Metastasis, which accounts for the majority of all cancer-related deaths, occurs through several steps, namely, local invasion, intravasation, transport, extravasation, and colonization. Glycyrrhizin has been reported to inhibit pulmonary metastasis in mice inoculated with B16 melanoma. This study aimed to identify the mechanism through which glycyrrhizin ameliorates the extravasation of melanoma cells into mouse lungs. Following B16 melanoma cell injection, mice were orally administered glycyrrhizin once every two days over 2 weeks; lung samples were then obtained and analyzed. Blood samples were collected on the final day, and cytokine plasma levels were determined. We found that glycyrrhizin ameliorated the extravasation of melanoma cells into the lungs and suppressed the plasma levels of interleukin-6, tumor necrosis factor-α, and transforming growth factor-β. Furthermore, glycyrrhizin ameliorated the lung tissue expression of high mobility group box-1 protein (HMGB1), receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR)-4, RAS, extracellular signal-related kinase, NF-κB, myeloid differentiation primary response 88, IκB kinase complex, epithelial-mesenchymal transition markers, and vascular endothelial growth factor-A. Our study demonstrates that glycyrrhizin ameliorates melanoma metastasis by regulating the HMGB1/RAGE and HMGB1/TLR-4 signal transduction pathways.
Concerns have recently grown about the health effects of secondhand smoke exposure and heated tobacco products. The analysis of tobacco smoke biomarkers is critical to assess the health effects of tobacco smoke exposure. For this purpose, the simultaneous determinations of exposure markers and health effect markers would provide a better evaluation of smoke exposure. In this study, nicotine metabolites (nicotine, cotinine, trans-3'-hydroxycotinine) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in urine were analyzed as exposure markers. The DNA damage markers, 7-methylguanine and 8-hydroxy-2'-deoxyguanosine, were simultaneously measured as health effect markers. The results revealed significant levels of urinary nicotine metabolites and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol in the subjects exposed to secondhand smoke and heated tobacco products. In addition, the urinary levels of 7-methylguanine and 8-hydroxy-2'-deoxyguanosine tended to be high for secondhand smoke and heated tobacco products exposures, as compared to those of non-smokers. These biomarkers will be useful for evaluating tobacco smoke exposure.
Dietary intervention to prevent Helicobacter pylori (H. pylori)-associated gastric diseases seems to be ideal with no risk of bacterial resistance, safe long-term intervention, and correcting pathogenic mechanisms including rejuvenation of precancerous atrophic gastritis and anti-mutagenesis. A transcriptome as set of all RNAs transcribed by certain tissues or cells demonstrates gene functions and reveals the molecular mechanism of specific biological processes against diseases. Here, we have performed RNAseq and bioinformatic analysis to explain proof of concept that walnut intake can rescue from H. pylori infection and explore unidentified mode of actions of walnut polyphenol extract (WPE). As results, BIRC3, SLC25A4, f3 transcription, VEGFA, AZU1, HMOX1, RAB3A, RELBTNIP1, ETFB, INPP5J, PPME1, RHOB, TPI1, FOSL1, JUND.RELB, KLF2, MUC1, NDRG1, ALDOA, ENO1, PFKP, GPI, GDF15, and NRTN genes were newly discovered to be enriched with WPE, whereas CCR4, BLNK, CCR7, CXCR4, CDO1, KLSG1, SELE, RASGRP2, PIK3R3, TSPAN32, HOXC-AS3, HCG8, BTNL8, and CXCL3 genes as inhibitory targets by WPE in H. pylori infection. We identified additional genes what WPE afforded actions of avoiding H. pylori-driven onco-inflammation and rejuvenating precancerous atrophic gastritis. Conclusively, after applying RNAseq analysis in order to document walnut intake for precision medicine against H. pylori infection, significant transcriptomic profiling applicable for validation were drawn.
We examined the effects of a test food containing anthocyanin, astaxanthin, and lutein on the eye function in healthy Japanese adults with eye fatigue after operating visual display terminals. Forty-four subjects were randomly but equally assigned to the active or placebo group. Two active or placebo capsules were taken once daily for 6 weeks. Accommodative function, tear film break-up time, visual acuity, the value of Schirmer’s test, macular pigment optical density level, muscle hardness, and a questionnaire were evaluated before and after a 6-week intervention. Each group included 20 subjects in the efficacy analysis. The active group showed a significant improvement in the percentage of pupillary response of an average of both eyes and dominant eye pre- and post-visual display terminal operation at 6 weeks compared with the placebo group. Moreover, the active group showed a significant improvement in the scores of “A sensation of trouble in focusing the eyes” and “Difficulty in seeing objects in one’s hand and nearby, or fine print” compared with the placebo group between before and after ingestion. Therefore, 6-weeks consumption of the test food inhibited a decrease in the accommodative function caused by visual display terminal operation (UMIN000036989).
The effects of acotiamide on gastrointestinal motility have not been sufficiently investigated. The aim of this study was to determine whether single preprandial acotiamide or mosapride intake might affect the gastric emptying rate using the 13C breath test. Here, 11 healthy volunteers participated in a randomized three-way crossover study. The subjects received acotiamide (100 mg) or mosapride (5 mg) or placebo before liquid test meal ingestion. Gastric emptying was estimated by determining following parameters: the time required for 50% emptying of the labeled meal (T1/2), lag time for 10% emptying of the labeled meal (Tlag), gastric emptying coefficient (GEC) and regression-estimated constants (β and κ). These parameters were calculated from a 13CO2 breath excretion curve using conventional formulas. The acotiamide, mosapride and placebo conditions were compared, revealing that for gastric emptying rates (values expressed as median), T1/2 (87.83571 min vs 79.95057 min vs 88.74378 min, p = 0.1496), Tlag (46.36449 min vs 42.2897 min vs 47.08094 min, p = 0.4966), GEC (4.382027 vs 4.211441 vs 4.248495, p = 0.8858), β (1.917728 vs 1.757062 vs 1.869141, p = 0.4066) and κ (0.834051 vs 0.819820 vs 0.789523, p = 0.1225) did not significantly differ. In this study, acotiamide (100 mg) or mosapride (5 mg) had no effect on gastric emptying.
Singlet oxygen prefers to react with an electron-rich double bonds. We observed that the oxidation rate for uric acid with singlet oxygen increased with increasing pH and the oxidation rate dramatically was elevated at around pH 5.4 and 9.8, which are the acidity constants of uric acid, pKa1 and pKa2, respectively. Furthermore, we observed that the absorbance near 200 nm and the molar extinction coefficient (ɛ) increased with increasing pH, similar to the change in oxidation rate. Computer calculations by Chong [Chong, J Theor Comput Sci 2013; 1(1)] revealed that uric acid elongates its C=N conjugated diene structure with increasing pH. This is correlated with an increase in the UV absorbance of C=C double bonds near 200 nm, and may indicate higher electron density in the double bonds. Therefore, we concluded that the increased oxidation rate is due to elongation of the C=N conjugated polyene system at higher pH. On the other hand, the major products were 4-hydroxyallantoin and parabanic acid (hydrolyzed to oxaluric acid at pH 10.7), suggesting that the reaction pathways were the same regardless of pH. Finally, possible reaction schemes are presented.
Leukocyte activation and the resulting oxidative stress induced by bioincompatible materials during hemodialysis impact the prognosis of patients. Despite multiple advances in hemodialysis dialyzers, the prognosis of hemodialysis patients with complications deeply related to oxidative stress, such as diabetes mellitus, remains poor. Thus, we re-evaluated the effects of hemodialysis on multiple reactive oxygen species using electron spin resonance-based methods for further improvement of biocompatibility in hemodialysis. We enrolled 31 patients in a stable condition undergoing hemodialysis using high-flux polysulfone dialyzers. The effects of hemodialysis on reactive oxygen species were evaluated by two methods: MULTIS, which evaluates serum scavenging activities against multiple hydrophilic reactive oxygen species, and i-STrap, which detects lipophilic carbon-center radicals. Similar to previous studies, we found that serum hydroxyl radical scavenging activity significantly improved after hemodialysis. Unlike previous studies, we discovered that scavenging activity against alkoxyl radical was significantly reduced after hemodialysis. Moreover, patients with diabetes mellitus showed a decrease in serum scavenging activity against alkyl peroxyl radicals and an increase in lipophilic carbon-center radicals after hemodialysis. These results suggest that despite extensive improvements in dialyzer membranes, the forms of reactive oxygen species that can be eliminated during dialysis are limited, and multiple reactive oxygen species still remain at increased levels during hemodialysis.
Polyphenols are abundant in vegetables and fruit. They have been shown to have various antitumor, antioxidant, and anti-inflammatory effects. Here, we extracted the lipid-soluble fraction of polyphenols from fermented sweet potato (Ipomoea batatas). These lipid-soluble polyphenols mainly contained caffeic acid derivatives with strong antioxidant ability, which we hypothesized to affect diseases for which oxidative stress is a factor, such as cancer. We therefore investigated the antitumor and chemo-sensitizing effects of lipid-soluble polyphenols on E0771 murine breast cancer cells. The lipid-soluble polyphenols accumulated in the cells’ cytoplasm due to its high lipophilicity, and reduced reactive oxygen species through its strong antioxidant activity. The lipid-soluble polyphenols also arrested the cell cycle at G0/G1 by suppressing Akt activity, and enhanced the cytotoxicity of anticancer agents. In this model, lipid-soluble polyphenols inhibited tumor growth and enhanced the efficacy of chemotherapy drugs. These results suggest the potential of lipid-soluble polyphenols as a functional food to support cancer therapy.
Frailty is a progressive age-related disorder associated with odds ratio for subsequent falls, disability, and mortality. This study analyzed the association between frailty odds ratios and diet quality using the Korean Healthy Eating Index in older individuals. Data were obtained for 2,660 community-dwelling individuals aged ≥60 years who participated in the 6th Korea National Health and Nutrition Survey (2014–2015). Frailty was diagnosed following the Fried phenotype index based on five criteria: unintentional weight loss, emotional exhaustion, low physical activity, slow walking speed, and weak grip strength. The participants were categorized as normal, pre-frail, and frail. Diet quality was assessed using Korean Healthy Eating Index scores calculated based on 24-h dietary recall. Compared to the group with the highest Korean Healthy Eating Index score, the group with low Korean Healthy Eating Index showed a 1.71-fold higher pre-frail odds ratio (95% CI 1.31–2.22, p<0.001) and 1.87-fold higher frail odds ratio (95% CI 1.21–2.91, p = 0.009). Also, compared to the group with the highest adequacy score, the group with the lowest score showed a 1.51-fold higher pre-frail odds ratio (95% CI 1.16–1.96, p = 0.010) and a 2.39-fold higher frail odds ratio (95% CI 1.48–3.86, p = 0.002). The findings of this study suggested that a high-quality diet, as assessed by Korean Healthy Eating Index, was negatively associated with the odds ratio of frailty.
Many people were forced to stay at home, including non-alcoholic steatohepatitis (NASH) patients, however it is unclear how this home-life has affected the prognosis of NASH. In this study, we examined the influences of living at home during the coronavirus disease 2019 (COVID-19) pandemic NASH patients. In this study, we compared the clinical parameters of NASH patients without COVID-19 infection 3 months before with those 3 months after the declaration of a state of emergency. In the results, the changes of aspartate transaminase and alanine aminotransferase in the 3 months before (aspartate transaminase, –3.6 ± 13.8 U/L; alanine aminotransferase, –6.8 ± 19.5 U/L) was significantly exacerbated in the 3 months after (aspartate transaminase, 2.3 ± 7.5 U/L; alanine aminotransferase, 1.7 ± 10.4 U/L). Furthermore, the changes of the fibrosis-4 index in the 3 months before (–0.27 ± 0.84) was also significantly exacerbated in the 3 months after (0.38 ± 0.96). In conclusion, liver dysfunctions in NASH patients were exacerbated due to the emergency declaration and outing restriction which accompanied COVID-19.
Vonoprazan is a potent inhibitor of gastric acid secretion and may have better response than proton pump inhibitors (PPIs) in the treatment of endoscopic submucosal dissection induced artificial ulcers. However, reported outcomes remain controversial. In this study, we conducted a prospective, randomized comparative trial to evaluate healing effects of vonoprazan and lansoprazole on endoscopic submucosal dissection (ESD)-induced ulcers. We enrolled 216 patients who underwent endoscopic submucosal dissection for early gastric neoplasms. They were randomly divided into vonoprazan (20 mg/day) and lansoprazole (30 mg/day) groups. The primary endpoint was the reduction rate of ulcer and complete healing (scar) ratio of ESD-induced ulcers at 4 and 8 weeks. Finally, 101 patients of the vonoprazan group and 95 patients of the lansoprazole group were included in the analysis. There were no significant differences in the reduction rate between the vonoprazan and lansoprazole groups at either timepoint (4 weeks, 94.0 vs 93.4%; 8 weeks, 99.8 vs 99.9%, respectively). The complete healing ratio at 4 and 8 weeks did not differ significantly between the vonoprazan and lansoprazole groups (4 weeks, 11.9 vs 12.6%; 8 weeks, 87.1 vs 86.3%, respectively). In the anti-H. pylori-antibody negative or positive patients, there were no significant differences in the reduction rate and complete healing ratio between the vonoprazan and lansoprazole groups. Regardless of treatment choice, the overall complete healing ratio at 8 weeks was significantly higher in the anti-H. pylori-antibody negative patients than the positive patients (p = 0.006). The healing effects of vonoprazan on ESD-induced ulcers were comparative to those of lansoprazole.
Patients with asymptomatic esophageal eosinophilia (aEE) do not exhibit clinical symptoms because of esophageal dysfunction, although they have endoscopic and histological findings similar to those of eosinophilic esophagitis (EoE). The cause of the symptoms and the differences between aEE and EoE are unclear. The aim of this study is to determine whether aEE and EoE are same disease entities by comparing immune-related tissue biomarkers using immunohistological staining. Esophageal biopsy specimens from 61 patients, including 18 with aEE and 43 with EoE, were analyzed. Immunofluorescence staining was performed to quantify the immune-related tissue biomarkers such as major basic protein, eosinophil-derived neurotoxin, eotaxin-3, and immunoglobulin G4. Data are presented as median (interquartile range). There were no significant differences in clinical, endoscopic, or histological features, between patients with aEE and EoE, with the exception of body mass index. There were no significant differences in all immune-related tissue biomarkers between both groups. In conclusions, EoE and aEE displayed similar immunohistological profiles. Hence, they may be similar disease entities with some common pathogenic mechanisms. Our findings suggest that patients with aEE also have histopathological esophageal inflammation.
We previously found that a single dose of theaflavins induced skeletal muscle metabolic changes. In this study, we examined the effect of theaflavins on disuse muscle atrophy model mice by hindlimb suspension. Mice were assigned to 4 groups; ground-vehicle, ground-theaflavins, suspension-vehicle, and suspension-theaflavins, dosed with theaflavins (250 mg/kg/day) for 2 weeks. The peak of myotube size of cross sectional area was significantly moved to the smaller side in the suspension-vehicle group compared with the ground-vehicle group, and these shifts were significantly reduced by the treatment with theaflavins in both soleus and extensor digitorum longus. The level of phosphorylated eukaryotic translation initiation factor 4E-binding protein (4EBP)-1, located downstream of the Akt/mTOR pathway, was significantly different between suspension-vehicle and suspension-theaflavins in soleus. The ratio of forkhead box O (FoxO) 3a to phosphorylated FoxO3a significantly increased in soleus or tended to rise in extensor digitorum longus of suspension-vehicle group compared with ground-vehicle. In contrast, these changes were not observed in suspension-theaflavins group. These results suggested that theaflavins inhibited the progress of disuse muscle atrophy through modulation of protein metabolism.
Intensive, prolonged exercise is known to induce gastrointestinal disorders such as diarrhea, with gut dysbiosis suggested as being one of the causatives. In the present study, we wanted to investigate the relationship between intensive exercise and the gut microbiota status. To that end, the microbiota, the moisture content and the bacterial metabolites (e.g., organic acids) of female endurance runners (n = 15) and those of non-athletic but healthy, age-matching female controls (n = 14) were compared. The analysis of the gut microbiota analysis showed that, unlike control subjects, female endurance runners had distinct microbiotas, with some bacteria found in higher abundances likely being involved in gut inflammation. The concentration of succinate, a gut bacterial metabolite regarded as undesirable when accumulated in the lumen, was significantly (p<0.05) higher in the female endurance runners. Faecalibacterium, that was significantly (p<0.05) abundant in female endurance runners, can produce succinate in certain environments and hence may contribute to succinate accumulation, at least partly. The present work suggested that the gut microbiotas of female endurance runners are seemingly dysbiotic when compared with those of control subjects. Further investigation of the mechanism by which intensive, prolonged exercise affects the gut microbiota is recommended.
Kynurenic acid, a tryptophan metabolite, acts as antagonist or agonist of several receptors. Hypobromous acid (HOBr) and hypochlorous acid (HOCl) are generated by eosinophils and neutrophils. At inflammation sites, kynurenic acid may encounter HOBr and HOCl to generate products. When kynurenic acid was incubated with HOBr under neutral conditions, kynurenic acid generated a single product almost exclusively. This was identified as 3-bromokynurenic acid. Kynurenic acid reacted with HOCl, generating two products. The major product was identified as 3-chlorokynurenic acid with its oxidative decarboxylation product, 3-chloro-4-hydroxy-2(1H)-quinolinone as a by-product. Free amino acids suppressed the reactions of kynurenic acid with HOBr and HOCl. Taurine suppressed the HOCl reaction but not the HOBr reaction. An eosinophil peroxidase system containing H2O2, NaCl, and NaBr reacted with kynurenic acid, generating 3-bromokynurenic acid under mildly acidic conditions. Although a myeloperoxidase system containing H2O2 and NaCl reacted with kynurenic acid to generate 3-chlorokynurenic acid under mildly acidic conditions, the product was altered to 3-bromokynurenic acid by addition of NaBr to the system. These results suggest that 3-bromokynurenic acid and 3-chlorokynurenic acid may be generated from kynurenic acid at inflammation sites in humans, although their formation will be suppressed by coexistent amino acids.
The relationship between serum uric acid and risk of stroke is still controversial. Therefore, we conducted a meta-analysis based on the cohort study to explore the relationship between serum uric acid and risk of stroke, and further illuminate whether there is a linear or non-linear relationship between them. We manually searched the database including Cochrane, PubMed, Embase, Web of Science, and selected cohort studies focusing on the relationship between serum uric acid and stroke risk. Random effect model was used for statistical analysis. Twenty-one cohort studies involving 818,098 participants were included. The pooled relative risk for the high-vs-low categories was 1.22 (95% CI: 1.15–1.30). In addition, there was a non-linear dose–response relationship between uric acid and stroke risk. Serum uric acid was in the range of 3–5 mg/dl, with the lowest risk of stroke. In conclusion, high serum uric acid level increases the risk of stroke, with a non-linear dose–response relationship.