Perioperative risk factors of preterm delivery after fetoscopic laser photocoagulation for twin-twin transfusion syndrome.

OBJECTIVE: To identify risk factors for preterm delivery (PTD) in patients who received fetoscopic laser photocoagulation (FLP) of placental anastomoses for twin-twin transfusion syndrome (TTTS). METHODS: This retrospective cohort study prospectively analyzed and recorded perioperative data in a cohort of patients who had FLP for TTTS, identifying perioperative risk factors for PTD using a Cox proportional hazard regression model. RESULTS: Of 304 patients included, 26 (8.6%) delivered within 4 weeks of FLP. Independent predictors of delivery within 4 weeks of FLP were a history of PTD (hazard ratio [HR]: 5.91, 95% confidence interval [CI]:1.21-28.82, p = 0.03), vaginal bleeding in the second trimester (HR: 6.62, 95% CI: 1.76-24.90, p < 0.01), and amnioreduction ≥1715 mL (HR: 3.16, 95% CI: 1.11-9.05, p < 0.03). CONCLUSION: Patients with a history of PTD, preoperative vaginal bleeding, and amnioreduction ≥1715 mL were more likely to deliver prematurely.

Allergic inflammation disrupts epithelial electrogenic electrolyte transport through cholinergic regulation in the mouse colon.

Intestinal transport of electrolytes is regulated by the enteric nervous system. Acetylcholine (ACh) is considered the most important neurotransmitter for electrolyte transport in the colon. However, electrolyte transport regulated by ACh is not fully understood in the colon. We investigated the regulation of electrogenic electrolyte transport by cholinergic agonists in the mouse colon by measuring the short-circuit current (Isc) using an Ussing chamber system. Muscarinic stimulation induced transient electrogenic Cl- secretion, and nicotinic stimulation induced electrogenic K+ secretion to the apical side in the normal mouse colon, and these effects were reduced in the colon of mice with food allergy (FA). Administration of prednisolone to mice with FA suppressed mild inflammation in the colon and allergic symptoms and thereby ameliorated the disruption of electrogenic electrolyte transport induced not only by cholinergic pathway activation but also by electrical field stimulation and intracellular cAMP signaling pathway activation in the colon. These results suggest that the electrogenic electrolyte transport function in the colon is impaired by FA-induced colonic inflammation and that the suppression of inflammation ameliorates the dysfunction of electrogenic electrolyte transport in the colon of mice with FA.

Intestinal epithelial BLT1 promotes mucosal repair.

Acute and chronic intestinal inflammation is associated with epithelial damage, resulting in mucosal wounds in the forms of erosions and ulcers in the intestinal tract. Intestinal epithelial cells (IECs) and immune cells in the wound milieu secrete cytokines and lipid mediators to influence repair. Leukotriene B4 (LTB4), a lipid chemokine, binds to its receptor BLT1 and promotes migration of immune cells to sites of active inflammation; however, a role for intestinal epithelial BLT1 during mucosal wound repair is not known. Here we report that BLT1 was expressed in IECs both in vitro and in vivo, where it functioned as a receptor not only for LTB4 but also for another ligand, resolvin E1. Intestinal epithelial BLT1 expression was increased when epithelial cells were exposed to an inflammatory microenvironment. Using human and murine primary colonic epithelial cells, we reveal that the LTB4/BLT1 pathway promoted epithelial migration and proliferation leading to accelerated epithelial wound repair. Furthermore, in vivo intestinal wound repair experiments in BLT1-deficient mice and bone marrow chimeras demonstrated an important contribution of epithelial BLT1 during colonic mucosal wound repair. Taken together, our findings show a potentially novel prorepair in IEC mechanism mediated by BLT1 signaling.

Relationship between unremoved cervical polyp in pregnancy and spontaneous preterm birth.

BACKGROUND: Cervical polyps removed during pregnancy have been reported to be associated with preterm birth; however, the association between unremoved cervical polyps and preterm birth has not been elucidated. OBJECTIVE: This study aimed to clarify the relationship between cervical polyps detected before 12 weeks of gestation managed expectantly and spontaneous preterm birth. STUDY DESIGN: This retrospective cohort study included pregnant women who visited a tertiary perinatal center before 12 weeks of gestation between January 2015 and December 2019. The exclusion criteria were as follows: multiple gestations, loss or termination of pregnancy before 12 weeks of gestation, major fetal anomalies, fetal chromosomal abnormalities, fetal demise, having undergone removal of cervical polyps before the first visit to our hospital, and moving to other hospitals before delivery. A vaginal speculum examination was routinely performed during a prenatal visit before 12 weeks of gestation. When a cervical polyp was detected on speculum examination, it was managed expectantly, unless gynecologic malignancy was suspected. Relationships between cervical polyps and spontaneous preterm birth before 34 weeks of gestation were evaluated using logistic regression analysis and Cox proportional-hazards analysis adjusted for known confounders for spontaneous preterm birth. RESULTS: A total of 4172 pregnant women were included, of whom 92 (2.2%) had a cervical polyp detected before 12 weeks of gestation. None of the women underwent polypectomy during pregnancy. The incidence of spontaneous preterm birth before 34 weeks of gestation was higher in pregnant women with cervical polyps than in those without them (5.4% vs 0.7%; P<.01). Logistic regression analysis revealed that cervical polyps were an independent risk factor for spontaneous preterm birth before 34 weeks of gestation (adjusted odds ratio, 4.09; 95% confidence interval, 1.70-9.81; P<.01). The adjusted hazard ratio for spontaneous preterm birth before 34 weeks of gestation among women with vs without cervical polyps was 2.95 (95% confidence interval, 1.32-6.62; P<.01). CONCLUSION: Cervical polyps detected before 12 weeks of gestation managed expectantly are a significant risk factor for spontaneous preterm birth before 34 weeks of gestation.

Umbilical cord prolapse after preterm premature rupture of membranes.

OBJECTIVE: To investigate the incidence of umbilical cord prolapse (UCP) and its influence on infant prognosis in pregnant women with preterm premature rupture of membranes (PPROM). MATERIALS AND METHODS: We conducted a retrospective cohort study in a single tertiary perinatal center between 2009 and 2017. Singleton pregnancies with PPROM that occurred between 22 and 33 weeks of gestation were included. Infantile composite adverse outcome consisted of death, severe intraventricular hemorrhage, cystic periventricular leukomalacia, necrotizing enterocolitis, and sepsis before discharge. Infantile outcomes were compared between pregnancies that were complicated by UCP and those that were not. RESULTS: Out of 208 singleton pregnancies included in the analysis, UCP occurred in 12 (5.8%) cases. The gestational age of pregnancies with UCP was significantly lesser than that of those without UCP. The incidence of infantile composite adverse outcome in patients with UCP was 16.7%, and this was not significantly higher than the incidence in patients without UCP (6.6%, P = 0.21). UCP was not shown to be associated with infantile composite adverse outcome in a multivariate regression model. Gestational age <25 weeks at delivery was significantly associated with infantile composite adverse outcome. CONCLUSIONS: The incidence of UCP was 5.8% among singleton pregnancies, with PPROM being managed expectantly between 22 and 33 weeks' gestation. Preterm UCP may not be associated with infantile adverse outcomes provided emergency cesarean delivery is available at all time.

Infantile survival and neurodevelopment at three years of age on delivery by the intended delivery mode in extremely preterm infants.

OBJECTIVE: To elucidate the impact of the intended delivery mode on long-term outcomes among extremely preterm infants. MATERIALS AND METHODS: Women who delivered singletons between 23 0/7 and 25 6/7 weeks of gestation from January 2010 to March 2014 and their infants were included in this study. The cases of fetal growth restriction and those with a chromosomal or major structural abnormality were excluded. The cases of fetal death that was diagnosed before labor onset and cases of non-reassuring fetal status, placental abruptions or umbilical cord prolapse that was diagnosed at labor onset were also excluded. The primary outcome was the incidence of composite adverse events, including death, cerebral palsy, or neurodevelopmental delay, at the age of three years. The composite adverse events, including death, grade III or IV intraventricular hemorrhage, cystic periventricular leukomalacia, necrotizing enterocolitis, focal intestinal perforation, and sepsis of neonatal period, were assessed as short-term outcomes. The association between the intended delivery mode and primary outcome, short-term outcome, and each component was analyzed using a multivariate logistic regression model. RESULTS: Eighty cases were included in the analyses. Primary outcomes could be assessed in 72 cases. Infantile composite adverse events before discharge were observed in 19 cases (24%). The prevalence of primary outcomes was 40% (29 cases). The intended delivery mode was not associated with primary and short-term outcomes and each component complication. CONCLUSION: An advantage of intended cesarean delivery in terms of prognosis at three years of age in extremely preterm infants was not observed.

Neuro-immune crosstalk and food allergy: Focus on enteric neurons and mucosal mast cells.

The nervous system and the immune system individually play important roles in regulating the processes necessary to maintain physiological homeostasis, respond to acute stress and protect against external threats. These two regulating systems for maintaining the living body had often been assumed to function independently. Allergies develop as a result of an overreaction of the immune system to substances that are relatively harmless to the body, such as food, pollen and dust mites. Therefore, it has been generally supposed that the development and pathogenesis of allergies can be explained through an immunological interpretation. Recently, however, neuro-immune crosstalk has attracted increasing attention. Consequently, it is becoming clear that there is close morphological proximity and physiological and pathophysiological interactions between neurons and immune cells in various peripheral tissues. Thus, researchers are now beginning to appreciate that neuro-immune interactions may play a role in tissue homeostasis and the pathophysiology of immune-mediated disease, but very little information is available on the molecular basis of these interactions. Mast cells are a part of the innate immune system implicated in allergic reactions and the regulation of host-pathogen interactions. Mast cells are ubiquitous in the body, and these cells are often found in close proximity to nerve fibers in various tissues, including the lamina propria of the intestine. Mast cells and neurons are thought to communicate bidirectionally to modulate neurophysiological effects and mast cell functions, which suggests that neuro-immune interactions may be involved in the pathology of allergic diseases.

Cholinergic anti-inflammatory pathway ameliorates murine experimental Th2-type colitis by suppressing the migration of plasmacytoid dendritic cells.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease. Several studies have demonstrated that α7 nicotinic acetylcholine receptors (α7nAChRs) exert anti-inflammatory effects on immune cells and nicotine suppress UC onset and relapse. Plasmacytoid dendritic cells (pDCs) reportedly accumulate in the colon of UC patients. Therefore, we investigated the pathophysiological roles of α7nAChRs on pDCs in the pathology of UC using oxazolone (OXZ)-induced Th2-type colitis with BALB/c mice. 2-deoxy-D-glucose, a central vagal stimulant suppressed OXZ colitis, and nicotine also ameliorated OXZ colitis with suppressing Th2 cytokines, which was reversed by α7nAChR antagonist methyllycaconitine. Additionally, α7nAChRs were expressed on pDCs, which were located very close to cholinergic nerve fibers in the colon of OXZ mice. Furthermore, nicotine suppressed CCL21-induced bone marrow-derived pDC migration due to Rac 1 inactivation, which was reversed by methyllycaconitine, a JAK2 inhibitor AG490 or caspase-3 inhibitor AZ-10417808. CCL21 was mainly expressed in the isolated lymphoid follicles (ILFs) of the colon during OXZ colitis. The therapeutic effect of cholinergic pathway on OXZ colitis probably through α7nAChRs on pDCs were attributed to the suppression of pDC migration toward the ILFs. Therefore, the activation of α7nAChRs has innovative therapeutic potential for the treatment of UC.

Incidences of complications associated with cervical cerclage by indication of the procedure.

AIM: To investigate the incidence of complications associated with cervical cerclage by indication. METHODS: This was a retrospective cohort study of women with singleton pregnancies who underwent cervical cerclage in a single perinatal center between 2008 and 2019. The participants were divided into three groups according to indication: history-indicated cerclage (HIC) group, ultrasound-indicated cerclage (UIC) group, and physical examination-indicated cerclage (PEIC) group. The incidences of perioperative complications within 2 weeks after the procedure, including intraoperative rupture of membranes, intraoperative bleeding, anesthesia complications, clinical chorioamnionitis, premature rupture of membranes (PROM), preterm delivery, and displacement of the suture, and those of peripartum complications, including difficult suture removal and cervical laceration, for each group were compared using Fisher's exact test or Pearson's chi-square test. Factors associated with severe adverse event, defined as PROM or delivery within 2 weeks after the procedure, were analyzed using multivariate logistic regression analysis. RESULTS: A total of 279 women (HIC, 38; UIC, 96; PEIC, 145) were enrolled. The incidence of perioperative complications was different among the three groups (7.9%, 10.4%, and 27.6%, respectively; p < 0.01), whereas that of peripartum complications was similar (18.4%, 11.5%, and 12.4%, respectively; p = 0.54). Severe adverse events occurred only in PEIC group, with an incidence of 18.6%. The associated factor for severe adverse events in PEIC group was prolapsed membranes into the vagina. CONCLUSIONS: Incidences of perioperative complications of cerclage differed among the indications. Women who underwent PEIC had higher risk of severe adverse events, especially when accompanied with prolapsed membranes into the vagina.

Incidence of chest X-ray abnormalities early in the third trimester of twin pregnancy and its relationship with the subsequent development of preeclampsia.

AIM: To clarify the incidence of abnormal findings on chest X-ray (CXR) early in the third trimester of twin pregnancy and its relationship with the development of preeclampsia and preeclampsia-related diseases. METHODS: This was a retrospective cohort study conducted among women with twin pregnancies who underwent chest radiography for preoperative screening early in the third trimester and delivered at our center at >34 weeks' gestation from 2013 to 2017. The primary outcome was the incidence of positive CXR findings, defined either as cardiomegaly or blunting of the costophrenic angle. The secondary outcome was the incidence of maternal complications, including preeclampsia; hemolytic, elevated liver enzymes, and low platelet syndrome; eclampsia; cerebrovascular disease; and placental abruption. We evaluated the significance of positive CXR findings, in addition to confounding factors, in the subsequent development of preeclampsia. RESULTS: During the study period, 358 twin pregnancies were identified, and 330 were finally enrolled. The incidence of positive CXR findings was 18.2%. The incidence of preeclampsia in the CXR-positive group was 36.7% (22/60), which was significantly higher than that in the CXR-negative group (7.0% [19/270]) (p < 0.01). Moreover, positive CXR findings were independently associated with subsequent preeclampsia (adjusted odds ratio: 9.15, 95% confidence interval: 4.13-20.3). CONCLUSION: In twin pregnancies, the incidence of CXR abnormalities early in the third trimester was 18.2%, even without the development of hypertension. This should be considered a significant risk factor for subsequent preeclampsia.

Re-evaluation of the predictive value of Quintero staging of twin-twin transfusion syndrome for fetal death after fetoscopic laser photocoagulation.

OBJECTIVE: To elucidate the significance of sonographic indices, including Doppler waveforms, that constitute the Quintero classification for predicting death of the recipient or donor after fetoscopic laser photocoagulation (FLP) for twin-twin transfusion syndrome (TTTS). METHODS: Prospectively collected data of twins who underwent FLP for TTTS were reviewed. Among the abnormal indices of ultrasound performed just before FLP, factors that were significantly associated with fetal and neonatal deaths in the log-rank test, including fetal demise of co-twins and preterm birth before 28 weeks of gestation, were introduced into the Cox proportional-hazards model to calculate risk ratio (RR). RESULTS: We included 235 cases with a prevalence of recipient and donor deaths of 7% and 14%, respectively. In the proportional-hazards model, absent or reversed umbilical artery end-diastolic velocity (UA AREDV) of recipients (n = 7) was independently associated with recipient death (RR = 6.97). In recipients without UA AREDV, reversed ductus venosus (DV) a-wave of recipients (RR = 3.55) was independently associated with recipient death. In donors, UA AREDV with a visible bladder (stage III atypical donor) was independently associated with donor death (RR = 4.24). CONCLUSION: Some individual components of the Quintero stage are associated with death of either recipient or donor twins following FLP.

Pathophysiological Roles of Neuro-Immune Interactions between Enteric Neurons and Mucosal Mast Cells in the Gut of Food Allergy Mice.

Recently, the involvement of the nervous system in the pathology of allergic diseases has attracted increasing interest. However, the precise pathophysiological role of enteric neurons in food allergies has not been elucidated. We report the presence of functional high-affinity IgE receptors (FcεRIs) in enteric neurons. FcεRI immunoreactivities were observed in approximately 70% of cholinergic myenteric neurons from choline acetyltransferase-eGFP mice. Furthermore, stimulation by IgE-antigen elevated intracellular Ca2+ concentration in isolated myenteric neurons from normal mice, suggesting that FcεRIs are capable of activating myenteric neurons. Additionally, the morphological investigation revealed that the majority of mucosal mast cells were in close proximity to enteric nerve fibers in the colonic mucosa of food allergy mice. Next, using a newly developed coculture system of isolated myenteric neurons and mucosal-type bone-marrow-derived mast cells (mBMMCs) with a calcium imaging system, we demonstrated that the stimulation of isolated myenteric neurons by veratridine caused the activation of mBMMCs, which was suppressed by the adenosine A3 receptor antagonist MRE 3008F20. Moreover, the expression of the adenosine A3 receptor gene was detected in mBMMCs. Therefore, in conclusion, it is suggested that, through interaction with mucosal mast cells, IgE-antigen-activated myenteric neurons play a pathological role in further exacerbating the pathology of food allergy.

Suppression of plasmacytoid dendritic cell migration to colonic isolated lymphoid follicles abrogates the development of colitis.

BACKGROUND: Dendritic cells (DCs) play a pivotal role in maintaining immunological homeostasis by orchestrating innate and adaptive immune responses via migration to inflamed sites and the lymph nodes (LNs). Plasmacytoid DCs (pDCs) have been reported to accumulate in the colon of inflammatory bowel disease (IBD) patients and dextran sulfate sodium (DSS)-induced colitis mice. However, the role of pDCs in the progression of colonic inflammation remains unclear. METHODS: 80 compounds in natural medicines were searched for inhibitors of pDC migration using bone marrow-derived pDCs (BMpDCs) and conventional DCs (BMcDCs). BALB/c mice were given 3% DSS in the drinking water to induce acute colitis. Compounds, which specifically inhibited pDC migration, were administrated into DSS-induced colitis mice. FINDINGS: Astragaloside IV (As-IV) and oxymatrine (Oxy) suppressed BMpDC migration but not BMcDC migration. In DSS-induced colitis mice, the number of pDCs was markedly increased in the colonic lamina propria (LP), and the expression of CCL21 was obviously observed in colonic isolated lymphoid follicles (ILFs). As-IV and Oxy reduced symptoms of colitis and the accumulation of pDCs in colonic ILFs but not in the colonic LP. Moreover, in a BMpDC adoptive transfer model, BMpDC migration to colonic ILFs was significantly decreased by treatment with As-IV or Oxy. INTERPRETATION: pDCs accumulated in the colon of colitis mice, and As-IV and Oxy ameliorated colitis by suppressing pDC migration to colonic ILFs. Accordingly, the selective inhibition of pDC migration may be a potential therapeutic approach for treating colonic inflammatory diseases.

Corrigendum to "Suppression of Dynamical Network Biomarker Signals at the Predisease State (Mibyou) before Metabolic Syndrome in Mice by a Traditional Japanese Medicine (Kampo Formula) Bofutsushosan".

[This corrects the article DOI: 10.1155/2020/9129134.].

Prevalence of umbilical artery Doppler waveform abnormality during the early second trimester and the subsequent variation of waveforms in monochorionic diamniotic twin pregnancies: A prospective cohort study.

AIM: To investigate the prevalence of qualitative abnormal umbilical artery Doppler waveforms (Abnormal UA) during the early second trimester and the subsequent variation of waveforms in monochorionic diamniotic (MCDA) twin pregnancies. METHODS: This prospective cohort study included 153 MCDA twin pregnancies. Pulsed Doppler examinations for UA were performed at four points, including the free-loop (FL) and near the placental cord insertion site (CI) of each UA, between 16 and 17 weeks' gestation. Cases were classified into positive diastolic waveforms (Type I), persistent Abnormal UA (Type II), and intermittent Abnormal UA (Type III). When the diastolic velocity in UA Doppler was positive twice after different sequential recordings, the cases were determined to have achieved normalization. Follow-up Doppler examinations of the UA were performed at 24, 28, and 32 weeks' gestation. RESULTS: Of all 153 cases, 38 (25%; 19 Type II and 19 Type III cases) showed Abnormal UA at the first examination. Abnormal UA was detectable at FL in all selective intrauterine growth restriction (sIUGR) cases, whereas it was noted only at CI site in some non-sIUGR cases. Abnormal UA normalized in 12 (63%) Type II and 15 (79%) Type III cases. CONCLUSIONS: A quarter of MCDA twin pregnancies in the early second trimester demonstrated Abnormal UA. In MCDA twins with Abnormal UA between 16 and 17 weeks' gestation, it is preferable to follow them up to consider the possibility of normalization of Abnormal UA as well as features of UA waveforms specific to FL and CI.

Influence of preoperative light vaginal bleeding for perinatal adverse outcomes on physical examination-indicated cerclage.

PURPOSE: To clarify the relationship between light vaginal bleeding (LVB) before physical examination-indicated cerclage (PEIC) and perinatal adverse outcomes. METHODS: This was a retrospective cohort study involving 94 singleton pregnancies undergoing PEIC <26 weeks of gestation at a single perinatal medical center between 2008 and 2015. The primary outcome was set as spontaneous preterm birth (sPTB) <34 weeks of gestation. The secondary outcomes were set as the second-trimester loss prior to 22 weeks of gestation, sPTB before 28 weeks of gestation, sPTB before 37 weeks of gestation, and stillbirth or neonatal death. Relationships between LVB and adverse outcomes were evaluated using logistic regression analysis. RESULTS: Preoperative LVB was detected in 16 cases (17.0%). Multivariate logistic regression analyses revealed that preoperative LVB was an independent risk factor for sPTB <34 weeks of gestation (adjusted odds ratio [aOR]: 8.42; 95% confidence interval [CI]: 1.72-41.1; p < .01), sPTB <28 weeks of gestation (aOR: 5.98; 95% CI: 1.67-21.4; p < .01) and perinatal death (aOR: 8.47; 95% CI: 1.11-64.5; p = .04). CONCLUSIONS: Vaginal bleeding prior to PEIC, even nonsignificant or self-limiting, is associated with sPTB before 28 or 34 weeks of gestation and perinatal death.

Prevalence of Extraplacental Anastomoses in Monochorionic Twin Pregnancies.

OBJECTIVES: To evaluate the prevalence of extraplacental anastomoses (EPA) and the factors associated. METHODS: A retrospective study including 144 placentas from monochorionic diamniotic (MCDA) twins delivering at one institution was performed. EPA were defined as any intertwin anastomosis located outside the chorionic plate on macroscopic inspection. The association with perinatal factors and with umbilical cord insertion site was analyzed. RESULTS: The prevalence of EPA was 4.9% (7/144). Velamentous cord insertion of both twins was significantly associated with the presence of EPA in the multivariate logistic regression model (p = 0.045). DISCUSSION: EPA was found in ≈5% of MCDA twin pregnancies.

Morphological elucidation of short-chain fatty acid receptor GPR41-positive enteric sensory neurons in the colon of mice with dextran sulfate sodium-induced colitis.

Although the etiology of inflammatory bowel disease (IBD) remains unclear, it has generally been accepted that abnormalities in the intestinal immune system and dysbiosis of the gut microbiota are involved in the pathology of IBD. Recently, short-chain fatty acids (SCFAs) produced by gut microbiota were reported to maintain intestinal homeostasis through their receptors, such as GPR41. However, there are contradictory reports about the role of GPR41 in intestinal inflammation. Consequently, the roles of GPR41 in dysbiosis induced by intestinal inflammation remain unclear. Thus, we investigated the distribution of GPR41 in the colonic mucosa of mice with dextran sulfate sodium (DSS)-induced colitis. GPR41-immunoreactive fibrous structures were observed in the colonic lamina propria and muscularis layer of normal mice. In addition, GPR41-immunoreactive fibrous structures partly colocalized with calcitonin gene-related peptide (CGRP; a neurotransmitter of cholinergic enteric sensory neurons)-immunoreactive nerve fibers in the colonic lamina propria, indicating that GPR41 is expressed in cholinergic intrinsic sensory neurons. Furthermore, both GPR41-immunoreactivities and CGRP-immunoreactivities were significantly increased in the lamina propria of the colon in mice with DSS-induced colitis. Interestingly, GPR41-immunoreactivities were often found in close proximity to F4/80+ macrophages in the colonic mucosa of normal mice, and their frequency was elevated in the colonic mucosa of mice with DSS-induced colitis. Therefore, the crosstalk between SCFA-sensing intrinsic sensory neurons and macrophages might be involved in the pathology of acute colitis.

Isoflavones Suppress Cyp26b1 Expression in the Murine Colonic Lamina Propria.

Isoflavones have many biological activities and are major bioactive components of kakkonto, a traditional Japanese herbal medicine. We previously reported that the combined therapy of oral immune therapy (OIT) and kakkonto downregulates the mRNA expression of Cyp26b1, a major retinoic acid (RA)-degrading enzyme, in the colon of food allergy mice and thereby ameliorates allergic symptoms. In this study, we evaluated the effects of various isoflavones on Cyp26b1 expression in primary cultured lamina propria (LP) cells isolated from the mouse colon. The mRNA expression of Cyp26b1 was extremely downregulated by all isoflavones tested in the LP cells except for puerarin. In particular, genistein and genistin markedly suppressed Cyp26b1 mRNA expression without affecting RA-synthesizing enzyme expression. Moreover, to evaluate the effects of isoflavones on allergic reactions, genistein and genistin were administered to ovalbumin (OVA)-induced food allergy mice. Oral administration of genistin suppressed the development of allergic symptoms. These results raise the possibility that isoflavones elevated the level of RA in the colon by inhibiting RA degradation and then the high concentration of RA in the colon might exert immunosuppressive and antiallergic effects on food allergy mice.

Interleukin-4 Receptor α Subunit Deficiency Alleviates Murine Intestinal Inflammation In Vivo Through the Enhancement of Intestinal Mucosal Barrier Function.

Disturbance of epithelial barrier function causes chronic intestinal inflammation such as inflammatory bowel disease. Several studies have reported that Th2 cytokines such as interleukin (IL)-4 and IL-13 play an important role in the regulation of intestinal barrier function. However, the precise role of the IL-4 receptor α subunit (IL-4Rα) in intestinal inflammation remains unclear. Thus, we used an experimental colitis model to investigate the role of IL-4Rα in intestinal inflammation. IL-4Rα-deficient (IL-4Rα-/-) mice and their littermate wild-type (WT) mice were used. Experimental colitis was induced by administration of 3% dextran sulfate sodium (DSS) in the drinking water for seven days. Treatment with DSS caused body weight loss, an increase in the disease activity index and histological abnormalities in WT colitis mice, all of which were significantly attenuated in IL-4Rα-/- colitis mice. Neutrophil infiltration in the colonic mucosa was reduced in IL-4Rα-/- colitis mice compared with WT colitis mice. NADPH oxidase 1 expression and reactive oxygen species production were increased in the colons of IL-4Rα-/- mice. Furthermore, elevated intestinal permeability induced by DSS treatment was suppressed in IL-4Rα-/- colitis mice. These results demonstrate that IL-4Rα-/- mice exhibit reduced susceptibility to DSS-induced colitis. Our present findings suggest that IL-4Rα deficiency enhances intestinal mucosal barrier function through the upregulation of NADPH oxidase 1-dependent reactive oxygen species production, thereby suppressing the development of intestinal inflammation.