Leucine-rich Alpha-2 Glycoprotein Levels Research Articles

Effects of initial periodontal therapy on leucine-rich alpha-2 glycoprotein levels in saliva from Japanese patients with chronic periodontitis

Examination of patients to detect periodontal disease is important for diagnosis and treatment planning, and accuracy of examination may be improved if salivary components can be applied for diagnosis. Leucine-rich α2 glycoprotein (LRG) is expressed in the serum of patients with inflammatory diseases, and salivary LRG may be applicable to the diagnosis of periodontal disease. To evaluate the effect of initial periodontal therapy (IPT) on clinical periodontal parameters such as probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), periodontal inflamed surface area (PISA), periodontal epithelial surface area (PESA), saliva samples were collected before and after IPT from 63 patients with chronic periodontitis. The amount of LRG protein in saliva was measured by enzyme-linked immunosorbent assay. Salivary LRG levels of 30 patients with Stage III, Grade B or C periodontitis (Severe group) were higher than the LRG levels of 33 patients with Stage Ⅰ or Ⅱ, Grade A periodontitis (Mild group). LRG levels in the Severe group significantly decreased after IPT. Positive correlations were found between salivary LRG levels and mean PD, CAL, BOP rate, PISA and PESA. These results suggest that there is an association between salivary LRG levels and severity of periodontitis.

Clinical Profiles of Leucine-Rich Alpha-2 Glycoprotein for Indicating Mucosal Healing in Ulcerative Colitis Patients under Administration of Molecular-Targeted Drug

Introduction: Leucine-rich alpha-2 glycoprotein (LRG) is a useful serum biomarker for monitoring disease activity during remission in ulcerative colitis (UC). Because LRG levels differ among patients, it is necessary to assess them after profiling patients, especially in patients with refractory UC undergoing treatment with molecular-targeted drugs. This study aimed to analyze LRG levels that indicate mucosal healing according to clinical characteristics and molecular-targeted drugs. Methods: Among 214 patients with UC treated with biologics or Janus kinase (JAK) inhibitors, this study evaluated 111 patients (174 measurements) who achieved mucosal healing based on colonoscopy performed within 2 months before and after LRG measurement and experienced no changes in disease status or treatment during the same period. We analyzed the relationship of LRG with clinical characteristics (including sex, age, body mass index, and disease type and duration) and molecular-targeted drugs. Results: Compared with men, women had significantly higher LRG levels (9.5 μg/mL vs. 11.3 μg/mL, p < 0.001). In addition, LRG levels were significantly higher in older patients (12.0 μg/mL vs. 9.8 μg/mL, p < 0.01). LRG levels were the highest in patients treated with vedolizumab and lower in patients treated with JAK inhibitors (vedolizumab: 12.7 μg/mL; tofacitinib: 8.9 μg/mL; upadacitinib: 8.5 μg/mL; and filgotinib: 9.1 μg/mL; p < 0.0001). Conclusion: Among the patients who achieved mucosal healing, LRG levels were significantly higher in women and older patients. LRG levels differed according to the molecular-targeted drug used and were higher with vedolizumab and lower with JAK inhibitors.

USEFULLNESS OF SERUM LEUCINE-RICH ALPHA2-GLYCOPROTEIN AND FECAL CALPROTECTIN ASSURROGATE MARKERS IN ULCERATIVE COLITIS

Abstract BACKGROUND AND AIM Serum Leucine-rich alpha-2 glycoprotein (LRG) was identified as a novel biomarker for rheumatoid arthritis and IBD by using a proteomics approach. Several studies have suggested that serum LRG levels and fecal calprotectin (fCal) were correlated with clinical activities in patients with ulcerative colitis (UC). We compared utility of these biomarkers for monitoring disease activity in UC. METHODS A single-center observational study was conducted at Kyushu University Hospital. A total of 101 patients who underwent colonoscopy during the period from February to December 2021 were enrolled. The associations between endoscopic and histological activity and biomarkers were investigated. Endoscopic activity was defined as Mayo endoscopic score (MES) of 1 or less for mucosal healing and 0 for complete mucosal healing. For histological activity (n=90), Geboes score of 2 or less was defined as histological remission. RESULTS Subjects ranged in age from 16 to 80 years (35 males and 66 females). There were 63 cases of total colitistype, 32 cases of left-sided colitis type, and 6 cases of proctitis type. The MES at enrollment were as follows: MES 0 in 41 cases, MES 1 in 33 cases, MES 2 in 19 cases, and MES 3 in 8 cases. In comparison between the mucosal healing and non-mucosal healing groups, LRG was significantly lower in the mucosal healing group (p&amp;lt;0.0001). The correlation coefficient of LRG with MES was r=0.614 (p&amp;lt;0.0001), which was higher than that of fCal, r=0.414 (p&amp;lt;0.0001). In ROC analysis with mucosal healing as the outcome, the AUC and cut-off value of LRG were 0.781 and 17.9 μg/ml, respectively, and for fCal were 0.850 and 396 μg/g, respectively. In the ROC analysis with complete mucosal healing as the outcome, the AUC for LRG was 0.690, which was lower than the AUC of 0.846 for fCal . When compared by histological remission, LRG was lower in the histological remission group (p&amp;lt;0.001). In the ROC analysis with histological remission as the outcome, the AUC for LRG was 0.722 (cutoff value 14.2 μg/ml) and for fCal was 0.837 (cutoff value 119 μg/g). CONCLUSION Both LRG and fCal are valuable biomarkers reflecting disease activity in UC.

P660 Serum Leucine-rich Alpha-2 Glycoprotein Can be a Biomarker for Selecting Anti-Cytokine Biologics in Patients with Inflammatory Bowel Disease: A Multicentre Prospective Cohort Study

Abstract Background Serum leucine-rich alpha-2 glycoprotein (LRG) is a biomarker reflecting endoscopic activity in patients with inflammatory bowel disease (IBD). However, it remains unclear whether serum LRG can predict the effectiveness of anti-cytokine biologics (biologics) in patients with IBD. This study aimed to evaluate whether serum LRG could predict the effectiveness and serum trough concentrations of biologics in patients with IBD. Methods This was a multicentre prospective cohort study including patients with IBD (including ulcerative colitis [UC] or Crohn’s disease [CD]) who received the biologics [ustekinumab (UST), anti-tumor necrosis factor (anti-TNF)] from January 2019 to March 2023 at 15 hospitals participating in the Osaka Gut Forum. The effectiveness of biologics was evaluated by clinical remission (CR) at week 8. We defined CR as a partial Mayo score of 2 or lower, with each subscore of 0 or 1 for UC and a CD activity index of &amp;lt; 150 for CD. Factors associated with CR at week 8 such as backgrounds, disease activities and concomitant medications at week 0 were analyzed by Cox proportional hazards model. For each biologic, we compared the effectiveness of biologics in the high LRG group with that in the low LRG group divided by the median serum LRG levels at week 0 (cut-off = 18.2 μg/mL). Results A total of 184 patients with IBD (UC, 80; CD, 104) were enrolled (UST/ anti-TNF, 119/ 65; biologic exposure, 31.5%; median disease duration, 6 years [Interquartile range (IQR) 1-14]). Median serum LRG levels at week 0 and serum C-reactive protein levels at week 0 were 18.2 μg/mL [IQR 12.5-28.1] and 0.19 mg/dL [IQR 0.03-0.77], respectively. At week 0, 63 (34.2%) and 64 (34.8%) patients concomitantly received corticosteroids and immunomodulators, respectively. In 184 patients with IBD, multivariate analysis revealed that serum LRG level at week 0 &amp;lt; 18.2 μg/mL was extracted as a significant factor for CR at week 8 (Odds ratio: OR 2.70, 95% confidence interval: CI 1.22-5.96). In patients who received UST, the proportion of CR at week 8 in the low-LRG group (76.9%) was significantly higher than that in the high-LRG group (59.3%, P = 0.038). In patients who received anti-TNF, however, the proportion of CR in the low-LRG group (84.6%) was not differ from that in the high-LRG group (82.1%, P = 0.781). Median serum trough concentrations of UST at week 8 in the low-LRG group (10.9 μg/mL, IQR 6.7-13.4) was significantly higher than that in the high-LRG group (5.3 μg/mL, IQR 2.4-8.3, P &amp;lt; 0.001). Conclusion Serum LRG could predict the effectiveness and serum trough concentrations of UST and be a biomarker for selecting biologics in patients with IBD.

The evaluation of salivary leucine-rich alpha-2 glycoprotein (LRG) and C-reactive protein (CRP) in humans with periodontal health or periodontal disease.

The purpose of the present research is to evaluate the salivary levels of leucine-rich alpha-2 glycoprotein (LRG) and C-reactive protein (CRP) in periodontal health and disease (gingivitis and stage III periodontitis) and also to compare the discriminative efficiencies of both biomarkers in periodontal disease. LRG is a new acute-phase protein whose functions are still being investigated. LRG and CRP are both biomarkers that are increased by inflammation. No clinical study has yet investigated the comparison of the level of LRG and CRP in periodontal health, gingivitis and periodontitis in saliva samples. A total of 60 individuals, including 20 periodontally healthy (control group/group C), 20 with gingivitis (group G), and 20 with Stage III periodontitis (group P), who were systemically healthy and non-smokers, participated in this study. Periodontal charts were used for recording clinical periodontal parameters and saliva LRG and CRP levels were measured by ELISA. Analyzing the area under the curve (AUC) was performed by the receiver-operating characteristics curve. Salivary levels of LRG and CRP were significantly higher in disease groups than in group C (p < .05). Positive statistically significant correlations were observed between both biomarkers and clinical parameters (p < .05). There was also a strong positive correlation between two biomarkers (p < .05). In distinguishing periodontal disease from periodontal health, LRG (AUC = 0.833) and CRP (AUC = 0.826) were found to have similar accuracy (p = .923). LRG and CRP may be useful and similarly effective biomarkers in the diagnosis of periodontal diseases based on the findings of this study.

Biomarkers for Monitoring of Changes in Disease Activity in Ulcerative Colitis.

In recent years, various biomarkers of ulcerative colitis (UC) have emerged; however, few studies have simultaneously examined the utility of multiple biomarkers for monitoring disease activity. Additionally, serum leucine-rich alpha-2 glycoprotein (LRG), a new biomarker, may show a blunt response to anti-TNF antibody therapy. This prospective study explored effective biomarkers that could monitor disease activity changes in patients with UC. In addition, we examined the effect of anti-TNF antibody therapy on changes in LRG. Blood and stool samples were collected twice from patients with UC: at baseline and at least 8 weeks later. Changes in serum LRG, interleukin (IL)-6, prealbumin (pre-Alb), high-sensitivity C-reactive protein (hs-CRP), CRP, and fecal calprotectin (FC) were measured and correlated with changes in disease activity. The relationship between anti-TNF antibody therapy and LRG levels was also examined in patients with the same disease activity. Forty-eight patients with UC (96 samples) were analyzed. ΔLRG and ΔIL-6 correlated strongly with the change in the partial Mayo (pMayo) score between the two time points (ΔpMayo) (r = 0.686, 0.635, respectively). In contrast, FC and IL-6 were particularly accurate predictors of clinical remission, and their area under the curves (AUCs) were significantly higher than that of CRP (AUC: 0.81, 0.76 vs. 0.50; p = 0.001, 0.005). No association was found between the administration of anti-TNF antibody preparations and the LRG values. Correlations were found between changes in UC disease activity and LRG, IL-6, pre-Alb, hs-CRP, CRP, and FC. LRG reflects disease activity during anti-TNF antibody therapy.

Usefulness of Serum Leucine-rich Alpha 2 Glycoprotein in Crohn's Disease: Is There Any Difference between Small Intestine and Colonic Lesions?

The usefulness of leucine-rich alpha 2 glycoprotein (LRG) to evaluate Crohn's disease (CD) activity differs among various intestinal lesions. We aimed to evaluate the association between endoscopic disease activity based on the Simple Endoscopic Score for Crohn's disease (SES-CD) and LRG level separately for small intestinal and colonic lesions. We examined the correlation between LRG level and SES-CD and performed receiver operating characteristic (ROC) analysis to determine the LRG cutoff value in 141 patients who underwent endoscopy (total 235 measurements). Furthermore, the LRG cutoff value was analyzed by comparing small intestinal and colonic lesions. LRG levels were significantly higher in patients without mucosal healing than in those with mucosal healing (15.9 μg/mL vs 10.5 μg/mL, P < .0001). The LRG cutoff value for mucosal healing was 14.3 μg/mL (area under the ROC curve [AUC]: 0.80; sensitivity: 0.89; specificity: 0.63). The LRG cutoff value for patients with type L1 was 14.3 μg/mL (sensitivity: 0.91; specificity: 0.53), and that for patients with type L2 was 14.0 μg/mL (sensitivity: 0.95; specificity: 0.73). The diagnostic performance (AUC) of LRG and C-reactive protein (CRP) for mucosal healing was, respectively, 0.75 and 0.60 (P = 0.01) in patients with type L1 and 0.80 and 0.85 (P = 0.90) in patients with type L2. The optimal LRG cutoff value for evaluating mucosal healing in CD is 14.3 μg/mL. LRG is more useful than CRP for predicting mucosal healing in patients with type L1. The superiority of LRG to CRP differs between small intestinal and colonic lesions.

Novel Utility of Leucine-Rich Alpha-2-Glycoprotein as a Biomarker in Ulcerative Colitis: A Predictor of Endoscopic Remission Independent of Symptoms

Introduction: Leucine-rich alpha-2-glycoprotein (LRG) is a potential biomarker for disease activity and reflects mucosal healing in patients with ulcerative colitis (UC). However, only a few studies have described a detailed sensitivity analysis of LRG in predicting mucosal healing in patients. This study aimed to evaluate the association between LRG and the endoscopic activity of UC and its predictability for mucosal healing and explore the utility and clinical application of LRG. Methods: The diagnostic accuracy of biomarkers, including LRG, in predicting the endoscopic activity of UC was evaluated. All consecutive patients who underwent total colonoscopy between April 2021 and September 2022 were included. The Mayo endoscopic subscore (MES) was used for assessing endoscopic activity. Furthermore, endoscopic remission was defined as an MES of ≤1. Clinical activity was evaluated based on stool frequency and bloody stool. Receiver operating characteristic curve analysis and binary logistic regression were performed to assess the diagnostic accuracy of the biomarkers. We evaluated LRG trends and treatment response in patients with MES ≥2 who underwent induction therapy. Results: This study comprised 214 patients. The proportions of endoscopically and clinically active patients were 33.6% and 49.1%, respectively. LRG had an area under the curve (AUC) of 0.856, with a higher diagnostic accuracy than other biomarkers, such as C-reactive protein, leukocyte, neutrophil, platelet, and albumin. The cutoff value for LRG was 15.6 μg/mL (sensitivity, 72.2%; specificity, 86.6%). Using the MES, patients with higher scores had higher LRG levels than those with lower scores. The cutoff value, AUC, sensitivity, and specificity varied with a higher AUC for left-sided colitis and pancolitis than for proctitis. Logistic regression analysis showed that LRG was an independent predictor of endoscopic remission using multivariate analysis, even with the factor of clinical activity. The change ratio of LRG pre- and post-treatment was statistically significant in the higher LRG group. Conclusion: LRG reflected endoscopic activity independently, regardless of clinical symptoms. An LRG below the cutoff value could indicate a significantly low probability of endoscopic activity in asymptomatic patients, and follow-up endoscopy (not for cancer screening) may be unnecessary. Furthermore, a higher LRG level might be more useful as an indicator of treatment efficacy.

Serum Leucine-Rich α2 Glycoprotein: A Novel Biomarker for Transmural Inflammation in Crohn's Disease.

Leucine-rich alpha-2 glycoprotein (LRG) is a newly studied biomarker for inflammatory diseases. This study aimed to investigate whether LRG can be used for evaluating transmural activity in patients with Crohn's disease (CD). We performed magnetic resonance enterography (MRE) in 227 consecutive patients with CD from June 2020 to August 2021. We prospectively compared MRE findings with clinical and laboratory data including LRG. MRE was evaluated using 2 validated scoring systems, and transmural inflammation was defined as having a maximum simplified magnetic resonance index of activity (sMaRIA) score of ≥4 and a 5-point classification score of ≥9, respectively. The correlation between LRG and the total MRE score showed a positive correlation ( r = 0.576 for the sMaRIA score, P < 0.01, and r = 0.633 for the 5-point score, P < 0.01). Serum concentrations of LRG significantly increased as MRE scores increased ( P < 0.01). The area under the curve of LRG for a sMaRIA score of ≥4 and a 5-point score of ≥9 was 0.845 and 0.869, respectively, which was significantly higher than that of CDAI ( P < 0.01) or C-reactive protein ( P < 0.01). LRG levels of ≥14 μg/mL had a 67% sensitivity and 90% specificity for a sMaRIA score of ≥4 and a 73% sensitivity and 89% specificity for a 5-point score of ≥9. Patients with high LRG levels were also strongly associated with CD-related hospitalization, surgery, and clinical relapse compared with those with low LRG levels ( P < 0.01 for all). LRG is a highly accurate serum biomarker for detecting transmural activity in patients with CD. Results need to be validated in further multicenter studies.

Serum leucine-rich alpha-2 glycoprotein levels in rheumatoid arthritis and spondyloarthritis: A promising biomarker

Background: In the early stages of the disease, some of the signs and symptoms of joint inflammation in rheumatoid arthritis (RA) may resemble that of spondyloarthritis (SpA). An examination that can help distinguish RA and SpA is warranted. One such examination is the measurement of serum leucine-rich alpha-2 glycoprotein (LRG) levels. This study aimed to measure serum LRG levels in RA and SpA patients and determine the role of LRG in the diagnosis of RA and SpA. Methods: This is a cross-sectional study consisting of 26 RA subjects and 26 SpA subjects. The SpA subjects were further grouped into ankylosing spondylitis (AS), psoriatic arthritis (PsA), and peripheral SpA. Measurement of serum LRG levels were conducted using ELISA. Difference between LRG levels of the two groups were compared using the Mann-Whitney test. Results: LRG levels were elevated in 76.9% and 84.6% of subjects with RA and SpA, respectively. The median LRG levels were higher in RA subjects (77.03 (27.16–107.73)) than SpA (68.67 (33.15–115.18)). There was no significant difference in LRG levels in RA and SpA subjects (p = .442). The RA and PsA group were predominated by diseases of moderate activity, 88.5% and 58.3%, respectively. In comparison, AS was dominated by high disease activity (85.7%). The highest median LRG levels in AR and SpA subjects were in new-onset patients (82.21 vs. 72.25 µg/dL). Conclusions: There was no significant difference in LRG levels between RA and SpA subjects. The role of LRG in the diagnosis of RA and SpA remains to be determined in future studies.

Usefulness of the Optimal Cutoff Value and Delta Value of Leucine-Rich Alpha 2 Glycoprotein in Ulcerative Colitis.

Leucine-rich alpha 2 glycoprotein (LRG) is a novel serum biomarker used to determine disease activity in inflammatory bowel disease. We investigated the association between endoscopic scores based on the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and LRG in ulcerative colitis (UC). A total of 1019 LRG measurements were obtained from 358 patients with UC. This study included 190 patients (199 measurements) who underwent colonoscopy within 3 months before and after LRG measurement with unchanged disease status or treatment during the same period. The patients were divided into those with and without UC relapse. We evaluated the correlation between LRG levels and UCEIS scores and performed a receiver operating characteristic curve analysis to determine the optimal LRG cutoff value. Delta values of LRG were then analyzed. LRG levels were positively correlated with UCEIS scores (correlation coefficient: 0.638; 95% CI: 0.548-0.714; P < .0001) in all disease types. The LRG cutoff value for mucosal healing was 12.6 µg mL-1 (area under the curve: 0.736; 95% CI: 0.651-0.821); this value had a sensitivity of 0.72 and a specificity of 0.66. In patients with UC relapse, the median delta value of LRG before and after relapse was 5 µg mL-1. LRG levels were positively correlated with the UCEIS scores. The optimal LRG cutoff value for determining mucosal healing was 12.6 µg mL-1. The median delta value of LRG before and after relapse was 5 µg mL-1.

Serum leucine-rich alpha-2 glycoprotein as a predictive factor of endoscopic remission in Crohn's disease.

The usefulness of fecal calprotectin (FC) and serum leucine-rich alpha-2 glycoprotein (LRG) assessing the activity of Crohn's disease (CD) remains to be fully demonstrated in Asia. The present study aimed to elucidate whether FC and LRG could predict endoscopic remission (ER) in Japanese patients with CD. Between October 2018 and July 2021, we prospectively observed treatment courses of CD patients treated with biologic agents. The optimal cutoff values of Crohn's Disease Activity Index (CDAI), serum C-reactive protein (CRP), serum albumin (Alb), FC, and LRG levels for predicting ER at week 52 were calculated using receiver operating characteristic (ROC) curves. We also analyzed the correlations between the achievement of clinical remission (CR) or biomarker remission (BR) at week 12/24/52 and ER at week 52. Among 53 patients who completed 52weeks of observation, 20 (37.7%) achieved ER at week 52. Using the calculated cutoff values, patients who achieved CR (CDAI≤112) or BR (CRP≤0.42mg/dL, Alb≥3.8g/dL, FC≤287μg/g, or LRG≤13.6μg/mL) at week 12/24/52 had a higher ER rate at week 52. FC-BR at week 12/24 showed low sensitivity (0.58/0.60)but high specificity (0.78/0.74)for predicting ER; LRG-BR at week 12/24 also showed low sensitivity (0.68/0.74) but high specificity (0.87/0.78). However, FC-BR and LRG-BR at week 52 had improved sensitivity (0.80/0.84) while specificity remained (0.79/0.85). From the early phase of biologic treatment, both FC and LRG had high specificity for predicting ER at week 52. LRG showed higher sensitivity than FC.

Leucine-Rich Alpha-2 Glycoprotein in Monitoring Disease Activity and Intestinal Stenosis in Inflammatory Bowel Disease.

Leucine-rich alpha-2 glycoprotein (LRG) is a novel biomarker for monitoring disease activity in inflammatory bowel disease (IBD). The aim of this study was to evaluate its utility in monitoring disease activity. In this retrospective study based on case records between August 2020 and July 2021 at our two centers, we examined the correlation between serum levels of LRG and C-reactive protein (CRP) with disease activity in IBD patients. Background factors related to serum LRG levels were also analyzed. Overall, 47 Crohn's disease (CD) and 123 ulcerative colitis (UC) patients were evaluated. In patients with CD, LRG and CRP levels correlated with Harvey-Bradshaw Index (HBI) and Simple Endoscopic Score for CD (SES-CD) (LRG and HBI, r = 0.397; LRG and SES-CD, r = 0.637; CRP and HBI, r = 0.253; CRP and SES-CD, r = 0.332). In patients with UC, LRG and CRP significantly correlated with the partial Mayo score (PMS) and Mayo endoscopic subscore (MES) (LRG and PMS, r = 0.3; CRP and PMS, r = 0.282; LRG and MES, r = 0.424; CRP and MES, r = 0.459). In CD patients with normal CRP, serum LRG level was significantly higher in those with mucosal inflammation than in those with mucosal healing (16.4 vs. 10.7 μg/ mL). Stenosis was associated with serum LRG levels in CD group using multiple regression analysis. Therefore, LRG is a useful biomarker for monitoring disease activity and mucosal inflammation, and indicates the status of intestinal stenosis in IBD patients.

Evaluation of Serum Leucine-Rich Alpha-2 Glycoprotein as a New Inflammatory Biomarker of Inflammatory Bowel Disease.

Studies on serum leucine-rich alpha-2 glycoprotein (LRG) in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are scarce; the methods for estimating disease activity are less established, particularly for CD. This study is aimed at evaluating the utility of serum LRG as a potential inflammatory marker for IBD and to investigate the LRG gene expression in peripheral blood mononuclear cells (PBMCs) as a possible source of serum LRG. Overall, 98 patients with UC and 96 patients with CD were prospectively enrolled and clinically evaluated; 92 age-matched individuals served as the healthy controls. The blood samples were analyzed for serum LRG levels and routine laboratory parameters. Disease activity was assessed clinically and endoscopically. Finally, LRG gene expression in the PBMCs from a different cohort (41 patients with UC, 34 patients with CD, and 30 healthy controls) was examined. The serum LRG levels were higher during active disease than during inactive disease; additionally, serum LRG levels were positively correlated with clinical disease activity, C-reactive protein (CRP) levels, and other laboratory parameters in patients with UC and CD and with endoscopic disease activity in UC. UC and CD showed comparable areas under the curve (AUC) values for determining clinical remission and differentiating between endoscopic remission associated with LRG and CRP. The levels of LRG mRNA were also increased in PBMCs from patients with UC and CD and reflected disease activity. These data suggest that serum LRG, originated partially from PBMCs, is an inflammatory marker in UC and CD. A large-scale well-designed study should be conducted in the future to more accurately reveal the clinical significance of LRG in patients with IBD.

Evaluation of leucine-rich alpha-2 glycoprotein as a biomarker of fetal infection.

This study aimed to determine the association between umbilical cord leucine-rich alpha-2 glycoprotein (LRG) and fetal infection and investigate the underlying mechanism of LRG elevation in fetuses. We retrospectively reviewed the medical records of patients who delivered at Osaka University Hospital between 2012 and 2017 and selected those with histologically confirmed chorioamnionitis (CAM), which is a common pregnancy complication that may cause neonatal infection. The participants were divided into two groups: CAM with fetal infection (CAM-f[+] group, n = 14) and CAM without fetal infection (CAM-f[−] group, n = 31). Fetal infection was defined by the histological evidence of funisitis. We also selected 50 cases without clinical signs of CAM to serve as the control. LRG concentrations in sera obtained from the umbilical cord were unaffected by gestational age at delivery, neonatal birth weight, nor the presence of noninfectious obstetric complications (all, p > 0.05). Meanwhile, the LRG levels (median, Interquartile range [IQR]) were significantly higher in the CAM-f(+) group (10.37 [5.21–13.7] μg/ml) than in the CAM-f(−) (3.61 [2.71–4.65] μg/ml) or control group (3.39 [2.81–3.93] μg/ml; p < 0.01). The area under the receiver operating characteristic (ROC) curve of LRG for recognizing fetal infection was 0.92 (optimal cutoff, 5.08 μg/ml; sensitivity, 86%; specificity, 88%). In a mouse CAM model established by lipopolysaccharide administration, the fetal LRG protein in sera and LRG mRNA in the liver were significantly higher than those in phosphate-buffered saline (PBS)-administered control mice (p < 0.01). In vitro experiments using a fetal liver-derived cell line (WRL68) showed that the expression of LRG mRNA was significantly increased after interleukin (IL)-6, IL-1β, and tumor necrosis factor- alpha (TNF-α) stimulation (p < 0.01); the induction was considerably stronger following IL-6 and TNF-α stimulation (p < 0.01). In conclusion, LRG is an effective biomarker of fetal infection, and fetal hepatocytes stimulated with inflammatory cytokines may be the primary source of LRG production in utero.

Leucine-rich alpha-2 glycoprotein (LRG): A novel acute phase protein expressed in Stage 3 Grade C periodontitis before and after periodontal therapy.

Leucine-rich alpha-2 glycoprotein (LRG) is a novel acute phase protein involved in inflammation-associated diseases and that considered to be induced by multiple proinflammatory cytokines. This study aimed to investigate gingival crevicular fluid (GCF) and serum levels of LRG, interleukin (IL)-6 and tumor necrosis factor (TNF)-α in patients with Stage 3 periodontitis before and after non-surgical periodontal treatment. Twenty-five Stage 3 periodontitis and twenty-five periodontally healthy individuals were enrolled in the study. Clinical periodontal measurements were recorded; periodontitis patients received non-surgical periodontal treatment, and GCF and serum samples were obtained at baseline and at 6weeks after treatment. LRG, IL-6 and TNF-α were determined by ELISA. GCF and serum LRG, IL-6 and TNF-α were significantly higher in periodontitis group than healthy controls (P<.001). A significant decrease in GCF and serum LRG, IL-6 and TNF-α was detected after periodontal treatment compared with baseline values of periodontitis patients (P<.001). Our findings revealed that LRG expression was increased in Stage 3 periodontitis both locally and systemically, and non-surgical periodontal therapy was effective in reducing LRG levels in GCF and serum of these patients.

Salivary biomarker for acute appendicitis in children: a pilot study.

Assays of salivary biomarkers for diagnosis are gaining popularity in pediatric diseases due to their non-invasive nature. Our pilot project aims to evaluate the utility of salivary leucine-rich-alpha-2-glycoprotein (LRG) in the diagnosis of pediatric acute appendicitis (AA). We prospectively recruited 34 patients, aged between 4 and 16years, admitted with acute abdominal pain suspicious of appendicitis. The patients' demography, clinical characteristics, laboratory investigations, imaging examination results, operative findings, and discharge diagnoses were recorded. We compared the diagnostic performance of the patients' total white counts, neutrophil percentages, C-reactive protein, and saliva LRG levels. Saliva samples were obtained using the SalivaBio Children's Swab and LRG levels were quantified using a commercially available LRG enzyme-linked immunosorbent assay (ELISA) kit. IRB approval was obtained. Seventeen patients had a confirmed diagnosis of appendicitis on histology. Another 17 were confirmed not to have appendicitis after a minimum of 24h of hospitalization, with further verification via telephone interview 2weeks later. The median levels of saliva LRG were elevated in patients with AA as compared to those without (P = 0.008). At a cutoff of LRG 0.33ng/μg, we obtained a diagnostic specificity of 100% and sensitivity of 35.3%. Our proof-of-concept study demonstrated the diagnostic potential of saliva LRG for appendicitis in children. The distinct advantage of saliva LRG assays is that the procedure is simple, pain-free, and requires no specialized skill. Further study with a larger cohort is needed to verify our results.

Leucine-rich alpha 2 glycoprotein is a new marker for active disease of tuberculosis

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a global health problem. At present, prior exposure to Mtb can be determined by blood-based interferon-gamma release assay (IGRA), but active TB is not always detectable by blood tests such as CRP and ESR. This study was undertaken to investigate whether leucine-rich alpha-2 glycoprotein (LRG), a new inflammatory biomarker, could be used to assess active disease of TB. Cynomolgus macaques pretreated with or without Bacille Calmette-Guerin (BCG) vaccination were inoculated with Mtb to induce active TB. Blood was collected over time from these animals and levels of LRG as well as CRP and ESR were quantified. In the macaques without BCG vaccination, Mtb inoculation caused extensive TB and significantly increased plasma CRP and LRG levels, but not ESR. In the macaques with BCG vaccination, whereas Mtb challenge caused pulmonary TB, only LRG levels were significantly elevated. By immunohistochemical analysis of the lung, LRG was visualized in epithelioid cells and giant cells of the granulation tissue. In humans, serum LRG levels in TB patients were significantly higher than those in healthy controls and declined one month after anti-tubercular therapy. These findings suggest that LRG is a promising biomarker when performed following IGRA for the detection of active TB.

Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein.

We previously showed that an inflammation‐related, molecule leucine‐rich alpha‐2 glycoprotein (LRG) enhances the transforming growth factor (TGF)‐β1‐induced phosphorylation of Smad proteins and is elevated in patients with pancreatic ductal adenocarcinoma (PDAC). As TGF‐β/Smad signaling is considered to play a key role in epithelial‐mesenchymal transition (EMT), we attempted to clarify the mechanism underlying LRG‐related EMT in relation to metastasis in PDAC. We cultured LRG‐overexpressing PDAC cells (Panc1/LRG) and evaluated the morphology, EMT‐related molecules and TGF‐β/Smad signaling pathway in these cells. We also assessed the LRG levels in plasma and resected specimens from patients with PDAC. Inflammatory cytokines induced LRG production in PDAC cells. A spindle‐like shape was visualized more frequently than other shapes in Panc1/LRG with TGF‐β1 exposure. The expression of E‐cadherin in Panc1/LRG was decreased with TGF‐β1 exposure. Invasion increased with TGF‐β1 stimulation of Panc1/LRG. The phosphorylation of smad2 in Panc1/LRG was increased in comparison with parental Panc1 under TGF‐β1 stimulation. In the plasma LRG‐high group, the recurrence rate tended to be higher and the recurrence‐free survival (RFS) tended to be worse in comparison with the plasma LRG‐low group. LRG enhanced EMT induced by TGF‐β signaling, thus indicating that LRG has a significant effect on the metastasis of PDAC.

Sputum Leucine-Rich Alpha-2 Glycoprotein as a Marker of Airway Inflammation in Asthma

BackgroundAsthma is a chronic inflammatory disease of airways, but an ideal biomarker that accurately reflects ongoing airway inflammation has not yet been established. The aim of this study was to examine the potential of sputum leucine-rich alpha-2 glycoprotein (LRG) as a new biomarker for airway inflammation in asthma.MethodsWe obtained induced sputum samples from patients with asthma (N = 64) and healthy volunteers (N = 22) and measured LRG concentration by sandwich enzyme-linked immunosorbent assay (ELISA). Ovalbumin (OVA)-induced asthma model mice were used to investigate the mechanism of LRG production during airway inflammation. The LRG concentrations in the bronchoalveolar lavage fluid (BALF) obtained from mice were determined by ELISA and mouse lung sections were stained with anti-LRG antibody and periodic acid-Schiff (PAS) reagent.ResultsSputum LRG concentrations were significantly higher in patients with asthma than in healthy volunteers (p = 0.00686). Consistent with patients’ data, BALF LRG levels in asthma model mice were significantly higher than in control mice (p = 0.00013). Immunohistochemistry of lung sections from asthma model mice revealed that LRG was intensely expressed in a subpopulation of bronchial epithelial cells, which corresponded with PAS-positive mucus producing cells.ConclusionThese findings suggest that sputum LRG is a promising biomarker of local inflammation in asthma.