A systems approach points to a therapeutic role for retinoids in asparaginase-associated pancreatitis.

Among drug-induced adverse events, pancreatitis is life-threatening and results in substantial morbidity. A prototype example is the pancreatitis caused by asparaginase, a crucial drug used to treat acute lymphoblastic leukemia (ALL). Here, we used a systems approach to identify the factors affecting asparaginase-associated pancreatitis (AAP). Connectivity Map analysis of the transcriptomic data showed that asparaginase-induced gene signatures were potentially reversed by retinoids (vitamin A and its analogs). Analysis of a large electronic health record database (TriNetX) and the U.S. Federal Drug Administration Adverse Events Reporting System demonstrated a reduction in AAP risk with concomitant exposure to vitamin A. Furthermore, we performed a global metabolomic screening of plasma samples from 24 individuals with ALL who developed pancreatitis (cases) and 26 individuals with ALL who did not develop pancreatitis (controls), before and after a single exposure to asparaginase. Screening from this discovery cohort revealed that plasma carotenoids were lower in the cases than in controls. This finding was validated in a larger external cohort. A 30-day dietary recall showed that the cases received less dietary vitamin A than the controls did. In mice, asparaginase administration alone was sufficient to reduce circulating and hepatic retinol. Based on these data, we propose that circulating retinoids protect against pancreatic inflammation and that asparaginase reduces circulating retinoids. Moreover, we show that AAP is more likely to develop with reduced dietary vitamin A intake. The systems approach taken for AAP provides an impetus to examine the role of dietary vitamin A supplementation in preventing or treating AAP.

Clinical Characteristics of Oral Allergy Syndrome in Children with Atopic Dermatitis and Birch Sensitization: a Single Center Study.

BACKGROUND: Oral allergy syndrome (OAS) is an immunoglobulin E (IgE)-mediated hypersensitivity that occurs frequently in older children with pollen sensitization. This study focused on the clinical characteristics of OAS in children with atopic dermatitis (AD) and birch sensitization. METHOD: s: A total of 186 patients aged 2-18 years with AD and birch sensitization were enrolled in this study between January 2016 and March 2017. Their levels of serum total IgE and birch- and ragweed-specific IgE (sIgE) were measured using ImmunoCAP (Thermo Fisher Scientific, Uppsala, Sweden). Information regarding causative foods and symptoms were obtained via interviews. The patients were divided into 3 groups according to their ages (group 1, 2-6 years; group 2, 7-12 years; and group 3, 13-18 years). RESULTS: Eighty-one of the 186 (43.5%) children with AD who were sensitized to birch pollen were diagnosed as having OAS. The prevalence of OAS in group 1 (the children who had AD and birch sensitization aged 2-6 years) was 36.6%. A greater predominance of men was noted in the non-OAS group (77.1%) compared to the OAS group (60.5%). Apples were the most common causative food in group 2 and 3 while kiwis were the most common cause of OAS in group 1. There was a statistically significant correlation between birch-sIgE levels and the prevalence of OAS (P = 0.000). The cut-off value was 6.77 kUA/L with 55.6% sensitivity and 79.0% specificity (area under the curve 0.653). CONCLUSION: In our study, the prevalence of OAS in children with AD and birch sensitization was 43.5%. Even in the preschool age group, the prevalence of OAS was considerable. Patients with high levels of birch-sIgE were more likely to have OAS. Clinicians should therefore be vigilant about OAS in patients with a high degree of sensitization to birch pollen and even young children if they have birch sensitization.

Triterpenoids from Ziziphus jujuba induce apoptotic cell death in human cancer cells through mitochondrial reactive oxygen species production.

Ziziphus jujuba var. inermis Rehder is an edible fruit-producing species of the Rhamnaceae family. In the present study, we isolated eight triterpenoids (1-8) from the fruits of Z. jujuba var. inermis and evaluated their apoptotic cell-death-inducing activities in human cancer cell lines (A549, PC-3, and MDA-MB-231). The structures of compounds 1-8 were determined by spectroscopic methods. Among these, four isomers of coumaroyl alphitolic acid showed potent cytotoxic activities on these cancer cells: 3-O-cis-p-coumaroyl alphitolic acid (3), 3-O-trans-p-coumaroyl alphitolic acid (4), 2-O-trans-p-coumaroyl alphitolic acid (5), and 2-O-cis-p-coumaroyl alphitolic acid (6). Moreover, compounds 3-6 induced apoptotic cell death in a concentration-dependent manner. We further investigated the apoptosis-inducing effects of compound 4 in PC-3 cells which triggered the cleavage of procaspase-3, procaspase-7, procaspase-8, bid, and PARP. Compound 4 increased both the mitochondrial reactive oxygen species (ROS) production and the phosphorylation of p38 MAPK (mitogen-activated protein kinase), but decreased the mitochondrial membrane potential. Pretreatment with Mito-TEMPO (a specific mitochondrial-targeted antioxidant) or a specific p38 inhibitor (SB203580) attenuated apoptotic cell death triggered by compound 4 which suggests that compound 4 may induce apoptotic cell death in these cancer cells by increasing the mitochondrial ROS production as well as the subsequent p38 MAPK activation. The study findings provide a rational base to use Ziziphus extracts for cancer treatments in traditional oriental medicine.

Mangiferin inhibits passive cutaneous anaphylaxis reaction and pruritus in mice.

The antiallergic effect of mangiferin isolated from the rhizome of Anemarrhena asphodeloides Bunge (family Liliaceae) was measured in vitro and in vivo. Orally and intraperitoneally administered mangiferin potently inhibited passive cutaneous anaphylaxis (PCA) reaction induced by IgE-antigen complex as well as pruritus induced by compound 48/80 in mice. Mangiferin also inhibited the expression of the proinflammatory cytokine TNF-alpha and the IgE-switching cytokine IL-4 as well as transcription factor NF-kappaB activation in RBL-2H3 cells stimulated by IgE-antigen complex. These findings suggest that mangiferin may improve PCA reaction and pruritus.

Timosaponin AIII, a saponin isolated from Anemarrhena asphodeloides, ameliorates learning and memory deficits in mice.

Anemarrhena asphodeloides Bunge (AA, family Liliaceae), which primarily contains xantones, such as mangiferin, and steroidal saponins, such as timosaponin AIII and sarsasapogenin, has been used as an anti-pyretic, anti-inflammatory, anti-diabetic, anti-platelet aggregation, and anti-depressant agent in traditional Chinese medicine. In the present study, the memory-enhancing effects of these saponins were investigated in scopolamine-treated mice. Among saponins, timosaponin AIII (TA3) significantly reversed the scopolamine-induced deficits in a passive avoidance test and in the Morris water maze test. TA3 also increased hippocampal acetylcholine levels in scopolamine-treated mice and dose-dependently inhibited acetylcholinesterase (AChE) activity (IC(50) value, 35.4 microM). When TA3 (50 mg/kg) was orally administered to mice and its blood concentration was measured by liquid chromatography and tandem mass spectrometry, the C(max) of TA3 occurred 4-6 h after TA3 treatment. The memory-enhancing effect of TA3 was greater when it was administered 5 h before the acquisition trial than 1 h before. Scopolamine treatment in mice increased brain levels of TNF-alpha and IL-1beta expression. However, treatment with TA3 and scopolamine inhibited the increase of TNF-alpha and IL-1beta expression. These results suggest that scopolamine may cause learning and memory deficits that are further complicated by inflammation. TA3 also inhibited the activation of NF-kappaB signaling in BV-2 microglia and in SK-N-SH neuroblastoma cells induced with TNF-alpha or scopolamine. Nevertheless, TA3 may ameliorate memory deficits, mainly by inhibiting AChE.

Mangiferin ameliorates scopolamine-induced learning deficits in mice.

The aim of this study was to evaluate the effects of Anemarrhena asphodeloides BUNGE (AA) on cholinergic memory deficits in mice. This agent has previously been used as an antipyretic, anti-inflammatory, anti-diabetic, and antidepressant in traditional Chinese medicine. Mangiferin was isolated from AA and showed a dose-dependent inhibition of acetylcholinesterase (AChE) activity (IC(50) value, 62.8 microM). Cholinergic dysfunction was induced in mice by administering scopolamine, and the animals were then tested using the passive avoidance test as well as the Morris water maze test. Mangiferin (20 mg/kg, p.o.) significantly reversed scopolamine-induced deficits in the passive avoidance test, and also improved escape latencies in training trials and increased swimming times in the Morris water maze test (p<0.05). Mangiferin also reduced acetylcholine and tumor necrosis factor (TNF)-alpha levels induced by scopolamine in mice brain (p<0.05) and inhibited nuclear factor (NF)-kappaB activation in scopolamine or TNF-alpha-stimulated BV-2 microglial cells. These results suggest that mangiferin can improve long-term cholinergic memory deficits by AChE inhibition or cholinergic receptor stimulation and inhibition of NF-kappaB activation.

Interesterification of olive oil with a fully hydrogenated fat in a batch reactor using step changes in temperature.

Interesterification of a 60:40 (wt/wt) mixture of olive oil and fully hydrogenated canola oil was carried out in a batch reactor using a commercial immobilized lipase from Thermomyces lanuginose as a biocatalyst. The effects of a stepwise change of temperature on the degree of conversion, the solid fat content (SFC) of the products, and the residual activity of the enzyme were investigated. As a reference condition, an interesterification trial was conducted at a constant temperature of 70 degrees C for 48 h. For trials in which a temperature of 70 degrees C was used for the first 4 h of reaction and a temperature of 60 degrees C was employed for the following 44 h, there were no significant differences (p < 0.05) in the overall degree of conversion relative to the reference condition. Oils interesterified for only 1 or 2 h at 70 degrees C had melting points higher than 60 degrees C, whereas an oil produced by interesterification at 70 degrees C for only 4 h had a melting point of 58 degrees C. There was little difference (p < 0.05) between the SFC profiles of the interesterification products prepared by two different temperature protocols (70 degrees C for 24 h; 70 degrees C for 4 h followed by 60 degrees C for 20 h). Use of the protocol involving a step decrease in temperature significantly decreased catalyst deactivation effects, thereby increasing the residual activity of the immobilized lipase.

The beneficial effect of the sap of Acer mono in an animal with low-calcium diet-induced osteoporosis-like symptoms.

The sap of Acer mono has been called 'bone-benefit-water' in Korea because of its mineral and sugar content. In particular, the calcium concentration of the sap of A. mono is 37.5 times higher than commercial spring water. In the current study, we examined whether A. mono sap could improve or prevent osteoporosis-like symptoms in a mouse model. Male mice (3 weeks old) were fed a low-calcium diet supplemented with 25, 50 or 100 % A. mono sap, commercial spring water or a high calcium-containing solution as a beverage for 7 weeks. There were no differences in weekly weight gain and food intake among all the groups. Mice that were given a low-calcium diet supplemented with commercial spring water developed osteoporosis-like symptoms. To assess the effect of sap on osteoporosis-like symptoms, we examined serum calcium concentration, and femur density and length, and carried out a histological examination. Serum calcium levels were significantly lower in mice that received a low-calcium diet supplemented with commercial spring water (the negative control group), and in the 25 % sap group compared to mice fed a normal diet, but were normal in the 50 and 100 % sap and high-calcium solution groups. Femur density and length were significantly reduced in the negative control and 25 % sap groups. These results indicate that a 50 % sap solution can mitigate osteoporosis-like symptoms induced by a low-calcium diet. We also examined the regulation of expression of calcium-processing genes in the duodenum and kidney. Duodenal TRPV6 and renal calbindin-D9k were up-regulated dose-dependently by sap, and the levels of these factors were higher than those attained in the spring water-treated control. The results demonstrate that the sap of A. mono ameliorates the low bone density induced by a low-calcium diet, most likely by increasing calcium ion absorption.

Antiasthmic effect of fermented Artemisia princeps in asthmic mice induced by ovalbumin.

Artemisia princeps Pampanini (AP) was fermented with Bifidobacterium infantis K-525 and its antiasthmic effect investigated. AP and fermented AP (FAP) reduced the IgE level in the blood of ovalbumin-induced asthmic mice. Moreover, FAP reduced the IgE, proinflammatory cytokine IL-6, and IL-4 levels in the trachea, as well as in the lung of the experimental asthmic mice, whereas AP only reduced the IgE and IL-6 levels in the lungs. Nonetheless, AP and FAP both inhibited the mRNA expression of IL-6 and TNF-alpha in IgE-induced RBL-2H3 cells. The in vivo antiasthmic effect of FAP was more potent than that of AP. Therefore, these findings suggest that the enhanced antiasthmic effect of AP after bifidus fermentation was possibly due to the regulation of the proinflammatory cytokine biosynthesis of IL-6 and TNF-alpha.

Inhibitory effect of schizandrin on passive cutaneous anaphylaxis reaction and scratching behaviors in mice.

To evaluate the antiallergic effect of the fruit of Schizandra chinensis Baill (Family Magnoliaceae), which inhibited the mouse passive cutaneous anaphylaxis (PCA) reaction in a preliminary experiment, its main constituent, schizandrin, was isolated and its antiallergic effect investigated. Schizandrin inhibited the PCA reaction induced by the IgE-antigen complex, the scratching behaviors induced by compound 48/80 and the serum IgE production induced by ovalbumin. Schizandrin also inhibited the in vitro degranulation of compound 48/80-induced rat peritoneal mast cells and IgE-induced RBL 2H3 cells. Schizandrin reduced the protein expressions of TNF-alpha and IL-4 in IgE-induced RBL 2H3 cells. These findings suggest that schizandrin can improve IgE-induced anaphylaxis and scratching behaviors.

In vitro and in vivo antiallergic effects of Glycyrrhiza glabra and its components.

Licorice (Glycyrrhiza glabra L., Leguminosae) is frequently used in traditional medicine to treat inflammatory and allergic diseases. In this study, the main components (glycyrrhizin, 18beta-glycyrrhetinic acid, isoliquiritin, and liquiritigenin) were isolated from licorice, and their anti-allergic effects, such as antiscratching behavior and IgE production-inhibitory activity, were evaluated both in vitro and in vivo. Liquiritigenin and 18beta-glycyrrhetinic acid most potently inhibited the degranulation of RBL-2H3 cells induced by IgE with the antigen (DNP-HSA) and rat peritoneal mast cells induced by compound 48/80. Liquiritigenin and 18beta-glycyrrhetinic acid potently inhibited the passive cutaneous anaphylactic reaction as well as the scratching behavior in mice induced by compound 48/80. These components inhibited the production of IgE in ovalbumin-induced asthma mice but liquiritigenin had little effect. This suggests that the antiallergic effects of licorice are mainly due to glycyrrhizin, 18beta-glycyrrhetinic acid, and liquiritigenin, which can relieve IgE-induced allergic diseases such as dermatitis and asthma.

Lactic acid bacteria increase antiallergic effect of Artemisia princeps pampanini SS-1.

Artemisia princeps Pampanini, which is called Ssajuarissuk in Korean (SS-1), was fermented with lactic acid bacteria (LAB) and their passive cutaneous anaphylaxis reaction-inhibitory activity was investigated. Of these fermented agents, SS-1 extract fermented with Bifidobacterium infantis K-525 (F-SS-1) most effectively inhibited the release of P-hexosamindase from RBL-2H3 cells induced IgE. In IgE-induced RBL-2H3 cells, F-SS-1 inhibited proinflammatory cytokines IL-6 and TNF-alpha mRNA expression. Oral administration of SS-1 and F-SS-1 to mice inhibited passive cutaneous anaphylaxis (PCA) reaction induced by IgE and scratching behaviors induced by compound 48/80. The inhibitory activity of F-SS-1 against scratching behaviors was more effective than that of SS-1. These findings suggest that the fermentation of SS-1 with LAB can increase its antiallergic activity.