What is the appropriate cut-off value of CRP to predict endoscopic remission in patients with ulcerative colitis in clinical remission?

PURPOSE: Noninvasive markers for predicting endoscopic remission (ER) in patients with ulcerative colitis (UC) who are in clinical remission (CR) are important for the determination of appropriate treatment modality. C-reactive protein (CRP) is a surrogate marker for assessing disease activity, albeit with a low sensitivity and specificity when the cut-off value is 0.3 or 0.5 mg/dL, which is usually considered normal. The CRP test has been improved, and even fine values within the normal range can be measured. The aim of this study was to determine the appropriate cut-off value of CRP below 0.3 mg/dL for the prediction of ER in UC patients with CR. METHODS: A total of 132 patients who underwent endoscopic evaluation during CR were retrospectively reviewed. Clinical and endoscopic activity was measured using a simple clinical colitis activity index (SCCAI) and Mayo endoscopic subscore (MES). ER was defined as MES 0 or 1. RESULTS: In UC patients in CR, the CRP level was significantly lower in ER (0.05, 0.03-2.57) vs. non-ER (0.14, 0.03-2.81) (p < 0.001). The CRP value predicted ER [area under the curve (AUC = 0.710)] with a sensitivity of 71.4% and a specificity of 71.7% at a cut-off value of 0.09 mg/dL. In contrast, the value of normal CRP (< 0.3 mg/dL) did not show sufficient predictive value (sensitivity, 27.3%; and specificity, 90.9%). CONCLUSIONS: In UC patients in CR, it may be helpful to lower the CRP cut-off value that predict ER other than 0.3 mg/dL, which is usually considered normal.

Atraric Acid Exhibits Anti-Inflammatory Effect in Lipopolysaccharide-Stimulated RAW264.7 Cells and Mouse Models.

Lichens, composite organisms resulting from the symbiotic association between the fungi and algae, produce a variety of secondary metabolites that exhibit pharmacological activities. This study aimed to investigate the anti-inflammatory activities of the secondary metabolite atraric acid produced by Heterodermia hypoleuca. The results confirmed that atraric acid could regulate induced pro-inflammatory cytokine, nitric oxide, prostaglandin E2, induced nitric oxide synthase and cyclooxygenase-2 enzyme expression in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Meanwhile, atraric acid downregulated the expression of phosphorylated IκB, extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NFκB) signaling pathway to exhibit anti-inflammatory effects in LPS-stimulated RAW264.7 cells. Based on these results, the anti-inflammatory effect of atraric acid during LPS-induced endotoxin shock in a mouse model was confirmed. In the atraric acid treated-group, cytokine production was decreased in the peritoneum and serum, and each organ damaged by LPS-stimulation was recovered. These results indicate that atraric acid has an anti-inflammatory effect, which may be the underlying molecular mechanism involved in the inactivation of the ERK/NFκB signaling pathway, demonstrating its potential therapeutic value for treating inflammatory diseases.

Role of Th2 cytokines on the onset of asthma induced by meta-xylene in mice.

meta-Xylene (m-xylene) is one of three isomers of xylene, which is widely used as a solvent and detergent in various industries and medical technology. Exposure to volatile organic compounds, such as m-xylene, causes pulmonary inflammation and airway inflammation, thereby contributing to the onset of asthma. Exposure to m-xylene increases acute wheezing and intensity of asthma symptom. However, the mechanism of the onset of asthma by m-xylene has not been studied yet. C57BL/6 mice were sensitized and challenged by m-xylene at 100 or 300 mg/kg. The mice were then sacrificed after the last challenge. Exposure to m-xylene increased the total number of inflammatory cells and the production of interleukin (IL)-4, IL-5, IL-13, and immunoglobulin E related to the Th2 immune response. In contrast, the production of interferon-γ related to the Th1 immune response was decreased. In addition, the airway resistance increased according to the airway hyper-responsiveness measurements. Finally, a histological analysis revealed infiltration of inflammatory cells, mucus production, and lung fibrosis. These results suggest that m-xylene is a potential risk factor for asthma and the onset of asthma is caused by TH2 cytokines.

Suppression Effect of Astaxanthin on Osteoclast Formation In Vitro and Bone Loss In Vivo.

Osteoporosis is characterized by a reduction of the bone mineral density (BMD) and microarchitectural deterioration of the bone, which lead to bone fragility and susceptibility to fracture. Astaxanthin (AST) has a variety of biological activities, such as a protective effect against asthma or neuroinflammation, antioxidant effect, and decrease of the osteoclast number in the right mandibles in the periodontitis model. Although treatment with AST is known to have an effect on inflammation, no studies on the effect of AST exposure on bone loss have been performed. Thus, in the present study, we examined the antiosteoporotic effect of AST on bone mass in ovariectomized (OVX) mice and its possible mechanism of action. The administration of AST (5, 10 mg/kg) for 6 weeks suppressed the enhancement of serum calcium, inorganic phosphorus, alkaline phosphatase, total cholesterol, and tartrate-resistant acid phosphatase (TRAP) activity. The bone mineral density (BMD) and bone microarchitecture of the trabecular bone in the tibia and femur were recovered by AST exposure. Moreover, in the in vitro experiment, we demonstrated that AST inhibits osteoclast formation through the expression of the nuclear factor of activated T cells (NFAT) c1, dendritic cell-specific transmembrane protein (DC-STAMP), TRAP, and cathepsin K without any cytotoxic effects on bone marrow-derived macrophages (BMMs). Therefore, we suggest that AST may have therapeutic potential for the treatment of postmenopausal osteoporosis.

Protective Effects of 2,3,5,4'-Tetrahydroxystilbene-2-O-ß-d-glucoside on Ovariectomy Induced Osteoporosis Mouse Model.

2,3,5,4'-Tetrahydroxystilbene-2-O-ß-d-glucoside (TSG), an active polyphenolic component of Polygonum multiflorum, exhibits many pharmacological activities including antioxidant, anti-inflammation, and anti-aging effects. A previous study demonstrated that TSG protected MC3T3-E1 cells from hydrogen peroxide (H2O2) induced cell damage and the inhibition of osteoblastic differentiation. However, no studies have investigated the prevention of ovariectomy-induced bone loss in mice. Therefore, we investigated the effects of TSG on bone loss in ovariectomized mice (OVX). Treatment with TSG (1 and 3 µg/g; i.p.) for six weeks positively affected body weight, uterine weight, organ weight, bone length, and weight change because of estrogen deficiency. The levels of the serum biochemical markers of calcium (Ca), inorganic phosphorus (IP), alkaline phosphatase (ALP), and total cholesterol (TCHO) decreased in the TSG-treated mice when compared with the OVX mice. Additionally, the serum bone alkaline phosphatase (BALP) levels in the TSG-treated OVX mice were significantly increased compared with the OVX mice, while the tartrate-resistant acid phosphatase (TRAP) activity was significantly reduced. Furthermore, the OVX mice treated with TSG showed a significantly reduced bone loss compared to the untreated OVX mice upon micro-computed tomography (CT) analysis. Consequently, bone destruction in osteoporotic mice as a result of ovariectomy was inhibited by the administration of TSG. These findings indicate that TSG effectively prevents bone loss in OVX mice; therefore, it can be considered as a potential therapeutic for the treatment of postmenopausal osteoporosis.

The Protective Effects of Astaxanthin on the OVA-Induced Asthma Mice Model.

Although astaxanthin has a variety of biological activities such as anti-oxidant effects, inhibitory effects on skin deterioration and anti-inflammatory effects, its effect on asthma has not been studied. In this paper, the inhibitory effect of astaxanthin on airway inflammation in a mouse model of ovalbumin (OVA)-induced asthma was investigated. We evaluated the number of total cells, Th1/2 mediated inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and airway hyperresponsiveness as well as histological structure. The level of total IgE, IgG1, IgG2a, OVA-specific IgG1, and OVA-specific IgG2a were also examined. The oral administration of 50 mg/mL astaxanthin inhibited the respiratory system resistance, elastance, newtonian resistance, tissue damping, and tissue elastance. Also, astaxanthin suppressed the total cell number, IL-4, and IL-5, and increased the IFN-γ in the BALF. In the sera, total IgE, IgG1, and OVA-specific IgG1 were reduced by astaxanthin exposure and IgG2a and OVA-specific IgG2a were enhanced via oral administration of astaxanthin. Infiltration of inflammatory cells in the lung, production of mucus, lung fibrosis, and expression of caspase-1 or caspase-3 were suppressed in OVA-induced asthmatic animal treated with astaxanthin. These results suggest that astaxanthin may have therapeutic potential for treating asthma via inhibiting Th2-mediated cytokine and enhancing Th1-mediated cytokine.

Histologic Activity and Steroid Use History Are Risk Factors of Clinical Relapse in Ulcerative Colitis With Mayo Endoscopic Subscore of 0 or 1.

BACKGROUND: The treatment goal of ulcerative colitis (UC) has changed from the control of symptoms to mucosal healing, previously evaluated mainly by endoscopy. Recently, the importance of histologic activity has emerged. Therefore, this study aimed to investigate the risk of clinical relapse according to histologic activity in UC with a Mayo endoscopic subsccore (MES) of 0 or 1. METHODS: In a retrospective cohort after our center's biopsy guideline for UC was instituted, 492 UC patients with an MES of 0 or 1 were enrolled and analyzed. The primary outcome was the development of a clinical relapse including changes in medication, hospitalization, colectomy, and the development of colorectal cancer during the follow-up period. RESULTS: During the median 549 days of follow-up, 92 (18.7%) patients had a clinical relapse. All the patients changed their medication, including 4 hospitalized patients. Histologic activity defined by a Geboes score of ≧3.1 (hazard ratio [HR], 1.732; P = .035) and steroid use history (HR, 1.762; P = .008) were independent factors associated with clinical relapse. When stratified, the 1- and 2-year incidence rates of clinical relapse were 4.1% and 10.6%, respectively, for patients with histologic improvement and no steroid use history, whereas the rates were 23.9% and 39.4% for patients with histologic activity and steroid use history. CONCLUSIONS: In UC with an MES of 0 or 1, histologic activity and steroid use history can be used to stratify the risk of clinical relapse.

Histologic activity defined by Geboes score of ≥3.1 and steroid use history are independent risk factors associated with clinical relapse in UC patients with Mayo endoscopic subscore of 0 or 1.

Deep learning model for distinguishing Mayo endoscopic subscore 0 and 1 in patients with ulcerative colitis.

The aim of this study was to address the issue of differentiating between Mayo endoscopic subscore (MES) 0 and MES 1 using a deep learning model. A dataset of 492 ulcerative colitis (UC) patients who demonstrated MES improvement between January 2018 and December 2019 at Samsung Medical Center was utilized. Specifically, two representative images of the colon and rectum were selected from each patient, resulting in a total of 984 images for analysis. The deep learning model utilized in this study consisted of a convolutional neural network (CNN)-based encoder, with two auxiliary classifiers for the colon and rectum, as well as a final MES classifier that combined image features from both inputs. In the internal test, the model achieved an F1-score of 0.92, surpassing the performance of seven novice classifiers by an average margin of 0.11, and outperforming their consensus by 0.02. The area under the receiver operating characteristic curve (AUROC) was calculated to be 0.97 when considering MES 1 as positive, with an area under the precision-recall curve (AUPRC) of 0.98. In the external test using the Hyperkvasir dataset, the model achieved an F1-score of 0.89, AUROC of 0.86, and AUPRC of 0.97. The results demonstrate that the proposed CNN-based model, which integrates image features from both the colon and rectum, exhibits superior performance in accurately discriminating between MES 0 and MES 1 in patients with UC.

Age and fibrosis index for the prediction of hepatocellular carcinoma risk in patients with high hepatitis B virus DNA but normal alanine aminotransferase.

AIM: Chronic hepatitis B patients positive for hepatitis B e antigen (HBeAg) with high serum hepatitis B virus (HBV) DNA levels but normal alanine aminotransferase (ALT) levels may develop hepatocellular carcinoma (HCC). However, ways to risk stratify are limited. METHODS: A retrospective cohort of 651 HBeAg positive, adult patients with high serum HBV DNA levels (>7 log IU/ml) but normal or mildly elevated ALT levels (<80 U/L) were analyzed. RESULTS: Age and FIB-4 index were independent factors associated with HCC development. When stratified, 5- and 10-year cumulative HCC incidence rates were 0 and 2.0% for patients aged <40 years with FIB-4 index <1.45, and were 5.9 and 32.7% for patients aged ≥40 years with FIB-4 index ≥1.45, respectively (P < 0.001). In patients with normal ALT levels (n = 301), the 10-year HCC incidence rate was 0% for patients aged <40 years with FIB-4 index <1.45, while 5- and 10-years HCC incidence rate was 4.5 and 27.1% for patients aged ≥40 years with FIB-4 index ≥1.45, respectively (P < 0.001). CONCLUSION: In patients with high HBV DNA but normal ALT levels, age and FIB-4 index could effectively stratify HCC risk, indicating that these parameters may guide management plans for this population.

Effect of Heat-killed Lactobacillus casei DKGF7 on a Rat Model of Irritable Bowel Syndrome.

Non-viable bacteria, referred to as "paraprobiotics," have attracted attention as potentially safer alternatives to probiotics. The aim of this study was to investigate the efficacy of heat-killed Lactobacillus casei DKGF7 on the symptomatic improvement of irritable bowel syndrome (IBS) in a rat disease model and to elucidate the underlying mechanisms that contribute to the beneficial effects of heat-killed probiotics. Seven male Wistar rats were induced with IBS by restraint stress and administered heat-killed L. casei DKGF7 for four weeks and then compared with seven rats in the control group. Stool consistency measured four weeks after initial treatment was the primary outcome measure. To investigate the mechanism of action of the heat-killed bacteria on IBS, we measured serum corticosterone levels, inflammatory cytokines in colon tissue, and expression of tight junction proteins (TJPs) in the epithelium. The treatment group showed significantly better stool consistency scores than the control group at week 4, as well as at every measured time point (all p values < 0.05). The treatment group showed lower serum corticosterone levels, lower colonic inflammatory cytokine levels, and higher expression of TJPs compared with the control group. Paraprobiotics such as heat-killed L. casei DKGF7 can improve stool consistency in a rat IBS model, which may indicate a potential therapeutic strategy for IBS treatment.

Changes in the Intestinal Microbiota of Patients with Inflammatory Bowel Disease with Clinical Remission during an 8-Week Infliximab Infusion Cycle.

This study investigated changes in the intestinal microbiota during 8-week infliximab maintenance therapy in inflammatory bowel disease (IBD) patients in clinical remission. Microbial compositional differences were analyzed according to the trough level of infliximab (TLI) and mucosal healing (MH) status. 16S rRNA gene-based microbiome profiling was performed on 10 and 74 fecal samples from 10 healthy volunteers and 40 adult IBD patients, respectively. Fecal sampling occurred at 1-2 weeks (1W) and 7-8 weeks (7W) after infliximab infusion. TLI was measured by ELISA at 8 weeks, immediately before the subsequent infusion; MH was evaluated by endoscopy within 3 months. There were no significant changes in microbial composition, species richness, or diversity indices between 1W and 7W. However, 7W samples from the patients with TLI ≥ 5 µg/mL showed an increased species richness compared with patients with TLI < 5 µg/mL, and patients with MH showed increased diversity compared with non-MH patients. Beta-diversity analysis showed clustering between samples in the MH and non-MH groups. LEfSe analysis identified differential composition of Faecalibacterium prausnitzii group according to TLI and MH. In conclusion, these results suggest the potential of fecal microbiota as a response indicator.

Effect of a Synbiotic Containing Lactobacillus paracasei and Opuntia humifusa on a Murine Model of Irritable Bowel Syndrome.

The administration of a combination of probiotics and prebiotics is expected to be a promising strategy for improving irritable bowel syndrome (IBS) symptoms. This study aimed to investigate the efficacy of a synbiotic containing Lactobacillus paracasei and Opuntia humifusa extract for symptomatic improvement of IBS in a murine model and to evaluate the mechanism underlying the beneficial effects of this synbiotic. A total of 20 male Wistar rats aged 8 weeks with IBS induced by restraint stress were assigned into four groups and administered L. paracasei as a probiotic and O. humifusa extract as a prebiotic for 4 weeks. The primary outcome was stool consistency at week 4. To evaluate the mechanism underlying the beneficial effects of the synbiotic, fecal microbial analysis was conducted, and the serum corticosterone levels, tumor necrosis factor-α (TNF-α) levels in the colon tissue, and expression of tight junction proteins were investigated. All three treatment groups showed significantly lower scores for stool consistency than the control group at week 4 (all p < 0.001). When compared with the control group, the synbiotic groups showed a significantly greater abundance of L. paracasei in fecal microbial analysis, lower serum corticosterone levels, lower TNF-α levels in the colon tissue, and higher expression of tight junction proteins. This novel synbiotic containing L. paracasei and O. humifusa extract can improve the stool consistency in a murine model of IBS. It may be a promising treatment option for IBS, and human studies are warranted.

Verification of the Functional Antioxidant Activity and Antimelanogenic Properties of Extracts of Poria cocos Mycelium Fermented with Freeze-Dried Plum Powder.

Here we examine the effects of extracts of Poria cocos mycelium fermented with freeze-dried plum powder (PPE) on the α-melanocyte stimulating hormone (α-MSH)-stimulated melanogenesis in cultured murine B16 melanoma cells (B16 cells), relative to the effects of Prunus extract. We found that an extract of Prunus fermentation showed significant inhibition of melanogenesis and tyrosinase activity with no effect on cell proliferation and was more active compared to Prunus extract alone. Furthermore, we confirmed that medium containing 3% Prunus was the optimal culture substrate for fermentation with Poria cocos. These results provide evidence that Prunus fermentation extract affects skin whiting in murine B16 melanoma cells (B16 cells). Prunus contains rutin, oxalic acid, succinic acid, and fumaric acid, which help in digestion and fatigue recovery. The rutin of Prunus mume is reported to have antioxidant and anti-inflammatory effects. Also, Prunus extract has a tyrosinase inhibitory activity for skin whiting through its antioxidant activity. Therefore, we believe the Prunus extract for Poria cocos fermentation can be provided as a potential mediator to induce skin whiting.