prepared by an ultrafiltration process. Palmyra palm syrup contained 10 vitamins, the most abundant being vitamin E. Overall, 38 volatile compounds were found and classified into six groups in the order of alcohols > acids > ketones > sulfurs > pyrazines > phenols and aldehyde. Volatile compounds depended on concentration, temperature, and ultrafiltration process. Protein content decreased because of participation in the Maillard reaction and increased 5-hydroxymethylfurfural (HMF) and total phenolic content. The HMF content was very low (0.02–14.95 mg/100 g). The radical scavenging activity of 2,2-diphenyl-1-1 picrylhydrazyl and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulphonic acid) in palmyra palm syrup with thermal process was higher than with ultrafiltration. This study established that ultrafiltration pretreatment of palmyra palm syrup generated a good appearance and reduced the HMF content, however, it negatively affected the volatile compounds and physicochemical characteristics.