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Colonic mucus layers protect intestinal tissues against intestinal bacteria. We investigated the effects of dietary fiber and its metabolites on mucus production in the colonic mucosa. Mice were fed a partially hydrolyzed guar gum (PHGG)-containing diet and a fiber-free diet (FFD). The colon mucus layer, fecal short-chain fatty acid (SCFA) levels, and gut microbiota were evaluated. Mucin 2 (MUC2) expression was assessed in SCFA-treated LS174T cells. The role of AKT in MUC2 production was investigated. The mucus layer in the colonic epithelium was significantly increased in the PHGG group compared with that in the FFD group. In the PHGG group, an increase in Bacteroidetes in the stool was observed, and fecal acetate, butyrate, propionate, and succinate levels were significantly increased. However, MUC2 production was significantly increased only in succinate-stimulated LS174T cells. The succinate-induced MUC2 production was associated with AKT phosphorylation. Succinate mediated the PHGG-induced increase in the colon mucus layer., (© 2023. The Author(s).)

Habitual exercise alters the intestinal microbiota composition, which may mediate its systemic benefits. We examined whether transplanting fecal microbiota from trained mice improved skeletal muscle metabolism in high-fat diet (HFD)-fed mice. Fecal samples from sedentary and exercise-trained mice were gavage-fed to germ-free mice. After receiving fecal samples from trained donor mice for 1 week, recipient mice had elevated levels of AMP-activated protein kinase (AMPK) and insulin growth factor-1 in skeletal muscle. In plasma, bile acid (BA) deconjugation was found to be promoted in recipients transplanted with feces from trained donor mice; free-form BAs also induced more AMPK signaling and glucose uptake than tauro-conjugated BAs. The transplantation of exercise-acclimated fecal microbiota improved glucose tolerance after 8 weeks of HFD administration. Intestinal microbiota may mediate exercise-induced metabolic improvements in mice by modifying circulating BAs. Our findings provide insights into the prevention and treatment of metabolic diseases., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Introduction: Premature ejaculation (PE) has negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy. In Japan, no oral drugs or devices are approved or used clinically to treat PE. The Men's Training Cup Keep Training (MTCK), a masturbation aid, was developed for PE. MTCK offers 5 grades of tightness and strength., Aim: We aimed to investigate the efficacy of the MTCK in patients who are unable to delay ejaculation., Methods: Inclusion criteria were 20- to 60-year-old men feeling distressed and frustrated by PE and who had the same sexual partners throughout the study period. Exclusion criteria were neurologic disease and uncontrolled diabetes mellitus, as well as the use of antidepressants, α-blockers, and 5α-reductase inhibitors. The protocol comprised an 8-week training period with the MTCK from level 1 to level 5, with each level used twice before moving to the next level., Outcome Measures: The main outcome measure was the extension of intravaginal ejaculation latency time (IELT). The secondary outcome measures were score improvements on the Premature Ejaculation Diagnostic Tool, Sexual Health Inventory for Men, Erection Hardness Score, and Difficulty in Performing Sexual Intercourse Questionnaire-5., Results: We enrolled 37 patients, and after 19 patients withdrew, 18 concluded the study without experiencing any adverse events. The mean patient age was 39.9 years. Geometric IELT after the 8-week training with the MTCK increased significantly (mean ± SE; 232.10 ± 72.16 seconds) vs baseline (103.91 ± 50.61 seconds, P  = .006). Mean scores on the Premature Ejaculation Diagnostic Tool, Difficulty in Performing Sexual Intercourse Questionnaire-5, and Erection Hardness Score after 8-week training improved significantly vs the baseline values. The mean score on the Sexual Health Inventory for Men did not improve significantly after the 8-week training, but domain 1 did significantly improve after 8 weeks of MTCK use., Clinical Implications: The MTCK may be one possible treatment option for patients who are unable to delay ejaculation., Strengths and Limitations: This is the first study to show that the MTCK is effective for patients who are unable to delay ejaculation. A major limitation is that the present study was not strictly limited to an IELT <3 minutes., Conclusions: The MTCK may offer benefits not only for delay of ejaculation but also for erectile function., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Background: We have hypothesized that different factors are involved in the severity of ACD and AD because some but not all patients with atopic dermatitis (AD) present with allergic conjunctival disease (ACD) including severe types such as atopic keratoconjunctivitis (AKC) with/without giant papillae. We previously reported that plasma miR-628-3p was up-regulated in AD with severe ACD, but not in severe AD without severe ACD or in our healthy controls. In this study, to investigate the pathogenesis of AD with and without severe ACD, we performed comprehensive plasma miRNA analysis and studied the function of some miRNAs which were significantly up-regulated in ACD. Methods: Transcriptomics analysis of miRNA was performed using the microarray platform from the plasma of nine individuals (AD, severe ACD, controls: n = 3 each). To confirm up-regulation of the 12 miRNAs of the eight miRNA groups we focused on, we performed quantitative miRNA polymerase chain reaction (PCR) assays using 80 plasma samples (AD: 23, severe ACD: 17, controls: 40). To study the function of the eight miRNAs which were significantly up-regulated in ACD, we transfected their mimic to THP-1 cells, a monocyte cell line, and performed comprehensive gene expression analysis of them. The up-regulation of gene expression of interest in transfected THP-1 cells with the hsa-let-7a-5p miRNA mimic was confirmed by quantitative RT-qPCR assay. Results: Quantitative miRNA PCR assays showed that hsa-let-7a-5p, hsa-let-7days-3p, hsa-let-7e-5p, and hsa-miR-151a-5p were significantly up-regulated in both AD-ACD + and AD-ACD - as were hsa-miR-130a-3p, hsa-miR-151a-3p, has-miR-27b-3p, and hsa-miR-146a-5p in AD-ACD + but not in AD-ACD - . The functions of each miRNA were investigated by comprehensive gene expression analysis of THP-1 cells transfected with each miRNA mimic. Of the eight miRNAs, hsa-let-7a-5p, hsa-let-7e-5p, has-miR-27b-3p, and hsa-miR-146a-5p mimic-transfected THP-1 cells showed the up-regulation of CXCL10 (IP-10; interferon gamma-induced protein 10), which might be one of the innate immune-related genes. Quantitative RT-qPCR assays of transfected THP-1 cells with the hsa-let-7a-5p miRNA mimic showed that the 17 genes up-regulated more than 10-fold in the comprehensive gene expression analysis, and TLR3, RIG-I, and MDA5, important innate immune-related genes, were significantly up-regulated. TNFSF13B, AIM2, USP41, STAP1, GBP4, CCL8, and IFI27, reportedly down-regulated by the hsa-miR-628-3p mimic, were also significantly up-regulated in the transfected cells. Conclusion: Hsa-let-7a-5p, which was significantly up-regulated in AD-ACD + and AD-ACD - , could positively regulate the important innate immune-related genes such as TLR3, RIG-I, and MDA5. It is possible that in an allergic disease such as atopic keratoconjunctivitis and/or dermatitis, innate immune responses might be positively regulated by hsa-let-7a-5p in the plasma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ueta, Nishigaki, Komai, Mizushima, Tamagawa-Mineoka, Naito, Katoh, Sotozono and Kinoshita.)

Purpose: Although patients with late-onset hypogonadism (LOH) often experience lower urinary tract symptoms (LUTS), LUTS are not generally included in LOH symptoms. No study has examined the direct relation of the Aging Males Symptoms rating scale (AMS) and the International Prostate Symptom Score (IPSS) with the quality of life (QOL) index. We analyzed the relation between the IPSS and QOL index and various factors including the AMS in patients with LOH syndromes., Materials and Methods: This study comprised 1,688 men with LOH symptoms who visited our hospital or affiliated clinic. Factors associated with the IPSS were assessed in terms of age, scores of several questionnaires including the AMS, endocrinological variables, and serum concentration of PSA. Among these same factors, those associated with the QOL index were also evaluated. Finally, the same analyses were repeated in 187 patients with low serum testosterone concentration (<3.0 ng/mL)., Results: In a multivariate analysis using the significant items from the univariate analysis, AMS, age, and Erection Hardness Score correlated significantly with the IPSS. A trend analysis using items other than the AMS as adjustment factors also confirmed the relationship between an increase in QOL index and an increase in AMS. Similar results were obtained in the analysis of patients with low serum testosterone concentration., Conclusions: We revealed that the relation of IPSS with the QOL index for LUTS is closely associated with the AMS for LOH, regardless of testosterone level. When patients complain of LOH symptoms, a careful, detailed inquiry into LUTS is required., Competing Interests: The authors have nothing to disclose., (Copyright © 2023 Korean Society for Sexual Medicine and Andrology.)

Purpose: Agaro-oligosaccharides (AGO), hydrolysis products of agarose, is known to have antioxidant and anti-inflammatory properties. Speculating that AGO is effective for preventing aging, we investigated the longevity-supporting effects of AGO and their mechanisms using Caenorhabditis elegans., Methods: Caenorhabditis elegans were fed AGO from young adulthood. The lifespan, locomotory activity, lipofuscin accumulation, and heat stress resistance of the worms were examined. To elucidate mechanisms of AGO-mediated longevity, we conducted comprehensive expression analysis using microarrays. Moreover, we used quantitative real-time PCR (qRT-PCR) to verify the genes showing differential expression levels. Furthermore, we measured the lifespan of loss-of-function mutants to determine the genes related to AGO-mediated longevity., Results: AGO extended the lifespan of C. elegans, reduced lipofuscin accumulation, and maintained vigorous locomotion. The microarray analysis revealed that the endoplasmic reticulum-unfolded protein response (ER-UPR) and insulin/insulin-like growth factor-1-mediated signaling (IIS) pathway were activated in AGO-fed worms. The qRT-PCR analysis showed that AGO treatment suppressed sir-2.1 expression, which is a negative regulator of ER-UPR. In loss-of-function mutant of sir-2.1, AGO-induced longevity and heat stress resistance were decreased or cancelled completely. Furthermore, the pro-longevity effect of AGO was decreased in loss-of-function mutants of abnormal Dauer formation (daf) -2 and daf-16, which are IIS pathway-related genes., Conclusion: AGO delays the C. elegans aging process and extends their lifespan through the activations of ER-UPR and the IIS pathway., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Smoking affects eating habits; however, few studies on smoking and the gut microbiota have reported the effects of diet in detail. This cross-sectional study aimed to determine the association between smoking and the gut microbiota, considering the impact of smoking on dietary intake. Dietary habits and the composition of the gut microbiota were assessed in 195 men with type 2 diabetes (164 non-current smokers and 31 current smokers) using a brief self-administered diet history questionnaire and 16S ribosomal RNA gene sequencing of fecal samples. The data were compared according to the current smoking status of the participants. Current smokers had high alcohol and sugar/sweetener intake and low fruit intake. The proportion of the Coprococcus genus was higher among current smokers. Multiple regression analysis adjusted for current smoking, age, exercise habits, alcohol intake, sugar and sweetener intake, and fruit intake showed that smoking was associated with the proportion of the Coprococcus genus. Current smoking was associated with both dietary intake and composition of the gut microbiota. Although dietary intake should be considered when investigating the association between smoking and the gut microbiota, the results suggest that the direct effect of smoking is more significant.

Mesalamine is a key drug in the treatment of ulcerative colitis (UC) for both induction and maintenance therapy. On the other hand, it is known that there are some cases of mesalamine intolerance that are difficult to distinguish from symptoms due to aggravation of UC. The aim of this study is to investigate the clinical characteristic of mesalamine intolerance in UC. A retrospective, observational study was conducted. We enrolled 31 patients who were diagnosed as mesalamine intolerance between April 2015 to March 2020. We examined clinical features, time to onset, drug types of mesalamine, DLST positive rate, colonoscopy findings, disease activity, and clinical course after diagnosis. The average dose of mesalamine was 3.69 g and DLST-positive was 57.1%. Within the first 2 weeks from the start of mesalamine, 51.6% showed symptoms of intolerance. The serum CRP level was relatively high at ≥10.0 mg/dl in 53.6% of the cases. There was no difference in clinical background, symptoms, or laboratory findings between patients with DLST-positive and negative. In this study, we clarified the clinical characteristics of mesalamine intolerant patients, and found no difference in the clinical background or success rate of desensitization therapy between positive and negative DLST cases., (Copyright © 2022 JCBN.)

Background/aims: Several studies have assessed the effect of cool temperature on colonic peristalsis. Transient receptor potential melastatin 8 (TRPM8) is a temperature-sensitive ion channel activated by mild cooling expressed in the colon. We examined the antispasmodic effect of cool temperature on colonic peristalsis in a prospective, randomized, single-blind trial and based on the video imaging and intraluminal pressure of the proximal colon in rats and TRPM8-deficient mice., Methods: In the clinical trial, we randomly assigned a total of 94 patients scheduled to undergo colonoscopy to 2 groups: the mildly cool water (n = 47) and control (n = 47) groups. We used 20 mL of 15°C water for the mildly cool water. The primary outcome was the proportion of subjects with improved peristalsis after treatment. In the rodent proximal colon, we evaluated the intraluminal pressure and performed video imaging of the rodent proximal colon with cool water administration into the colonic lumen. Clinical trial registry website (Trial No. UMIN-CTR; UMIN000030725)., Results: In the randomized controlled trial, after treatment, the proportion of subjects with no peristalsis with cool water was significantly higher than that in the placebo group (44.7% vs 23.4%; P < 0.05). In the rodent colon model, cool temperature water was associated with a significant decrease in colonic peristalsis through its suppression of the ratio of peak frequency ( P < 0.05). Cool temperature-treated TRPM8-deficient mice did not show a reduction in colonic peristalsis compared with wild-type mice., Conclusion: For the first time, this study demonstrates that cool temperature-dependent suppression of colonic peristalsis may be associated with TRPM8 activation.

Background: Recent progress in ulcerative colitis (UC) treatment has been remarkable, and various medications have been applied. However, some patients with UC are refractory to treatment and convert to surgery., Aim: To investigate the role of colonic mucosal Wnt-5a expression in the pathogenesis of UC and the effect of bioactive Wnt-5a peptide on colitis in mice., Methods: Wnt-5a peptide was intraperitoneally administered to mice every day from the beginning of dextran sulfate sodium (DSS) treatment. The severity of colitis was evaluated based on body weight change, colonic length, and histological scores. Colonic mucosal TNF-α and KC mRNA expression levels were measured. This study included 70 patients with UC in clinical remission. Wnt-5a, TNFα, and IL-8 mRNA expression in the rectal mucosa were measured by quantitative real-time polymerase chain reaction using biopsy materials. Wnt-5a mRNA expression levels were compared between patients who relapsed and those in remission. We examined the correlation of Wnt-5a expression with TNF-α and IL-8 expression., Results: Wnt-5a peptide significantly attenuated the severity of DSS-induced colitis. Moreover, mucosal TNF-α and KC mRNA expression were significantly suppressed by Wnt-5a peptide treatment. Wnt-5a mRNA levels were significantly lower in patients with subsequent relapse than in those who remained in remission. Mucosal Wnt-5a was inversely correlated with TNF α and IL-8 expression., Conclusion: Wnt-5a peptide suppressed colitis in mice, and decreased Wnt-5a expression was strongly associated with relapse in patients with UC. Wnt-5a may have an inhibitory effect on mucosal inflammation in UC, and Wnt-5a peptide could be a new therapeutic strategy., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

It has been observed that healthy tissues are spared at ultra-high dose rate (UHDR: >40 Gy/s), so called FLASH effect. To elucidate the mechanism of FLASH effect, we evaluate changes in radiation chemical yield (G value) of 7-hydroxy-coumarin-3-carboxylic acid (7OH-C3CA), which is formed by the reaction of hydroxyl radicals with coumarin-3-carboxylic acid (C3CA), under carbon ions (140 MeV/u) and protons (27.5 and 55 MeV) in a wide-dose-rate range up to 100 Gy/s. The relative G value, which is the G value at each dose rate normalized by that at the conventional dose (CONV: 0.1 Gy/s >), 140 MeV/u carbon-ion beam is almost equivalent to 27.5 and 55 MeV proton beams. This finding implies that UHDR irradiations using carbon-ion beams have a potential to spare healthy tissues. Furthermore, we evaluate the G value of 7OH-C3CA under the de-oxygenated condition to investigate roles of oxygen to the generation of 7OH-C3CA effect. The G value of 7OH-C3CA under the de-oxygenated condition is lower than that under the oxygenated condition. The G value of 7OH-C3CA under the de-oxygenated condition is higher than those under UHDR irradiations. By direct measurements of the oxygen concentration during 55 MeV proton irradiations, the oxygen concentration drops by 0.1%/Gy, which is independent of the dose rate. When the oxygen concentration directly affects to yields of 7OH-C3CA, the rate of decrease in the oxygen concentration may be correlated with that of decrease in the G value of 7OH-C3CA. However, the reduction rate of G value under UHDR is significantly higher than the oxygen consumption. This finding implied that the influence of the reaction between water radiolysis species formed by neighborhood tracks could be strongly related to the mechanisms of UHDR effect., (©2022 by Radiation Research Society. All rights of reproduction in any form reserved.)

Granulocyte-colony stimulating factor (G-CSF) stimulates bone marrow progenitor cell proliferation and enhances neutrophil production. Exogenous G-CSF administration is indicated for chemotherapy-induced neutropenia management. However, there is a paucity of basic research examining the effects of the concomitant use of G-CSF and chemotherapy on myeloid cells in vivo. Whether concomitant G-CSF and chemotherapy adversely affect myeloid cell proliferation have not been determined. Herein, we examined the effects of the concomitant use of pegfilgrastim and 5-fluorouracil on myeloid cells and peripheral blood cells in mouse models. Balb/c mice were treated intraperitoneally with 5-fluorouracil (20 μg/g b.w.) or a vehicle as a control for 5 days, and pegfilgrastim was administered subcutaneously at 1 μg/g b.w. on day 3. As a result, we demonstrated that the concomitant use of pegfilgrastim suppressed the 5-fluorouracil-induced decrease of granulocytic cells in both bone marrow and peripheral blood in mice. To assess the clinical efficacy of early administration of pegfilgrastim during docetaxel, cisplatin, and 5-fluorouracil therapy in patients with esophageal cancer, we retrospectively identified 42 consecutive patients treated with this regimen. The incidence of both febrile neutropenia and grade 4 neutropenia was significantly lower in patients who received pegfilgrastim than in those who did not receive it (P = 0.002 and P = 0.002, respectively). These results suggest that the concomitant use of pegfilgrastim and chemotherapy, consisting of continuous infusions of 5-fluorouracil, improved chemotherapy-induced neutropenia without detrimental effects on proliferating myeloid granulocytic cells., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aim: Complete endoscopic mucosal healing is defined as a Mayo endoscopic subscore of 0. Some patients diagnosed with a Mayo endoscopic subscore 0 may present with subsequent clinical relapse. Here, we aimed to demonstrate mucosal cytokine profile as a predictor of clinical relapse in ulcerative colitis patients with a Mayo endoscopic subscore of 0 as a marker of mucosal healing., Methods: We conducted prospective observational pilot study to examine the relationship between mucosal cytokine expression and subsequent relapse of UC patients diagnosed with a Mayo endoscopic subscore of 0. We enrolled 55 patients, and expression of cytokines tumor necrosis factor-α, interferon γ, interleukin-1β, interleukin-2, interleukin-4, interleukin-5, interleukin-6, interleukin-7, interleukin-8, interleukin-9, interleukin-10, interleukin-12, interleukin-13, interleukin-15, interleukin-17A, interleukin-17F, interleukin-18, interleukin-21, interleukin-22, interleukin-23, interleukin-27, and interleukin-33 was measured by quantitative real-time PCR using rectal mucosa biopsy materials. Cytokine expression levels were compared between patients who relapsed between March 1, 2016, and March 30, 2020, of the study period and those who remained in remission., Results: Ten cytokines, including interleukin-2, interleukin-4, interleukin-8, interleukin-10, interleukin-12, interleukin-15, interleukin-17A, interleukin-21, interleukin-23, and interleukin-33, were significantly elevated in patients with subsequent relapse compared with those who remained in remission. Interleukin-8 expression was the most useful predictor., Conclusions: In the rectal mucosa of ulcerative colitis patients with Mayo endoscopic subscore 0, levels of several cytokines were elevated in cases of subsequent relapse. Among these, interleukin-8 expression was the most useful for predicting relapse., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The microbiota associated with relapse in patients with quiescent ulcerative colitis (qUC) remains unclear. Our objective was to analyze the fecal microbiota of Japanese patients with qUC and identify the relapse-associated microbiota. In this study, 59 patients with qUC and 59 healthy controls (HCs) were enrolled (UMIN 000019486), and their fecal microbiota was compared using 16S rRNA gene amplicon sequencing. We followed their clinical course up to 3.5 years and analyzed the relapse-associated microbiota. Potential functional changes in the fecal microbiota were evaluated using PICRUSt software and the Kyoto Encyclopedia of Genes and Genomes database. There were significant differences in fecal microbiota diversity between HC and qUC subjects, with 13 taxa characterizing each subject. Despite no significant difference in variation of microbiota in a single sample (α diversity) between patients in sustained remission and relapsed patients, the variation in microbial communities between samples (β diversity) was significantly different. Prevotella was more abundant in the sustained remission patients, whereas Faecalibacterium and Bifidobacterium were more abundant in the relapsed patients. We clustered the entire cohort into four clusters, and Kaplan-Meier analysis revealed the subsequent clinical course of each cluster was different. We identified 48 metabolic pathways associated with each cluster using linear discriminant analysis effect size. We confirmed the difference in microbiota between patients with qUC and HCs and identified three genera associated with relapse. We found that the clusters based on these genera had different subsequent clinical courses and activated different metabolic pathways.

MEK inhibitors are among the most successful molecularly targeted agents used as cancer therapeutics. However, to treat cancer more efficiently, resistance to MEK inhibitor-induced cell death must be overcome. Although previous genetic approaches based on comprehensive gene expression analysis or RNAi libraries led to the discovery of factors involved in intrinsic resistance to MEK inhibitors, a feasible combined treatment with the MEK inhibitor has not yet been developed. Here, we show that a chemoproteoinformatics approach identifies ligands overcoming the resistance to cell death induced by MEK inhibition as well as the target molecule conferring this resistance. First, we used natural products, perillyl alcohol and sesaminol, which induced cell death in combination with the MEK inhibitor trametinib, as chemical probes, and identified ribosomal protein S5 (RPS5) as their common target protein. Consistently, trametinib induced cell death in RPS5-depleted cancer cells via upregulation of the apoptotic proteins BIM and PUMA. Using molecular docking and molecular dynamics (MD) simulations, we then screened FDA- and EMA-approved drugs for RPS5-binding ligands and found that acetylsalicylic acid (ASA, also known as aspirin) directly bound to RPS5, resulting in upregulation of BIM and PUMA and induction of cell death in combination with trametinib. Our chemoproteoinformatics approach demonstrates that RPS5 confers resistance to MEK inhibitor-induced cell death, and that aspirin could be repurposed to sensitize cells to MEK inhibition by binding to RPS5., (© The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.)

Clinical incidences of pressure ulcers in the elderly and intractable skin ulcers in diabetic patients are increasing because of the aging population and an increase in the number of diabetic patients worldwide. Although various agents are used to treat pressure and skin ulcers, these ulcers are often refractory and deteriorate the patients' quality of life. Therefore, a novel therapeutic agent with a novel mechanism of action is required. Carbon monoxide (CO) contributes to many physiological and pathophysiological processes, including anti-inflammatory activity; therefore, it can be a therapeutic gaseous molecule. Recent studies have revealed that CO accelerates wound healing in gastrointestinal tract injuries. However, it remains unclear whether CO promotes cutaneous wound healing. Therefore, we aimed to evaluate the therapeutic effects of topical application of a CO-containing solution and elucidate the underlying mechanism. A full-thickness skin wound generated on the back of diabetic mice was treated topically with CO or vehicle. Sustained release of CO was achieved using polyacrylic acid (PAA) as a thickener. The administration of CO-containing PAA aqueous solution resulted in a significant acceleration in wound recovery without elevating serum CO levels in association with increased angiogenesis and supported by elevated expression of vascular endothelial growth factor mRNA in the wound granulomatous tissues. These data suggest that CO might represent a novel therapeutic agent for the treatment of cutaneous wounds., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cancer cachexia and the associated skeletal muscle wasting are considered poor prognostic factors, although effective treatment has not yet been established. Recent studies have indicated that the pathogenesis of skeletal muscle loss may involve dysbiosis of the gut microbiota and the accompanying chronic inflammation or altered metabolism. In this study, we evaluated the possible effects of modifying the gut microenvironment with partially hydrolyzed guar gum (PHGG), a soluble dietary fiber, on cancer-related muscle wasting and its mechanism using a colon-26 murine cachexia model. Compared with a fiber-free (FF) diet, PHGG contained fiber-rich (FR) diet-attenuated skeletal muscle loss in cachectic mice by suppressing the elevation of the major muscle-specific ubiquitin ligases Atrogin-1 and MuRF1, as well as the autophagy markers LC3 and Bnip3. Although tight-junction markers were partially reduced in both FR and FF diet-fed cachectic mice, the abundance of Bifidobacterium, Akkermansia, and unclassified S24-7 family increased by FR diet, contributing to the retention of the colonic mucus layer. The reinforcement of the gut barrier function resulted in the controlled entry of pathogens into the host system and reduced circulating levels of lipopolysaccharide-binding protein (LBP) and IL-6, which in turn led to the suppression of proteolysis by downregulating the ubiquitin-proteasome system and autophagy pathway. These results suggest that dietary fiber may have the potential to alleviate skeletal muscle loss in cancer cachexia, providing new insights for developing effective strategies in the future., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Gut microbiota are involved in both host health and disease and can be stratified based on bacteriological composition. However, gut microbiota clustering data are limited for Asians. In this study, fecal microbiota of 1803 Japanese subjects, including 283 healthy individuals, were analyzed by 16S rRNA sequencing and clustered using two models. The association of various diseases with each community type was also assessed. Five and fifteen communities were identified using partitioning around medoids (PAM) and the Dirichlet multinominal mixtures model, respectively. Bacteria exhibiting characteristically high abundance among the PAM-identified types were of the family Ruminococcaceae (Type A) and genera Bacteroides , Blautia , and Faecalibacterium (Type B); Bacteroides , Fusobacterium , and Proteus (Type C); and Bifidobacterium (Type D), and Prevotella (Type E). The most noteworthy community found in the Japanese subjects was the Bifidobacterium -rich community. The odds ratio based on type E, which had the largest population of healthy subjects, revealed that other types (especially types A, C, and D) were highly associated with various diseases, including inflammatory bowel disease, functional gastrointestinal disorder, and lifestyle-related diseases. Gut microbiota community typing reproducibly identified organisms that may represent enterotypes peculiar to Japanese individuals and that are partly different from those of indivuals from Western countries.

Intestinal ischemia-reperfusion (IR) injury is a complex, multifactorial, and pathophysiological condition with high morbidity and mortality, leading to serious difficulties in treatment, especially in humans. Heme oxygenase (HO) is the rate-limiting enzyme involved in heme catabolism. HO-1 (an inducible form) confers cytoprotection by inhibiting inflammation and oxidation. Furthermore, nuclear factor-erythroid 2-related factor 2 (Nrf2) positively regulates HO-1 transcription, whereas BTB and CNC homolog 1 (Bach1) competes with Nrf2 and represses its transcription. We investigated the role and potential mechanism of action of HO-1 in intestinal IR injury. Intestinal ischemia was induced for 45 min followed by 4 h of reperfusion in wild-type, Bach1-deficient, and Nrf2-deficient mice, and a carbon monoxide (CO)-releasing molecule (CORM)-3 was administered. An increase in inflammatory marker levels, nuclear factor-κB (NF-κB) activation, and morphological impairments were observed in the IR-induced intestines of wild-type mice. These inflammatory changes were significantly attenuated in Bach1-deficient mice or those treated with CORM-3, and significantly exacerbated in Nrf2-deficient mice. Treatment with an HO-1 inhibitor reversed this attenuation in IR-induced Bach1-deficient mice. Bach1 deficiency and treatment with CORM-3 resulted in the downregulation of NF-κB activation and suppression of adhesion molecules. Together, Bach1, Nrf2, and CO are valuable therapeutic targets for intestinal IR injury.

Partially hydrolyzed guar gum (PHGG) is a soluble dietary fiber derived through controlled enzymatic hydrolysis of guar gum, a highly viscous galactomannan derived from the seeds of Cyamopsis tetragonoloba . Here, we examined the therapeutic potential of dietary supplementation with PHGG against sarcopenic obesity using Db/Db mice. Db/Db mice fed a normal diet alone or a fiber-free diet, or supplemented with a diet containing PHGG (5%), were examined. PHGG increased grip strength and the weight of skeletal muscles. PHGG increased the short-chain fatty acids (SCFAs) concentration in feces and sera. Concerning innate immunity, PHGG decreased the ratio of inflammatory cells, while increasing the ratio of anti-inflammatory cells in the small intestine. The present study demonstrated the preventive effect of PHGG on sarcopenic obesity. Changes in nutrient absorption might be involved through the promotion of an anti-inflammatory shift of innate immunity in the intestine accompanied by an increase in SCFA production by PHGG.

Background and Aim: Efficient intestinal wound healing is essential for good prognoses of ulcerative colitis (UC). Although bile acids and the transmembrane G-protein-coupled receptor (TGR) 5 have been reported to affect wound healing in intestinal epithelial cells, the detailed underlying mechanisms are unclear. Here, we investigated the role of TGR5 in wound healing in the context of colonic epithelial cells in the presence of bile acids., Methods: The expression of TGR5 in the colonic epithelium of both a dextran sulfate sodium (DSS)-induced colitis mouse model (recovery phase), and UC patients in clinical remission, was evaluated. Young adult mouse colonic epithelial (YAMC) cells were then used to evaluate wound healing after treatment with deoxycholic acid (DCA); TGR5 was silenced in YAMC cells via shRNA-transfection, and a wound-healing assay in the presence of DCA was performed. Furthermore, we investigated the role of the activation of AKT in the context of wound healing., Results: The expression of TGR5 was decreased in the colonic epithelium of both mice with DSS-induced colitis and UC patients. Additionally, DCA significantly delayed wound healing in YAMC cells but not in TGR5 silenced ones. Of note, the DCA-induced activation of AKT signaling in YAMC cells was inhibited by TGR5 silencing, and AKT inhibitors prevented the wound healing delay induced by DCA., Conclusions: Overall, we show that DCA delays wound healing in the context of colonic epithelial cells through AKT activation. These results may support the development of new therapeutic approaches for epithelial regeneration in UC., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Although extensive evidence indicates that the gut microbiota plays a crucial role in regulating glucose homeostasis, the exact regulatory mechanism remains unclear. This study aimed to investigate the effect of broad-spectrum antibiotics on the expression of glucose transporters, histomorphology of the small intestine, and glucose metabolism in mice. C57BL/6 mice were administered drinking water with or without a broad-spectrum antibiotic combination for 4 weeks. Thereafter, an oral glucose tolerance test was performed. Body weight, small intestine histopathology, mRNA levels of glucose transporters (SGLT1 and GLUT2) and intestinal transcription factors (CDX1 and CDX2) were evaluated. SGLT1 and CDX1 were upregulated in the small intestine upon antibiotic administration compared with that in the control group. The height and surface area of the jejunal villi were significantly higher upon antibiotic administration than in the control group. Fasting glucose levels were significantly higher upon antibiotic administration than in the control group. The present results indicate that treatment with broad-spectrum antibiotics upregulates SGLT1 and CDX1 and induces hyperplasia in the small intestine, thus increasing fasting blood glucose levels. Our results further the current understanding of the effects of broad-spectrum antibiotics on the gut microbiota and glucose homeostasis that may have future clinical implications., (Copyright © 2022 JCBN.)

Background: Food allergy (FA) is a common disease in children; thus, a high level of safety is required for its prevention and treatment. Colonic regulatory T cells (Tregs) have been suggested to attenuate FA. We investigated the Treg-inducing ability and anti-FA effects of carotenoids, a pigment contained in vegetables and fruits., Methods: C57BL/6N mice were fed a diet containing 0.01% (w/w) of lycopene, β-carotene, astaxanthin or lutein for 4 weeks, and the population of colonic Tregs was assessed. Subsequently, to evaluate the Treg-inducing ability of lycopene, splenic naïve CD4 + T cells from BALB/c mice were cultured with anti-CD3/CD28 antibody, TGF-β and lycopene, and the frequencies of Tregs were examined. The effect of 0.1% (w/w) lycopene containing diet on FA was investigated in OVA-induced FA model BALB/c mice., Results: In screening, only lycopene significantly increased the frequency and number of colonic Tregs. Lycopene also increased Treg differentiation in splenic naïve CD4 + T cells. In FA mice, lycopene feeding significantly increased the number of colonic Tregs and attenuated allergic symptoms. The expression levels of IL-4, IL-9 and IL-13 mRNA in colonic mucosa were also significantly reduced by lycopene. IL-9 is known to induce proliferation of mast cells, and we found that lycopene feeding significantly reduced the number of mast cells in the colonic mucosa of FA mice., Conclusion: Our results suggest that lycopene, a carotenoid present in many common foods on the market, may have the potential to induce colonic Tregs and suppress FA symptoms., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

We found that specific biomedical Ti and its alloys, such as CP Ti, Ti-29Nb-13Ta-4.6Zr, and Ti-36Nb-2Ta-3Zr-0.3O, form a bright white oxide layer after a particular oxidation heat treatment. In this paper, the interfacial microstructure of the oxide layer on Ti-29Nb-13Ta-4.6Zr and the exfoliation resistance of commercially pure (CP) Ti, Ti-29Nb-13Ta-4.6Zr, and Ti-36Nb-2Ta-3Zr-0.3O were investigated. The alloys investigated were oxidized at 1273 or 1323 K for 0.3-3.6 ks in an air furnace. The exfoliation stress of the oxide layer was high in Ti-29Nb-13Ta-4.6Zr and Ti-36Nb-2Ta-3Zr-0.3O, and the maximum exfoliation stress was as high as 70 MPa, which is almost the same as the stress exhibited by epoxy adhesives, whereas the exfoliation stress of the oxide layer on CP Ti was less than 7 MPa, regardless of duration time. The nanoindentation hardness and frictional coefficients of the oxide layer on Ti-29Nb-13Ta-4.6Zr suggested that the oxide layer was hard and robust enough for artificial tooth coating. The cross-sectional transmission electron microscopic observations of the microstructure of oxidized Ti-29Nb-13Ta-4.6Zr revealed that a continuous oxide layer formed on the surface of the alloys. The Au marker method revealed that both in- and out-diffusion occur during oxidation in Ti-29Nb-13Ta-4.6Zr and Ti-36Nb-2Ta-3Zr-0.3O, whereas only out-diffusion governs oxidation in CP Ti. The obtained results indicate that the high exfoliation resistance of the oxide layer on Ti-29Nb-13Ta-4.6Zr and Ti-36Nb-2Ta-3Zr-0.3O are attributed to their dense microstructures composing of fine particles, and a composition-graded interfacial microstructure. On the basis of the results of our microstructural observations, the oxide formation mechanism of the Ti-Nb-Ta-Zr alloy is discussed.

Consumption of yacon ( Smallanthus sonchifolius ) is associated with beneficial effects such as prevention of metabolic diseases. Yacon root is known to contain various bioactive components including indigestible carbohydrates, but the alteration of intestinal environment after treatment with yacon has not been fully investigated. This study investigated yacon-containing diet effects on the intestinal environment in mice, including microbial composition, short-chain fatty acid levels, and mucus content. After mice were administered yacon-containing diet for 4 weeks, 16S rRNA gene sequencing analyses revealed their fecal microbiota profiles. Organic acid concentrations in cecal contents were measured using an HPLC system. Compared to the control group, yacon-containing diet-received mice had significantly higher the concentrations of succinic acid, lactic acid, acetic acid, and propionic acid. The fecal mucin content was also higher in yacon-containing diet-received mice. Results of 16S rRNA gene sequencing analyses showed that the relative abundances of 27 taxa differed significantly in yacon-containing diet-received mice. Furthermore, results show effects of yacon administration on intestinal inflammation using 2,4,6-trinitrobenzene sulfonic acid induced colitis model in mice. Increased colonic damage and myeloperoxidase activity after 2,4,6-trinitrobenzene sulfonic acid treatment were suppressed in yacon-containing diet-received mice. Results suggest that oral intake of yacon root modulates the intestinal environment, thereby inhibiting intestinal inflammation., Competing Interests: YN received scholarship funds from EA Pharma Co., Ltd.; a collaboration research fund from Taiyo Kagaku Co., Ltd.; and received lecture fees by Mylan EPD Co., Takeda Pharma. Co., Ltd., Mochida Pharma. Co., Ltd., EA Pharma Co., Ltd., Otsuka Pharma. Co., Ltd., and Miyarisan Pharma. Co., Ltd. The present research was partly supported by these funds. Neither the funding agency nor any outside organization has participated in the study design or have any competing interests. These pharmaceutical companies had final approval of the manuscript. The other authors have no conflicts of interest to disclose., (Copyright © 2021 JCBN.)

This cross-sectional study aimed to clarify the characteristic gut microbiota of Japanese patients with type 2 diabetes (T2DM) using t-distributed stochastic neighbor embedding analysis and the k-means method and to clarify the relationship with background data, including dietary habits. The gut microbiota data of 383 patients with T2DM and 114 individuals without T2DM were classified into red, blue, green, and yellow groups. The proportions of patients with T2DM in the red, blue, green, and yellow groups was 86.8% (112/129), 69.8% (81/116), 76.3% (90/118), and 74.6% (100/134), respectively; the red group had the highest prevalence of T2DM. There were no intergroup differences in sex, age, or body mass index. The red group had higher percentages of the Bifidobacterium and Lactobacillus genera and lower percentages of the Blautia and Phascolarctobacterium genera. Higher proportions of patients with T2DM in the red group used α-glucosidase inhibitors and glinide medications and had a low intake of fermented soybean foods, including miso soup, than those in the other groups. The gut microbiota pattern of the red group may indicate characteristic changes in the gut microbiota associated with T2DM in Japan. These results also suggest that certain diabetes drugs and fermented foods may be involved in this change. Further studies are needed to confirm the relationships among traditional dietary habits, the gut microbiota, and T2DM in Japan.

Spike timing-dependent plasticity (STDP), which is widely studied as a fundamental synaptic update rule for neuromorphic hardware, requires precise control of continuous weights. From the viewpoint of hardware implementation, a simplified update rule is desirable. Although simplified STDP with stochastic binary synapses was proposed previously, we find that it leads to degradation of memory maintenance during learning, which is unfavourable for unsupervised online learning. In this work, we propose a stochastic binary synaptic model where the cumulative probability of the weight change evolves in a sigmoidal fashion with potentiation or depression trials, which can be implemented using a pair of switching devices consisting of serially connected multiple binary memristors. As a benchmark test we perform simulations of unsupervised learning of MNIST images with a two-layer network and show that simplified STDP in combination with this model can outperform conventional rules with continuous weights not only in memory maintenance but also in recognition accuracy. Our method achieves 97.3% in recognition accuracy, which is higher than that reported with standard STDP in the same framework. We also show that the high performance of our learning rule is robust against device-to-device variability of the memristor's probabilistic behaviour., (© 2021. The Author(s).)

Background: Colonoscopy is the gold standard for detecting earlier stages of CRC, although screening of patients is difficult because of invasiveness, low compliance and procedural health risks. Therefore, the need for new screening methods for CRC is rising. Previous studies have demonstrated the diagnostic ability of serum BAs; however, the results have been inconsistent. In this study, we conducted a comprehensive analysis of serum BAs from patients with CRC and verified their diagnostic ability to detect CRC., Methods: A total of 56 CRC patients ( n  = 14 each of stages I-IV), 59 patients with colonic adenoma and 60 healthy controls were included. Age and sex were matched for each group. Serum BA compositions were measured by LC-MS/MS and serum concentration of 30 types of BAs were analysed by discriminant analysis with multidimensional scaling method., Results: Free CA, 3epi-DCA&CDCA, 3-dehydro CA, GCA and TCA were extracted as principal component (PC) 1 and free 3-dehydroDCA as PC 2 by canonical discriminant function coefficients. The verification of discriminability using cross-validation method revealed that the correct classification rate was 66.3% for original data and 52.6% for cross-validation data., Conclusions: A combined analysis using comprehensive serum BA concentration can be an efficient method for screening CRC.

Background: The gut-liver axis has attracted much interest in the context of chronic liver disease pathogenesis. Prebiotics such as dietary fibers were shown to attenuate non-alcoholic fatty liver disease (NAFLD) by modulating gut microbiota. Partially hydrolyzed guar gum (PHGG), a water-soluble dietary fiber, has been reported to alleviate the symptoms of various intestinal diseases and metabolic syndromes. However, its effects on NAFLD remain to be fully elucidated., Aim: To determine whether treatment with PHGG attenuates NAFLD development in mice through the gut-liver axis., Methods: Seven-week-old male C57BL/6J mice with increased intestinal permeability were fed a control or atherogenic (Ath) diet (a mouse model of NAFLD) for 8 wk, with or without 5% PHGG. Increased intestinal permeability was induced through chronic intermittent administration of low-dose dextran sulfate sodium. Body weight, liver weight, macroscopic findings in the liver, blood biochemistry [aspartate aminotransferase (AST) and alanine aminotransferase (ALT), total cholesterol, triglyceride, free fatty acids, and glucose levels], liver histology, myeloperoxidase activity in liver tissue, mRNA expression in the liver and intestine, serum endotoxin levels in the portal vein, intestinal permeability, and microbiota and short-chain fatty acid (SCFA) profiles in the cecal samples were investigated., Results: Mice with increased intestinal permeability subjected to the Ath diet showed significantly increased serum AST and ALT levels, liver fat accumulation, liver inflammatory (tumor necrosis factor-α and monocyte chemotactic protein-1) and fibrogenic (collagen 1a1 and α smooth muscle actin) marker levels, and liver myeloperoxidase activity, which were significantly attenuated by PHGG treatment. Furthermore, the Ath diet combined with increased intestinal permeability resulted in elevated portal endotoxin levels and activated toll-like receptor (TLR) 4 and TLR9 expression, confirming that intestinal permeability was significantly elevated, as observed by evaluating the lumen-to-blood clearance of fluorescein isothiocyanate-conjugated dextran. PHGG treatment did not affect fatty acid metabolism in the liver. However, it decreased lipopolysaccharide signaling through the gut-liver axis. In addition, it significantly increased the abundance of cecal Bacteroides and Clostridium subcluster XIVa. Treatment with PHGG markedly increased the levels of SCFAs, particularly, butyric acid, acetic acid, propionic acid, and formic acid, in the cecal samples., Conclusion: PHGG partially prevented NAFLD development in mice through the gut-liver axis by modulating microbiota and downstream SCFA profiles., Competing Interests: Conflict-of-interest statement: All authors have nothing to disclose., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

The effects of a magnetic field longitudinal to the ion beam track on the generation of hydroxyl radicals (•OH) and hydrogen peroxide (H 2 O 2 ) in water were investigated. A longitudinal magnetic field was reported to enhance the biological effects of the ion beam. However, the mechanism of the increased cell death by a longitudinal magnetic field has not been clarified. The local density of •OH generation was estimated by a method based on the EPR spin-trapping. A series of reaction mixtures containing varying concentrations (0.76‒2278 mM) of DMPO was irradiated by 16 Gy of carbon- or iron-ion beams at the Heavy-Ion Medical Accelerator in Chiba (HIMAC, NIRS/QST, Chiba, Japan) with or without a longitudinal magnetic field (0.0, 0.3, or 0.6 T). The DMPO-OH yield in the sample solutions was measured by X-band EPR and plotted versus DMPO density. O 2 -dependent and O 2 -independent H 2 O 2 yields were measured. An aliquot of ultra-pure water was irradiated by carbon-ion beams with or without a longitudinal magnetic field. Irradiation experiments were performed under air or hypoxic conditions. H 2 O 2 generation in irradiated water samples was quantified by an EPR spin-trapping, which measures •OH synthesized from H 2 O 2 by UVB irradiation. Relatively sparse •OH generation caused by particle beams in water were not affected by loading a magnetic field on the beam track. O 2 -dependent H 2 O 2 generation decreased and oxygen-independent H 2 O 2 generation increased after loading a magnetic field parallel to the beam track. Loading a magnetic field to the beam track made •OH generation denser or made dense •OH more reactive.

Background: The role of IL-12/23 in the pathogenesis of ulcerative colitis (UC) is unclear. We analyzed mucosal IL-12/23 expression and its relationship with endoscopic severity, histological activity, and UC relapse., Methods: Rectal biopsies were collected from 70 UC patients with clinical remission. IL-12, IL-23, IFN-γ, IL-17A, and IL-17F mRNA expression was measured by real-time PCR. Endoscopic severity and histological activity were evaluated using the Mayo endoscopic subscore (MES) and the Geboes score, respectively., Results: The longest follow-up period was 51 months. Thirty-four patients relapsed during the study period. Samples from these subsequently relapsed patients formed the "relapse" group, while those from patients that did not relapse formed the "remission" group. IL-12 (P = 0.0003) and IL-23 (P = 0.014) mRNA expression was significantly higher in the relapse than the remission group. Expression of IL-23 (P = 0.015) but not IL-12 (P = 0.374) was correlated with MES. However, in patients with an MES of 0 and 1, IL-12 expression was statistically higher in the relapse than the remission group (P = 0.0015, P = 0.0342). IL-12 and IL-23 expression did not vary significantly between histologically active and inactive mucosa; both were higher in histologically inactive patients in the remission group (IL-12: P = 0.0002, IL-23: P = 0.046)., Conclusions: Rectal IL-12 and IL-23 expression was elevated in the relapse group, but IL-12 was more strongly associated with UC relapse, irrespective of endoscopic severity and histological activity. Mucosal IL-12 was elevated in patients with deep mucosal healing. Our results suggest an important role of IL-12 in UC pathogenesis and the molecular mechanism of UC relapse.

A development project for hypo-fractionated multi-ion therapy has been initiated at the National Institute of Radiological Sciences in Japan. In the treatment, helium, carbon, oxygen, and neon ions will be used as primary beams with pencil beam scanning. A ripple filter (RiFi), consisting of a thin plastic or aluminum plate with a fine periodic ridge and groove structure, has been used to broaden the Bragg peak of heavy-ion beams in the beam direction. To sufficiently broaden the Bragg peak of helium-, carbon-, oxygen-, and neon-ion beams with suppressed lateral scattering and surface dose inhomogeneity, in this study, we tested a plate made of a lung substitute material, Gammex LN300, as the RiFi. The planar integrated dose distribution of a 183.5 MeV u -1 neon-ion beam was measured behind a 3 cm thick LN300 plate in water. The Bragg peak of the pristine beam was broadened following the normal distribution with the standard deviation σ value of 1.29 mm, while the range of the beam was reduced by 8.8 mm by the plate. To verify the LN300 performance as the RiFi in multi-ion therapy, we measured the pencil beam data of helium-, carbon-, oxygen- and neon-ion beams penetrating the 3 cm thick LN300 plate. The data were then modeled and used in a treatment planning system to achieve a uniform 10% survival of human undifferentiated carcinoma cells within a cuboid target by the beam for each of the different ion species. The measured survival fractions were reasonably reproduced by the planned ones for all the ion species. No surface dose inhomogeneity was observed for any ion species even when the plate was placed close to the phantom surface. The plate made of lung substitute material, Gammex LN300, is applicable as the RiFi in multi-ion therapy with helium-, carbon-, oxygen- and neon-ion beams., (© 2021 Institute of Physics and Engineering in Medicine.)

In this study, the survival fraction (SF) and relative biological effectiveness (RBE) of pancreatic cancer cells exposed to spread-out Bragg peak helium, carbon, oxygen, and neon ion beams are estimated from the measured microdosimetric spectra using a microdosimeter and the application of the microdosimetric kinetic (MK) model. To measure the microdosimetric spectra, a 3D mushroom silicon-on-insulator microdosimeter connected to low noise readout electronics (MicroPlus probe) was used. The parameters of the MK model were determined for pancreatic cancer cells such that the calculated SFs reproduced previously reported in vitro SF data. For a cuboid target of 10 × 10 × 6 cm 3 , treatment plans of helium, carbon, oxygen, and neon ion beams were designed using in-house treatment planning software (TPS) to achieve a 10% SF of pancreatic cancer cells throughout the target. The physical doses and microdosimetric spectra of the planned fields were measured at different depths in polymethyl methacrylate phantoms. The biological effects, such as SF, RBE, and RBE-weighted dose at different depths along the fields were predicted from the measurements. The predicted SFs at the target region were generally in good agreement with the planned SF from the TPS in most cases.

The inhalation of carbon monoxide (CO) gas and the administration of CO-releasing molecules were shown to inhibit the development of intestinal inflammation in a murine colitis model. However, it remains unclear whether CO promotes intestinal wound healing. Herein, we aimed to evaluate the therapeutic effects of the topical application of CO-saturated saline enemas on intestinal inflammation and elucidate the underlying mechanism. Acute colitis was induced with trinitrobenzene sulfonic acid (TNBS) in male Wistar rats. A CO-saturated solution was prepared via bubbling 50% CO gas into saline and was rectally administrated twice a day after colitis induction; rats were sacrificed 3 or 7 days after induction for the study of the acute or healing phases, respectively. The distal colon was isolated, and ulcerated lesions were measured. In vitro wound healing assays were also employed to determine the mechanism underlying rat intestinal epithelial cell restitution after CO treatment. CO solution rectal administration ameliorated acute TNBS-induced colonic ulceration and accelerated ulcer healing without elevating serum CO levels. The increase in thiobarbituric acid-reactive substances and myeloperoxidase activity after induction of acute TNBS colitis was also significantly inhibited after CO treatment. Moreover, the wound healing assays revealed that the CO-saturated medium enhanced rat intestinal epithelial cell migration via the activation of Rho-kinase. In addition, the activation of Rho-kinase in response to CO treatment was confirmed in the inflamed colonic tissue. Therefore, the rectal administration of a CO-saturated solution protects the intestinal mucosa from inflammation and accelerates colonic ulcer healing through enhanced epithelial cell restitution. CO may thus represent a novel therapeutic agent for the treatment of inflammatory bowel disease., (Copyright © 2020. Published by Elsevier Inc.)

Background: Species-level genetic characterization of complex bacterial communities has important clinical applications in both diagnosis and treatment. Amplicon sequencing of the 16S ribosomal RNA (rRNA) gene has proven to be a powerful strategy for the taxonomic classification of bacteria. This study aims to improve the method for full-length 16S rRNA gene analysis using the nanopore long-read sequencer MinION™. We compared it to the conventional short-read sequencing method in both a mock bacterial community and human fecal samples., Results: We modified our existing protocol for full-length 16S rRNA gene amplicon sequencing by MinION™. A new strategy for library construction with an optimized primer set overcame PCR-associated bias and enabled taxonomic classification across a broad range of bacterial species. We compared the performance of full-length and short-read 16S rRNA gene amplicon sequencing for the characterization of human gut microbiota with a complex bacterial composition. The relative abundance of dominant bacterial genera was highly similar between full-length and short-read sequencing. At the species level, MinION™ long-read sequencing had better resolution for discriminating between members of particular taxa such as Bifidobacterium, allowing an accurate representation of the sample bacterial composition., Conclusions: Our present microbiome study, comparing the discriminatory power of full-length and short-read sequencing, clearly illustrated the analytical advantage of sequencing the full-length 16S rRNA gene.

Aims/introduction: Gut dysbiosis is generally associated with type 2 diabetes mellitus. However, the effect of habitual dietary intake on gut dysbiosis in Japanese patients with type 2 diabetes mellitus has not yet been explicated. This study investigated whether alteration of the gut microbiota was influenced by dietary intake of sucrose in Japanese patients with type 2 diabetes mellitus., Materials and Methods: In this cross-sectional study, 97 patients with type 2 diabetes mellitus and 97 healthy individuals were matched by age and sex, and then, fecal samples were obtained. Next-generation sequencing of the 16S ribosomal ribonucleic acid gene was carried out, and functional profiles for the gut microbiota were analyzed. We selected the top 30 gut microbial genera and top 20 functional profiles for the gut microbiota specified by the weighted average difference method. The association between gut microbial genera or functional profiles and habitual dietary intake was investigated by Spearman's rank correlation coefficient, and then, clustering analysis was carried out to clarify the impact of habitual dietary intake., Results: The Actinobacteria phylum was highly abundant in patients with type 2 diabetes mellitus, whereas the Bacteroidetes phylum was less abundant. Diabetic-type gut microbes, specifically Bacteroides and Bifidobacterium, were altered by sucrose intake at the genus level. Furthermore, sucrose intake was associated with glycolysis/gluconeogenesis in the diabetic-type functional profiles of the gut microbiota., Conclusions: The gut microbiota and functional profiles for the gut microbiota in patients with type 2 diabetes mellitus were significantly different from those in healthy individuals. Furthermore, we showed that sucrose intake was closely associated with these differences., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

To investigate the role of miRNA in the pathogenesis underlying ocular surface complications in patients with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in the chronic stage. Using oligonucleotide microarrays, we performed comprehensive miRNA analysis of the conjunctival epithelium of SJS/TEN patients with severe ocular complications (SOC) in the chronic stage (n = 3). Conjunctival epithelium of patients with conjunctival chalasis (n = 3) served as the control. We confirmed the down- and up-regulation of miRNA of interest by quantitative real-time polymerase chain reaction (RT-PCR) assays using the conjunctival epithelium from 6 SJS/TEN with SOC patients and 7 controls. We focused on miRNA-455-3p, which is significantly upregulated in the conjunctival epithelium of the SJS/TEN patients, and investigated its function by inhibiting miR-455-3p in primary human conjunctival epithelial cells (PHCjEs). Comprehensive miRNA expression analysis showed that the expression of 5 kinds of miRNA was up-regulated more than fivefold, and that the expression of another 5 kinds of miRNA was down-regulated by less than one-fifth. There was a significant difference between the SJS/TEN patients and the controls [analysis of variance (ANOVA) p < 0.05]. Quantitative miRNA PCR assay showed that hsa-miR-31* and hsa-miR-455-3p were significantly up-regulated in the conjunctival epithelium of the SJS/TEN patients. Comprehensive gene expression analysis of PHCjEs transfected with the hsa-miR-455-3p inhibitor and quantitative RT PCR assay showed that ANKRD1, CXCL8, CXCL2, GEM, PTGS2, RNASE8, IL6, and CXCL1 were down-regulated by the hsa-miR-455-3p inhibitor. Quantitative RT-PCR, focused on the genes that tended to be up-regulated in SJS/TEN with SOC, revealed that the expression of IL1A, KPRP, IL36G, PPP1R3C, and ADM was significantly down-regulated in PHCjEs transfected with the hsa-miR-455-3p inhibitor. Our results suggest that miRNA-455-3p could regulate many genes including innate immune related genes in human conjunctival epithelium, and that its up-regulation contributes to the pathogenesis on the ocular surface in SJS/TEN patients with the SOC in the chronic stage. Our findings may lead to the development of new treatments using the miRNA-455-3p inhibitor.

The human gut microbiota is involved in host health and disease development. Therefore, lifestyle-related diseases such as hypertension (HT), hyperlipidemia (HL), and type 2 diabetes mellitus (T2D) may alter the composition of gut microbiota. Here, we investigated gut microbiota changes related to these diseases and their coexistence. This study involved 239 Japanese subjects, including healthy controls (HC). The fecal microbiota was analyzed through the isolation of bacterial genomic DNA obtained from fecal samples. Although there were no significant differences in the microbial structure between groups, there was a significant difference in the α-diversity between HC and the patients in whom two diseases coexisted. Moreover, Actinobacteria levels were significantly increased, whereas Bacteroidetes levels were significantly decreased in all disease groups. At the genus level, Bifidobacterium levels were significantly increased in the HL and T2D groups, as were those of Collinsella in all disease groups. In contrast, Alistipes levels were significantly lower in the HL group. Furthermore, metabolic enzyme families were significantly increased in all disease groups. Interestingly, the structure and function of the gut microbiota showed similar profiles in all the studied diseases. In conclusion, several changes in the structure of the gut microbiota are associated with T2D, HT, and HL in Japanese subjects.

Higher consumption of trans fatty acid (TFA) is a risk factor for several inflammatory diseases including inflammatory bowel disease (IBD). However, the detailed mechanisms by which TFA intake affects IBD pathology remain unclear. We demonstrate here that elaidate, a trans-isomer of oleate, enhances interleukin (IL)-1β production through the activation of NLRP3 inflammasome in mouse bone marrow-derived macrophages (BMDMs). Oleate has no effect on IL-1β production. Elaidate also induces oxidative stress and activates endoplasmic reticulum stress in BMDMs. The elaidate-induced IL-1β production is suppressed by co-treatments with antioxidants and a chemical chaperone. Furthermore, we analyze the effects of elaidate administration on intestinal inflammation using 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model in mice. Increased colonic damage and myeloperoxidase activity after TNBS treatment are elevated by elaidate administration. Also, TNBS treatment induces IL-1β production in colonic mucosa; elaidate administration enhances the induction. We believe that these data reveal some mechanisms by which the TFA intake is associated with increased risk for IBD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Metabolic syndrome, whose main diagnostic component is obesity, is a risk factor for lifestyle-related diseases, type 2 diabetes, and cardiovascular disease. Diet is known to affect the prevalence of metabolic syndrome. However, the effect of diet on metabolic syndrome in Japanese subjects has not been thoroughly explored. In the present study, we investigated the effect of carotenoid-rich vegetables, particularly lycopene- and lutein-rich vegetables, on the metabolic syndrome in obese Japanese men. We conducted an 8-week long randomized, double-blinded, controlled clinical trial in which, 28 middle-aged (40 ≤ age < 65) Japanese men with high body mass index (BMI ≥ 25) were randomized into four dietary groups: high lycopene + high lutein (HLyHLu), high lycopene + low lutein (HLyLLu), low lycopene + high lutein (LLyHLu), and low lycopene + low lutein (LLyLLu). Our results showed that daily beverage-intake increased the plasma levels of carotenoids without adverse effects, and the visceral fat level was significantly decreased in all the groups. The waist circumference was significantly decreased only in the HLyLLu group, whereas the CoQ10 oxidation rate was decreased in all the groups. The gene expression profiles of whole blood samples before and after ingestion differed only in the LLyLLu group, indicating the effect of carotenoids on gene expression profile. In conclusion, our results suggest that dietary uptake of carotenoid-rich vegetables increases their concentration in blood and reduces the intra-abdominal visceral fat.

Background: Constipation is one of the most common gastrointestinal complaints. Although the causes of constipation are varied, dietary habits have a significant influence. Excessive fat intake is suggested as one of the main causes of constipation; however, the exact mechanism is unknown., Aims: To investigate whether a high-fat diet (HFD) causes constipation in mice and to clarify the underlying mechanism, focusing on the amount of colonic mucus., Methods: Six-week-old male C57BL/6 mice were randomly divided into two groups: mice fed with HFD and those with normal chow diet (NCD). Fecal weight, water content, total gastrointestinal transit time, and colon transit time were measured to determine whether the mice were constipated. The colonic mucus was evaluated by immunostaining and quantified by spectrometry. Malondialdehyde (MDA) was measured using the thiobarbituric acid (TBA) test as a marker for oxidative stress., Results: Compared to the NCD group, the weight of feces was less in the HFD group. In the functional experiment, the total gastrointestinal transit time and colon transit time were longer in the HFD group. Furthermore, HFD significantly reduced the amount of colonic mucus. In addition, the reduction in colonic mucus caused by surfactant resulted in constipation in the NCD group., Conclusions: HFD causes constipation with delayed colon transit time possibly via the reduction in colonic mucus in mice.

Background and Aims: Patients with inflammatory bowel disease [IBD], especially Crohn's disease, often develop zinc deficiency. However, the precise mechanisms by which zinc deficiency affects IBD pathology, particularly intestinal macrophage function, remain unclear. We studied the effects of zinc deficiency on the development and progression of colitis in mice., Methods: To induce colitis, mice were treated with 2,4,6-trinitrobenzene sulphonic acid. Rag1-/- mice were then given injections of naïve CD4+CD62L+ T cells. The respective degrees of mucosal injury of mice that had received a zinc chelator (TPEN; N,N,N',N'-tetrakis [2-pyridylmethyl]ethylenediamine) and of control mice were subsequently compared. Colonic lamina propria mononuclear cells were isolated by enzymatic digestion and were examined using flow cytometry. To generate mouse bone marrow-derived macrophages [BMDMs], bone marrow cells were stimulated with mouse macrophage-colony stimulating factor., Results: Zinc deficiency aggravates colonic inflammation through the activation of type 17 helper T [Th17] cells in mice. Flow cytometric analysis revealed that zinc deficiency significantly increases the proportion of pro-inflammatory [M1] macrophages in colonic lamina propria mononuclear cells obtained from inflamed colon. Interferon-γ plus lipopolysaccharide-mediated M1 skewing alters the expression of zinc transporters in BMDMs and thereby decreases the intracellular free zinc. TPEN treatment mimicking the effects of the M1 skewing up-regulates IL-23p19 expression, which is strongly related to Th17 development. Furthermore, the nuclear accumulation of interferon-regulatory factor 5 is closely involved in IL-23p19 induction in zinc-deficient macrophages., Conclusions: Zinc deficiency aggravates colonic inflammation through activation of the IL-23/Th17 axis. This activation is controlled by subcellular distribution of interferon-regulatory factor 5., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from simple hepatic steatosis commonly associated with obesity, to non-alcoholic steatohepatitis, which can progress to fibrosis, cirrhosis and hepatocellular carcinoma. Recent reports have indicated the crucial role of gut microbiota and their metabolites in the progression of NAFLD. In the present review, we demonstrated the influence of oral administration of (-)-epigallocatechin-3-gallate (EGCG) on the gut microbiota, serum bile acid profile, and gene expression in the liver in mice fed a high-fat diet (HFD). EGCG significantly inhibited the increase in histological fatty deposit and triglyceride accumulation in the liver induced by HFD, and improved intestinal dysbiosis. One of important findings is that the abundance of Proteobacteria and Defferibacteres phylums increased markedly in the HFD group, and this increase was significantly suppressed in the EGCG group. Interestingly, taurine-conjugated cholic acid (TCA) increased in the HFD group, like the mirror image against a marked decrease in the cholic acid (CA) value, and this increase was markedly inhibited in the EGCG group. TCA is not a simple serum biomarker for liver injury but TCA may be a causal factor to disturb lipid metabolism. The distribution of correlation coefficients by Heatmap analysis showed that the abundance of Akkermansia and Parabacteroides genus showed a positive correlation with CA and a negative correlation with TCA, and significantly increased in the EGCG group as compared with the HFD group. In addition, nutrigenomics approaches demonstrated that sirtuin signaling, EIF2 pathway and circadian clock are involved in the anti-steatotic effects of EGCG. In the present paper, we summarized recent update data of EGCG function focusing on intestinal microbiota and their interaction with host cells., Competing Interests: YN received scholarship fund from EA Pharma. Co. Ltd. and collaboration research fund from FUJIFILM Medical Co., Ltd. and Taiyo Kagaku Co., Ltd., and has been paid lecture fees by Mylan EPD Co., Takeda Pharma. Co. Ltd., Mochida Pharma. Co. Ltd., EA Pharma. Co. Ltd., Otsuka Pharma. Co. Ltd., Nippon Kayaku Co. Ltd., and Miyarisan Pharma. Co. Ltd.. The present research was partly funded by these funds. Neither the funding agency nor any outside organization has participated in study design or have any competing of interest. These companies had final approval of the manuscript., (Copyright © 2020 JCBN.)

Despite the advances in assisted reproductive technology, approximately 8-12% of the individuals worldwide who are willing to conceive are unable to do so. Fertility depends on a receptive state of the endometrium and hormonal adaptations as well as the immune system. Local and systemic immunities are greatly influenced by the microbiota. The aim of the present study was to compare the gut microbiota in female patients with that in infertility with fertile control subjects and to evaluate the effect of prebiotic partially hydrolyzed guar gum supplementation on gut dysbiosis and the outcome of pregnancy in patients treated with assisted reproductive technology. Dietary fiber can reconstitute the host intestinal microbiota and modify the immune function; however, clinical data regarding the effect of dietary fiber treatment on the success of assisted reproductive technology is lacking. To investigate the gut microbiota in fertile and infertile females, we conducted 16S metagenomic analysis of fecal samples. In total 18 fertile female subjects and 18 patients with infertility matched by age were recruited, and fecal samples were obtained to analyze the gut microbiome using 16S rRNA V3-V4 sequencing. The unweighted and weighted principal coordinate analyses showed a trend indicating microbial structural differences in β-diversity between these two groups. The abundance of the phylum Verrucomicrobia was higher in patients with infertility. At the genus level, a decrease in the abundance of the genera Stenotrophomonas , Streptococcus , and Roseburia and an increase in the abundance of the genera Unclassified [ Barnesiellaceae ] and Phascolarctobacterium was observed in patients with infertility. Twelve patients agreed to receive the combined therapy comprising embryo transfer by assisted reproductive technology and oral supplementation with partially hydrolyzed guar gum. The success of pregnancy by this combined therapy was 58.3% (7/12), and the failure was 41.7% (5/12). Predictive factors for pregnancy before treatment were characterized by a decrease in the abundance of Paraprevotella and Blautia and an increase in the abundance of Bifidobacterium . Predictive factors for pregnancy before treatment were characterized by a decrease in the abundance of Paraprevotella and Blautia and an increase tendency in the abundance of Bifidobacterium . In conclusion, the present study showed differences in the abundance of gut microbiota between fertile and infertile groups; moreover, partially hydrolyzed guar gum supplementation helped improve gut dysbiosis and the success of pregnancy in females with infertility., Competing Interests: YN received scholarship funds from EA Pharma. Co. Ltd.; a collaboration research fund from Taiyo Kagaku Co., Ltd.; and received lecture fees by Mylan EPD Co., Takeda Pharma. Co. Ltd., Mochida Pharma. Co. Ltd., EA Pharma. Co. Ltd., Otsuka Pharma. Co. Ltd., and Miyarisan Pharma. Co. Ltd. The present research was partly supported by these funds. Neither the funding agency nor any outside organization has participated in the study design or have any competing interests. These companies have approved the final version of the manuscript., (Copyright © 2020 JCBN.)

Epithelial‑mesenchymal transition (EMT) is considered a crucial event in the development of cancer metastasis. Metformin is a drug used in the treatment of type 2 diabetes. Recently, increasing evidence has indicated that metformin possesses anti‑tumor activities. However, the effects of metformin on EMT and metastases in pancreatic cancer remain unknown. Thus, the present study investigated whether metformin inhibits EMT of human pancreatic cancer cell lines. Pancreatic cancer cells were stimulated with transforming growth factor β1 (TGF‑β1), an activator of EMT signaling, with or without metformin. After 48 h, the levels of epithelial and mesenchymal markers were evaluated by western blot analysis, immunocytochemistry and RT‑qPCR. Cancer cell migration was evaluated by an in vitro wound healing assay. The cells stimulated with TGF‑β1 acquired an elongated and fusiform morphology, which was inhibited by metformin. The wound healing assay revealed that metformin significantly suppressed the TGF‑β1‑stimulated migration of pancreatic cancer cells. Following treatment with metformin, E‑cadherin expression (epithelial marker) was upregulated, and the levels of mesenchymal markers were downregulated, which had been increased by TGF‑β1 in these cells. Exposure of the cells to TGF‑β1 activated the Smad2/3 and Akt/mammalian target of rapamycin (mTOR) pathways, and this effect was inhibited by metformin, suggesting that metformin inhibits TGF‑β1‑induced‑EMT through the down‑regulation of the Smad pathway in PANC‑1 cells and the downregulation of the Akt/mTOR pathway in BxPC‑3 cells. In an animal model of surgical orthotopic implantation, metformin inhibited liver metastasis without a significant reduction in the size of the primary pancreatic tumor. On the whole, the findings of the present study suggest that metformin inhibits EMT and cancer metastasis through the Smad or Akt/mTOR pathway.

Background and Aim: Mucosal healing is an important clinical goal in patients with inflammatory bowel disease. Recently, short-chain fatty acids (SCFAs) have been reported to have multifaceted effects to host. However, the effects of SCFAs on wound healing in intestinal epithelial cells are unclear. In the present study, we investigated the effects of acetate, one of the major SCFAs, on the wound healing of murine colonic epithelial cells., Methods: Young adult mouse colonic epithelial cells were used to determine the effect of acetate using wound healing assay. Mitogen-activated protein kinase and Rho kinase inhibitor were used to elucidate intracellular signal of wound healing treated with acetate. Meanwhile, Rho activation assays were utilized to measure Rho activation levels. To assess in vivo effects, C57B6 mice with dextran sodium sulfate for 7 days were treated with enema administration of acetate for 7 days. Body weight, disease activity index, colon length, and mucosal break ratio in histology were examined., Results: Acetate enhanced wound healing and fluorescence intensity of actin stress fiber compared with control. These effects were canceled with pretreatment of c-Jun N-terminal kinase (JNK) inhibitor or Rho kinase inhibitor. Furthermore, JNK inhibitor reduced the activation of Rho induced by acetate. In the dextran sodium sulfate-induced colitis model, the mice with enema treatment of acetate significantly exhibited recovery., Conclusions: In this study, we demonstrated that acetate promoted murine colonic epithelial cell wound healing via activation of JNK and Rho signaling pathways. These findings suggested that acetate could have applications as a therapeutic agent for patients with intestinal mucosal damage, such as inflammatory bowel disease., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The National Institute of Radiological Sciences (NIRS) has initiated a development project for hypo-fractionated multi-ion therapy. In the treatment, heavy ions up to neon ions will be used as a primary beam, which is a high linear energy transfer (LET) radiation. The fractionated dose of the treatment will be 10 Gy or more. The microdosimetric kinetic (MK) model overestimates the biological effectiveness of high-LET and high-dose radiations. To address this issue, the stochastic microdosimetric kinetic (SMK) model has been developed as an extension of the MK model. By taking the stochastic nature of domain-specific and cell nucleus-specific energies into account, the SMK model could estimate the biological effectiveness of radiations with wide LET and dose ranges. Previously, the accuracy of the SMK model was examined by comparison of estimated and reported survival fractions of human cells exposed to pristine helium-, carbon-, and neon-ion beams. In this study, we verified the SMK model in treatment planning of scanned helium-, carbon-, oxygen-, and neon-ion beams as well as their combinations through the irradiations of human undifferentiated carcinoma and human pancreatic cancer cells. Treatment plans were made with the ion-species beams to achieve a uniform 10% survival of the cells within a cuboid target. The planned survival fractions were reasonably reproduced by the measured survival fractions in the whole region from the plateau to the fragment tail for all planned irradiations. The SMK model offers the accuracy and simplicity required in hypo-fractionated multi-ion therapy treatment planning.

The National Institute of Radiological Sciences has investigated multiple-ion therapy using energetic beams of helium, carbon, oxygen, and neon ions, to improve treatment outcomes of refractory cancer. For this therapy, it is necessary to ensure the helium-ion beam purity to avoid irradiation by unwanted ions. Here, we develop a measurement method for monitoring beam purity. This method can measure the charge number of the ions in a high-purity beam using an ionization chamber and Faraday cup. In addition, it can be used to detect the contamination of the clinical helium-ion beam. We perform beam experiments to evaluate our beam-purity monitoring method and predict that our method is capable of detecting contamination below 1%.

In charged-particle therapy treatment planning, the patient is conventionally modeled as variable-density water, i.e. stopping effective density ρ S , and the planar integrated dose distribution measured in water (PID) is applied for patient dose calculation based on path length scaling with the ρ S . This approximation assures the range accuracy of charged-particle beams. However, it causes dose calculation errors due to water nonequivalence of body tissues in nuclear interactions originating from compositional differences. We had previously proposed and validated a PID correction method for the errors in carbon-ion radiotherapy. In the present study, we verify the PID correction method for helium-, oxygen-, and neon-ion beams. The one-to-one relationships between ρ S and the nuclear effective density ρ N of body tissues were constructed for helium-, carbon-, oxygen-, and neon-ion beams, and were used to correct the PIDs to account for the dose calculation errors in patient. The correction method was tested for non-water materials with un-scanned and scanned ion beams. In un-scanned beams penetrating the materials, the dose calculation errors of up to 5.9% were observed at the Bragg peak region, while they were reduced to  ⩽0.9% by the PID correction method. In scanned beams penetrating olive oil, the dose calculation errors of up to 2.7% averaged over the spread-out Bragg peak were observed, while they were reduced to  ⩽0.4% by the correction method. To investigate the influence of water nonequivalence of body tissues on tumor dose, we carried out a treatment planning study for prostate and uterine cases. The tumor over-doses of 0.9%, 1.8%, 2.0%, and 2.2% were observed in the uterine case for the helium-, carbon-, oxygen-, and neon-ion beams, respectively. These dose errors could be diminished by the PID correction method. The present results verify that the PID correction method is simple, practical, and accurate for treatment planning of these four ion species.