Shikonin, an anti-inflammatory compound of “Shikon”, inhibits the neutrophil superoxide (O2•−) generation by NADPH oxidase 2 (Nox2); however, the mechanisms of how shikonin affects Nox2 activity remained unclear. We aimed to elucidate the relationship between the inhibition of Nox2 activity and influences on intracellular Ca2+ concentration ([Ca2+]i) by shikonin. For this purpose, we used a simultaneous monitoring system for detecting changes in [Ca2+]i (by fluorescence) and O2•− generation (by chemiluminescence) and evaluated the effects of shikonin on neutrophil-like HL-60 cells stimulated with N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP). Since fMLP activates Nox2 by elevation in [Ca2+]i via fluxes such as inositol 1,4,5-trisphosphate-induced Ca2+ release (IICR) and store-operated Ca2+ entry (SOCE), we also evaluated the effects of shikonin on IICR and SOCE. Shikonin dose-dependently inhibited the fMLP-induced elevation in [Ca2+]i and O2•− generation (IC50 values of 1.45 and 1.12 µM, respectively) in a synchronized manner. Analyses of specific Ca2+ fluxes showed that shikonin inhibits IICR and IICR-linked O2•− generation (IC50 values: 0.28 and 0.31 µM for [Ca2+]i and O2•−, respectively), as well as SOCE and SOCE-linked O2•− generation (IC50 values: 0.39 and 0.25 µM for [Ca2+]i and O2•−, respectively). These results suggested that shikonin inhibits the O2•− generation by Nox2 in fMLP-stimulated neutrophils by targeting Ca2+ fluxes such as IICR and SOCE.
We explored the effect of astaxanthin on vascular endothelial growth factor in the aqueous humor, by measuring vascular endothelial growth factor levels and oxidation-related parameters, including O2•− scavenging activity, H2O2 level, and total hydroperoxide level in the aqueous humor, obtained from 35 patients before and after astaxanthin administration. We evaluated the relationship between vascular endothelial growth factor and the oxidation-related parameters as well as the patient’s diabetic status, age, and sex. Vascular endothelial growth factor levels did not change significantly but O2•− scavenging activity and total hydroperoxide level significantly (p<0.05) increased and decreased, respectively. Both pre- and post- astaxanthin intake, vascular endothelial growth factor and total hydroperoxide levels were positively correlated (Pearson: r = 0.42, p<0.05; r = 0.55, p<0.01, respectively). Analysis of vascular endothelial growth factor levels and O2•− scavenging activities gave a negative correlation but only pre-astaxanthin intake (r = −0.37, p<0.05). Differences in levels pre- and post-astaxanthin only showed association between vascular endothelial growth factor and total hydroperoxide (r = 0.49, p<0.01) analyzed by multiple linear regression. Using multivariate analysis, pre-astaxanthin vascular endothelial growth factor level was associated with two factors of total hydroperoxide and O2•− scavenging activity (r = 0.49, p<0.05), and post-astaxanthin vascular endothelial growth factor level with two factors of total hydroperoxide and sex (r = 0.60, p<0.01). Astaxanthin intake may have affected vascular endothelial growth factor level through its antioxidant effects by increasing O2•− scavenging activity and suppressing peroxide production.
The oxidation of guanosine to 8-oxo-2'-deoxyguanosine (8-oxo-dG) in DNA is closely associated with induction of various diseases, but the endogenous oxidant species involved remains unclear. Hydrogen peroxides (H2O2) have been considered to be the oxidant, while lipid peroxides are another possible oxidant because generated easily in bio-membranes surrounding DNA. The oxidant potency was compared between lipid peroxides and H2O2. Linoleic acid hydroperoxides (LOOH) formed 8-oxo-dG at a higher level than H2O2 in guanosine or double-stranded DNA. In the presence of a physiological concentration of Fe2+ to produce hydroxyl radicals, LOOH was also a stronger oxidant. In a lipid micelle, LOOH markedly produced 8-oxo-dG at a concentration one-tenth of that of H2O2. Upon adding to rat hepatic mitochondria, phosphatidylcholine hydroperoxides produced 8-oxo-dG abundantly. Employing HepG2 cells after pretreated with glutathione peroxidase inhibitor, LOOH formed 8-oxo-dG more abundantly than H2O2. Then, antioxidants to suppress the 8-oxo-dG formation were examined, when the nuclei of pre-incubated HepG2 with antioxidants were exposed to LOOH. Water-soluble ascorbic acid, trolox, and N-acetyl cysteine showed no or weak antioxidant potency, while lipid-soluble 2,6-dipalmitoyl ascorbic acid, α-tocopherol, and lipid-soluble phytochemicals exhibited stronger potency. The present study shows preferential formation of 8-oxo-dG upon LOOH and the inhibition by lipid-soluble antioxidants.
Fucoidan is a sulfated polysaccharide from brown sea algae. In the present study, it was demonstrated that oral administration of F-fucoidan from Saccharina japonica possessed anti-allergic effects using the passive cutaneous anaphylaxis reaction, but not by intraperitoneal administration. The inhibitory mechanism was dependent on galectin-9, which belongs to a soluble lectin family that recognizes β-galactoside and prevents IgE binding to mast cells. The anti-allergy properties of F-fucoidan were cancelled by an intravenous dose of anti-galectin-9 antibody or lactose, which bind competitively with galectin-9 before the passive cutaneous anaphylaxis reaction. F-fucoidan increased the expression level of galectin-9 mRNA in intestinal epithelial cells and serum galectin-9 levels. Oral treatment with F-fucoidan suppressed allergic symptoms through the induction of galectin-9. This is the first report that F-fucoidan can induce the secretion of galectin-9.
In this study, we investigated the anti-obesity effects of soybean paste—Cheonggukjang, fermented with poly gamma glutamic acid producing Bacillus licheniformis-67 in diet induced obese C57BL/6J mice. Forty male C57BL/6J mice aged 4 weeks were divided into four dietary groups; normal diet control, high fat diet control, high fat diet containing 30% of unfermented soybean and high fat diet containing 30% Cheonggukjang fermented with Bacillus licheniformis-67. After 13 weeks of dietary intervention the mice were sacrificed; serum and tissue samples were examined. Serum and hepatic lipid profile, blood glucose, insulin, leptin level were lower (<0.05) along with the body weight and epididymal fat pad weight in the 30% Cheonggukjang supplemented group compared with the high fat diet control group. The expression level of lipid anabolic gene was significantly decreased; whereas the expression level of lipid catabolic genes were significantly increased in the 30% Cheonggukjang supplemented group compared to the high fat diet control group. Collectively, these results suggested that intake of Cheonggukjang fermented with Bacillus licheniformis-67 significantly prevents obesity related parameters.
Pre-germinated brown rice (PGBR) can ameliorate hyperlipidemia, but the action mechanism is not clear. We focus the mechanisms of PGBR prevented hyperlipidemia. Six-week-old mice were divided into: standard-regular diet (SRD), high-fat diet (HFD) and HFD with PGBR (HFD + PGBR) groups for 16 weeks. The HFD group has higher concentrations of TG, TC, HDL and Non-HDL in the blood, and a higher atherosclerosis index (AI). The TG levels in the liver, and TG, bile acid levels in the feces were enhanced; and the total adipocytokines level in adipose tissue was reduced. The HFD group had higher protein expressions of SREBP-1, SCD-1, FAS, LDLR, and CYP7α1 in the liver. Moreover, the greater expressions of SREBP-1, SCD-1, FAS and the less expressions of PPAR-α and adiponectin were in adipose tissue. In the HFD + PGBR group, the PGBR regulated the levels of TG, TC, HDL, Non-HDL, AI and adipocytokines. PGBR increased more cholesterol and bile acid exhaust in feces. The SREBP-1, SCD-1, FAS, HMGCR, LDLR, CYP7α1 and PPAR-α proteins in the liver; and the SREBP-1, SCD-1, FAS, PPAR-α and adiponectin proteins in adipose tissue were reversed by PGBR. Taken together, PGBR can improve lipid synthesis and metabolism, and we suggest PGBR is a recommendable food for controlling hyperlipidemia.
Decreases in saliva secretion compromise food mastication and swallowing, reduce mucosal immune function, and increase the risk for oral diseases like dental caries. Chlorella is a green alga that contains a variety of nutrients including amino acids, vitamins, and minerals. In our previous study, Chlorella-derived multicomponent supplementation did not affect salivary flow rates in healthy young individuals, but Chlorella-derived supplementation attenuated a decrease in saliva secretion that was observed during a kendo training camp. Hence, we hypothesized that Chlorella-derived supplementation increases saliva secretion in individuals with lower rates of saliva flow. Sixty-four subjects took Chlorella-derived tablets for four weeks. Before and after supplementation, saliva samples were collected by chewing cotton. In the complete study group, there was no difference in saliva production before and after supplementation (1.91 ± 0.11 ml/min before vs 2.01 ± 0.12 ml/min after). Analysis of subgroups based on saliva production before supplementation found an increase in saliva secretion in the lower saliva flow group (1.18 ± 0.06 vs 1.38 ± 0.08 ml/min), but no change in the higher saliva flow group (2.63 ± 0.11 vs 2.64 ± 0.15 ml/min). These results suggest that Chlorella-derived multicomponent supplementation increases saliva production in individuals with lower levels of saliva secretion.
This study aimed to evaluate causative factors for prolonged hospitalization based on hospitalization status, type of hospital ward, and comorbidities, specifically diabetes mellitus and infectious diseases, in 20,876 patients hospitalized in Saga University Hospital from April 1, 2012, to February 28, 2015. Prolonged hospitalization was defined as hospital days exceeding period 3 in the diagnosis procedure combination system. Among all factors, causative (risk) factors for prolonged hospitalization were evaluated by multiple logistic regression analysis. Multivariate analysis indicated causative factors for prolonged hospitalization were aging, comorbid diabetes mellitus, time spent in the intensive care unit, and infectious diseases contracted during hospitalization. The risk factors for contracting infectious diseases during hospitalization were aging, male sex, comorbid diabetes mellitus, and increased number of days spent in period 3 in the diagnosis procedure combination code. These data indicated that critical factors for discharge from hospital within an appropriate time frame were prevention of infectious diseases during hospitalization, and a fast and effective therapeutic approach to patients in the intensive care unit.
Overexpression of IGF-1R has been demonstrated in gastrointestinal cancers, and its expression is reported as the result of the loss of tumor suppressors. IL-16 is involved in the pathophysiological process of chronic inflammatory diseases. The aim of this study is to determine the changes in the expression of IGF-1R in intestinal metaplasia (IM) and gastric cancer (GC) as well as the effect of Helicobacter pylori (H. pylori) and IL-16 on cell proliferation and IGF-1R expression in gastric cells. AGS cells were incubated with combinations of IL-16 and H. pylori. Gastric cell proliferation was studied by BrdU uptake. In H. pylori infected mucosa, IGF-1R was significantly higher in IM than chronic gastritis (CG), and also higher in GC than CG and IM. H. pylori significantly decreased BrdU uptake. IL-16 increased BrdU uptake and IGF-1R on AGS cells which had been decreased by H. pylori. Co-incubation with IL-16 increased the expression of IGF-1R mRNA in H. pylori infected cells. We conclude that the expression of IGF-1R in H. pylori infected gastric mucosa may indicate an early stage of carcinogenesis. The IL-16 secretion by H. pylori can be a trigger for the expression of IGF-1R, and it may also be a factor for gastric carcinogenesis.
To investigate the effect of vitamin A and Zn supplementation on vitamin A status, haemoglobin level and defecation of children with persistent diarrhea, a total of 160 paediatric patients were randomly assigned to one of four intervention groups: daily supplementation of 1,500 IU VA for 14 days; daily Zn supplementation for 14 days; daily supplementation with both VA and Zn for 14 days; no supplementation. One hundred twenty-seven children with persistent diarrhea finished intervention (33 were lost to follow-up). Among the 127 children, 41 (32.28%) had anaemia, 104 (81.89%) had a VA deficiency and 38 (29.92%) had an iron insufficiency. Supplementation with VA or VA + Zn enhanced the serum VA levels and ameliorated anaemia. Supplementation with Zn and VA + Zn for 5 days significantly improved defecation, where the VA + Zn treatment resulted in superior outcomes. After 14 days of intervention, the total effectiveness rates were 93.94%, 96.77% and 96.67% in the three groups, significantly greater than that of the non-supplementation group (72.73%). These results indicate that single VA or concurrent VA + Zn supplementation can improve vitamin A status, haemoglobin level and defecation. However, concurrent VA + Zn supplementation is the optimal option and can shorten the duration of persistent diarrhea and markedly improve nutritional status. (www.clinicaltrials.gov registration number: ChiCTR-IOR-14005498)
Altered gut microbial ecology contributes to the development of metabolic diseases including obesity. In this study, we performed 16S rRNA sequence analysis of the gut microbiota profiles of obese and lean Japanese populations. The V3–V4 hypervariable regions of 16S rRNA of fecal samples from 10 obese and 10 lean volunteers were sequenced using the Illumina MiSeqTMII system. The average body mass index of the obese and lean group were 38.1 and 16.6 kg/m2, respectively (p<0.01). The Shannon diversity index was significantly higher in the lean group than in the obese group (p<0.01). The phyla Firmicutes and Fusobacteria were significantly more abundant in obese people than in lean people. The abundance of the phylum Bacteroidetes and the Bacteroidetes/Firmicutes ratio were not different between the obese and lean groups. The genera Alistipes, Anaerococcus, Corpococcus, Fusobacterium and Parvimonas increased significantly in obese people, and the genera Bacteroides, Desulfovibrio, Faecalibacterium, Lachnoanaerobaculum and Olsenella increased significantly in lean people. Bacteria species possessing anti-inflammatory properties, such as Faecalibacterium prausnitzii, increased significantly in lean people, but bacteria species possessing pro-inflammatory properties increased in obese people. Obesity-associated gut microbiota in the Japanese population was different from that in Western people.
Some patients with gastroesophageal reflux disease experience persistent reflux symptoms despite proton pump inhibitor therapy. These symptoms reduce their health-related quality of life. Our aims were to evaluate the relationship between proton pump inhibitor efficacy and health-related quality of life and to evaluate predictive factors affecting treatment response in Japanese patients. Using the gastroesophageal reflux disease questionnaire, 145 gastroesophageal reflux disease patients undergoing proton pump inhibitor therapy were evaluated and classified as responders or partial-responders. Their health-related quality of life was then evaluated using the 8-item Short Form Health Survey, the Pittsburgh Sleep Quality Index, and the Hospital Anxiety and Depression Scale questionnaires. Sixty-nine patients (47.6%) were partial responders. These patients had significantly lower scores than responders in 5/8 subscales and in the mental health component summary of the 8-item Short Form Health Survey. Partial responders had significantly higher Pittsburgh Sleep Quality Index and Hospital Anxiety and Depression Scale scores, including anxiety and depression scores, than those of responders. Non-erosive reflux disease and double proton pump inhibitor doses were predictive factors of partial responders. Persistent reflux symptoms, despite proton pump inhibitor therapy, caused mental health disorders, sleep disorders, and psychological distress in Japanese gastroesophageal reflux disease patients.
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