Background
Indigo Naturalis (IN) is used as a traditional herbal medicine for ulcerative colitis (UC). However, the mechanisms of action of IN have not been clarified. We aimed to evaluate the ...efficacy of IN for ameliorating colonic inflammation. We further investigated the mechanisms of action of IN.
Methods
Colitis severity was assessed in dextran sodium sulfate-induced colitis and trinitrobenzene sulfonic acid-induced colitis models with or without the oral administration of IN or indigo, which is a known major component of IN. Colonic lamina propria (LP) mononuclear cells isolated from IN-treated mice were analyzed with quantitative reverse transcription polymerase chain reaction (qRT-PCR) and flow cytometry. LP and splenic mononuclear cells cultured in vitro with IN or indigo were also analyzed. The role of the candidate receptor for indigo, the aryl hydrocarbon receptor (AhR), was analyzed using
Ahr
-deficient mice.
Results
Colitis severity was significantly ameliorated in the IN and indigo treatment groups compared with the control group. The mRNA expression levels of interleukin (
Il
)-
10
and
Il-22
in the LP lymphocytes were increased by IN treatment. The treatment of splenocytes with IN or indigo increased the expression of anti-inflammatory cytokines and resulted in the expansion of IL-10-producing CD4
+
T cells and IL-22-producing CD3
−
RORγt
+
cells, but not CD4
+
Foxp3
+
regulatory T cells. The amelioration of colitis by IN or indigo was abrogated in
Ahr
-deficient mice, in association with diminished regulatory cytokine production.
Conclusions
IN and indigo ameliorated murine colitis through AhR signaling activation, suggesting that AhR could be a promising therapeutic target for UC.
This experimental study aimed to assess the efficacy of hydrogen gas inhalation against spinal cord ischemia–reperfusion injury and reveal its mechanism by measuring glutamate concentration in the ...ventral horn using an in vivo microdialysis method.
Male Sprague-Dawley rats were divided into the following 6 groups: sham, only spinal ischemia, 3% hydrogen gas (spinal ischemia + 3% hydrogen gas), 2% hydrogen gas (spinal ischemia + 2% hydrogen gas), 1% hydrogen gas (spinal ischemia + 1% hydrogen gas), and hydrogen gas dihydrokainate (spinal ischemia + dihydrokainate selective inhibitor of glutamate transporter-1 + 3% hydrogen gas). Hydrogen gas inhalation was initiated 10 minutes before the ischemia. For the hydrogen gas dihydrokainate group, glutamate transporter-1 inhibitor was administered 20 minutes before the ischemia. Immunofluorescence was performed to assess the expression of glutamate transporter-1 in the ventral horn.
The increase in extracellular glutamate induced by spinal ischemia was significantly suppressed by 3% hydrogen gas inhalation (P < .05). This effect was produced in increasing order: 1%, 2%, and 3%. Conversely, the preadministration of glutamate transporter-1 inhibitor diminished the suppression of spinal ischemia-induced glutamate increase observed during the inhalation of 3% hydrogen gas. Immunofluorescence indicated the expression of glutamate transporter-1 in the spinal ischemia group was significantly decreased compared with the sham group, which was attenuated by 3% hydrogen gas inhalation (P < .05).
Our study demonstrated hydrogen gas inhalation exhibits a protective and concentration-dependent effect against spinal ischemic injury, and glutamate transporter-1 has an important role in the protective effects against spinal cord injury.
H2 inhalation was initiated 10 minutes before the ischemia, and SCI was performed by clamping the descending aorta. The increase in extracellular glutamate induced by spinal ischemia was significantly suppressed by 3% H2 inhalation, whereas the preadministration of glutamate transporter-1 inhibitor diminished the suppression of spinal ischemia-induced glutamate increase observed during the inhalation of 3% H2. Immunofluorescence indicated the expression of glutamate transporter-1 in the SCI group was significantly decreased compared with the sham group, which was attenuated by 3% H2 inhalation (P < .05). Our study demonstrated H2 inhalation exhibits a protective and concentration-dependent effect against spinal ischemic injury, and glutamate transporter-1 has an important role in the protective effects against spinal cord injury. Display omitted
We aimed to investigate the protective effect of remote ischemic preconditioning against spinal cord ischemia and find a clue to its mechanism by measuring glutamate concentrations in the spinal ...ventral horn.
Male Sprague-Dawley rats were divided into 5 groups (n = 6 in each group) as follows: sham; SCI (only spinal cord ischemia); RIPC/SCI (perform remote ischemic preconditioning before spinal cord ischemia); MK-801/RIPC/SCI (administer MK-801, N-methyl-D-aspartate receptor antagonist, before remote ischemic preconditioning); and MK-801/SCI (administer MK-801 without remote ischemic preconditioning). Remote ischemic preconditioning was achieved by brief limb ischemia 80 minutes before spinal cord ischemia. MK-801 (1 mg/kg, intravenous) was administered 60 minutes before remote ischemic preconditioning. The glutamate concentration in the ventral horn was measured by microdialysis for 130 minutes after spinal cord ischemia. Immunofluorescence was also performed to evaluate the expression of N-methyl-D-aspartate receptor 2B subunit in the ventral horn 130 minutes after spinal cord ischemia.
The glutamate concentrations in the spinal cord ischemia group were significantly higher than in the sham group at all time points (P < .01). Remote ischemic preconditioning attenuated the spinal cord ischemia–induced glutamate increase. When MK-801 was preadministered before remote ischemic preconditioning, glutamate concentration was increased after spinal cord ischemia (P < .01). Immunofluorescence showed that remote ischemic preconditioning prevented the increase in the expression of N-methyl-D-aspartate receptor 2B subunit on the surface of motor neurons (P = .047).
Our results showed that remote ischemic preconditioning prevented spinal cord ischemia–induced extracellular glutamate increase in ventral horn and suppressed N-methyl-D-aspartate receptor 2B subunit expression.
Display omitted
Psychologic stress can affect the pathogenesis of inflammatory bowel disease (IBD), but the precise contribution of psychologic stress to IBD remains unclear. We investigated the association of ...psychologic stress with disease activity in patients with IBD, especially in terms of mental state and sleep condition.
This was a multi-center observational study comprising 20 institutions. Data were collected using survey forms for doctors and questionnaires for patients, and the association of psychologic stress with clinical parameters was investigated. Mental state was evaluated using the Center for Epidemiologic Studies Depression (CES-D) scale, and sleep condition was evaluated by querying patients about the severity of insomnia symptoms.
A total of 1078 IBD patients were enrolled, including 303 patients with Crohn's disease and 775 patients with ulcerative colitis. Seventy-five percent of IBD patients believed that psychologic stress triggered an exacerbation of their disease (PSTE group) and 25% did not (non-PSTE group). The CES-D scores were significantly higher for patients with clinically active disease than for those in remission in the PSTE group (median (interquartile range) = 7 (4-9.5) vs. 5 (3-7), p < .0001), but not in the non-PSTE group (5 (2-8) vs. 4 (3-7), p = 0.78). Female sex and disease exacerbation by factors other than psychologic stress were independent factors of psychologic stress-triggered disease exacerbation. Also, patients with insomnia had higher disease activity than those without insomnia, especially in the PSTE group.
A worsened mental state correlates with disease activity in IBD patients, especially those who believe that their disease is exacerbated by psychologic stress.
To assess the effect of systemic vascular resistance (SVR) on the reliability of the ClearSight system (Edwards Lifesciences, Irvine, CA) for measuring blood pressure (BP) and cardiac output (CO).
...Observational study.
University hospital.
Twenty-five patients undergoing cardiac surgery.
None.
BP, measured using ClearSight and an arterial line, and CO, measured using ClearSight and a pulmonary artery catheter, were recorded before (T1) and two minutes after phenylephrine or ephedrine administration. Bland-Altman analysis was used to compare BP and CO measurements at T1. A polar plot was used to assess trending abilities. Patients were divided into the following three groups according to the SVR index (SVRI) at T1: low (<1,200 dyne s/cm5/m2), normal (1,200-25,00 dyne s/cm5/m2), and high (>2,500 dyne s/cm5/m2). The bias in BP and CO was –4.8 ± 8.9 mmHg and 0.10 ± 0.81 L/min, respectively, which was correlated significantly with SVRI (p < 0.05). The percentage error in CO was 40.6%, which was lower in the normal SVRI group (33.3%) than the low and high groups (46.3% and 47.7%, respectively). The angular concordance rate was 96.3% and 95.4% for BP and 87.0% and 92.5% for CO after phenylephrine and ephedrine administration, respectively. There was a low tracking ability for CO changes after phenylephrine administration in the low-SVRI group (angular concordance rate 33.3%).
The ClearSight system showed an acceptable accuracy in measuring BP and tracking BP changes in various SVR states; however, the accuracy of CO measurement and its trending ability in various SVR states was poor.
Background
This study investigated the ability of stroke volume variation (SVV) during deep breathing to discriminate fluid responders among spontaneously breathing patients.
Methods
Thirty patients ...undergoing general anaesthesia were enrolled and assessed before anaesthetic induction. Haemodynamic variables, including stroke volume (SV) and SVV, were measured using the ClearSight system during normal breathing. After these measurements, each patient was required to maintain deep breathing (6 breaths min−1) and haemodynamic variables were recorded. Then, the table was adjusted to the Trendelenburg position (15°) for 2 minutes, and haemodynamic variables were measured. Receiver operating characteristic curves were created for SVV during normal and deep breathing, and the difference in SVV between normal and deep breathing (ΔSVV) to discriminate fluid responders (SV increase >10% after changing position). The correlation between SV increase and ΔSVV was examined using Pearson's correlation coefficient. The grey zone approach was used to assess the inconclusive range of the haemodynamic variables.
Results
Receiver operating characteristic curve analysis indicated that ΔSVV showed good reliability in predicting fluid responsiveness (AUC: 0.850; 95% CI: 0.672‐0.953; threshold: 4%, sensitivity: 75.0%, specificity: 88.9%, while SVV during normal breathing did not (AUC: 0.579; 95% CI: 0.386‐0.756). Although SVV during deep breathing exhibited acceptable predictability (AUC: 0.778; 95% CI: 0.589‐0.908), the sensitivity was not good (58.3%). With the grey zone approach, the inconclusive range of ΔSVV was small with the range of 1.4%‐4.2% (23% of patients).
Conclusion
Deep breathing could improve the reliability of dynamic indices in spontaneously breathing patients.
Trial registration
UMIN‐CTR, identifer: UMIN000027970. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000032040
Despite the indication that the hypothalamo-pituitary-adrenal (HPA) axis is activated during treadmill running, there have not been any studies focusing on the relationship between exercise intensity ...and region-specific neural activities in hypothalamus. To address this, rats were subjected to 30
min of running, either at middle (supra-LT, 25
m
min
−1) or low speeds (sub-LT, 15
m
min
−1), and c-Fos-(+) cells were counted and compared with control rats. Significant increases in blood glucose and lactate levels, and plasma ACTH and osmolality levels were observed during supra-LT running. Only supra-LT running significantly increased c-Fos induction in various hypothalamic regions, namely, the medial preoptic area (MPO), periventricular nucleus (Pe), suprachiasmatic nucleus (SCN), supraoptic nucleus (SON), parvocellular division of the paraventricular nucleus (pPVN), anterior hypothalamic area (AH), arcuate nucleus (ARC) and posterior hypothalamic nucleus (PH). However, sub-LT caused no effect on c-Fos accumulation. This indicates that the hypothalamus responds uniquely to running in a threshold-like pattern distinct from the speed-dependent pattern previously reported for the medulla oblongata
Ohiwa et al., 2006a,b. In addition, these results showed a physiologic basis for mild exercise useful for establishing our minimum running stress (MRS) rat model, or the running conditions that minimize the activation of the HPA axis.
The present study aimed to evaluate the reliability of hemodynamic changes induced by lung recruitment maneuver (LRM) in predicting stroke volume (SV) increase after fluid loading (FL) in prone ...position.
Thirty patients undergoing spine surgery in prone position were enrolled. Lung-protective ventilation (tidal volume, 6-7 mL/kg; positive end-expiratory pressure, 5 cmH
O) was provided to all patients. LRM (30 cmH
O for 30 s) was performed. Hemodynamic variables including mean arterial pressure (MAP), heart rate, SV, SV variation (SVV), and pulse pressure variation (PPV) were simultaneously recorded before, during, and at 5 min after LRM and after FL (250 mL in 10 min). Receiver operating characteristic curves were generated to evaluate the predictability of SVV, PPV, and SV decrease by LRM (ΔSV
) for SV responders (SV increase after FL > 10%). The gray zone approach was applied for ΔSV
.
Areas under the curve (AUCs) for ΔSV
, SVV, and PPV to predict SV responders were 0.778 (95% confidence interval: 0.590-0.909), 0.563 (0.371-0.743), and 0.502 (0.315-0.689), respectively. The optimal threshold for ΔSV
was 30% (sensitivity, 92.3%; specificity, 70.6%). With the gray zone approach, the inconclusive values ranged 25 to 75% for ΔSV
(including 50% of enrolled patients).
In prone position, LRM-induced SV decrease predicted SV increase after FL with higher reliability than traditional dynamic indices. On the other hand, considering the relatively large gray zone in this study, future research is needed to further improve the clinical significance.
UMIN Clinical Trial Registry UMIN000027966 . Registered 28th June 2017.
The indigenous bacteria create natural cohabitation niches together with mucosal Abs in the gastrointestinal (GI) tract. Here we report that opportunistic bacteria, largely Alcaligenes species, ...specifically inhabit host Peyer's patches (PPs) and isolated lymphoid follicles, with the associated preferential induction of antigen-specific mucosal IgA Abs in the GI tract. Alcaligenes were identified as the dominant bacteria on the interior of PPs from naïve, specific-pathogen-free but not from germ-free mice. Oral transfer of intratissue uncultured Alcaligenes into germ-free mice resulted in the presence of Alcaligenes inside the PPs of recipients. This result was further supported by the induction of antigen-specific Ab-producing cells in the mucosal (e.g., PPs) but not systemic compartment (e.g., spleen). The preferential presence of Alcaligenes inside PPs and the associated induction of intestinal secretory IgA Abs were also observed in both monkeys and humans. Localized mucosal Ab-mediated symbiotic immune responses were supported by Alcaligenes-stimulated CD11c⁺ dendritic cells (DCs) producing the Ab-enhancing cytokines TGF-β, B-cell-activating factor belonging to the TNF family, and IL-6 in PPs. These CD11c⁺ DCs did not migrate beyond the draining mesenteric lymph nodes. In the absence of antigen-specific mucosal Abs, the presence of Alcaligenes in PPs was greatly diminished. Thus, indigenous opportunistic bacteria uniquely inhabit PPs, leading to PP-DCs-initiated, local antigen-specific Ab production; this may involve the creation of an optimal symbiotic environment on the interior of the PPs.
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