Novel Gut Microbiota Modulator, Which Markedly Increases Akkermansia muciniphila Occupancy, Ameliorates Experimental Colitis in Rats.

BACKGROUND: Since gut microbiota is involved in the pathogenesis of inflammatory bowel disease (IBD), antibiotics or probiotics may be attractive options for the treatment of IBD. Akkermansia muciniphila is expected as a next-generation probiotic for IBD, and OPS-2071 is a novel quinolone with potent antibacterial activity against Clostridioides difficile. AIMS: The aim of this study is to assess the potential of OPS-2071 as a gut microbiota modulator for IBD. METHODS: Minimum inhibitory concentrations of several bacteria in the human intestinal microbiota were determined. Microbiota changes in the feces were typed using metagenomic analysis after oral administration of OPS-2071 (100 mg/kg) twice a day to normal rats. The amounts of mucin were determined using the Fecal Mucin Assay Kit. The effects of OPS-2071 (1, 3, 10 mg/kg) twice a day on fecal symptoms and fecal microbiota were evaluated in a colitis rat model induced by free access to drinking water containing 3% dextran sulfate sodium for 10 days. RESULTS: OPS-2071 showed notably low antibacterial activity against only A. muciniphila in spite of higher antimicrobial activity against other strains of intestinal bacteria. OPS-2071 rapidly and dramatically increased the occupancy of A. muciniphila as well as the amount of mucin in the feces of normal rats. OPS-2071 (10 mg/kg) significantly suppressed the exacerbation of stool scores, especially the bloody stool score, with the increase in A. muciniphila occupancy. CONCLUSIONS: OPS-2071 is expected to be a new therapeutic option for IBD as a gut microbiota modulator by significantly increasing A. muciniphila occupancy.

Association between postpartum depression and social support satisfaction levels at four months after childbirth.

This study clarifies the association between postpartum depression (PPD) and satisfaction with social support after childbirth through an anonymous survey of 427 postpartum mothers. Mothers' PPD was found to be significantly associated with satisfaction levels regarding formal-instrumental support (OR: 0.32, 95% CI: 0.162-0.632), informal-instrumental support (OR: 0.547, 95% CI: 0.313-0.955), and informal-psychological support (OR: 0.591, 95% CI: 0.384-0.912) in a multivariate logistic regression analysis. To prevent PPD, specialists as formal support providers must provide qualified care based on comprehensive judgments, and families as informal support providers should help with childcare, housework, and mental support.

Examining Japanese women's preferences for a new style of postnatal care facility and its attributes.

Perinatal care in rural Japan is currently facing a crisis because of the lack of medical staff, especially obstetricians. In this study, a new style of postnatal care facility that combines both medical and nonmedical support is considered. Contrary to most postnatal care facilities in Japan, this new postnatal care facility accepts a puerperant from the cooperating maternity facility soon after birth (≤2 days). We conducted a hypothetical choice experiment to investigate whether this new postnatal care facility could be accepted by women in Gero City, Hida, Gifu Prefecture and how these women evaluate different kinds of postnatal care services. The results show that after a 2-day hospital stay, women from Gero City preferred to move to the new postnatal care facility over the other alternatives (continued hospitalization or discharge home). In addition, the estimated choice probabilities for selecting the postnatal care facility under different scenarios show a high level of acceptance for this new postnatal care facility.

Intra-oral administration of rebamipide liquid prevents tongue injuries induced by X-ray irradiation in rats.

PURPOSE: Oral mucositis is a common and serious side effect in patients who undergo cytotoxic cancer therapies. The purpose of this study was to investigate the preventive effects of rebamipide on radiation-induced glossitis model in rats. METHODS: Glossitis was induced by a single dose of 15 Gy of X-rays to the snouts of rats (day 0). A novel form of rebamipide liquid comprising its submicronized crystals was administered intra-orally. The preventive effect of rebamipide on tongue injuries was macroscopically evaluated on day 7 following irradiation. The pretreatment period, dosing frequency, and dose dependency of rebamipide were examined. RESULTS: Two percent rebamipide liquid, administered six times a day for 14 days from day -7 to day 6, significantly decreased the ulcer-like area. However, no significant effect was observed when rebamipide was given either from day -4 or from day -1. Four or six times daily, 2% rebamipide liquid significantly inhibited the ulcer-like injury area ratio, but not when given twice daily. Rebamipide liquid, 1, 2, and 4% six times daily significantly reduced the area ratios of total injury and ulcer-like injury in a dose-dependent manner. Gene expression and protein levels of proinflammatory cytokines and chemokines were dramatically elevated in the irradiated tongues of control rats on day 7 without rebamipide liquid treatment. They were dose-dependently and significantly suppressed in rebamipide-treated groups. CONCLUSION: Intra-oral administration of rebamipide liquid prevented oral mucositis dose-dependently accompanied by the suppression of inflammatory expression in the radiation-induced rats' glossitis model.

Rebamipide does not interfere with the antitumor effect of radiotherapy or chemotherapy in human oral tumor-bearing nude mice.

Recent studies have shown that rebamipide, which suppresses reactive oxygen species, prevents chemoradiotherapy-induced oral mucositis in patients with head and neck cancers. However, anticancer action of radiotherapy and chemotherapy is believed to be partially associated with generation of reactive oxygen species. The aim of this study was to determine whether rebamipide interferes with the antitumor action of radiotherapy and chemotherapy. The effect of rebamipide on tumor cell growth was investigated using a human oral squamous carcinoma cell line, HSC-2, in vitro and in vivo. Rebamipide showed no significant effect on cell or tumor growth in HSC-2 tumor-bearing nude mice. Influences of rebamipide on the antitumor action of radiotherapy and of chemotherapy with cisplatin or docetaxel were investigated using the same animal model. In radiotherapy, the tumor was treated with 2.5 Gy of X-rays for 5 days, and rebamipide (300 mg/kg p.o.) was administered during irradiation periods. In chemotherapy, tumor-bearing mice were treated once with cisplatin (8 mg/kg, i.v.) or docetaxel (15 mg/kg i.v.) and rebamipide (300 mg/kg p.o.) was administered for 5 days following the antitumor drug treatment. Rebamipide did not interfere with the antitumor action of radiotherapy and chemotherapy.

Rebamipide protects small intestinal mucosal injuries caused by indomethacin by modulating intestinal microbiota and the gene expression in intestinal mucosa in a rat model.

The effect of rebamipide, a mucosal protective drug, on small intestinal mucosal injury caused by indomethacin was examined using a rat model. Indomethacin administration (10 mg/kg, p.o.) induced intestinal mucosal injury was accompanied by an increase in the numbers of intestinal bacteria particularly Enterobacteriaceae in the jejunum and ileum. Rebamipide (30 and 100 mg/kg, p.o., given 5 times) was shown to inhibit the indomethacin-induced small intestinal mucosal injury and decreased the number of Enterococcaceae and Enterobacteriaceae in the jejunal mucosa to normal levels. It was also shown that the detection rate of segmented filamentous bacteria was increased by rebamipide. PCR array analysis of genes related to inflammation, oxidative stress and wound healing showed that indomethacin induced upregulation and downregulation of 14 and 3 genes, respectively in the rat jejunal mucosa by more than 5-fold compared to that of normal rats. Rebamipide suppressed the upregulated gene expression of TNFα and Duox2 in a dose-dependent manner. In conclusion, our study confirmed that disturbance of intestinal microbiota plays a crucial role in indomethacin-induced small intestinal mucosal injury, and suggests that rebamipide could be used as prophylaxis against non-steroidal anti-inflammatory drugs -induced gastrointestinal mucosal injury, by modulating microbiota and suppressing mucosal inflammation in the small intestine.

Novel submicronized rebamipide liquid with moderate viscosity: significant effects on oral mucositis in animal models.

This study aimed at developing a novel rebamipide liquid for an effective treatment of oral mucositis. The healing effects of a variety of liquids comprising submicronized rebamipide crystals were investigated using a rat cauterization-induced oral ulcer model. Whereas 2% rebamipide liquid comprising micro-crystals did not exhibit significant curative effect, 2% rebamipide liquids comprising submicronized crystals with moderate viscosities exhibited healing effects following intra-oral administration. The 2% and 4% optimized rebamipide liquids showed significant healing effects in the rat oral ulcer model (p<0.01). In addition, in the rat radiation-induced glossitis model, whereby the injury was caused to the tongue by exposing only around the rat's snout to a 15 Gy of X-irradiation, the 2% optimized rebamipide liquid significantly reduced the percent area of ulcerated injury (p<0.05). In conclusion, the submicronized rebamipide liquid with moderate viscosity following intra-oral administration showed better both healing effect in the rat oral ulcer model and preventive effect in the rat irradiation-induced glossitis model.

Establishment of an X-ray irradiation-induced glossitis model in rats: biphasic elevation of proinflammatory cytokines and chemokines.

Oral mucositis is a frequent and serious side effect in patients who receive radiotherapy for head and neck cancer. The purpose of this study was to develop a noninvasive and quantitative model of oral mucositis in rats, investigate the pathophysiology, and evaluate the efficacy of pharmacological interventions. Rats received a single dose of 15 Gy of X-rays to the snout after shielding of the remainder of the rat body with lead plates to protect the body from irradiation (day 0). After irradiation, the macroscopic area of tongue injury gradually increased. The total area of injury and the ulcer-like area reached a maximum on day 7 and then gradually decreased until disappearance on day 28. Expression of proinflammatory cytokines and chemokines occurred transiently within 1-4 hours after irradiation and returned to a normal level at 24 hours. This expression was again observed from days 3 to 5 and increased significantly on day 7, which approximately coincided with the histologic severity of tissue damage. Subcutaneous administration of palifermin at 3 mg/kg per day for 3 consecutive days before irradiation completely prevented ulcer formation in this model. In conclusion, we established a novel model of glossitis in rats, induced by X-ray irradiation, in which biphasic elevations of expression of proinflammatory cytokines and chemokines could be monitored. This model is considered useful to investigate the pathophysiology of oral mucositis and evaluate the preventive effect of pharmacological interventions on oral mucositis induced by X-ray irradiation.

Highly coupled ATP synthesis by F1-ATPase single molecules.

F1-ATPase is the smallest known rotary motor, and it rotates in an anticlockwise direction as it hydrolyses ATP. Single-molecule experiments point towards three catalytic events per turn, in agreement with the molecular structure of the complex. The physiological function of F1 is ATP synthesis. In the ubiquitous F0F1 complex, this energetically uphill reaction is driven by F0, the partner motor of F1, which forces the backward (clockwise) rotation of F1, leading to ATP synthesis. Here, we have devised an experiment combining single-molecule manipulation and microfabrication techniques to measure the yield of this mechanochemical transformation. Single F1 molecules were enclosed in femtolitre-sized hermetic chambers and rotated in a clockwise direction using magnetic tweezers. When the magnetic field was switched off, the F1 molecule underwent anticlockwise rotation at a speed proportional to the amount of synthesized ATP. At 10 Hz, the mechanochemical coupling efficiency was low for the alpha3beta3gamma subcomplex (F1-epsilon)), but reached up to 77% after reconstitution with the epsilon-subunit (F1+epsilon)). We provide here direct evidence that F1 is designed to tightly couple its catalytic reactions with the mechanical rotation. Our results suggest that the epsilon-subunit has an essential function during ATP synthesis.

Impact of specialization in gynecology and obstetrics departments on pregnant women's choice of maternity institutions.

In April 2008, specialization in gynecology and obstetrics departments was introduced in the Sennan area of Osaka prefecture in Japan that aimed at solving the problems of regional provisions of obstetrics services (e.g., shortage of obstetricians, overworking of obstetricians, and provision of specialist maternity services for high-risk pregnancies). Under this specialization, the gynecology and obstetrics departments in two city hospitals were combined and reconstructed into two centers, i.e., the gynecological care center in Kaizuka City Hospital and the prenatal care center in Izumisano City Hospital. This paper investigates to what extent and how this specialization affected pregnant women's choices of the prenatal care center and other maternity institutions. We used birth certificate data of 15,927 newborns from the Sennan area between April 1, 2007 and March 30, 2010, for Before and After Analysis to examine changes in pregnant women's choices of maternity institutions before and after the specialization was instituted. Our results indicated that this specialization scheme was, to some extent, successful on the basis of providing maternity services for high-risk pregnancies at the prenatal care center (i.e., Izumisano City Hospital) and having created a positive effect by pregnant women to other facilities in the nearby area.

A cost-benefit analysis on the specialization in departments of obstetrics and gynecology in Japan.

In April 2008, the specialization in departments of obstetrics and gynecology was conducted in Sennan area of Osaka prefecture in Japan, which aims at solving the problems of regional provision of obstetrical service. Under this specialization, the departments of obstetrics and gynecology in two city hospitals were combined as one medical center, whilst one hospital is in charge of the department of gynecology and the other one operates the department of obstetrics. In this paper, we implement a cost-benefit analysis to evaluate the validity of this specialization. The benefit-cost ratio is estimated at 1.367 under a basic scenario, indicating that the specialization can generate a net benefit. In addition, with a consideration of different kinds of uncertainty in the future, a number of sensitivity analyses are conducted. The results of these sensitivity analyses suggest that the specialization is valid in the sense that all the estimated benefit-cost ratios are above 1.0 in any case.

Acceleration of the ATP-binding rate of F1-ATPase by forcible forward rotation.

F1-ATPase (F1) is a reversible ATP-driven rotary motor protein. When its rotary shaft is reversely rotated, F1 produces ATP against the chemical potential of ATP hydrolysis, suggesting that F1 modulates the rate constants and equilibriums of catalytic reaction steps depending on the rotary angle of the shaft. Although the chemomechanical coupling scheme of F1 has been determined, it is unclear how individual catalytic reaction steps depend on its rotary angle. Here, we report direct evidence that the ATP-binding rate of F1 increases upon the forward rotation of the rotor, and its binding affinity to ATP is enhanced by rotation.

Rebamipide enema is effective for treatment of experimental dextran sulfate sodium induced colitis in rats.

We investigated therapeutic efficacy of rebamipide using dextran sulfate sodium (DSS) induced colitis model in rats. Three percent DSS solution was given to rats for 9 days. After that, we evaluated the drug efficacy on colitis sustained with continuous drinking of 1% DSS. Twice-daily treatment with 0.3% or 1% rebamipide for 14 days significantly ameliorated the stool abnormality in the colitis model, preferentially suppressed hematochezia. The colonic mucosal lesion, determined by Alcian blue staining on day 24, was significantly reduced by rebamipide enema in a dose-dependent manner. Either rebamipide or 5-aminosalycilic acid (5-ASA) enema treated once daily significantly ameliorated colitis. The minimum effective dose of rebamipide was 0.3% in once-daily treatment, and that of 5-ASA was 10%. In a mechanistic study, the epithelial cell sheet formation of the T84 colon cancer cell was measured as an increase in generation of trans-epithelial electrical resistance in vitro. Rebamipide accelerated the increase, while 5-ASA conversely suppressed it. These results suggest that rebamipide enema is effective for treatment of experimental ulcerative colitis (UC).