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Takei K, Inokuchi T, Hiraoka S, Ishiguro M, Toyosawa J, Aoyama Y, Igawa S, Takeuchi K, Yamasaki Y, Kinugasa H, Takahara M, Kawano S, Mitsuhashi T, Otsuka M. Efficient diagnosis for endoscopic remission in Crohn's diseases by the combination of three non-invasive markers. BMC Gastroenterol 2025; 25:364. [PMID: 40355822 PMCID: PMC12070669 DOI: 10.1186/s12876-025-03880-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Accepted: 04/10/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Serum C-reactive protein (CRP), leucine-rich alpha-2 glycoprotein (LRG), and fecal calprotectin (Fcal) are non-invasive markers used to assess Crohn's disease (CD) severity. However, the accuracy of these markers alone is often limited, and most previous reports have evaluated the efficacy of each marker individually. We aimed to improve the diagnostic performance of endoscopic remission (ER) of CD by combining these 3 markers. METHODS We tested the diagnostic ability of various combinations of these 3 markers for endoscopic severity in 230 consecutive patients with CD from September 2014 to July 2023. The modified Simple Endoscopic Score for Crohn's disease (mSES-CD) was used to determine endoscopic severity. RESULTS Each of the 3 markers was correlated with mSED-CD (LRG: r = 0.69, CRP: r = 0.60, and Fcal: r = 0.67). A combination of 2 of the 3 markers did not increase the diagnostic accuracy of ER. However, by combining all 3 markers, the diagnostic ability for ER was improved in comparison to the diagnostic ability of the 3 individual markers, assuming that ER was obtained if 2 or 3 markers were negative. The sensitivity, specificity, and accuracy were 89%, 83%, and 86%, respectively. Additionally, we established a 2-step method using Fcal values after evaluating the 2 serum markers. This method was most useful for reducing both the patient burden and costs. CONCLUSIONS The newly established 2-step method allowed for a higher accuracy in the non-invasive diagnosis of ER when the 3 markers were combined.
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Affiliation(s)
- Kensuke Takei
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2 - 5- 1 Shikata-Cho, Kita-Ku, Okayama, 700 - 8558, Japan
| | - Toshihiro Inokuchi
- Research Center for Intestinal Health Science, Okayama University, Okayama, Japan
| | - Sakiko Hiraoka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2 - 5- 1 Shikata-Cho, Kita-Ku, Okayama, 700 - 8558, Japan.
| | - Mikako Ishiguro
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2 - 5- 1 Shikata-Cho, Kita-Ku, Okayama, 700 - 8558, Japan
| | - Junki Toyosawa
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2 - 5- 1 Shikata-Cho, Kita-Ku, Okayama, 700 - 8558, Japan
| | - Yuki Aoyama
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2 - 5- 1 Shikata-Cho, Kita-Ku, Okayama, 700 - 8558, Japan
| | - Shoko Igawa
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2 - 5- 1 Shikata-Cho, Kita-Ku, Okayama, 700 - 8558, Japan
| | - Keiko Takeuchi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2 - 5- 1 Shikata-Cho, Kita-Ku, Okayama, 700 - 8558, Japan
| | - Yasushi Yamasaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2 - 5- 1 Shikata-Cho, Kita-Ku, Okayama, 700 - 8558, Japan
| | - Hideaki Kinugasa
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2 - 5- 1 Shikata-Cho, Kita-Ku, Okayama, 700 - 8558, Japan
| | - Masahiro Takahara
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2 - 5- 1 Shikata-Cho, Kita-Ku, Okayama, 700 - 8558, Japan
| | - Seiji Kawano
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2 - 5- 1 Shikata-Cho, Kita-Ku, Okayama, 700 - 8558, Japan
| | - Toshiharu Mitsuhashi
- Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2 - 5- 1 Shikata-Cho, Kita-Ku, Okayama, 700 - 8558, Japan
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Tretiak S, Mendes Maia T, Rijsselaere T, Van Immerseel F, Ducatelle R, Impens F, Antonissen G. Comprehensive analysis of blood proteome response to necrotic enteritis in broiler chicken. Vet Res 2025; 56:88. [PMID: 40275387 PMCID: PMC12023520 DOI: 10.1186/s13567-025-01519-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Accepted: 03/14/2025] [Indexed: 04/26/2025] Open
Abstract
Necrotic enteritis (NE) in broiler chickens is caused by the overgrowth of toxin-producing strains of Clostridium (C.) perfringens. This study aims to analyze the blood proteome of broiler chickens affected by NE, providing insights into the host's response to the infection. Using MS/MS-based proteomics, blood plasma samples from broilers with necrotic lesions of different severity were analyzed and compared to healthy controls. A total of 412 proteins were identified, with 63 showing significant differences; for 25 of those correlation with disease severity was observed. Functional analysis revealed that proteins affected by NE were predominantly associated with the immune and signaling processes and extracellular matrix (ECM) structures. Notably, regulated proteins were significantly involved in bioprocesses related to complement activation, acute phase reaction, proteolysis and humoral immune response. The proteomics findings suggest that the changes in plasma proteins in response to NE are driven by the host's intensified efforts to counteract the infection, demonstrating a.o. activation of ECM-degrading proteases (MMP2, TIMP2), acute phase response (HPS5, CP, EXFABP, TF, VNN) and notable reduction in basement membrane (BM) and ECM-related peptides (PLOD2, POSTN, COL1A1/2, HSPG2, NID2) detected in the blood of NE-affected birds. Moreover, the findings underscore a coordinated effort of the host to mitigate the C. perfringens infection via activating immune (a.o., C3, CFH, MASP2, MBL2) and acute phase (CP, ORM, TF, ExFAB) related proteins. This study provides a deeper understanding of the host-pathogen interactions and identifies potential biomarkers and targets for therapeutic intervention. Data are available via ProteomeXchange with identifier PXD054172.
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Affiliation(s)
- Svitlana Tretiak
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Livestock Gut Health Team (LiGHT) Ghent, Ghent University, 9820, Merelbeke, Belgium
- Impextraco NV, Wiekevorstsesteenweg 38, 2220, Heist-op-den-Berg, Belgium
| | - Teresa Mendes Maia
- VIB-UGent Center for Medical Biotechnology, VIB, 9052, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, 9052, Ghent, Belgium
- VIB Proteomics Core, VIB, 9052, Ghent, Belgium
| | - Tom Rijsselaere
- Impextraco NV, Wiekevorstsesteenweg 38, 2220, Heist-op-den-Berg, Belgium
| | - Filip Van Immerseel
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Livestock Gut Health Team (LiGHT) Ghent, Ghent University, 9820, Merelbeke, Belgium
| | - Richard Ducatelle
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Livestock Gut Health Team (LiGHT) Ghent, Ghent University, 9820, Merelbeke, Belgium
| | - Francis Impens
- VIB-UGent Center for Medical Biotechnology, VIB, 9052, Ghent, Belgium.
- Department of Biomolecular Medicine, Ghent University, 9052, Ghent, Belgium.
- VIB Proteomics Core, VIB, 9052, Ghent, Belgium.
| | - Gunther Antonissen
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Livestock Gut Health Team (LiGHT) Ghent, Ghent University, 9820, Merelbeke, Belgium.
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Issa IA, Issa T. Assessing endoscopic remission in small bowel Crohn's disease: Are markers enough? World J Gastrointest Endosc 2025; 17:106083. [PMID: 40291128 PMCID: PMC12019123 DOI: 10.4253/wjge.v17.i4.106083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/23/2025] [Accepted: 04/03/2025] [Indexed: 04/14/2025] Open
Abstract
Mucosal healing in Crohn's disease (CD) has been established as a crucial target of treatment, leading to long term remission and decrease in complication rates. Endoscopy still serves as the gold standard for assessment, particularly in the small bowel where balloon or capsule enteroscopy is frequently needed. However, these modalities are often unavailable, expensive, and invasive, posing risks to patients. Consequently, the identification of accessible and reliable biomarkers, especially in small intestinal CD, remains a challenge. The study by Ohno et al, published in this issue, further illuminates this field. It confirms the potential role of fecal biomarker leucine-rich α2 glycoprotein (LRG) and validates findings from previous smaller trials. Comparing to other markers LRG showed a much higher predictive value for mucosal healing of the small bowel, making it a useful option for small intestinal CD follow up. In this editorial, we explore the optimal marker of inflammation or mucosal healing in CD, particularly in the small bowel. We provide an overview of available conventional biomarkers and introduce several novel biomarkers, including an update on emerging technologies and innovations.
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Affiliation(s)
- Iyad A Issa
- Department of Gastroenterology and Hepatology, Harley Street Medical Center, Abu Dhabi 41475, United Arab Emirates
| | - Taly Issa
- Medical School, University of Nicosia, Nicosia 24005, Lefkosía, Cyprus
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Ojaghi Shirmard F, Pourfaraji SM, Saeedian B, Bagheri T, Ismaiel A, Matsumoto S, Babajani N. The usefulness of serum leucine-rich alpha-2 glycoprotein as a novel biomarker in monitoring inflammatory bowel disease: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2025:00042737-990000000-00488. [PMID: 39976047 DOI: 10.1097/meg.0000000000002952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Inflammatory bowel disease (IBD) is a condition of unknown origin. It does not have a definite cure and its response to various treatments can be evaluated based on symptom-based measures, invasive procedures, or biomarker levels, highlighting the need for an accurate biomarker. Since C-reactive protein (CRP) and fecal calprotectin have their shortcomings, the need for a novel biomarker remains critical. Systematic searches of PubMed, Scopus, Web of Science, and Embase were performed In January 2024. PROSPERO number is CRD42024507383. We assessed the accuracy of leucine-rich alpha-2 glycoprotein (LRG) in identifying disease activity among patients with IBD using a bivariate diagnostic random-effects model. Fourteen studies involving 1794 individuals conducted in Japan were selected for our systematic review. The sensitivity and specificity of LRG levels for detecting disease activity were analyzed in patients with IBD and in two subgroups (ulcerative colitis and Crohn's disease). The synthesized sensitivity and specificity were 75.4% [95% confidence interval (CI), 68.9-80.9%] and 77.3% (95% CI, 69.9-83.2%), respectively, in patients with IBD, 73.1% (95% CI, 62.7-81.5%) and 81.9% (95% CI, 73.9-87.8%), respectively, in patients with CD, and the secondary analysis of the ulcerative colitis subgroup showed a pooled sensitivity and specificity of 72.8 and 59.7%, respectively. Our systematic review and meta-analysis demonstrated that LRG could be useful in detecting IBD activity. It is superior for detecting disease activity, especially in patients with normal CRP levels. The LRG was more accurate in monitoring disease activity in patients with CD than in patients with IBD.
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Affiliation(s)
| | | | - Behrad Saeedian
- School of Medicine
- Digestive Diseases Research Institute (DDRI), Tehran University of Medical Sciences, Tehran, Iran
| | | | - Abdulrahman Ismaiel
- 2nd Department of Internal Medicine, 'Iuliu Hatieganu' University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Satohiro Matsumoto
- Department of Gastroenterology, Jichi Medical University Saitama Medical Center, Saitama, Japan
| | - Nastaran Babajani
- School of Medicine
- Digestive Diseases Research Institute (DDRI), Tehran University of Medical Sciences, Tehran, Iran
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Ohno M, Nishida A, Otsuki A, Yokota Y, Imai T, Bamba S, Inatomi O. Leucine-rich alpha-2 glycoprotein as a superior biomarker to C-reactive protein for detecting small bowel lesions in Crohn's disease. World J Gastrointest Endosc 2025; 17:100793. [PMID: 39989852 PMCID: PMC11843037 DOI: 10.4253/wjge.v17.i2.100793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 01/06/2025] [Accepted: 01/18/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Achievement of endoscopic healing (EH) is significant in the clinical practice of inflammatory bowel disease as it is correlated with improved prognosis. Existing biomarkers, including C-reactive protein (CRP), have relatively low accuracy for predicting EH, especially in small intestinal lesions in Crohn's disease (CD); thus, noninvasive and more accurate biomarkers are required. Leucine-rich alpha-2 glycoprotein (LRG), a 50-kD protein, is produced under inflammatory conditions and has been reported to be useful in assessing disease activity in inflammatory bowel disease. However, the usefulness of LRG in small intestinal lesions in CD remains inconclusive. AIM To determine the usefulness of LRG for EH in small bowel lesions in CD and compare it with CRP. METHODS This study included 133 consecutive patients with CD who underwent balloon-assisted enteroscopy between June 2021 and March 2024 at Shiga University of Medical Science Hospital (Otsu, Japan). We retrospectively analyzed endoscopic scores in each of the ileum and colon and four markers including LRG, CRP, albumin, and Harvey-Bradshaw index (HBI). Spearman's rank correlation coefficient and receiver operating characteristic analysis were performed. RESULTS Either active ileal or colonic lesions exhibited significant differences in LRG, CRP, albumin, and HBI compared with EH. CRP, albumin, and HBI showed a worse correlation with endoscopic activity in the ileum than that in the colon; however, LRG did not show a worse correlation (colon, r = 0.5218; ileum, r = 0.5602). Receiver operating characteristic analysis revealed that LRG for EH in the ileum and colon had the same cutoff values of 12.4 μg/mL. Comparing the areas under the curve of LRG and CRP for predicting EH in the ileum revealed a significantly higher areas under the curve of LRG (95% confidence interval, 0.017-0.194; P = 0.024), whereas the two showed no significant difference in the colon. CONCLUSION LRG is a useful biomarker in assessing the endoscopic activity of CD and is more useful than CRP in the small intestine.
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Affiliation(s)
- Masashi Ohno
- Department of Medicine, Shiga University of Medical Science, Otsu 520-2192, Shiga, Japan
| | - Atsushi Nishida
- Department of Medicine, Shiga University of Medical Science, Otsu 520-2192, Shiga, Japan
| | - Akinori Otsuki
- Department of Medicine, Shiga University of Medical Science, Otsu 520-2192, Shiga, Japan
| | - Yoshihiro Yokota
- Department of Medicine, Shiga University of Medical Science, Otsu 520-2192, Shiga, Japan
| | - Takayuki Imai
- Department of Medicine, Shiga University of Medical Science, Otsu 520-2192, Shiga, Japan
| | - Shigeki Bamba
- Department of Fundamental Nursing, Shiga University of Medical Science, Otsu 520-2192, Shiga, Japan
| | - Osamu Inatomi
- Department of Medicine, Shiga University of Medical Science, Otsu 520-2192, Shiga, Japan
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Aoyama Y, Hiraoka S, Yasutomi E, Inokuchi T, Tanaka T, Takei K, Igawa S, Takeuchi K, Takahara M, Toyosawa J, Yamasaki Y, Kinugasa H, Kato J, Okada H, Otsuka M. Changes of leucine-rich alpha 2 glycoprotein could be a marker of changes of endoscopic and histologic activity of ulcerative colitis. Sci Rep 2025; 15:5248. [PMID: 39939376 PMCID: PMC11822068 DOI: 10.1038/s41598-025-89615-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 02/06/2025] [Indexed: 02/14/2025] Open
Abstract
Leucine-rich alpha 2 glycoprotein (LRG) is one of the serum biomarkers for disease activity of ulcerative colitis (UC). We focused on the correlation between the changes of LRG and the changes of endoscopic and histologic activity of UC, in comparison to the changes of fecal calprotectin (Fcal), fecal immunochemical test (FIT), and C-reactive protein (CRP). Seventy-nine patients with two or more colonoscopies were enrolled, and 123 paired colonoscopies and 121 paired biopsies were examined. With regard to the change of endoscopic/histologic activity between the preceding and subsequent colonoscopy, there was improvement (n = 29/45), unchanging (n = 63/36), and worsening (n = 31/40). The correlations between the changes of marker levels and endoscopic/histologic activity were Fcal; r = 0.50/0.39 and FIT; r = 0.41/0.40, LRG; r = 0.42/0.40 and CRP; r = 0.22/0.17. Furthermore, when the correlation between the changes of LRG levels and the changes of endoscopic/histological activity was compared with those of other markers, the correlation of LRG tended to be superior to those of CRP (CRP vs. LRG; p = 0.08/0.01). LRG is equivalent to fecal markers and superior to CRP, when inferring changes in disease activity of UC based on changes in its level.
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Affiliation(s)
- Yuki Aoyama
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Sakiko Hiraoka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
| | - Eriko Yasutomi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Toshihiro Inokuchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Takehiro Tanaka
- Department of Pathology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan
| | - Kensuke Takei
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Shoko Igawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Keiko Takeuchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Masahiro Takahara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Junki Toyosawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Yasushi Yamasaki
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Hideaki Kinugasa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology, Japanese Red Cross Society Himeji Hospital, Himeji, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
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Igarashi N, Takai H, Ogata Y. Effects of initial periodontal therapy on leucine-rich alpha-2 glycoprotein levels in saliva from Japanese patients with chronic periodontitis. J Oral Sci 2025; 67:10-13. [PMID: 39581585 DOI: 10.2334/josnusd.24-0226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2024]
Abstract
PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSION These results suggest that there is an association between salivary LRG levels and severity of periodontitis.
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Affiliation(s)
- Naomi Igarashi
- Department of Periodontology, Nihon University School of Dentistry at Matsudo
| | - Hideki Takai
- Department of Periodontology, Nihon University School of Dentistry at Matsudo
- Research Institute of Oral Science, Nihon University School of Dentistry at Matsudo
| | - Yorimasa Ogata
- Department of Periodontology, Nihon University School of Dentistry at Matsudo
- Research Institute of Oral Science, Nihon University School of Dentistry at Matsudo
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Ouhara K, Takemura T, Taniguchi Y, Fujimori R, Tamura T, Akane Y, Matsuda S, Hamamoto Y, Shintani T, Kajiya M, Munenaga S, Iwata T, Fujita T, Mizuno N. Leucine-rich alpha-2-glycoprotein 1 affects bone destruction via IL-6 in mouse periodontitis model. Oral Dis 2024; 30:5294-5304. [PMID: 38656694 PMCID: PMC11610699 DOI: 10.1111/odi.14952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 03/14/2024] [Accepted: 03/25/2024] [Indexed: 04/26/2024]
Abstract
OBJECTIVE To investigate the production of leucine-rich α-2-glycoprotein-1 (LRG1) in periodontitis patients and its effectiveness as a new diagnostic marker for periodontitis. SUBJECTS AND METHODS In vitro experiments were conducted to analyze LRG1 mRNA expression in human gingival epithelial cells and fibroblasts via quantitative real-time PCR. In vivo experiments were conducted to analyze LRG1 localization in periodontitis patients. The correlation between the serum LRG1 levels and alveolar bone resorption in the mouse periodontitis model was also investigated. RESULTS A positive correlation existed between the periodontal inflamed surface area and serum LRG1 levels (Spearman's rank correlation coefficient: 0.60). LRG1 mRNA expression in human gingival epithelial cells and fibroblasts was upregulated by Porphyromonas gingivalis stimulation or tumor necrosis factor-α stimulation. Interleukin-6 in human gingival epithelial cells and fibroblasts induced the production of LRG1 and transforming growth factor-β. LRG1 levels in the periodontal tissue and serum in the periodontitis model were higher than those in control mice. LRG1 local administration resulted in alveolar bone resorption, whereas the administration of interleukin-6R antibody inhibited bone resorption. CONCLUSIONS LRG1 levels in serum and periodontal tissue are upregulated in periodontitis and are implicated in periodontal tissue destruction through interleukin-6 production.
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Affiliation(s)
- Kazuhisa Ouhara
- Department of Periodontal Medicine, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Tasuku Takemura
- Department of Periodontal Medicine, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Yuri Taniguchi
- Department of Periodontal Medicine, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Ryousuke Fujimori
- Department of Periodontal Medicine, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Tetsuya Tamura
- Department of Periodontal Medicine, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Yuki Akane
- Department of Periodontal Medicine, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Shinji Matsuda
- Department of Periodontal Medicine, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Yuta Hamamoto
- Department of Periodontal Medicine, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Tomoaki Shintani
- Department of Innovation and Precision DentistryHiroshima University HospitalHiroshimaJapan
| | - Mikihito Kajiya
- Department of Innovation and Precision DentistryHiroshima University HospitalHiroshimaJapan
| | - Syuichi Munenaga
- Department of Periodontal Medicine, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Tomoyuki Iwata
- Department of Periodontal Medicine, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Tsuyoshi Fujita
- Department of Periodontal Medicine, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
| | - Noriyoshi Mizuno
- Department of Periodontal Medicine, Graduate School of Biomedical and Health SciencesHiroshima UniversityHiroshimaJapan
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Wang Y, Jiang Y, Xie M, Qi B, Pu K, Du W, Zhang Q, Ma M, Chen Z, Guo Y, Qian H, Wang K, Tian T, Fu L, Zhang X. Cross-Sectional and Longitudinal Associations of Serum LRG1 with Severity and Prognosis Among Adult Community-Acquired Pneumonia Patients. J Inflamm Res 2024; 17:7951-7962. [PMID: 39502939 PMCID: PMC11537034 DOI: 10.2147/jir.s485932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 10/28/2024] [Indexed: 11/08/2024] Open
Abstract
Background Leucine-rich α-2 glycoprotein 1 (LRG1) is associated with various inflammatory lung diseases. Nevertheless, the connection between LRG1 and adult community-acquired pneumonia (CAP) individuals was still not well understood. Through a prospective cohort study, the correlations of serum LRG1 with severity and prognosis were evaluated in CAP patients. Methods The study encompassed 327 patients who received the diagnosis of CAP. We collected fasting venous blood and clinical features. Serum LRG1 was detected by ELISA. CAP severity was assessed using various scoring systems. The prognostic outcomes were observed through follow-up visits. Results The level of serum LRG1 at admission was gradually increased with CAP severity scores. Serum LRG1 level shown positive associations with inflammatory indices, including C-reactive protein (CRP), procalcitonin (PCT), and interleukin-6 (IL-6). Linear and logistic regression analyses suggested that serum LRG1 at admission was positively associated with severity scores and the risk of death in CAP patients. Serum LRG1 in combination with CAP severity scores significantly increased the predictive powers for severity and death compared with single serum LRG1 or severity scores. Conclusion The study revealed positive connections of serum LRG1 levels with severity and poor prognosis in CAP patients, suggesting LRG1 partakes into the physiological processes of CAP. Serum LRG1 may be regarded as a potential biomarker in predicting the severity and death among CAP patients.
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Affiliation(s)
- Yingli Wang
- Bengbu Medical University Graduate School, Bengbu, Anhui, People’s Republic of China
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China
| | - Yalin Jiang
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China
| | - Meiling Xie
- Bengbu Medical University Graduate School, Bengbu, Anhui, People’s Republic of China
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China
| | - Bin Qi
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China
| | - Kunpeng Pu
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China
| | - Wenjie Du
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China
| | - Qingqing Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China
| | - Mengmeng Ma
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China
| | - Ziyong Chen
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China
| | - Yongxia Guo
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China
| | - Hui Qian
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China
| | - Kaiqin Wang
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China
| | - Tulei Tian
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China
| | - Lin Fu
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Xiaofei Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, People’s Republic of China
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Zheng X, Yang L, Shen X, Pan J, Chen Y, Chen J, Wang H, Meng J, Chen Z, Xie S, Li Y, Zhu B, Zhu W, Qin L, Lu L. Targeting Gsk3a reverses immune evasion to enhance immunotherapy in hepatocellular carcinoma. J Immunother Cancer 2024; 12:e009642. [PMID: 39174053 PMCID: PMC11340705 DOI: 10.1136/jitc-2024-009642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/30/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND Immune escape is an important feature of hepatocellular carcinoma (HCC). The overall response rate of immune checkpoint inhibitors (ICIs) in HCC is still limited. Revealing the immune regulation mechanisms and finding new immune targets are expected to further improve the efficacy of immunotherapy. Our study aims to use CRISPR screening mice models to identify potential targets that play a critical role in HCC immune evasion and further explore their value in improving immunotherapy. METHODS We performed CRISPR screening in two mice models with different immune backgrounds (C57BL/6 and NPG mice) and identified the immunosuppressive gene Gsk3a as a candidate for further investigation. Flow cytometry was used to analyze the impact of Gsk3a on immune cell infiltration and T-cell function. RNA sequencing was used to identify the changes in neutrophil gene expression induced by Gsk3a and alterations in downstream molecules. The therapeutic value of the combination of Gsk3a inhibitors and anti-programmed cell death protein-1 (PD-1) antibody was also explored. RESULTS Gsk3a, as an immune inhibitory target, significantly promoted tumor growth in immunocompetent mice rather than immune-deficient mice. Gsk3a inhibited cytotoxic T lymphocytes (CTLs) function by inducing neutrophil chemotaxis. Gsk3a promoted self-chemotaxis of neutrophil expression profiles and neutrophil extracellular traps (NETs) formation to block T-cell activity through leucine-rich α-2-glycoprotein 1 (LRG1). A significant synergistic effect was observed when Gsk3a inhibitor was in combination with anti-PD-1 antibody. CONCLUSIONS We identified a potential HCC immune evasion target, Gsk3a, through CRISPR screening. Gsk3a induces neutrophil recruitment and NETs formation through the intermediate molecule LRG1, leading to the inhibition of CTLs function. Targeting Gsk3a can enhance CTLs function and improve the efficacy of ICIs.
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Affiliation(s)
- Xin Zheng
- Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Luyu Yang
- Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Xiaotian Shen
- Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Junjie Pan
- Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Yiran Chen
- Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Jixuan Chen
- Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Hao Wang
- Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Jiaqi Meng
- Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Zhenchao Chen
- Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Sunzhe Xie
- Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Yitong Li
- Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Bolun Zhu
- Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Wenwei Zhu
- Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Lunxiu Qin
- Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Lu Lu
- Department of General Surgery, Hepatobiliary Surgery Center, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
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Fujimoto M, Hosono Y, Serada S, Suzuki Y, Ohkawara T, Murata O, Quick A, Suzuki K, Kaneko Y, Takeuchi T, Naka T. Leucine-rich α2-glycoprotein as a useful biomarker for evaluating disease activity in rheumatoid arthritis. Mod Rheumatol 2024; 34:1072-1075. [PMID: 38141246 DOI: 10.1093/mr/road112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Revised: 11/26/2023] [Accepted: 12/05/2023] [Indexed: 12/25/2023]
Affiliation(s)
- Minoru Fujimoto
- Division of Allergy and Rheumatology, Department of Internal Medicine, School of Medicine Iwate Medical University, Yahaba-cho, Japan
| | - Yuji Hosono
- Division of Allergy and Rheumatology, Department of Internal Medicine, School of Medicine Iwate Medical University, Yahaba-cho, Japan
| | - Satoshi Serada
- Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba-cho, Japan
| | - Yuji Suzuki
- Division of Allergy and Rheumatology, Department of Internal Medicine, School of Medicine Iwate Medical University, Yahaba-cho, Japan
| | - Tomoharu Ohkawara
- Division of Allergy and Rheumatology, Department of Internal Medicine, School of Medicine Iwate Medical University, Yahaba-cho, Japan
| | - Okinori Murata
- Division of Allergy and Rheumatology, Department of Internal Medicine, School of Medicine Iwate Medical University, Yahaba-cho, Japan
| | - Ayumi Quick
- Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba-cho, Japan
| | - Katuya Suzuki
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kaneko
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Tsutomu Takeuchi
- Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Tetsuji Naka
- Division of Allergy and Rheumatology, Department of Internal Medicine, School of Medicine Iwate Medical University, Yahaba-cho, Japan
- Institute for Biomedical Sciences Molecular Pathophysiology, Iwate Medical University, Yahaba-cho, Japan
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Tatsumi Y, Kakimoto K, Hara A, Mizuta N, Numa K, Kinoshita N, Nakazawa K, Koshiba R, Hirata Y, Ota K, Miyazaki T, Nakamura S, Sakagami K, Arimitsu S, Ito H, Nishikawa H. Correction: Tatsumi et al. Biomarkers for Monitoring of Changes in Disease Activity in Ulcerative Colitis. J. Clin. Med. 2023, 12, 7165. J Clin Med 2024; 13:3923. [PMID: 38999556 PMCID: PMC11242456 DOI: 10.3390/jcm13133923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Accepted: 06/12/2024] [Indexed: 07/14/2024] Open
Abstract
Text Correction [...].
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Affiliation(s)
- Yoshihiro Tatsumi
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki City 569-8686, Japan
| | - Kazuki Kakimoto
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki City 569-8686, Japan
- Kinshukai Infusion Clinic, Osaka-shi 530-0011, Japan
| | - Azusa Hara
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki City 569-8686, Japan
- Kinshukai Infusion Clinic, Osaka-shi 530-0011, Japan
| | - Noboru Mizuta
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki City 569-8686, Japan
| | - Keijiro Numa
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki City 569-8686, Japan
| | - Naohiko Kinoshita
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki City 569-8686, Japan
| | - Kei Nakazawa
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki City 569-8686, Japan
| | - Ryoji Koshiba
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki City 569-8686, Japan
| | - Yuki Hirata
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki City 569-8686, Japan
- Kinshukai Infusion Clinic, Osaka-shi 530-0011, Japan
| | - Kazuhiro Ota
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki City 569-8686, Japan
| | - Takako Miyazaki
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki City 569-8686, Japan
- Kinshukai Infusion Clinic, Osaka-shi 530-0011, Japan
| | - Shiro Nakamura
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki City 569-8686, Japan
| | | | | | - Hiroaki Ito
- Kinshukai Infusion Clinic, Osaka-shi 530-0011, Japan
| | - Hiroki Nishikawa
- 2nd Department of Internal Medicine, Osaka Medical and Pharmaceutical University, Takatsuki City 569-8686, Japan
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Hong SM, Baek DH. Diagnostic Procedures for Inflammatory Bowel Disease: Laboratory, Endoscopy, Pathology, Imaging, and Beyond. Diagnostics (Basel) 2024; 14:1384. [PMID: 39001273 PMCID: PMC11241288 DOI: 10.3390/diagnostics14131384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024] Open
Abstract
Diagnosing inflammatory bowel disease (IBD) can often be challenging, and differentiating between Crohn's disease and ulcerative colitis can be particularly difficult. Diagnostic procedures for IBD include laboratory tests, endoscopy, pathological tests, and imaging tests. Serological and stool tests can be easily performed in an outpatient setting and provide critical diagnostic clues. Although endoscopy is an invasive procedure, it offers essential diagnostic information and allows for tissue biopsy and therapeutic procedures. Video capsule endoscopy and device-assisted enteroscopy are endoscopic procedures used to evaluate the small bowel. In addition to endoscopy, magnetic resonance imaging, computed tomography, and ultrasound (US) are valuable tools for small bowel assessment. Among these, US is noninvasive and easily utilized, making its use highly practical in daily clinical practice. Endoscopic biopsy aids in the diagnosis of IBD and is crucial for assessing the histological activity of the disease, facilitating a thorough evaluation of disease remission, and aiding in the development of treatment strategies. Recent advances in artificial intelligence hold promise for enhancing various aspects of IBD management, including diagnosis, monitoring, and precision medicine. This review compiles current procedures and promising future tools for the diagnosis of IBD, providing comprehensive insights.
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Affiliation(s)
- Seung Min Hong
- Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea
| | - Dong Hoon Baek
- Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea
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Clough J, Colwill M, Poullis A, Pollok R, Patel K, Honap S. Biomarkers in inflammatory bowel disease: a practical guide. Therap Adv Gastroenterol 2024; 17:17562848241251600. [PMID: 38737913 PMCID: PMC11085009 DOI: 10.1177/17562848241251600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 04/12/2024] [Indexed: 05/14/2024] Open
Abstract
Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn's disease (CD), is a costly condition in terms of morbidity and healthcare utilization, with an increasing prevalence now approaching 1% in the Western world. Endoscopic assessment of IBD remains the gold standard for diagnosis, evaluation of treatment response and determination of post-operative recurrence, but is expensive and invasive. Biomarkers can facilitate non-invasive disease assessment, with C-reactive protein and faecal calprotectin as the most widely available biomarkers in current clinical practice. This narrative review summarizes the evidence for their use in both UC and CD and offers practical guidance for healthcare providers taking into account the limitations of biomarker interpretation. We present evidence for the future use of novel biomarkers in IBD and discuss how biomarker discovery could deliver the goal of precision medicine in IBD.
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Affiliation(s)
- Jennie Clough
- St George’s University Hospitals NHS Foundation Trust, London, UK
- School of Immunology and Microbial Sciences, King’s College London, London, UK
| | - Michael Colwill
- St George’s University Hospitals NHS Foundation Trust, London, UK
| | - Andrew Poullis
- St George’s University Hospitals NHS Foundation Trust, London, UK
| | - Richard Pollok
- St George’s University Hospital NHS Foundation Trust
- Institute of Infection and Immunity, St George’s University, London, UK
| | - Kamal Patel
- St George’s University Hospitals NHS Foundation Trust, London, UK
| | - Sailish Honap
- St George’s University Hospitals NHS Foundation Trust, London, UK
- School of Immunology and Microbial Sciences, King’s College London, London, UK
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France
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15
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Okita M, Nakashima K, Yamamura T, Matsui S. Systematic Review and Meta-Analysis of the Use of Serum Leucine-Rich Alpha-2 Glycoprotein to Assess Crohn's Disease Activity. Inflamm Bowel Dis 2024; 30:780-787. [PMID: 37506169 DOI: 10.1093/ibd/izad128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Indexed: 07/30/2023]
Abstract
BACKGROUND Although fecal calprotectin is the most widely used biomarker for assessing Crohn's disease activity, serum leucine-rich alpha-2 glycoprotein has recently attracted attention, especially in Japan. Here we performed a systematic review and meta-analysis of serum leucine-rich alpha-2 glycoprotein to obtain evidence for its accuracy in assessing Crohn's disease activity. METHODS On February 1, 2023, we performed searches of PubMed, Web of Science, and CENTRAL. The Prospero number is CRD42023396034. The primary outcomes were the sensitivity and specificity of serum leucine-rich alpha-2 glycoprotein for assessing Crohn's disease activity. We used a bivariate generalized linear mixed model, assuming a binomial distribution at the test level and a bivariate normal distribution at the between-test level. RESULTS We selected 9 studies involving 797 individuals in our systematic review. Regarding the primary outcomes, the synthesized sensitivity and specificity of serum leucine-rich alpha-2 glycoprotein were 77.0% (95% confidence interval, 67.8% to 84.2%) and 81.1% (95% confidence interval, 72.6% to 87.4%), respectively. The area under the curve was 0.86, and the partial area under the curve was 0.78. Regarding between-study heterogeneity, both the I2 value by Zhou and Dendukuri approach and the I2 value by Holling sample size-adjusted approaches were 0%. CONCLUSIONS Our systematic review and meta-analysis of serum leucine-rich alpha-2 glycoprotein demonstrated its accuracy in assessing Crohn's disease activity. Further studies are needed to demonstrate its clinical utility and clinical validity.
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Affiliation(s)
- Muneyori Okita
- Department of Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Keita Nakashima
- Department of Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takeshi Yamamura
- Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shigeyuki Matsui
- Department of Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Dritsoula A, Camilli C, Moss SE, Greenwood J. The disruptive role of LRG1 on the vasculature and perivascular microenvironment. Front Cardiovasc Med 2024; 11:1386177. [PMID: 38745756 PMCID: PMC11091338 DOI: 10.3389/fcvm.2024.1386177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 04/17/2024] [Indexed: 05/16/2024] Open
Abstract
The establishment of new blood vessels, and their subsequent stabilization, is a critical process that facilitates tissue growth and organ development. Once established, vessels need to diversify to meet the specific needs of the local tissue and to maintain homeostasis. These processes are tightly regulated and fundamental to normal vessel and tissue function. The mechanisms that orchestrate angiogenesis and vessel maturation have been widely studied, with signaling crosstalk between endothelium and perivascular cells being identified as an essential component. In disease, however, new vessels develop abnormally, and existing vessels lose their specialization and function, which invariably contributes to disease progression. Despite considerable research into the vasculopathic mechanisms in disease, our knowledge remains incomplete. Accordingly, the identification of angiocrine and angiopathic molecules secreted by cells within the vascular microenvironment, and their effect on vessel behaviour, remains a major research objective. Over the last decade the secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1), has emerged as a significant vasculopathic molecule, stimulating defective angiogenesis, and destabilizing the existing vasculature mainly, but not uniquely, by altering both canonical and non-canonical TGF-β signaling in a highly cell and context dependent manner. Whilst LRG1 does not possess any overt homeostatic role in vessel development and maintenance, growing evidence provides a compelling case for LRG1 playing a pleiotropic role in disrupting the vasculature in many disease settings. Thus, LRG1 has now been reported to damage vessels in various disorders including cancer, diabetes, chronic kidney disease, ocular disease, and lung disease and the signaling processes that drive this dysfunction are being defined. Moreover, therapeutic targeting of LRG1 has been widely proposed to re-establish a quiescent endothelium and normalized vasculature. In this review, we consider the current status of our understanding of the role of LRG1 in vascular pathology, and its potential as a therapeutic target.
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Affiliation(s)
- Athina Dritsoula
- UCL Institute of Ophthalmology, University College London, London, United Kingdom
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Özer E, Yilmaz HE, Narin F, Sağlam M. The evaluation of salivary leucine-rich alpha-2 glycoprotein (LRG) and C-reactive protein (CRP) in humans with periodontal health or periodontal disease. J Periodontal Res 2024; 59:387-394. [PMID: 38126217 DOI: 10.1111/jre.13223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 11/29/2023] [Accepted: 12/01/2023] [Indexed: 12/23/2023]
Abstract
OBJECTIVE 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. BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSION LRG and CRP may be useful and similarly effective biomarkers in the diagnosis of periodontal diseases based on the findings of this study.
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Affiliation(s)
- Ece Özer
- Department of Periodontology, Faculty of Dentistry, Izmir Katip Celebi University, Izmir, Turkey
| | - Huriye Erbak Yilmaz
- Department of Medical Biochemistry, School of Medicine, Izmir Katip Celebi University, Izmir, Turkey
- Izmir Biomedicine Genome Center, Dokuz Eylul University, Izmir, Turkey
| | - Figen Narin
- Department of Medical Biochemistry, School of Medicine, Izmir Katip Celebi University, Izmir, Turkey
| | - Mehmet Sağlam
- Department of Periodontology, Faculty of Dentistry, Izmir Katip Celebi University, Izmir, Turkey
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Ma L, Wang W, Zhao Y, Liu M, Ye W, Li X. Application of LRG mechanism in normal pressure hydrocephalus. Heliyon 2024; 10:e23940. [PMID: 38223707 PMCID: PMC10784321 DOI: 10.1016/j.heliyon.2023.e23940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 11/02/2023] [Accepted: 12/15/2023] [Indexed: 01/16/2024] Open
Abstract
Normal pressure hydrocephalus (NPH) is a prevalent type of hydrocephalus, including secondary normal pressure hydrocephalus (SNPH) and idiopathic normal pressure hydrocephalus (INPH). However, its clinical diagnosis and pathological mechanism are still unclear. Leucine-rich α-2 glycoprotein (LRG) is involved in various human diseases, including cancer, diabetes, cardiovascular disease, and nervous system diseases. Now the physiological mechanism of LRG is still being explored. According to the current research results on LRG, we found that the agency of LRG has much to do with the known pathological process of NPH. This review focuses on analyzing the LRG signaling pathways and the pathological mechanism of NPH. According to the collected literature evidence, we speculated that LRG probably be involved in the pathological process of NPH. Finally, based on the mechanism of LRG and NPH, we also summarized the evidence of molecular targeted therapies for future research and clinical application.
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Affiliation(s)
| | | | - Yongqiang Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Menghao Liu
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Wei Ye
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
| | - Xianfeng Li
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150086, China
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Irie K, Yamamoto T. Serum leucine-rich α2-glycoprotein is a useful biomarker for generalized pustular psoriasis. Exp Dermatol 2024; 33:e14942. [PMID: 37770416 DOI: 10.1111/exd.14942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 08/23/2023] [Accepted: 09/11/2023] [Indexed: 09/30/2023]
Affiliation(s)
- Kinuko Irie
- Department of Dermatology, Fukushima Medical University, Fukushima, Japan
| | - Toshiyuki Yamamoto
- Department of Dermatology, Fukushima Medical University, Fukushima, Japan
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Kawamoto A, Takenaka K, Hibiya S, Kitazume Y, Shimizu H, Fujii T, Saito E, Ohtsuka K, Okamoto R. Combination of leucine-rich alpha-2 glycoprotein and fecal markers detect Crohn's disease activity confirmed by balloon-assisted enteroscopy. Intest Res 2024; 22:65-74. [PMID: 37939721 PMCID: PMC10850704 DOI: 10.5217/ir.2023.00092] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/13/2023] [Accepted: 10/05/2023] [Indexed: 11/10/2023] Open
Abstract
BACKGROUND/AIMS Endoscopic activity confirmed by enteroscopy is associated with poor clinical outcome in Crohn's disease (CD). We investigated which of the existing biomarkers best reflects endoscopic activity in CD patients including the small bowel, and whether their combined use can improve accuracy. METHODS One hundred and four consecutive patients with ileal and ileocolonic type CD who underwent balloon-assisted enteroscopy (BAE) from October 2021 to August 2022 were enrolled, with clinical and laboratory data prospectively collected and analyzed. RESULTS Hemoglobin, platelet count, C-reactive protein, leucine-rich alpha-2 glycoprotein (LRG), fecal calprotectin, and fecal hemoglobin all showed significant difference in those with ulcers found on BAE. LRG and fecal calprotectin showed the highest areas under the curve (0.841 and 0.853) for detecting ulcers. LRG showed a sensitivity of 78% and specificity of 80% at a cutoff value of 13 μg/mL, whereas fecal calprotectin showed a sensitivity of 91% and specificity of 67% at a cutoff value of 151 μg/g. Dual positivity for LRG and fecal calprotectin, as well as LRG and fecal hemoglobin, both predicted ulcers with an improved specificity of 92% and 100%. A positive LRG or fecal calprotectin/hemoglobin showed an improved sensitivity of 96% and 91%. Positivity for LRG and either of the fecal biomarkers was associated with increased risk of hospitalization, surgery, and relapse. CONCLUSIONS The biomarkers LRG, fecal calprotectin, and fecal hemoglobin can serve as noninvasive and accurate tools for assessing activity in CD patients confirmed by BAE, especially when used in combination.
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Affiliation(s)
- Ami Kawamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Endoscopic Unit, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kento Takenaka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shuji Hibiya
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Endoscopic Unit, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshio Kitazume
- Department of Radiology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiromichi Shimizu
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshimitsu Fujii
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Eiko Saito
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuo Ohtsuka
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Endoscopic Unit, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ryuichi Okamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Tokyo, Japan
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21
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Park J. Which biomarkers best reflect the degree of inflammation in Crohn's disease? Intest Res 2024; 22:1-2. [PMID: 38327001 PMCID: PMC10850703 DOI: 10.5217/ir.2023.00161] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 11/14/2023] [Indexed: 02/09/2024] Open
Affiliation(s)
- Jihye Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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22
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Lucaciu LA, Seicean R, Uifălean A, Iacobescu M, Iuga CA, Seicean A. Unveiling Distinct Proteomic Signatures in Complicated Crohn's Disease That Could Predict the Disease Course. Int J Mol Sci 2023; 24:16966. [PMID: 38069288 PMCID: PMC10707401 DOI: 10.3390/ijms242316966] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 12/18/2023] Open
Abstract
Crohn's disease (CD) is characterized by a chronic, progressive inflammation of the gastrointestinal tract often leading to complications, such as strictures and fistulae. Currently, there are no validated tools anticipating short- and long-term outcomes at an early stage. This investigation aims to elucidate variations in protein abundance across distinct CD phenotypes with the objective of uncovering potential biomarkers implicated in disease advancement. Serum samples collected from 30 CD patients and 15 healthy age-matched controls (HC) were subjected to depletion of highly abundant proteins and to a label-free mass spectrometry analysis. Twenty-four proteins were shown to be significantly different when comparing CD with HC. Of these, WD repeat-containing protein 31 (WDR31), and proteins involved in the acute inflammatory response, leucine-rich alpha-2-glycoprotein (LRG1) and serum amyloid A1 (SAA1), were more abundant in the aggressive subgroup. Against standard biomarkers, a positive correlation between SAA1 and WDR31 and C-reactive protein (CRP) was found. In this study, a unique serum biomarker panel for aggressive CD was identified, which could aid in predicting the disease course.
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Affiliation(s)
- Laura A. Lucaciu
- Department of Gastroenterology and Hepatology, “Iuliu Haţieganu” University of Medicine and Pharmacy, Croitorilor 19-21, 400162 Cluj-Napoca, Romania; (L.A.L.); (A.S.)
| | - Radu Seicean
- Department of General Surgery, First Surgical Clinic, “Iuliu Haţieganu” University of Medicine and Pharmacy, Clinicilor 3-5, 400006 Cluj-Napoca, Romania;
| | - Alina Uifălean
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, “Iuliu Haţieganu” University of Medicine and Pharmacy, Louis Pasteur 6, 400349 Cluj-Napoca, Romania; (A.U.); (C.A.I.)
| | - Maria Iacobescu
- Department of Proteomics and Metabolomics, MEDFUTURE-Research Centre for Advanced Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, Louis Pasteur 4, 400349 Cluj-Napoca, Romania
| | - Cristina A. Iuga
- Department of Pharmaceutical Analysis, Faculty of Pharmacy, “Iuliu Haţieganu” University of Medicine and Pharmacy, Louis Pasteur 6, 400349 Cluj-Napoca, Romania; (A.U.); (C.A.I.)
- Department of Proteomics and Metabolomics, MEDFUTURE-Research Centre for Advanced Medicine, “Iuliu Haţieganu” University of Medicine and Pharmacy, Louis Pasteur 4, 400349 Cluj-Napoca, Romania
| | - Andrada Seicean
- Department of Gastroenterology and Hepatology, “Iuliu Haţieganu” University of Medicine and Pharmacy, Croitorilor 19-21, 400162 Cluj-Napoca, Romania; (L.A.L.); (A.S.)
- “Prof. Dr. Octavian Fodor” Regional Institute of Gastroenterology and Hepatology, Croitorilor Street No. 19-21, 400162 Cluj-Napoca, Romania
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Yamazato M, Yanai S, Oizumi T, Eizuka M, Yamada S, Toya Y, Uesugi N, Sugai T, Matsumoto T. Appropriate leucine-rich α-2 glycoprotein cut-off value for Japanese patients with ulcerative colitis. World J Clin Cases 2023; 11:7753-7760. [DOI: 10.12998/wjcc.v11.i32.7753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/18/2023] [Accepted: 11/02/2023] [Indexed: 11/16/2023] Open
Abstract
BACKGROUND It has been suggested that serum leucine-rich α-2 glycoprotein (LRG) could be a novel monitoring biomarker for the assessment of disease activity in inflammatory bowel disease. In particular, the relationship between LRG levels and the endoscopically assessed activity of ulcerative colitis (UC) has become a matter of interest.
AIM To clarify appropriate LRG cut-off values for the prediction of endoscopic and histologic remission in Japanese patients with UC.
METHODS This was a cross-sectional, single-center, observational study of Japanese patients with UC. Among 213 patients with UC, in whom LRG was measured from September 2020 to February 2022, we recruited 30 patients for whom a total colonoscopy and measurements of LRG and C-reactive protein (CRP) were performed on the same day. We retrospectively analyzed correlations between the LRG and CRP levels and endoscopic indices, including the Mayo endoscopic subscore and UC endoscopic index of severity.
RESULTS Correlations between the LRG values and the Mayo endoscopic subscore or UC endoscopic index of severity were significant (r = 0.754, P < 0.0001; r = 0.778, P < 0.0001, respectively). There were also significant correlations between CRP levels and Mayo endoscopic subscore or UC endoscopic index of severity (r = 0.599, P = 0.0005; r = 0.563, P = 0.0012, respectively), although the correlation coefficients were higher for LRG. The LRG cut-off value for predicting endoscopic remission was 13.4 μg/mL for a Mayo endoscopic subscore of 0 [area under the curve (AUC): 0.871; 95% confidence interval (CI): 0.744–0.998], and 13.4 μg/mL for an UC endoscopic index of severity of 0 or 1 (AUC: 0.904; 95%CI: 0.792–1.000).
CONCLUSION LRG may be a surrogate marker for endoscopic activity in UC, with a cut-off value of around 13.4 μg/mL for endoscopically inactive disease.
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Affiliation(s)
- Masanao Yamazato
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Yahaba 028-3695, Japan
| | - Shunichi Yanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Yahaba 028-3695, Japan
| | - Tomofumi Oizumi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Yahaba 028-3695, Japan
| | - Makoto Eizuka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Yahaba 028-3695, Japan
| | - Shun Yamada
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Yahaba 028-3695, Japan
| | - Yosuke Toya
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Yahaba 028-3695, Japan
| | - Noriyuki Uesugi
- Division of Molecular Diagnostic Pathology, Iwate Medical University, Yahaba 028-3695, Japan
| | - Tamotsu Sugai
- Division of Molecular Diagnostic Pathology, Iwate Medical University, Yahaba 028-3695, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Iwate Medical University, Yahaba 028-3695, Japan
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Shimoyama T, Yamamoto T, Yoshiyama S, Nishikawa R, Umegae S. Leucine-Rich Alpha-2 Glycoprotein Is a Reliable Serum Biomarker for Evaluating Clinical and Endoscopic Disease Activity in Inflammatory Bowel Disease. Inflamm Bowel Dis 2023; 29:1399-1408. [PMID: 36334015 DOI: 10.1093/ibd/izac230] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Leucine-rich alpha-2 glycoprotein (LRG) is a novel serum biomarker for inflammation in inflammatory bowel disease (IBD). This prospective study aimed to compare the value of LRG with C-reactive protein (CRP) and fecal calprotectin for evaluating clinical and endoscopic disease activity in patients with IBD. METHODS At entry, clinical and endoscopic disease activity was assessed in 267 patients with IBD (ulcerative colitis [UC] 203; Crohn's disease [CD] 64), and the levels of LRG, CRP and fecal calprotectin were measured. The accuracy of the biomarkers for the detection of clinical and endoscopic disease activity was determined by the area under the receiver operating characteristic curve. RESULTS Leucine-rich alpha-2 glycoprotein showed a significant relationship with the clinical and endoscopic severity in both UC and CD (both diseases, P < .0001). In the clinical assessment of UC, the accuracy of LRG was significantly higher than that of CRP (0.73 vs 0.63; P < .001). In the endoscopic assessment of UC, the accuracy of LRG was significantly higher than that of CRP (P = .01), but it was significantly lower than that of fecal calprotectin (P = .009; LRG, 0.80; CRP, 0.72; fecal calprotectin, 0.91). In the clinical and endoscopic assessment of CD, the accuracy was not significantly different between the biomarkers (clinical activity: LRG, 0.71; CRP, 0.64; fecal calprotectin, 0.66; in endoscopic activity: LRG, 0.79; CRP, 0.78; fecal calprotectin, 0.81). CONCLUSIONS Leucine-rich alpha-2 glycoprotein is a reliable serum biomarker for the assessment of clinical and endoscopic disease activity in patients with IBD. It can be an alternative to CRP for the assessment of UC.
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Affiliation(s)
- Takahiro Shimoyama
- Inflammatory Bowel Disease Center, Yokkaichi Hazu Medical Center, Yokkaichi, Mie, Japan
| | - Takayuki Yamamoto
- Inflammatory Bowel Disease Center, Yokkaichi Hazu Medical Center, Yokkaichi, Mie, Japan
| | - Shigeyuki Yoshiyama
- Inflammatory Bowel Disease Center, Yokkaichi Hazu Medical Center, Yokkaichi, Mie, Japan
| | - Ryutaro Nishikawa
- Inflammatory Bowel Disease Center, Yokkaichi Hazu Medical Center, Yokkaichi, Mie, Japan
| | - Satoru Umegae
- Inflammatory Bowel Disease Center, Yokkaichi Hazu Medical Center, Yokkaichi, Mie, Japan
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25
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Yekani M, Memar MY. Immunologic biomarkers for bacterial meningitis. Clin Chim Acta 2023; 548:117470. [PMID: 37419301 DOI: 10.1016/j.cca.2023.117470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 07/03/2023] [Accepted: 07/04/2023] [Indexed: 07/09/2023]
Abstract
Meningitis is defined as the inflammation of the meninges that is most often caused by various bacterial and viral pathogens, and is associated with high rates of mortality and morbidity. Early detection of bacterial meningitis is essential to appropriate antibiotic therapy. Alterations in immunologic biomarkers levels have been considered the diagnostic approach in medical laboratories for the identifying of infections. The early increasing immunologic mediators such as cytokines and acute phase proteins (APPs) during bacterial meningitis have made they significant indicators for laboratory diagnosis. Immunology biomarkers showed wide variable sensitivity and specificity values that influenced by different reference values, selected a certain cutoff point, methods of detection, patient characterization and inclusion criteria, as well as etiology of meningitis and time of CSF or blood specimens' collection. This study provides an overview of different immunologic biomarkers as diagnostic markers for the identification of bacterial meningitis and their efficiencies in the differentiating of bacterial from viral meningitis.
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Affiliation(s)
- Mina Yekani
- Department of Microbiology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Yousef Memar
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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26
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Umezawa N, Mizoguchi F, Maejima Y, Kimura N, Hasegawa H, Hosoya T, Fujimoto M, Kohsaka H, Naka T, Yasuda S. Leucine-rich alpha-2 glycoprotein as a potential biomarker for large vessel vasculitides. Front Med (Lausanne) 2023; 10:1153883. [PMID: 37215715 PMCID: PMC10196172 DOI: 10.3389/fmed.2023.1153883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 04/20/2023] [Indexed: 05/24/2023] Open
Abstract
Objectives Serum levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) have been used as useful biomarkers for reflecting the activity of large vessel vasculitides (LVV). However, a novel biomarker that could have a complementary role to these markers is still required. In this retrospective observational study, we investigated whether leucine-rich α-2 glycoprotein (LRG), a known biomarker in several inflammatory diseases, could be a novel biomarker for LVVs. Methods 49 eligible patients with Takayasu arteritis (TAK) or giant cell arteritis (GCA) whose serum was preserved in our laboratory were enrolled. The concentrations of LRG were measured with an enzyme-linked immunosorbent assay. The clinical course was reviewed retrospectively from their medical records. The disease activity was determined according to the current consensus definition. Results The serum LRG levels were higher in patients with active disease than those in remission, and decreased after the treatments. While LRG levels were positively correlated with both CRP and erythrocyte sedimentation rate, LRG exhibited inferior performance as an indicator of disease activity compared to CRP and ESR. Of 35 CRP-negative patients, 11 had positive LRG. Among the 11 patients, two had active disease. Conclusion This preliminary study indicated that LRG could be a novel biomarker for LVV. Further large studies should be required to promise the significance of LRG in LVV.
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Affiliation(s)
- Natsuka Umezawa
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Fumitaka Mizoguchi
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Yasuhiro Maejima
- Department of Cardiovascular Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Naoki Kimura
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hisanori Hasegawa
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tadashi Hosoya
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Minoru Fujimoto
- Department of Clinical Immunology, Kochi Medical School, Kochi University, Kochi, Japan
- Division of Allergy and Rheumatology, Department of Internal Medicine, School of Medicine Iwate Medical University, Yahaba, Japan
| | - Hitoshi Kohsaka
- Rheumatology Center, Chiba-Nishi General Hospital, Matsudo, Japan
| | - Tetsuji Naka
- Department of Clinical Immunology, Kochi Medical School, Kochi University, Kochi, Japan
- Division of Allergy and Rheumatology, Department of Internal Medicine, School of Medicine Iwate Medical University, Yahaba, Japan
| | - Shinsuke Yasuda
- Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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27
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Abazari O, Shakibaee A, Shahriary A, Arabzadeh E, Hofmeister M. Hepatoprotective effects of moderate-intensity interval training along with ginger juice in an old male rat model. Pflugers Arch 2023; 475:437-452. [PMID: 36692542 DOI: 10.1007/s00424-023-02787-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 01/03/2023] [Accepted: 01/04/2023] [Indexed: 01/25/2023]
Abstract
Aging is a natural process coupled with oxidative stress and chronic inflammation, gradually associated with losing organ function over time. Therefore, the objective of the current work was to peruse the protective effects of 8-week moderate-intensity interval training (MIIT) and ginger extract supplementation on some biomarkers of oxidative stress, inflammation, and lipid metabolism in the liver of elderly males Wistar rats (animal study with ethical code IR.BMSU.REC.1401.015). A total of thirty-two 22-month-aged male Wistar rats were randomly assigned to four groups: (1) control, (2) MIIT, (3) ginger, and (4) MIIT + ginger. After 8 weeks of treadmill training and ginger extract supplementation, the biochemical parameters (liver enzyme and lipid profile), inflammatory mediators (leucine-rich α-2 glycoprotein 1 (LRG1), tumor necrosis factor-alpha, and interleukin-6), pro-oxidant (malondialdehyde), antioxidant biomarkers (catalase, superoxide dismutase, total antioxidant capacity), some lipid metabolism regulators (carnitine palmitoyltransferase 1, adipose triglyceride lipase, acetyl-CoA carboxylase, CD36, and AMP-activated protein kinase), and liver histopathological changes were appraised. The acquired findings pointed out that MIIT combined with ginger extract appreciably diminished the serum levels of LRG1, liver enzymes, and lipid profile relative to the other groups after 8 weeks of intervention. Furthermore, ginger + MIIT caused a great improvement in the liver levels of antioxidant biomarkers, pro-oxidant, pro-inflammatory biomarkers, lipid metabolism regulators, and liver tissue impairment compared to the other groups. The findings suggested that MIIT + ginger was more effective in improving examined indices relative to the other groups.
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Affiliation(s)
- Omid Abazari
- Student Research Committee, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Abolfazl Shakibaee
- Exercise Physiology Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Alireza Shahriary
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ehsan Arabzadeh
- Exercise Physiology Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Martin Hofmeister
- Department of Food and Nutrition, Consumer Centre of the German Federal State of Bavaria, Munich, Germany
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Tintor G, Jukić M, Šupe-Domić D, Jerončić A, Pogorelić Z. Diagnostic Accuracy of Leucine-Rich α-2-Glycoprotein 1 as a Non-Invasive Salivary Biomarker in Pediatric Appendicitis. Int J Mol Sci 2023; 24:ijms24076043. [PMID: 37047015 PMCID: PMC10094467 DOI: 10.3390/ijms24076043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/19/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
The aim of this study is to evaluate the diagnostic accuracy of leucine-rich α-2-glycoprotein 1 (LRG1) in saliva as a novel biomarker for acute appendicitis in the pediatric population. From October 2021 to June 2022, 92 children aged 5 to 17 years who presented with acute abdomen and suspected acute appendicitis were enrolled in this prospective study. The parameters documented included demographic and clinical information, as well as operative and postoperative data. Patients were divided into two groups: those with acute appendicitis who underwent laparoscopic appendectomy (n = 46) and those without appendicitis (n = 46). The total white blood cell (WBC) count, percent of neutrophils, C-reactive protein (CRP) level, and salivary LRG1 were compared between groups. A commercially available enzyme-linked immunosorbent assay (ELISA) LRG kit was used to measure the LRG levels. The median salivary LRG1 level was significantly higher in the group of children with pathohistologically confirmed acute appendicitis compared to the control group: 233.45 ng/mL (IQR 114.9, 531.2) vs. 55.95 ng/mL (IQR 51.5, 117.9), p < 0.001. LRG1 had an overall good receiver-operator characteristic area under the curve of 0.85 (95% CI 0.76-0.92; p < 0.001). The optimal LRG1 cutoff with best separation between acute appendicitis and the controls was >352.6 ng/mL (95% CI from >270.7 to >352.6). Although the specificity was 100% at this cutoff, the sensitivity for identifying appendicitis was 36%. In addition, a significant difference was found between groups in the laboratory values of all inflammatory markers tested: WBC, absolute neutrophil count, and CRP (p < 0.001 for all). Although LRG1 in saliva showed a good AUC parameter and significantly higher values in patients with acute appendicitis compared to the controls, its usefulness in the patient population who present at emergency departments with abdominal pain is debatable. Future studies should focus on investigating its diagnostic potential.
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Affiliation(s)
- Goran Tintor
- Department of Plastic Reconstructive and Aesthetic Surgery, University Hospital of Split, 21 000 Split, Croatia
- Department of Surgery, School of Medicine, University of Split, 21 000 Split, Croatia
| | - Miro Jukić
- Department of Surgery, School of Medicine, University of Split, 21 000 Split, Croatia
- Department of Pediatric Surgery, University Hospital of Split, 21 000 Split, Croatia
| | - Daniela Šupe-Domić
- Department of Medical Laboratory Diagnostics, University Hospital of Split, 21 000 Split, Croatia
| | - Ana Jerončić
- Department of Research in Biomedicine and Health, School of Medicine, University of Split, 21 000 Split, Croatia
| | - Zenon Pogorelić
- Department of Surgery, School of Medicine, University of Split, 21 000 Split, Croatia
- Department of Pediatric Surgery, University Hospital of Split, 21 000 Split, Croatia
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Tintor G, Jukić M, Šupe-Domić D, Jerončić A, Pogorelić Z. Diagnostic Utility of Serum Leucine-Rich α-2-Glycoprotein 1 for Acute Appendicitis in Children. J Clin Med 2023; 12:2455. [PMID: 37048540 PMCID: PMC10094962 DOI: 10.3390/jcm12072455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/15/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
PURPOSE The aim of this study is to assess the diagnostic utility of serum leucine-rich α-2-glycoprotein 1 (LRG1) in pediatric patients with acute abdominal pain, admitted to the emergency surgical unit, in order to make a prompt and accurate diagnosis of acute appendicitis. PATIENTS AND METHODS Pediatric patients older than 5 years of age who presented to the emergency department from 15 October 2021 to 30 June 2022 with acute abdominal pain and suspected acute appendicitis were prospectively recruited in the study. Demographic and clinical data, as well as operative and postoperative data, were recorded. A total of 92 patients were equally distributed into two groups: children with acute appendicitis who underwent laparoscopic appendectomy and non-appendicitis patients, presenting with non-specific abdominal pain. LRG1 levels were determined using a commercially available LRG1 enzyme-linked immunosorbent assay (ELISA) kit. Serum LRG1 levels, as well as other inflammatory markers (white blood cell count (WBC), C-reactive protein (CRP) and absolute neutrophil count) were compared between groups. RESULTS The median level of LRG1 in serum was significantly higher in the group of children with pathohistologically confirmed acute appendicitis than in the control group, at 350.3 µg/mL (interquartile range (IQR) 165.2-560.3) and 25.7 µg/mL (IQR 14.7-36.8) (p < 0.001), respectively. Receiver operating characteristic area under the curve for LRG1 from serum was 1.0 (95% CI 0.96-1.00; p < 0.001) and the value of >69.1 µg/mL was found to perfectly separate acute appendicitis cases from controls. Additionally, as expected, each of the examined laboratory inflammatory markers provided a significantly higher values in the acute appendicitis group compared to the control group: WBC 14.6 × 109/L (IQR 12.7, 18.7) vs. 7.0 × 109/L (IQR 5.4, 9.0) (p < 0.001), CRP 16.3 mg/dL (IQR 6.9, 50.4) vs. 2.2 mg/dL (IQR 2, 2) (p < 0.001) and absolute neutrophil count 84.6% (IQR 79.5, 89.0) vs. 59.5% (IQR 51.5, 68.6) (p < 0.001). CONCLUSIONS LRG1 in the serum was found to be a promising novel biomarker, with excellent differentiation of acute appendicitis from non-appendicitis cases in children presenting with non-specific abdominal pain.
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Affiliation(s)
- Goran Tintor
- Department of Plastic Reconstructive and Aesthetic Surgery, University Hospital of Split, 21000 Split, Croatia;
- Department of Surgery, School of Medicine, University of Split, 21000 Split, Croatia;
| | - Miro Jukić
- Department of Surgery, School of Medicine, University of Split, 21000 Split, Croatia;
- Department of Pediatric Surgery, University Hospital of Split, 21000 Split, Croatia
| | - Daniela Šupe-Domić
- Department of Medical Laboratory Diagnostics, University Hospital of Split, 21000 Split, Croatia;
- Department of Health Studies, University of Split, 21000 Split, Croatia
| | - Ana Jerončić
- Department of Research in Biomedicine and Health, School of Medicine, University of Split, 21000 Split, Croatia;
| | - Zenon Pogorelić
- Department of Surgery, School of Medicine, University of Split, 21000 Split, Croatia;
- Department of Pediatric Surgery, University Hospital of Split, 21000 Split, Croatia
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Ohmichi T, Kasai T, Shinomoto M, Kitani-Morii F, Fujino Y, Menjo K, Mizuno T. Serum leucine-rich α2 glycoprotein as a potential biomarker for systemic inflammation in Parkinson's disease. PLoS One 2023; 18:e0282153. [PMID: 36812242 PMCID: PMC9946247 DOI: 10.1371/journal.pone.0282153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 02/07/2023] [Indexed: 02/24/2023] Open
Abstract
There is ample epidemiological and animal-model evidence suggesting that intestinal inflammation is associated with the development of Parkinson's disease (PD). Leucine-rich α2 glycoprotein (LRG) is a serum inflammatory biomarker used to monitor the activity of autoimmune diseases, including inflammatory bowel diseases. In this study, we aimed to investigate whether serum LRG could be used a biomarker of systemic inflammation in PD and to help distinguish disease states. Serum LRG and C-reactive protein (CRP) levels were measured in 66 patients with PD and 31 age-matched controls. We found that serum LRG levels were statistically significantly higher in the PD group than in the control group (PD: 13.9 ± 4.2 ng/mL, control: 12.1 ± 2.7 ng/mL, p = 0.036). LRG levels were also correlated with Charlson comorbidity index (CCI) and CRP levels. LRG levels in the PD group were correlated with Hoehn and Yahr stages (Spearman's r = 0.40, p = 0.008). LRG levels were statistically significantly elevated in PD patients with dementia as compared to those without dementia (p = 0.0078). Multivariate analysis revealed a statistically significant correlation between PD and serum LRG levels after adjusting for serum CRP levels, and CCI (p = 0.019). We conclude that serum LRG levels could be considered a potential biomarker for systemic inflammation in PD.
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Affiliation(s)
- Takuma Ohmichi
- Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takashi Kasai
- Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan
- * E-mail:
| | - Makiko Shinomoto
- Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Fukiko Kitani-Morii
- Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Department of Molecular Pathobiology of Brain Diseases, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Yuzo Fujino
- Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kanako Menjo
- Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Toshiki Mizuno
- Department of Neurology, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Kobayashi M, Nakamura O, Kitahara Y, Inoue N, Tsukui Y, Hasegawa Y, Hiraishi H, Yabuki A, Muraoka A, Osuka S, Iwase A. Serum leucine-rich α2-glycoprotein as a possible marker for inflammatory status in endometriosis. Reprod Med Biol 2023; 22:e12536. [PMID: 37608861 PMCID: PMC10441181 DOI: 10.1002/rmb2.12536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 07/10/2023] [Accepted: 08/07/2023] [Indexed: 08/24/2023] Open
Abstract
Purpose This study aimed to investigate whether serum leucine-rich α2-glycoprotein (LRG) is a useful diagnostic biomarker for endometriosis, including the evaluation of treatment efficacy and exploration of LRG production in endometriotic lesions. Methods Forty-three women with endometriomas were compared to 22 women with benign ovarian cysts and 30 women who underwent assisted reproduction as controls. Changes in serum LRG levels were assessed before and after surgery, and during dienogest treatment. LRG expression in endometriotic tissue samples was evaluated using immunoblotting. Results Serum LRG levels in the endometrioma group (80.0 ± 36.3 μg/mL) were significantly higher than those in the benign ovarian cyst (65.1 ± 27.0 μg/mL, p = 0.0265) and control (57.8 ± 22.3 μg/mL, p = 0.0028) groups. Serum LRG levels after endometrioma surgery were significantly lower than preoperative levels (p = 0.0484). Serum LRG levels consistently decreased during dienogest treatment. LRG expression levels were significantly higher in endometriotic tissues than in the normal endometrium. Conclusion Serum LRG, possibly derived from local and systemic origins, could be used as a potential biomarker for the diagnosis and treatment of endometriosis.
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Affiliation(s)
- Mio Kobayashi
- Department of Obstetrics and GynecologyGunma University Graduate School of MedicineMaebashiJapan
| | - Orie Nakamura
- Department of Obstetrics and GynecologyGunma University Graduate School of MedicineMaebashiJapan
| | - Yoshikazu Kitahara
- Department of Obstetrics and GynecologyGunma University Graduate School of MedicineMaebashiJapan
| | - Naoki Inoue
- Department of Obstetrics and GynecologyGunma University Graduate School of MedicineMaebashiJapan
| | - Yumiko Tsukui
- Department of Obstetrics and GynecologyGunma University Graduate School of MedicineMaebashiJapan
| | - Yuko Hasegawa
- Department of Obstetrics and GynecologyGunma University Graduate School of MedicineMaebashiJapan
| | - Hikaru Hiraishi
- Department of Obstetrics and GynecologyGunma University Graduate School of MedicineMaebashiJapan
| | - Atsushi Yabuki
- Department of Obstetrics and GynecologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Ayako Muraoka
- Department of Obstetrics and GynecologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Satoko Osuka
- Department of Obstetrics and GynecologyNagoya University Graduate School of MedicineNagoyaJapan
| | - Akira Iwase
- Department of Obstetrics and GynecologyGunma University Graduate School of MedicineMaebashiJapan
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Filipović M, Flegar D, Aničić S, Šisl D, Kelava T, Kovačić N, Šućur A, Grčević D. Transcriptome profiling of osteoclast subsets associated with arthritis: A pathogenic role of CCR2 hi osteoclast progenitors. Front Immunol 2022; 13:994035. [PMID: 36591261 PMCID: PMC9797520 DOI: 10.3389/fimmu.2022.994035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 11/14/2022] [Indexed: 12/23/2022] Open
Abstract
Introduction The existence of different osteoclast progenitor (OCP) subsets has been confirmed by numerous studies. However, pathological inflammation-induced osteoclastogenesis remains incompletely understood. Detailed characterization of OCP subsets may elucidate the pathophysiology of increased osteoclast activity causing periarticular and systemic bone resorption in arthritis. In our study, we rely on previously defined OCP subsets categorized by the level of CCR2 expression as circulatory-like committed CCR2hi OCPs, which are substantially expanded in arthritis, and marrow-resident CCR2lo OCPs of immature phenotype and behavior. Methods In order to perform transcriptome characterization of those subsets in the context of collagen-induced arthritis (CIA), we sorted CCR2hi and CCR2lo periarticular bone marrow OCPs of control and arthritic mice, and performed next-generation RNA sequencing (n=4 for each group) to evaluate the differential gene expression profile using gene set enrichment analysis with further validation. Results A disparity between CCR2hi and CCR2lo subset transcriptomes (863 genes) was detected, with the enrichment of pathways for osteoclast differentiation, chemokine and NOD-like receptor signaling in the CCR2hi OCP subset, and ribosome biogenesis in eukaryotes and ribosome pathways in the CCR2lo OCP subset. The effect of intervention (CIA) within each subset was greater in CCR2hi (92 genes) than in CCR2lo (43 genes) OCPs. Genes associated with the osteoclastogenic pathway (Fcgr1, Socs3), and several genes involved in cell adhesion and migration (F11r, Cd38, Lrg1) identified the CCR2hi subset and distinguish CIA from control group, as validated by qPCR (n=6 for control mice, n=9 for CIA mice). The latter gene set showed a significant positive correlation with arthritis clinical score and frequency of CCR2hi OCPs. Protein-level validation by flow cytometry showed increased proportion of OCPs expressing F11r/CD321, CD38 and Lrg1 in CIA, indicating that they could be used as disease markers. Moreover, osteoclast pathway-identifying genes remained similarly expressed (Fcgr1) or even induced by several fold (Socs3) in preosteoclasts differentiated in vitro from CIA mice compared to pre-cultured levels, suggesting their importance for enhanced osteoclastogenesis of the CCR2hi OCPs in arthritis. Conclusion Our approach detected differentially expressed genes that could identify distinct subset of OCPs associated with arthritis as well as indicate possible therapeutic targets aimed to modulate osteoclast activity.
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Affiliation(s)
- Maša Filipović
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Darja Flegar
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Sara Aničić
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Dino Šisl
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Tomislav Kelava
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Nataša Kovačić
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia,Department of Anatomy, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Alan Šućur
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia,*Correspondence: Alan Šućur, ; Danka Grčević,
| | - Danka Grčević
- Department of Physiology and Immunology, University of Zagreb School of Medicine, Zagreb, Croatia,Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia,*Correspondence: Alan Šućur, ; Danka Grčević,
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Choi CHJ, Barr W, Zaman S, Model C, Park A, Koenen M, Lin Z, Szwed SK, Marchildon F, Crane A, Carroll TS, Molina H, Cohen P. LRG1 is an adipokine that promotes insulin sensitivity and suppresses inflammation. eLife 2022; 11:e81559. [PMID: 36346018 PMCID: PMC9674348 DOI: 10.7554/elife.81559] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 11/06/2022] [Indexed: 11/11/2022] Open
Abstract
While dysregulation of adipocyte endocrine function plays a central role in obesity and its complications, the vast majority of adipokines remain uncharacterized. We employed bio-orthogonal non-canonical amino acid tagging (BONCAT) and mass spectrometry to comprehensively characterize the secretome of murine visceral and subcutaneous white and interscapular brown adip ocytes. Over 600 proteins were identified, the majority of which showed cell type-specific enrichment. We here describe a metabolic role for leucine-rich α-2 glycoprotein 1 (LRG1) as an obesity-regulated adipokine secreted by mature adipocytes. LRG1 overexpression significantly improved glucose homeostasis in diet-induced and genetically obese mice. This was associated with markedly reduced white adipose tissue macrophage accumulation and systemic inflammation. Mechanistically, we found LRG1 binds cytochrome c in circulation to dampen its pro-inflammatory effect. These data support a new role for LRG1 as an insulin sensitizer with therapeutic potential given its immunomodulatory function at the nexus of obesity, inflammation, and associated pathology.
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Affiliation(s)
- Chan Hee J Choi
- Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD ProgramNew YorkUnited States
- Laboratory of Molecular Metabolism, Rockefeller UniversityNew YorkUnited States
| | - William Barr
- Laboratory of Molecular Metabolism, Rockefeller UniversityNew YorkUnited States
| | - Samir Zaman
- Laboratory of Molecular Metabolism, Rockefeller UniversityNew YorkUnited States
| | - Corey Model
- Laboratory of Molecular Metabolism, Rockefeller UniversityNew YorkUnited States
| | - Annsea Park
- Department of Immunobiology, Yale UniversityNew HavenUnited States
| | - Mascha Koenen
- Laboratory of Molecular Metabolism, Rockefeller UniversityNew YorkUnited States
| | - Zeran Lin
- Laboratory of Molecular Metabolism, Rockefeller UniversityNew YorkUnited States
| | - Sarah K Szwed
- Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD ProgramNew YorkUnited States
- Laboratory of Molecular Metabolism, Rockefeller UniversityNew YorkUnited States
| | - Francois Marchildon
- Laboratory of Molecular Metabolism, Rockefeller UniversityNew YorkUnited States
| | - Audrey Crane
- Laboratory of Molecular Metabolism, Rockefeller UniversityNew YorkUnited States
| | - Thomas S Carroll
- Bioinformatics Resouce Center, Rockefeller UniversityNew YorkUnited States
| | - Henrik Molina
- Proteomics Resource Center, Rockefeller UniversityNew YorkUnited States
| | - Paul Cohen
- Laboratory of Molecular Metabolism, Rockefeller UniversityNew YorkUnited States
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Roodenrijs NMT, Welsing PMJ, van Roon J, Schoneveld JLM, van der Goes MC, Nagy G, Townsend MJ, van Laar JM. Mechanisms underlying DMARD inefficacy in difficult-to-treat rheumatoid arthritis: a narrative review with systematic literature search. Rheumatology (Oxford) 2022; 61:3552-3566. [PMID: 35238332 PMCID: PMC9434144 DOI: 10.1093/rheumatology/keac114] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/07/2022] [Accepted: 02/14/2022] [Indexed: 12/03/2022] Open
Abstract
Management of RA patients has significantly improved over the past decades. However, a substantial proportion of patients is difficult-to-treat (D2T), remaining symptomatic after failing biological and/or targeted synthetic DMARDs. Multiple factors can contribute to D2T RA, including treatment non-adherence, comorbidities and co-existing mimicking diseases (e.g. fibromyalgia). Additionally, currently available biological and/or targeted synthetic DMARDs may be truly ineffective ('true' refractory RA) and/or lead to unacceptable side effects. In this narrative review based on a systematic literature search, an overview of underlying (immune) mechanisms is presented. Potential scenarios are discussed including the influence of different levels of gene expression and clinical characteristics. Although the exact underlying mechanisms remain largely unknown, the heterogeneity between individual patients supports the assumption that D2T RA is a syndrome involving different pathogenic mechanisms.
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Affiliation(s)
- Nadia M T Roodenrijs
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht
| | - Paco M J Welsing
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht
| | - Joël van Roon
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht
| | | | - Marlies C van der Goes
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht
- Department of Rheumatology, Meander Medical Center, Amersfoort, The Netherlands
| | - György Nagy
- Department of Rheumatology & Clinical Immunology
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Michael J Townsend
- Biomarker Discovery OMNI, Genentech Research & Early Development, South San Francisco, CA, USA
| | - Jacob M van Laar
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht
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Alhammad R, Abu-Farha M, Hammad MM, Thanaraj TA, Channanath A, Alam-Eldin N, Al-Sabah R, Shaban L, Alduraywish A, Al-Mulla F, Rahman A, Abubaker J. Increased LRG1 Levels in Overweight and Obese Adolescents and Its Association with Obesity Markers, Including Leptin, Chemerin, and High Sensitivity C-Reactive Protein. Int J Mol Sci 2022; 23:ijms23158564. [PMID: 35955698 PMCID: PMC9369195 DOI: 10.3390/ijms23158564] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 02/05/2023] Open
Abstract
Leucine-rich α-2 glycoprotein1 (LRG1) is a member of the leucine-rich repeat (LRR) family that is implicated in multiple diseases, including cancer, aging, and heart failure, as well as diabetes and obesity. LRG1 plays a key role in diet-induced hepatosteatosis and insulin resistance by mediating the crosstalk between adipocytes and hepatocytes. LRG1 also promotes hepatosteatosis by upregulating de novo lipogenesis in the liver and suppressing fatty acid β-oxidation. In this study, we investigated the association of LRG1 with obesity markers, including leptin and other adipokines in adolescents (11−14 years; n = 425). BMI-for-age classification based on WHO growth charts was used to define obesity. Plasma LRG1 was measured by ELISA, while other markers were measured by multiplexing assay. Median (IQR) of LRG1 levels was higher in obese (30 (25, 38) µg/mL) and overweight (30 (24, 39) µg/mL) adolescents, compared to normal-weight participants (27 (22, 35) µg/mL). The highest tertile of LRG1 had an OR [95% CI] of 2.55 [1.44, 4.53] for obesity. LRG1 was positively correlated to plasma levels of high sensitivity c-reactive protein (HsCRP) (ρ = 0.2), leptin (ρ = 0.2), and chemerin (ρ = 0.24) with p < 0.001. Additionally, it was positively associated with plasma level of IL6 (ρ = 0.17) and IL10 (ρ = 0.14) but not TNF-α. In conclusion, LRG1 levels are increased in obese adolescents and are associated with increased levels of adipogenic markers. These results suggest the usefulness of LRG1 as an early biomarker for obesity and its related pathologies in adolescents.
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Affiliation(s)
- Rashed Alhammad
- Department of Pharmacology, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait;
| | - Mohamed Abu-Farha
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City 15462, Kuwait; (M.A.-F.); (M.M.H.); (N.A.-E.)
| | - Maha M. Hammad
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City 15462, Kuwait; (M.A.-F.); (M.M.H.); (N.A.-E.)
| | - Thangavel Alphonse Thanaraj
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City 15462, Kuwait; (T.A.T.); (A.C.); (F.A.-M.)
| | - Arshad Channanath
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City 15462, Kuwait; (T.A.T.); (A.C.); (F.A.-M.)
| | - Nada Alam-Eldin
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City 15462, Kuwait; (M.A.-F.); (M.M.H.); (N.A.-E.)
| | - Reem Al-Sabah
- Department of Community Medicine and Behavioural Sciences, Faculty of Medicine, Kuwait University, Safat 13110, Kuwait;
| | - Lemia Shaban
- Department of Food Science and Nutrition, College of Life Sciences, Kuwait University, Safat 13060, Kuwait;
| | - Abdulrahman Alduraywish
- Department of Internal Medicine, College of Medicine, Jouf University, Sakaka 72388, Saudi Arabia;
| | - Fahd Al-Mulla
- Genetics and Bioinformatics Department, Dasman Diabetes Institute, Kuwait City 15462, Kuwait; (T.A.T.); (A.C.); (F.A.-M.)
| | - Abdur Rahman
- Department of Food Science and Nutrition, College of Life Sciences, Kuwait University, Safat 13060, Kuwait;
- Correspondence: (A.R.); (J.A.); Tel.: +965-2463-3321 (A.R.); +965-2224-2999 (ext. 3563) (J.A.)
| | - Jehad Abubaker
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Kuwait City 15462, Kuwait; (M.A.-F.); (M.M.H.); (N.A.-E.)
- Correspondence: (A.R.); (J.A.); Tel.: +965-2463-3321 (A.R.); +965-2224-2999 (ext. 3563) (J.A.)
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Narazaki M, Kishimoto T. Current status and prospects of IL-6–targeting therapy. Expert Rev Clin Pharmacol 2022; 15:575-592. [DOI: 10.1080/17512433.2022.2097905] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Masashi Narazaki
- Department of Advanced Clinical and Translational Immunology, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan
- Department of Respiratory Medicine, Clinical Immunology, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan
- Department of Immunopathology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Tadamitsu Kishimoto
- Laboratory of Immune Regulation, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
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The Current Status of Molecular Biomarkers for Inflammatory Bowel Disease. Biomedicines 2022; 10:biomedicines10071492. [PMID: 35884797 PMCID: PMC9312796 DOI: 10.3390/biomedicines10071492] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/20/2022] [Accepted: 06/21/2022] [Indexed: 12/12/2022] Open
Abstract
Diagnosis and prognosis of inflammatory bowel disease (IBD)-a chronic inflammation that affects the gastrointestinal tract of patients-are challenging, as most clinical symptoms are not specific to IBD, and are often seen in other inflammatory diseases, such as intestinal infections, drug-induced colitis, and monogenic diseases. To date, there is no gold-standard test for monitoring IBD. Endoscopy and imaging are essential diagnostic tools that provide information about the disease's state, location, and severity. However, the invasive nature and high cost of endoscopy make it unsuitable for frequent monitoring of disease activity in IBD patients, and even when it is possible to replace endoscopy with imaging, high cost remains a concern. Laboratory testing of blood or feces has the advantage of being non-invasive, rapid, cost-effective, and standardizable. Although the specificity and accuracy of laboratory testing alone need to be improved, it is increasingly used to monitor disease activity or to diagnose suspected IBD cases in combination with endoscopy and/or imaging. The literature survey indicates a dearth of summarization of biomarkers for IBD testing. This review introduces currently available non-invasive biomarkers of clinical importance in laboratory testing for IBD, and discusses the trends and challenges in the IBD biomarker studies.
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38
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Dritsoula A, Dowsett L, Pilotti C, O'Connor MN, Moss SE, Greenwood J. Angiopathic activity of LRG1 is induced by the IL-6/STAT3 pathway. Sci Rep 2022; 12:4867. [PMID: 35318338 PMCID: PMC8938720 DOI: 10.1038/s41598-022-08516-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 03/07/2022] [Indexed: 12/14/2022] Open
Abstract
Leucine-rich α-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that under physiological conditions is produced predominantly by the liver. In disease, its local induction promotes pathogenic neovascularisation while its inhibition leads to reduced dysfunctional angiogenesis. Here we examine the role of interleukin-6 (IL-6) in defective angiogenesis mediated by LRG1. IL-6 treatment induced LRG1 expression in endothelial cells and ex vivo angiogenesis cultures and promoted vascular growth with reduced mural cell coverage. In Lrg1-/- explants, however, IL-6 failed to stimulate angiogenesis and vessels exhibited improved mural cell coverage. IL-6 activated LRG1 transcription through the phosphorylation and binding of STAT3 to a conserved consensus site in the LRG1 promoter, the deletion of which abolished activation. Blocking IL-6 signalling in human lung endothelial cells, using the anti-IL6 receptor antibody Tocilizumab, significantly reduced LRG1 expression. Our data demonstrate that IL-6, through STAT3 phosphorylation, activates LRG1 transcription resulting in vascular destabilisation. This observation is especially timely in light of the potential role of IL-6 in COVID-19 patients with severe pulmonary microvascular complications, where targeting IL-6 has been beneficial. However, our data suggest that a therapy directed towards blocking the downstream angiopathic effector molecule LRG1 may be of greater utility.
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Affiliation(s)
- Athina Dritsoula
- Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.
| | - Laura Dowsett
- Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK
| | - Camilla Pilotti
- Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK
| | - Marie N O'Connor
- Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK
| | - Stephen E Moss
- Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK
| | - John Greenwood
- Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK
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Camilli C, Hoeh AE, De Rossi G, Moss SE, Greenwood J. LRG1: an emerging player in disease pathogenesis. J Biomed Sci 2022; 29:6. [PMID: 35062948 PMCID: PMC8781713 DOI: 10.1186/s12929-022-00790-6] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 01/11/2022] [Indexed: 12/15/2022] Open
Abstract
The secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1) was first described as a key player in pathogenic ocular neovascularization almost a decade ago. Since then, an increasing number of publications have reported the involvement of LRG1 in multiple human conditions including cancer, diabetes, cardiovascular disease, neurological disease, and inflammatory disorders. The purpose of this review is to provide, for the first time, a comprehensive overview of the LRG1 literature considering its role in health and disease. Although LRG1 is constitutively expressed by hepatocytes and neutrophils, Lrg1-/- mice show no overt phenotypic abnormality suggesting that LRG1 is essentially redundant in development and homeostasis. However, emerging data are challenging this view by suggesting a novel role for LRG1 in innate immunity and preservation of tissue integrity. While our understanding of beneficial LRG1 functions in physiology remains limited, a consistent body of evidence shows that, in response to various inflammatory stimuli, LRG1 expression is induced and directly contributes to disease pathogenesis. Its potential role as a biomarker for the diagnosis, prognosis and monitoring of multiple conditions is widely discussed while dissecting the mechanisms underlying LRG1 pathogenic functions. Emphasis is given to the role that LRG1 plays as a vasculopathic factor where it disrupts the cellular interactions normally required for the formation and maintenance of mature vessels, thereby indirectly contributing to the establishment of a highly hypoxic and immunosuppressive microenvironment. In addition, LRG1 has also been reported to affect other cell types (including epithelial, immune, mesenchymal and cancer cells) mostly by modulating the TGFβ signalling pathway in a context-dependent manner. Crucially, animal studies have shown that LRG1 inhibition, through gene deletion or a function-blocking antibody, is sufficient to attenuate disease progression. In view of this, and taking into consideration its role as an upstream modifier of TGFβ signalling, LRG1 is suggested as a potentially important therapeutic target. While further investigations are needed to fill gaps in our current understanding of LRG1 function, the studies reviewed here confirm LRG1 as a pleiotropic and pathogenic signalling molecule providing a strong rationale for its use in the clinic as a biomarker and therapeutic target.
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Affiliation(s)
- Carlotta Camilli
- Institute of Ophthalmology, University College London, London, UK.
| | - Alexandra E Hoeh
- Institute of Ophthalmology, University College London, London, UK
| | - Giulia De Rossi
- Institute of Ophthalmology, University College London, London, UK
| | - Stephen E Moss
- Institute of Ophthalmology, University College London, London, UK
| | - John Greenwood
- Institute of Ophthalmology, University College London, London, UK
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40
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He S, Ryu J, Liu J, Luo H, Lv Y, Langlais PR, Wen J, Dong F, Sun Z, Xia W, Lynch JL, Duggirala R, Nicholson BJ, Zang M, Shi Y, Zhang F, Liu F, Bai J, Dong LQ. LRG1 is an adipokine that mediates obesity-induced hepatosteatosis and insulin resistance. J Clin Invest 2021; 131:148545. [PMID: 34730111 DOI: 10.1172/jci148545] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Accepted: 10/27/2021] [Indexed: 11/17/2022] Open
Abstract
Dysregulation in adipokine biosynthesis and function contributes to obesity-induced metabolic diseases. However, the identities and functions of many of the obesity-induced secretory molecules remain unknown. Here, we report the identification of leucine-rich alpha-2-glycoprotein 1 (LRG1) as an obesity-associated adipokine that exacerbates high fat diet-induced hepatosteatosis and insulin resistance. Serum levels of LRG1 were markedly elevated in obese humans and mice compared to their respective controls. LRG1 deficiency in mice greatly alleviated diet-induced hepatosteatosis, obesity, and insulin resistance. Mechanistically, LRG1 bound with high selectivity to the liver and promoted hepatosteatosis by increasing de novo lipogenesis and suppressing fatty acid β-oxidation. LRG1 also inhibited hepatic insulin signaling by down-regulating insulin receptor substrates 1 and 2. Our study identified LRG1 as a key molecule that mediates the crosstalk between adipocytes and hepatocytes in diet-induced hepatosteatosis and insulin resistance. Suppressing LRG1 expression and function may be a promising strategy for the treatment of obesity-related metabolic diseases.
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Affiliation(s)
- Sijia He
- Department of Pharmacology, University of Texas Health at San Antonio, San Antonio, United States of America
| | - Jiyoon Ryu
- Department of Cell Systems & Anatomy, University of Texas Health at San Antonio, San Antonio, United States of America
| | - Juanhong Liu
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Hairong Luo
- Department of Metabolism and Endocrinology Clinical Research Center for Met, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ying Lv
- Novo Nordisk Research Centre China, Novo Nordisk Research Centre China, Beijing, China
| | - Paul R Langlais
- Department of Medicine, University of Arizona, Tucson, United States of America
| | - Jie Wen
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Feng Dong
- Department of Biochemistry and Structural Biology, University of Texas Health at San Antonio, San Antonio, United States of America
| | - Zhe Sun
- Novo Nordisk Research Centre China, Novo Nordisk Research Centre China, Beijing, China
| | - Wenjuan Xia
- Novo Nordisk Research Centre China, Novo Nordisk Research Centre China, Beijing, China
| | - Jane L Lynch
- Department of Pediatrics, University of Texas Health at San Antonio, San Antonio, United States of America
| | - Ravindranath Duggirala
- Department of Human Genetics and South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley, McAllen, United States of America
| | - Bruce J Nicholson
- Department of Biochemistry and Structural Biology, University of Texas Health at San Antonio, San Antonio, United States of America
| | - Mengwei Zang
- Department of Molecular Medicine, University of Texas Health at San Antonio, San Antonio, United States of America
| | - Yuguang Shi
- Department of Pharmacology, University of Texas Health at San Antonio, San Antonio, United States of America
| | - Fang Zhang
- Novo Nordisk Research Centre China, Novo Nordisk Research Centre China, Beijing, China
| | - Feng Liu
- Department of Pharmacology, University of Texas Health at San Antonio, San Antonio, United States of America
| | - Juli Bai
- Department of Pharmacology, University of Texas Health at San Antonio, San Antonio, United States of America
| | - Lily Q Dong
- Department of Cellular and Structural Biology, University of Texas Health at San Antonio, San Antonio, United States of America
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Singhal M, Gengenbacher N, Pari AAA, Kamiyama M, Hai L, Kuhn BJ, Kallenberg DM, Kulkarni SR, Camilli C, Preuß SF, Leuchs B, Mogler C, Espinet E, Besemfelder E, Heide D, Heikenwalder M, Sprick MR, Trumpp A, Krijgsveld J, Schlesner M, Hu J, Moss SE, Greenwood J, Augustin HG. Temporal multi-omics identifies LRG1 as a vascular niche instructor of metastasis. Sci Transl Med 2021; 13:eabe6805. [PMID: 34516824 PMCID: PMC7614902 DOI: 10.1126/scitranslmed.abe6805] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Metastasis is the primary cause of cancer-related mortality. Tumor cell interactions with cells of the vessel wall are decisive and potentially rate-limiting for metastasis. The molecular nature of this cross-talk is, beyond candidate gene approaches, hitherto poorly understood. Using endothelial cell (EC) bulk and single-cell transcriptomics in combination with serum proteomics, we traced the evolution of the metastatic vascular niche in surgical models of lung metastasis. Temporal multiomics revealed that primary tumors systemically reprogram the body’s vascular endothelium to perturb homeostasis and to precondition the vascular niche for metastatic growth. The vasculature with its enormous surface thereby serves as amplifier of tumor-induced instructive signals. Comparative analysis of lung EC gene expression and secretome identified the transforming growth factor–β (TGFβ) pathway specifier LRG1, leucine-rich alpha-2-glycoprotein 1, as an early instructor of metastasis. In the presence of a primary tumor, ECs systemically up-regulated LRG1 in a signal transducer and activator of transcription 3 (STAT3)–dependent manner. A meta-analysis of retrospective clinical studies revealed a corresponding up-regulation of LRG1 concentrations in the serum of patients with cancer. Functionally, systemic up-regulation of LRG1 promoted metastasis in mice by increasing the number of prometastatic neural/glial antigen 2 (NG2)+ perivascular cells. In turn, genetic deletion of Lrg1 hampered growth of lung metastasis. Postsurgical adjuvant administration of an LRG1-neutralizing antibody delayed metastatic growth and increased overall survival. This study has established a systems map of early primary tumor-induced vascular changes and identified LRG1 as a therapeutic target for metastasis.
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Affiliation(s)
- Mahak Singhal
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany
- Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Nicolas Gengenbacher
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany
- Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Ashik Ahmed Abdul Pari
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany
- Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Miki Kamiyama
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany
- Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Ling Hai
- Junior Group Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Bianca J. Kuhn
- Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
- Divison of Proteomics of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - David M. Kallenberg
- Department of Cell Biology, UCL Institute of Ophthalmology, London EC1V 9EL, United Kingdom
| | - Shubhada R. Kulkarni
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany
- Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Carlotta Camilli
- Department of Cell Biology, UCL Institute of Ophthalmology, London EC1V 9EL, United Kingdom
| | - Stephanie F. Preuß
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany
- Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Barbara Leuchs
- Vector Development & Production Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Carolin Mogler
- Institute of Pathology, TUM School of Medicine, 81675 Munich, Germany
| | - Elisa Espinet
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany
- Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany
| | - Eva Besemfelder
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany
| | - Danijela Heide
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Martin R. Sprick
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany
- Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany
| | - Andreas Trumpp
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany
- Divison of Stem Cells and Cancer, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany
- German Cancer Consortium, 69120 Heidelberg, Germany
| | - Jeroen Krijgsveld
- Divison of Proteomics of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Matthias Schlesner
- Junior Group Bioinformatics and Omics Data Analytics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Biomedical Informatics, Data Mining and Data Analytics, Augsburg University, 86159 Augsburg, Germany
| | - Junhao Hu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201203 Shanghai, China
| | - Stephen E. Moss
- Department of Cell Biology, UCL Institute of Ophthalmology, London EC1V 9EL, United Kingdom
| | - John Greenwood
- Department of Cell Biology, UCL Institute of Ophthalmology, London EC1V 9EL, United Kingdom
| | - Hellmut G. Augustin
- Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), 69120 Heidelberg, Germany
- Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
- German Cancer Consortium, 69120 Heidelberg, Germany
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Aoyama Y, Inaba T, Takahashi S, Yasuhara H, Hiraoka S, Morimoto T, Colvin HS, Wato M, Ando M, Nakamura S, Mizobuchi K, Okada H. Anti-proteinase 3 antineutrophil cytoplasmic antibody reflects disease activity and predicts the response to steroid therapy in ulcerative colitis. BMC Gastroenterol 2021; 21:325. [PMID: 34425765 PMCID: PMC8381492 DOI: 10.1186/s12876-021-01903-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 08/13/2021] [Indexed: 01/06/2023] Open
Abstract
Background Serum anti-proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) is a disease-specific antibody against granulomatosis with polyangiitis. PR3-ANCA is a useful serological marker for disease severity in ulcerative colitis (UC). The purpose of this study was to investigate whether PR3-ANCA levels could also predict the success of induction therapy and to compare its performance against other markers, including serum CRP and fecal hemoglobin. Methods This was a multicenter retrospective study. In total, 159 patients with active-phase UC underwent colonoscopy. Disease activity was measured using the Mayo endoscopic subscore (MES). PR3-ANCA positivity and the response to induction therapy, either 5-aminosalicylic acid or steroid, were assessed. PR3-ANCA, CRP, and fecal hemoglobin were measured during the active phase, and during clinical remission. Results Eighty-five (53.5%) of 159 patients with active UC were positive for PR3-ANCA. PR3-ANCA titers were significantly higher in the group of patients with MES 3 compared to patients with MES 1 (P = 0.002) or MES 2 (P = 0.035). Steroid therapy was administered to 56 patients with a median partial Mayo score of 7 (5–9), which is equivalent to moderate-to-severe disease activity. PR3-ANCA positivity of non-responders to steroid therapy was significantly higher than that of responders (71.9% vs, 41.7%, P = 0.030), whereas CRP and fecal hemoglobin were not predictive of steroid response. Multivariate analysis demonstrated that PR3-ANCA positivity was associated with non-response to steroid therapy (odds ratio 5.19; 95% confidence interval, 1.54–17.5; P = 0.008). Of the 37 patients treated to clinical remission who were also positive for PR3-ANCA during the active phase, 27 had an MES of ≥ 1, and 10 patients had an MES of 0. In clinical remission, the proportion of patients with MES 0 in 17 patients whose PR3-ANCA became negative was significantly higher than that in 20 patients whose PR3-ANCA remained positive (47.1% vs. 10.0%, P = 0.023). Conclusions PR3-ANCA not only serves as a marker of disease activity, but also predicts the failure of steroid therapy in moderate-to-severe UC. Trial registration: This study was retrospectively registered in the UMIN Clinical Trials Registry System (000039174) on January 16, 2020.
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Affiliation(s)
- Yuki Aoyama
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, 1-2-1 Asahi-machi, Takamatsu, Kagawa, 760-8557, Japan
| | - Tomoki Inaba
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, 1-2-1 Asahi-machi, Takamatsu, Kagawa, 760-8557, Japan
| | - Sakuma Takahashi
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, 1-2-1 Asahi-machi, Takamatsu, Kagawa, 760-8557, Japan.
| | - Hisae Yasuhara
- Department of Gastroenterology, Mitoyo General Hospital, 708 Himehama, Toyohama-cho, Kan-onji, Kagawa, 769-1695, Japan
| | - Sakiko Hiraoka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Takeshi Morimoto
- Department of Clinical Epidemiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Hugh Shunsuke Colvin
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, 1-2-1 Asahi-machi, Takamatsu, Kagawa, 760-8557, Japan
| | - Masaki Wato
- Department of Gastroenterology, Kagawa Prefectural Central Hospital, 1-2-1 Asahi-machi, Takamatsu, Kagawa, 760-8557, Japan
| | - Midori Ando
- Department of Pathology, Kagawa Prefectural Central Hospital, 1-2-1 Asahi-machi, Takamatsu, Kagawa, 760-8557, Japan
| | - Satoko Nakamura
- Department of Pathology, Kagawa Prefectural Central Hospital, 1-2-1 Asahi-machi, Takamatsu, Kagawa, 760-8557, Japan
| | - Koichi Mizobuchi
- Department of Pathology, Kagawa Prefectural Central Hospital, 1-2-1 Asahi-machi, Takamatsu, Kagawa, 760-8557, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
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Serum biomarker discovery related to pathogenesis in acute coronary syndrome by proteomic approach. Biosci Rep 2021; 41:228672. [PMID: 34002800 PMCID: PMC8182988 DOI: 10.1042/bsr20210344] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/06/2021] [Accepted: 05/17/2021] [Indexed: 12/23/2022] Open
Abstract
Acute coronary syndrome (ACS) results from inadequate supply of blood flow from the coronary arteries to the heart or ischemia. ACS has an extremely high morbidity and mortality. The levels of biomarkers currently used for detection of ACS also increase in response to myocardial necrosis and other diseases and are not elevated immediately after symptoms appear, thus limiting their diagnostic capacity. Therefore, we aimed to discover new ACS diagnostic biomarkers with high sensitivity and specificity that are specifically related to ACS pathogenesis. Sera from 50 patients with ACS and healthy controls (discovery cohort) each were analyzed using mass spectrometry (MS) to identify differentially expressed proteins, and protein candidates were evaluated as ACS biomarkers in 120 people in each group (validation cohort). α-1-acid glycoprotein 1 (AGP1), complement C5 (C5), leucine-rich α-2-glycoprotein (LRG), and vitronectin (VN) were identified as biomarkers whose levels increase and gelsolin (GSN) as a biomarker whose levels decrease in patients with ACS. We concluded that these biomarkers are associated with the pathogenesis of ACS and can predict the onset of ACS prior to the appearance of necrotic biomarkers.
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Yasutomi E, Inokuchi T, Hiraoka S, Takei K, Igawa S, Yamamoto S, Ohmori M, Oka S, Yamasaki Y, Kinugasa H, Takahara M, Harada K, Furukawa M, Itoshima K, Okada K, Otsuka F, Tanaka T, Mitsuhashi T, Kato J, Okada H. Leucine-rich alpha-2 glycoprotein as a marker of mucosal healing in inflammatory bowel disease. Sci Rep 2021; 11:11086. [PMID: 34045529 PMCID: PMC8160157 DOI: 10.1038/s41598-021-90441-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/20/2021] [Indexed: 02/04/2023] Open
Abstract
Leucine-rich alpha-2 glycoprotein (LRG) may be a novel serum biomarker for patients with inflammatory bowel disease. The association of LRG with the endoscopic activity and predictability of mucosal healing (MH) was determined and compared with those of C-reactive protein (CRP) and fecal markers (fecal immunochemical test [FIT] and fecal calprotectin [Fcal]) in 166 ulcerative colitis (UC) and 56 Crohn's disease (CD) patients. In UC, LRG was correlated with the endoscopic activity and could predict MH, but the performance was not superior to that of fecal markers (areas under the curve [AUCs] for predicting MH: LRG: 0.61, CRP: 0.59, FIT: 0.75, and Fcal: 0.72). In CD, the performance of LRG was equivalent to that of CRP and Fcal (AUCs for predicting MH: LRG: 0.82, CRP: 0.82, FIT: 0.70, and Fcal: 0.88). LRG was able to discriminate patients with MH from those with endoscopic activity among UC and CD patients with normal CRP levels. LRG was associated with endoscopic activity and could predict MH in both UC and CD patients. It may be particularly useful in CD.
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Affiliation(s)
- Eriko Yasutomi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Toshihiro Inokuchi
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Sakiko Hiraoka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan.
| | - Kensuke Takei
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Shoko Igawa
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Shumpei Yamamoto
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Masayasu Ohmori
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Shohei Oka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Yasushi Yamasaki
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Hideaki Kinugasa
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Masahiro Takahara
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Keita Harada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Masaki Furukawa
- Department of Laboratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Kouichi Itoshima
- Department of Laboratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Ken Okada
- Department of Laboratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Fumio Otsuka
- Department of Laboratory Medicine, Okayama University Hospital, Okayama, Japan
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Takehiro Tanaka
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Toshiharu Mitsuhashi
- Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
| | - Jun Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
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Kakar M, Berezovska MM, Broks R, Asare L, Delorme M, Crouzen E, Zviedre A, Reinis A, Engelis A, Kroica J, Saxena A, Petersons A. Serum and Urine Biomarker Leucine-Rich Alpha-2 Glycoprotein 1 Differentiates Pediatric Acute Complicated and Uncomplicated Appendicitis. Diagnostics (Basel) 2021; 11:860. [PMID: 34064691 PMCID: PMC8151968 DOI: 10.3390/diagnostics11050860] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/04/2021] [Accepted: 05/07/2021] [Indexed: 12/28/2022] Open
Abstract
PURPOSE This prospective, single-center cohort study analyzes the potential of inflammatory protein mediator leucine-rich alpha-2 glycoprotein 1 (LRG1) for the early and accurate diagnosis of acute appendicitis (AA), and differentiation of acute complicated (AcA) from uncomplicated appendicitis (AuA). METHODS Participants were divided into the AcA, AuA, and control groups, and their serum (s-LRG1) and urine LRG1 (u-LRG1) levels were assayed preoperatively on the second and fifth postoperative days. RESULTS 153 patients participated, 97 had AA. Preoperative u-LRG1 with a cut-off value of 0.18 μg/mL generated an area under the receiver operated characteristic (AUC) curve of 0.70 (95% CI 0.62-0.79) for AA versus control (p < 0.001), while the results for AcA versus AuA were not significant (AUC 0.60, 95% CI 0.49-0.71, p = 0.089). The s-LRG1 levels of AA versus the control with a cut-off value of 51.69 μg/mL generated an AUC of 0.94 (95% CI 0.91-0.99, p < 0.001). The cut-off value of s-LRG1 was 84.06 μg/mL for diagnosis of AcA from AuA, and therefore, significant (AUC 0.69, 95% CI 0.59-0.80, p = 0.001). CONCLUSIONS LRG1 exhibited excellent diagnostic performance as an inexpensive, non-invasive, rapid, and accurate biomarker able to reflect the pathogenesis of AA. LRG1 has the potential to replace advanced imaging to diagnose clinically ambiguous AA cases.
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Affiliation(s)
- Mohit Kakar
- Department of Pediatric Surgery, Children’s Clinical University Hospital, LV-1004 Riga, Latvia; (M.M.B.); (A.Z.); (A.E.); (A.P.)
- Department of Pediatric Surgery, Riga Stradins University, LV-1007 Riga, Latvia
| | - Marisa Maija Berezovska
- Department of Pediatric Surgery, Children’s Clinical University Hospital, LV-1004 Riga, Latvia; (M.M.B.); (A.Z.); (A.E.); (A.P.)
- Department of Pediatric Surgery, Riga Stradins University, LV-1007 Riga, Latvia
| | - Renars Broks
- Department of Biology and Microbiology, Riga Stradins University, LV-1007 Riga, Latvia; (R.B.); (A.R.); (J.K.)
| | - Lasma Asare
- Statistical Unit, Riga Stradins University, LV-1007 Riga, Latvia;
| | - Mathilde Delorme
- Faculty of Medicine, Riga Stradins University, LV-1007 Riga, Latvia; (M.D.); (E.C.)
| | - Emile Crouzen
- Faculty of Medicine, Riga Stradins University, LV-1007 Riga, Latvia; (M.D.); (E.C.)
| | - Astra Zviedre
- Department of Pediatric Surgery, Children’s Clinical University Hospital, LV-1004 Riga, Latvia; (M.M.B.); (A.Z.); (A.E.); (A.P.)
- Department of Pediatric Surgery, Riga Stradins University, LV-1007 Riga, Latvia
| | - Aigars Reinis
- Department of Biology and Microbiology, Riga Stradins University, LV-1007 Riga, Latvia; (R.B.); (A.R.); (J.K.)
| | - Arnis Engelis
- Department of Pediatric Surgery, Children’s Clinical University Hospital, LV-1004 Riga, Latvia; (M.M.B.); (A.Z.); (A.E.); (A.P.)
- Department of Pediatric Surgery, Riga Stradins University, LV-1007 Riga, Latvia
| | - Juta Kroica
- Department of Biology and Microbiology, Riga Stradins University, LV-1007 Riga, Latvia; (R.B.); (A.R.); (J.K.)
| | - Amulya Saxena
- Department of Pediatric Surgery, Chelsea Children’s Hospital, Chelsea and Westminster NHS Fdn Trust, Imperial College London, London SW10 9NH, UK;
| | - Aigars Petersons
- Department of Pediatric Surgery, Children’s Clinical University Hospital, LV-1004 Riga, Latvia; (M.M.B.); (A.Z.); (A.E.); (A.P.)
- Department of Pediatric Surgery, Riga Stradins University, LV-1007 Riga, Latvia
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Nakajima H, Nakajima K, Takaishi M, Ohko K, Serada S, Fujimoto M, Naka T, Sano S. The Skin-Liver Axis Modulates the Psoriasiform Phenotype and Involves Leucine-Rich α-2 Glycoprotein. THE JOURNAL OF IMMUNOLOGY 2021; 206:1469-1477. [PMID: 33648938 DOI: 10.4049/jimmunol.2000502] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 01/27/2021] [Indexed: 01/04/2023]
Abstract
Leucine-rich α-2 glycoprotein (LRG), one of the acute phase proteins mainly produced by the liver, similar to C-reactive protein, has been recognized as an inflammatory biomarker for rheumatoid arthritis and inflammatory bowel diseases. We recently demonstrated that LRG was also increased in the sera of psoriasis patients and correlated well with disease activity with a sensitivity and specificity much higher than C-reactive protein; however, whether LRG mechanistically contributed to the pathogenesis of psoriasis remained unclear. In this study, we explored the role of LRG in psoriasiform inflammation using LRG-knockout (KO) mice in an imiquimod (IMQ)-mediated model. Following topical treatment with IMQ, serum levels of LRG and its expression in the liver were abruptly elevated. Similarly, an acute surge of proinflammatory cytokines was observed in the liver, including IL-1β, TNF-α, and IL-6, although LRG-KO mice showed delayed responses. LRG-KO mice showed less skin inflammation in the IMQ model than wild-type mice. K5.Stat3C mice developed psoriasis-like lesions following tape stripping, which also abruptly induced LRG expression in the liver. A deficiency of Lrg mitigated tape stripping-induced lesions, similar to the IMQ model. These results indicate that LRG modulates both feed-forward and feedback loops of cytokines in the skin-liver axis involved with psoriasiform inflammation.
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Affiliation(s)
- Hideki Nakajima
- Department of Dermatology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan; and
| | - Kimiko Nakajima
- Department of Dermatology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan; and
| | - Mikiro Takaishi
- Department of Dermatology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan; and
| | - Kentaro Ohko
- Department of Dermatology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan; and
| | - Satoshi Serada
- Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan
| | - Minoru Fujimoto
- Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan
| | - Tetsuji Naka
- Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan
| | - Shigetoshi Sano
- Department of Dermatology, Kochi Medical School, Kochi University, Nankoku 783-8505, Japan; and
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Shin M, Park SH, Mun S, Lee J, Kang HG. Biomarker Discovery of Acute Coronary Syndrome Using Proteomic Approach. Molecules 2021; 26:molecules26041136. [PMID: 33672727 PMCID: PMC7924321 DOI: 10.3390/molecules26041136] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/11/2021] [Accepted: 02/17/2021] [Indexed: 11/17/2022] Open
Abstract
Acute coronary syndrome (ACS) is a condition in which the coronary artery supplying blood to the heart is infarcted via formation of a plaque and thrombus, resulting in abnormal blood supply and high mortality and morbidity. Therefore, the prompt and efficient diagnosis of ACS and the need for new ACS diagnostic biomarkers are important. In this study, we aimed to identify new ACS diagnostic biomarkers with high sensitivity and specificity using a proteomic approach. A discovery set with samples from 20 patients with ACS and 20 healthy controls was analyzed using mass spectrometry. Among the proteins identified, those showing a significant difference between each group were selected. Functional analysis of these proteins was conducted to confirm their association with functions in the diseased state. To determine ACS diagnostic biomarkers, standard peptides of the selected protein candidates from the discovery set were quantified, and these protein candidates were validated in a validation set consisting of the sera of 50 patients with ACS and 50 healthy controls. We showed that hemopexin, leucine-rich α-2-glycoprotein, and vitronectin levels were upregulated, whereas fibronectin level was downregulated, in patients with ACS. Thus, the use of these biomarkers may increase the accuracy of ACS diagnosis.
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Affiliation(s)
- Miji Shin
- Department of Senior Healthcare, Graduate School, Eulji University, Seongnam 13135, Korea; (M.S.); (S.M.)
| | - Sang Hyun Park
- Department of Internal Medicine, School of Medicine, Eulji University, Daejeon 34824, Korea;
| | - Sora Mun
- Department of Senior Healthcare, Graduate School, Eulji University, Seongnam 13135, Korea; (M.S.); (S.M.)
| | - Jiyeong Lee
- Department of Biomedical Laboratory Science, School of Medicine, Eulji University, Uijeongbu 11759, Korea
- Correspondence: (J.L.); (H.-G.K.); Tel.: +82-42-259-1752 (J.L.); +82-31-740-7315 (H.-G.K.)
| | - Hee-Gyoo Kang
- Department of Senior Healthcare, Graduate School, Eulji University, Seongnam 13135, Korea; (M.S.); (S.M.)
- Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, Seongnam 13135, Korea
- Correspondence: (J.L.); (H.-G.K.); Tel.: +82-42-259-1752 (J.L.); +82-31-740-7315 (H.-G.K.)
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Kajimoto E, Endo M, Fujimoto M, Matsuzaki S, Fujii M, Yagi K, Kakigano A, Mimura K, Tomimatsu T, Serada S, Takeuchi M, Yoshino K, Ueda Y, Kimura T, Naka T. Evaluation of leucine-rich alpha-2 glycoprotein as a biomarker of fetal infection. PLoS One 2020; 15:e0242076. [PMID: 33211747 PMCID: PMC7676652 DOI: 10.1371/journal.pone.0242076] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 10/27/2020] [Indexed: 11/21/2022] Open
Abstract
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.
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Affiliation(s)
- Etsuko Kajimoto
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Obstetrics and Gynecology, Japan Community Health Care Organization Osaka Hospital, Osaka, Japan
| | - Masayuki Endo
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
- Department of Children and Women’s Health, Osaka University Graduate School of Medicine, Osaka, Japan
- Division of Health Science, Graduate School of medicine, StemRIM Institute of Regeneration-Inducting Medicine, Osaka University, Osaka, Japan
| | - Minoru Fujimoto
- Center for Intractable Immune Disease, Kochi Medical School, Kochi University, Kochi, Japan
- * E-mail:
| | - Shinya Matsuzaki
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Makoto Fujii
- Division of Health Science, Graduate School of medicine, StemRIM Institute of Regeneration-Inducting Medicine, Osaka University, Osaka, Japan
| | - Kazunobu Yagi
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Aiko Kakigano
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kazuya Mimura
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takuji Tomimatsu
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Satoshi Serada
- Center for Intractable Immune Disease, Kochi Medical School, Kochi University, Kochi, Japan
| | - Makoto Takeuchi
- Department of Pathology, Osaka Women’s and Children’s Hospital, Osaka, Japan
| | - Kiyoshi Yoshino
- Department of Obstetrics and Gynecology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Yutaka Ueda
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tadashi Kimura
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tetsuji Naka
- Center for Intractable Immune Disease, Kochi Medical School, Kochi University, Kochi, Japan
- Laboratory of Immune Signal, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
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Keles Yucel ZP, Balli U. Leucine-rich alpha-2 glycoprotein (LRG): A novel acute phase protein expressed in Stage 3 Grade C periodontitis before and after periodontal therapy. J Periodontol 2020; 92:104-112. [PMID: 33128400 DOI: 10.1002/jper.20-0358] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 09/16/2020] [Accepted: 10/20/2020] [Indexed: 11/06/2022]
Abstract
BACKGROUND 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. METHODS 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 6 weeks after treatment. LRG, IL-6 and TNF-α were determined by ELISA. RESULTS 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). CONCLUSION 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.
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Affiliation(s)
| | - Umut Balli
- Department of Periodontology, Faculty of Dentistry, Bulent Ecevit University, Zonguldak, Turkey
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50
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Messner CB, Demichev V, Wendisch D, Michalick L, White M, Freiwald A, Textoris-Taube K, Vernardis SI, Egger AS, Kreidl M, Ludwig D, Kilian C, Agostini F, Zelezniak A, Thibeault C, Pfeiffer M, Hippenstiel S, Hocke A, von Kalle C, Campbell A, Hayward C, Porteous DJ, Marioni RE, Langenberg C, Lilley KS, Kuebler WM, Mülleder M, Drosten C, Suttorp N, Witzenrath M, Kurth F, Sander LE, Ralser M. Ultra-High-Throughput Clinical Proteomics Reveals Classifiers of COVID-19 Infection. Cell Syst 2020; 11:11-24.e4. [PMID: 32619549 PMCID: PMC7264033 DOI: 10.1016/j.cels.2020.05.012] [Citation(s) in RCA: 384] [Impact Index Per Article: 76.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 05/22/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023]
Abstract
The COVID-19 pandemic is an unprecedented global challenge, and point-of-care diagnostic classifiers are urgently required. Here, we present a platform for ultra-high-throughput serum and plasma proteomics that builds on ISO13485 standardization to facilitate simple implementation in regulated clinical laboratories. Our low-cost workflow handles up to 180 samples per day, enables high precision quantification, and reduces batch effects for large-scale and longitudinal studies. We use our platform on samples collected from a cohort of early hospitalized cases of the SARS-CoV-2 pandemic and identify 27 potential biomarkers that are differentially expressed depending on the WHO severity grade of COVID-19. They include complement factors, the coagulation system, inflammation modulators, and pro-inflammatory factors upstream and downstream of interleukin 6. All protocols and software for implementing our approach are freely available. In total, this work supports the development of routine proteomic assays to aid clinical decision making and generate hypotheses about potential COVID-19 therapeutic targets.
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Affiliation(s)
- Christoph B Messner
- The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London NW11AT, UK
| | - Vadim Demichev
- The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London NW11AT, UK; Department of Biochemistry, The University of Cambridge, Cambridge CB21GA, UK
| | - Daniel Wendisch
- Charité Universitätsmedizin, Berlin, Department of Infectious Diseases and Respiratory Medicine, 10117 Berlin, Germany
| | - Laura Michalick
- Charité Universitätsmedizin, Institute of Physiology, 10117 Berlin, Germany
| | - Matthew White
- The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London NW11AT, UK
| | - Anja Freiwald
- Charité Universitätsmedizin, Core Facility - High-Throughput Mass Spectrometry, 10117 Berlin, Germany; Charité Universitätsmedizin, Department of Biochemistry, 10117 Berlin, Germany
| | - Kathrin Textoris-Taube
- Charité Universitätsmedizin, Core Facility - High-Throughput Mass Spectrometry, 10117 Berlin, Germany
| | - Spyros I Vernardis
- The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London NW11AT, UK
| | - Anna-Sophia Egger
- The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London NW11AT, UK
| | - Marco Kreidl
- The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London NW11AT, UK
| | - Daniela Ludwig
- Charité Universitätsmedizin, Department of Biochemistry, 10117 Berlin, Germany
| | - Christiane Kilian
- Charité Universitätsmedizin, Department of Biochemistry, 10117 Berlin, Germany
| | - Federica Agostini
- Charité Universitätsmedizin, Department of Biochemistry, 10117 Berlin, Germany
| | - Aleksej Zelezniak
- The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London NW11AT, UK; Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg 412 96, Sweden
| | - Charlotte Thibeault
- Charité Universitätsmedizin, Berlin, Department of Infectious Diseases and Respiratory Medicine, 10117 Berlin, Germany
| | - Moritz Pfeiffer
- Charité Universitätsmedizin, Berlin, Department of Infectious Diseases and Respiratory Medicine, 10117 Berlin, Germany
| | - Stefan Hippenstiel
- Charité Universitätsmedizin, Berlin, Department of Infectious Diseases and Respiratory Medicine, 10117 Berlin, Germany
| | - Andreas Hocke
- Charité Universitätsmedizin, Berlin, Department of Infectious Diseases and Respiratory Medicine, 10117 Berlin, Germany
| | - Christof von Kalle
- Berlin Institute of Health (BIH) and Charité Universitätsmedizin, Clinical Study Center (CSC), 10117 Berlin, Germany
| | - Archie Campbell
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; Usher Institute, University of Edinburgh, Nine, Edinburgh Bioquarter, 9 Little France Road, Edinburgh EH16 4UX, UK
| | - Caroline Hayward
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - David J Porteous
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Riccardo E Marioni
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
| | - Claudia Langenberg
- The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London NW11AT, UK; MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Kathryn S Lilley
- Department of Biochemistry, The University of Cambridge, Cambridge CB21GA, UK
| | - Wolfgang M Kuebler
- Charité Universitätsmedizin, Institute of Physiology, 10117 Berlin, Germany
| | - Michael Mülleder
- Charité Universitätsmedizin, Core Facility - High-Throughput Mass Spectrometry, 10117 Berlin, Germany
| | - Christian Drosten
- Charité Universitätsmedizin, Department of Virology, 10117 Berlin, Germany
| | - Norbert Suttorp
- Charité Universitätsmedizin, Berlin, Department of Infectious Diseases and Respiratory Medicine, 10117 Berlin, Germany
| | - Martin Witzenrath
- Charité Universitätsmedizin, Berlin, Department of Infectious Diseases and Respiratory Medicine, 10117 Berlin, Germany
| | - Florian Kurth
- Charité Universitätsmedizin, Berlin, Department of Infectious Diseases and Respiratory Medicine, 10117 Berlin, Germany; Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
| | - Leif Erik Sander
- Charité Universitätsmedizin, Berlin, Department of Infectious Diseases and Respiratory Medicine, 10117 Berlin, Germany
| | - Markus Ralser
- The Francis Crick Institute, Molecular Biology of Metabolism Laboratory, London NW11AT, UK; Charité Universitätsmedizin, Department of Biochemistry, 10117 Berlin, Germany.
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