New perspectives on different Sacha inchi seed oil extractions and its applications in the food and cosmetic industries.

Sacha inchi oil is growing in demand worldwide owing to its high fatty acid content of linolenic acid (44.30%-51.62%) and linoleic acid (34.08%-36.13%). In addition, Sacha inchi oil also contains phytosterols, such as stigmasterols (346- 456 µg/g), sitosterols (435-563 µg/g), and campesterols (10.47% ± 4.36%). Its main tocopherol is gamma-tocopherol (120.41-125.69 mg/100 g). The antinutrients in Sacha inchi seeds can be reduced by roasting prior to extraction. Various extractions, including both conventional and novel methods, have been used to extract Sacha inchi oil. However, the variety of extraction methods and origins of the seeds change the nutrient profiles, antinutrient content, and physicochemical properties. Incorporation of Sacha inchi oil into food products can increase its nutritional value, and it works as a moisturizing agent in cosmetic products. To obtain Sacha inchi oil with the desired properties and nutritional profile, this review summarizes the effects of different Sacha inchi seed oil extraction methods and processes on chemical compounds, antinutrient content, and physicochemical properties, including their potential and recent applications in food and cosmetic industries.

Sacha inchi oil yield, bioactive compounds, and physicochemical qualities are affected by cultivation area, seed chemical profile, extraction method, and conditions.Sacha inchi oil contains high amounts of linolenic and linoleic acid.Sacha inchi seeds contain heat-labile and heat-stable antinutrients, which are found in traces in the oil.Sacha inchi oil acts as a lipid source, animal fat substitute, and preservative, and increases nutritional value when added to food.Sacha inchi oil acts as a moisturizing agent.Sacha inchi is a promising new oil source for food and cosmetics, where demand has grown in Europe, the United States, and Asia.

Recent Research on Different Parts and Extracts of Opuntia dillenii and Its Bioactive Components, Functional Properties, and Applications.

Opuntia dillenii (O. dillenii) is a plant belonging to the Cactaceae family that is abundant in tropical and subtropical regions worldwide. O. dillenii is consumed as a local delicacy and has no other current use. To understand the nutritional value of O. dillenii in human health and its application in the food, cosmetic, and drug industries, this review summarizes information on the chemical compounds (pure α-pyrone compounds, flavonoids, phenolic acids, polysaccharides, minerals, fatty acids, and betalains) and biological properties (anti-diabetic, anti-hyperglycemic, antihyperlipidemic, anti-atherosclerotic, anti-inflammatory, analgesic, antimicrobial, antifungal, antiviral, anti-spermatogenic, anticancer, antilarval, anti-angiogenic, and antioxidant) of extracts from each part of the plant (fruit juice, fruit peel, cladode, and seeds) (aqueous, ethanolic, and methanolic), and seed oil. In addition, data related to the recent applications of O. dillenii in various industries (e.g., edible coatings, food supplements, cosmetics, nanoparticles, and wastewater treatment) are provided.

Mechanism and inhibitory effects of cactus (Opuntia dillenii) extract on melanocytes and its potential application for whitening cosmetics.

Penghu cactus (Opuntia dillenii [Ker.] Haw) is a cactus plant that commonly grows in Penghu Island, Taiwan, Republic of China (ROC). However, still lack of scientific study on the Opuntia dillenii [Ker.] Haw extract on skin-whitening-associated tyrosinase activity and melanin production. The activities of its extract in melanogenesis were investigated in this article. In this experiment, we used an extract from the Penghu cactus (Opuntia dillenii [Ker.] Haw) to study its tyrosinase inhibition, anti-melanin generation, UV-protection effects and wound healing capacity in B16-F10 melanocytes. Without reducing cell growth greatly or causing cell death, 20 g/L cactus extract effectively inhibited the melanin production of B16-F10 cells, and melanogenesis was induced by 3-isobutyl-1-methylxanthine. The cactus extract could also promote cell proliferation. Cactus extract treatment decreased the mRNA expression of insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) and increased that of transforming growth factor ß (TGF-ß). Thus, it could reduce cell melanin production and promote cell growth but by also reducing IGF-1 and VEGF mRNA expression, may reduce wound scarring and prevent tumor proliferation and swelling. Increasing TGF-ß mRNA expression can help increase collagen to remove wrinkles and help in wound healing. Skin patch test results agreed with in vitro results with B16-F10 melanoma cells. The cactus extract significantly inhibited tyrosinase activity and reduced melanin production, showing a whitening effect on skin tests. Cactus may be a good natural candidate for inhibiting melanin production and promoting cell proliferation.

Targeting histone deacetylase-3 blocked epithelial-mesenchymal plasticity and metastatic dissemination in gastric cancer.

BACKGROUND AND PURPOSE: Histone deacetylase (HDAC) inhibitors (HDIs) can modulate the epithelial-mesenchymal transition (EMT) progression and inhibit the migration and invasion of cancer cells. Emerging as a novel class of anti-cancer drugs, HDIs are attracted much attention in the field of drug discovery. This study aimed to discern the underlying mechanisms of Honokiol in preventing the metastatic dissemination of gastric cancer cells by inhibiting HDAC3 activity/expression. EXPERIMENTAL APPROACH: Clinical pathological analysis was performed to determine the relationship between HDAC3 and tumor progression. The effects of Honokiol on pharmacological characterization, functional, transcriptional activities, organelle structure changes, and molecular signaling were analyzed using binding assays, differential scanning calorimetry, luciferase reporter assay, HDAC3 activity, ER stress response element activity, transmission electron microscopy, immune-blotting, and Wnt/ß-catenin activity assays. The in vivo effects of Honokiol on peritoneal dissemination were determined by a mouse model and detected by PET/CT tomography. KEY RESULTS: HDAC3 over-expression was correlated with poor prognosis. Honokiol significantly abolished HDAC3 activity (Y298) via inhibition of NFκBp65/CEBPß signaling, which could be reversed by the over-expression of plasmids of NFκBp65/CEBPß. Treatments with 4-phenylbutyric acid (a chemical chaperone) and calpain-2 gene silencing inhibited Honokiol-inhibited NFκBp65/CEBPß activation. Honokiol increased ER stress markers and inhibited EMT-associated epithelial markers, but decreased Wnt/ß-catenin activity. Suppression of HDAC3 by both Honokiol and HDAC3 gene silencing decreased cell migration and invasion in vitro and metastasis in vivo. CONCLUSIONS AND IMPLICATIONS: Honokiol acts by suppressing HDAC3-mediated EMT and metastatic signaling. By prohibiting HDAC3, metastatic dissemination of gastric cancer may be blocked. Conceptual model showing the working hypothesis on the interaction among Honokiol, HDAC3, and ER stress in the peritoneal dissemination of gastric cancer. Honokiol targeting HDAC3 by ER stress cascade and mitigating the peritoneal spread of gastric cancer. Honokiol-induced ER stress-activated calpain activity targeted HDAC3 and blocked Tyr298 phosphorylation, subsequently blocked cooperating with EMT transcription factors and cancer progression. The present study provides evidence to demonstrate that HDAC3 is a positive regulator of EMT and metastatic growth of gastric cancer cells. The findings here imply that overexpressed HDAC3 is a potential therapeutic target for honokiol to reverse EMT and prevent gastric cancer migration, invasion, and metastatic dissemination. • Honokiol significantly abolished HDAC3 activity on catalytic tyrosine 298 residue site. In addition, Honokiol-induced ER stress markedly inhibited HDAC3 expression via inhibition of NFκBp65/CEBPß signaling. • HDAC3, which is a positive regulator of metastatic gastric cancer cell growth, can be significantly inhibited by Honokiol. • Opportunities for HDAC3 inhibition may be a potential therapeutic target for preventing gastric cancer metastatic dissemination.

An In Vivo Study to Evaluate the Efficacy of Blue Shark (Prionace glauca) Cartilage Collagen as a Cosmetic.

The "blue shark", Prionace glauca (class: Chondrichthyes), is a pelagic shark species commonly found in tropical and temperate oceans. This shark is mainly sold in Asian countries as food and as traditional Chinese medicine. According to the Red List of the International Union for the Conservation of Nature, P. glauca is classified as low-risk to near endangered. P. glauca cartilage contains collagen type II, which makes it suitable as a bioactive ingredient in cosmeceutical products. This study evaluated the effects of a gel containing various concentrations (0.125-5%) of lyophilized hydrolyzed P. glauca cartilage on the human inner wrist skin compared to a placebo (base). A skin properties evaluation test was conducted before and after applying various concentrations (0.125-5%) of the P. glauca cartilage gel for 10 and 20 min on the inner wrists of participants using a skin analyzer that determined the moisture level, oil level, texture level, complexion level, and the 3D level. Adding lyophilized hydrolyzed shark cartilage (LHSC) significantly improved the moisture, texture, and complexion of the skin while controlling oil and providing a wrinkle-smoothing effect. The result indicated that LHSC formulations were prepared at different concentrations, and they had significantly enhanced effects on skin hydration and elasticity (texture) and the smoothing of wrinkles (3D level). The LHSC also effectively controlled oil secretion and the complexion.

Long-Term Exposures to Air Pollutants and Risk of Peripheral Arterial Occlusive Disease: A Nationwide Cohort Study in Taiwan.

Air pollution is one of the most alarming environmental issues which causes multiple health hazards. An association between air pollution and cardiovascular diseases has been established through many prior studies. In this study, we aimed to evaluate the risk of long-term exposure to air pollution (PM2.5, CO, and NO2) and its association with the risk of developing peripheral arterial occlusive disease (PAOD). PAOD is a condition involving impairment of perfusion of blood in the distal parts of the aorta due to narrowing of the arteries (arterial stenosis) and has been reported as a risk factor for developing cardiovascular diseases. Furthermore, the risk of PAOD increases with age, and hence is a serious public health issue and a cause for concern, especially for an aging society such as Taiwan. Two national-scale databases from Taiwan, the national health insurance database (NHIRD) and the Taiwan air quality-monitoring database (TAQMD), were linked to conduct this cohort study between 2003 and 2013. Cox proportional hazards regression with time-dependent modeling was used to evaluate the hazard ratio (HR) for PAOD with respect to daily exposure to air pollutants. The concentrations of each of the pollutants of interest (PM2.5, NO2, and CO) were categorized into four categories according to the daily average concentration of air pollutants for every quarter of the year, Q1 to Q4 (Q4 = highest). The cumulative incidence of PAOD was examined by Kaplan-Meier analysis with two-tailed log-rank test. A total of 1,598 PAOD cases were identified during the 10-year follow-up period, along with 98,540 non-PAOD controls. In the multivariate analysis, after adjusting for age, gender, urbanization level, residential area, baseline comorbidities, and medications, the adjusted HRs were PM2.5 = 1.14 (95% CI 1.13-1.16), NO2 = 1.03 (95% CI 1.02-1.04), and CO = 2.35 (95% CI 1.95-2.84). Kaplan-Meier analysis showed that CO (P < 0.0001) and PM2.5 (P < 0.0001) concentrations were strongly and positively associated with the cumulative incidence of PAOD during the follow-up period. Findings from this study established that prolonged exposure to air pollutants CO and PM2.5 are significant factors that, among other well-known causes, may also play a potential role in PAOD pathogenesis.

Risk for hypoglycemic emergency with levofloxacin use, a population-based propensity score matched nested case-control study.

Potential association between oral levofloxacin use and hypoglycemic emergency (HE) have been established. However, a large epidemiological study is required to verify this observation. This study aimed to determine if use of oral levofloxacin increased the risk of HE. The nationwide database between 1999 and 2013, including 1.6 million patients with type 2 diabetes (T2D), was used to conduct a nested case-control study. Cases and controls comprised of patients with and without HE, respectively. To avoid indication bias the control subjects were chosen through propensity score matching with cases in a 10-fold ratio. T2D severity was classified based on the adjusted diabetic complication severity index score. 26,695 and 266,950 matched patients with T2D, were finally used as cases and controls, respectively, for the analysis. Multivariate logistic regression analysis showed that antibiotic use was associated with an increased risk for HE (adjusted odds ratio (aOR) = 6.08, 95% confidence interval (95% CI): 5.79-6.38). When compared with antibiotic non-users, those who used fluoroquinolones and sulfonamides displayed the highest (aOR = 12.05, 95% CI: 10.66-13.61) and second highest (aOR = 7.20, 95% CI: 6.29-8.24) risks of HE, respectively. The associated risk for HE was significantly higher with levofloxacin than that with cephalosporins (aOR = 5.13, 95% CI: 2.28-11.52) and penicillin (aOR = 9.40, 95% CI: 2.25-39.24). In the joint effect analyses, the risk for HE increased with the combination of levofloxacin with insulin (aOR = 8.42, 95% CI: 1.91-37.00) or sulfonylurea (aOR = 3.56, 95% CI: 1.12-11.33). Use of oral levofloxacin, compared to that of other antibiotics, was found to be significantly associated with HE in T2D patients. Clinicians should exercise caution while prescribing levofloxacin, especially when combined with insulin or sulfonylurea.

Calcined Oyster Shell Powder as a Natural Preservative for Maintaining Quality of White Shrimp (Litopenaeus vannamei).

Oyster shell waste has led to many problems, including displeasing odors, pollution of the seaside, and harm to the environment. Using calcined oyster shells as a natural preservative might solve the problem of oyster shell waste. We studied the use of calcined oyster shell powder (COSP) as a natural preservative for improving shrimp shelf-life over 12 days under refrigerated conditions. As compared with the control, COSP treatment effectively retarded pH change, reduced the formation of total volatile basic nitrogen, and inhibited bacterial growth during refrigerated storage. In addition, shrimp muscle lipid oxidation measured by peroxide value (PV) and thiobarbituric acid (TBA) was decreased during storage. The quality was preserved up to 12 days with 2.0-4.0% COSP treatment as compared with only 6 days for un-treated shrimp. The development of preservatives for aquatic products is expected to delay growth of and spoilage by microorganisms in the refrigerated state, thus providing more barrier protection for aquatic food safety.

Ultrasound-aided diagnosis of preclinical phases of psoriatic arthritis in biologic-naïve psoriasis patients with or without arthralgia.

OBJECTIVES: The evolution of psoriasis (PsO) to psoriatic arthritis (PsA) has been proposed recently. There are three phases that occur in sequence prior to classifiable PsA: PsO patients, PsO patients with a positive imaging, and PsO patients with arthralgia not explained by other diagnosis. The purpose of this study was to compare the differences among preclinical phases using ultrasound and clinical assessment. METHODS: Patients with psoriasis were recruited. Patients who had been previously diagnosed with psoriatic arthritis or who had used biologics were excluded. A 52-joint ultrasound (52j US) assessment and clinical assessments including the swollen joint count, tender joint count, erythrocyte sediment rate, C-reactive protein, dactylitis score, enthesitis score, psoriasis severity, and nail psoriasis severity, were performed. RESULTS: A total of 188 eligible psoriasis patients were enrolled. Physical examination revealed 39 patients (20%) with at least one swollen joint. The 52j US assessment demonstrated 90 patients (47%) having at least one joint with grey-scale score 2-3. All patients were further stratified into PsO patients (n=58), PsO patients with a positive imaging, (n=59), PsO patients with arthralgia not explained by other diagnosis (n=27), and classifiable PsA (n=39). There were no differences in clinical characteristics other than tender joint count found among the three preclinical phases of PsA. Dactylitis score, swollen joint count and heatly assessment questionnaire score were significantly higher in classifiable PsA. CONCLUSIONS: Nearly half of the psoriasis patients without previously diagnosed psoriatic arthritis would be classified into the preclinical phases of psoriatic arthritis based on the 52j US and clinical assessments. Ultrasound assessment is helpful for identifying psoriasis patients who are in the preclinical phases of psoriatic arthritis, particularly for those without arthralgia.

Bioactive and Physicochemical Characteristics of Natural Food: Palmyra Palm (Borassus flabellifer Linn.) Syrup.

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.

Exploiting Honokiol-induced ER stress CHOP activation inhibits the growth and metastasis of melanoma by suppressing the MITF and ß-catenin pathways.

There is increasing global incidence of highly metastatic melanoma and therapeutic strategies like those focusing on the downstream beta-catenin/MITF axis of invading melanoma cells are urgently needed. Targeting endoplasmic reticulum (ER) stress can promote cancer cell death and inhibit epithelial mesenchymal transition (EMT) in metastatic tumors. This study aimed to determine if Honokiol could promote ER stress-dependent apoptosis and regulate metastatic melanoma. The therapeutic efficacy of Honokiol was assessed using the highly metastatic melanoma xenograft mouse model for peritoneal metastasis and evaluated by computed tomography imaging. The ER stress marker, Calpain-10, delineated a novel proteolytic cleavage enzyme, while CHOP/GADD153-regulated apoptosis was used for gene silencing to determine the role of the ß-catenin/MITF axis in melanoma cells. The results showed that Honokiol effectively decreased peritoneal dissemination and organ metastasis via ER stress activation and EMT marker inhibition. Knockdown Calpain-10 or CHOP/GADD153 blocked all of the biological effects in Honokiol-induced ß-catenin/MITF cleavage, ERSE or TCF/LEF luciferase activity, and ß-catenin kinase activity. These findings suggest that Honokiol can significantly thwart the progression of highly metastatic melanoma using the ß-catenin/MITF axis via prompt Calpain-10 and CHOP/GADD153 regulated cascades.

Contrast Medium Exposure During Computed Tomography and Risk of Development of End-Stage Renal Disease in Patients With Chronic Kidney Disease: A Nationwide Population-Based, Propensity Score-Matched, Longitudinal Follow-Up Study.

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 <2 exposure per year on average, and ≥2 exposure per year on average. After adjusting for confounders, we identified a much higher risk for developing ESRD in the 2 groups of >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.

Melatonin set out to ER stress signaling thwarts epithelial mesenchymal transition and peritoneal dissemination via calpain-mediated C/EBPß and NFκB cleavage.

Peritoneal dissemination of tumor has high mortality and is associated with the loss of epithelial features, acquisition of motile mesenchymal morphology characteristics, and invasive properties by tumor cells. Melatonin is an endogenously produced molecule in all plant species that is known to exert antitumor activity, but to date, its underlying mechanisms and antiperitoneal metastasis efficacy is not well defined. This study determined the antiperitoneal dissemination potential of melatonin in vivo and assessed its association with the inhibition of epithelial-to-mesenchymal transition (EMT) signaling mechanism by endoplasmic reticulum (ER) stress, which may be a major molecular mechanism of melatonin against cancer. The results demonstrate that melatonin inhibited peritoneal metastasis in vivo and activated ER stress in Cignal ERSE Reporter Assay, organelle structure in transmission electron microscopy images, calpain activity, and protein biomarkers like p-elf2α. Moreover, the overexpression of transcription factor C/EBPß in gastric cancer interacted with NFκB and further regulates COX-2 expression. These were dissociated and downregulated by melatonin, as proven by immunofluorescence imaging, immunoprecipitation, EMSA, and ChIP assay. Melatonin or gene silencing of C/EBPß decreased the EMT protein markers (E-cadherin, Snail, and Slug) and Wnt/beta-catenin activity by Topflash activity, and increased ER stress markers. In an animal study, the results of melatonin therapy were consistent with those of in vitro findings and attenuated systemic proangiogenesis factor production. In conclusion, C/EBPß and NFκB inhibition by melatonin may impede both gastric tumor growth and peritoneal dissemination by inducing ER stress and inhibiting EMT.

Iodinated Contrast Medium Exposure During Computed Tomography Increase the Risk of Subsequent Development of Thyroid Disorders in Patients Without Known Thyroid Disease: A Nationwide Population-Based, Propensity Score-Matched, Longitudinal Follow-Up Study.

To investigate the association between iodinated contrast medium (ICM) exposure during computed tomography (CT) and the subsequent development of thyroid disorders in patients without known thyroid disease in Taiwan, an iodine-sufficient area. We conducted a population-based cohort study by using data from 1996 to 2012 in the Taiwan National Health Insurance Research Database. A total of 33,426 patients who underwent ICM-enhanced CT were included as the study cohort. To avoid selection bias, we used propensity score and matched for the index year (defined as the year of first ICM exposure) to retrieve 33,426 patients as the comparison cohort. No patients in the 2 cohorts had any known thyroid disease before the index year. Patients with a history of amiodarone treatment or coronary angiography and those with <1 year follow-up were excluded. Participants were followed until a new diagnosis of thyroid disorder or December 31, 2011. Hazard ratios (HRs) with 95% confidence interval (95% CI) were calculated using the Cox proportional hazards regression. An association was identified between ICM exposure and the subsequent development of thyroid disorders after adjustment for potential confounders (adjusted HR = 1.17; 95% CI: 1.07-1.29; P = 0.001). Male patients and patients' ages ≥40 years in the ICM-exposure cohort had a higher adjusted HR for developing thyroid disorders than did those in the non-ICM-exposure cohort. Hypothyroidism had the highest adjusted HR (HR = 1.37; 95% CI: 1.06-1.78; P < 0.05) among all thyroid disorders and had a higher risk of development or detection during >0.5-year post-ICM exposure compared with that during ≤0.5-year post-ICM exposure (HR = 1.26; 95% CI: 1.01-1.58; P < 0.05). Repeated ICM exposure increased the risk of thyroid disorders in patients who accepted >1 time of ICM per year on average compared with those who accepted ≤1 time per year on average (adjusted HR = 3.04; 95% CI: 2.47-3.73; P < 0.001). This study identified ICM exposure during CT as a risk factor for the subsequent development of thyroid disorders in patients without known thyroid disease, particularly in patients with repeated exposure.

Honokiol confers immunogenicity by dictating calreticulin exposure, activating ER stress and inhibiting epithelial-to-mesenchymal transition.

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)-ß1 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 thwarts gastric tumor growth and peritoneal dissemination by inhibiting Tpl2 in an orthotopic model.

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-ß1 (TGFß1) 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. TGFß1 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.

Pseudoatrophic macules associated with neurofibromatosis-1.

A 14-year-old boy with neurofibromatosis type 1 presented with two ill-demarcated, grayish-white, and atrophic patches on his left back, which were confirmed as neurofibroma by histopathologic examinations. This clinical presentation of neurofibroma has rarely been reported in patients with neurofibromatosis.