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Mandal A, Banerjee S, Ghosh S, Sil PC. Taurine alleviates colitis by regulating oxidative stress, inflammatory responses, ER stress, and apoptotic pathways. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04106-x. [PMID: 40227309 DOI: 10.1007/s00210-025-04106-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 03/25/2025] [Indexed: 04/15/2025]
Abstract
Colitis is an inflammatory condition affecting the colon, characterized by oxidative stress, ER stress, and apoptosis, which leads to severe tissue damage. Existing treatments are associated with significant side effects, necessitating the exploration of alternative therapeutic agents. Taurine is a commonly consumed bioactive sulfur-containing amino acid, recognized for its cyto-protective property. In this study, we are using a male Wistar rat model for 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis and treated them with taurine. Colitis development was indicated by repeated loose bloody stools, reduced appetite, and weight loss. Macroscopic examination revealed an inflamed colon surface with ulcerations, while histopathology showed a destroyed crypt structure and damage to the epithelial and mucosal layers in the colitis-affected rats. However, taurine administration reverses such adverse effects of colitis. Taurine significantly mitigates the oxidative stress by upregulating the level of anti-oxidant molecules, such as CAT, GST and SOD, which were significantly down-regulated in colitis. In addition, increased levels of inflammatory molecules (TNF-α, IL- 1β, IL- 6, MCP- 1, ICAM- 1, and VCAM- 1) in colitis were reduced by taurine supplementation. Furthermore, we observed taurine alleviates colitis induced up-regulation of important endoplasmic reticulum (ER) stress markers like, CHOP, GRP78, calpain 1, and caspase 12. We have also demonstrated that taurine supplementation reverses colitis induced apoptosis by assessing the modulation of apoptotic markers (Bax, Bcl- 2, caspase 9 and caspase 3). Furthermore, no instances of toxicity from taurine were observed. Thus, taurine shows a potential to be utilized as a therapeutic agent for colitis with further detailed investigation.
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Affiliation(s)
- Ankita Mandal
- Division of Molecular Medicine, Bose Institute, P- 1/12, CIT Scheme VII M, Kolkata, 700054, West Bengal, India
| | - Sharmistha Banerjee
- Division of Molecular Medicine, Bose Institute, P- 1/12, CIT Scheme VII M, Kolkata, 700054, West Bengal, India
| | - Sumit Ghosh
- Division of Molecular Medicine, Bose Institute, P- 1/12, CIT Scheme VII M, Kolkata, 700054, West Bengal, India
| | - Parames C Sil
- Division of Molecular Medicine, Bose Institute, P- 1/12, CIT Scheme VII M, Kolkata, 700054, West Bengal, India.
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2
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Venge P, Tejera VC, Petersson C, Xu S, Larsson A, Simrén M, Öhman L, Törnblom H. Elevated Fecal Biomarkers of Colo-Rectal Epithelial Cell Activity in Irritable Bowel Syndrome. Neurogastroenterol Motil 2025; 37:e14984. [PMID: 39688084 PMCID: PMC11996011 DOI: 10.1111/nmo.14984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 11/18/2024] [Accepted: 12/03/2024] [Indexed: 12/18/2024]
Abstract
BACKGROUND Irritable bowel syndrome (IBS) is a common functional gastro-intestinal disorder characterized by discomfort with constipation and/or diarrhea with unclear pathophysiology. We aimed to determine the activities of colorectal eosinophils, neutrophils and epithelial cells by biomarkers in feces reflecting these activities. METHODS Fecal samples were collected from 185 patients with IBS before and after 8 weeks of placebo or mesalazine treatment and from 40 healthy subjects. Calprotectin, eosinophil derived neurotoxin (EDN), eosinophil cationic protein (ECP), human neutrophil lipocalin (HNL) (pab/765) or dimer, human phospholipase BII-precursor (HPLBII-P) and myeloperoxidase (MPO) were measured by ELISA. Symptom scores were evaluated by diaries. RESULTS HPLBII-P, HNL (pab/765) and EDN, proteins secreted by intestinal epithelial cells, were elevated in IBS patients as compared to healthy subjects (p < 0.0001-p = 0.008). In contrast, the neutrophil proteins calprotectin, MPO and HNL dimer were unaltered. The eosinophilic protein ECP was lower in IBS (p = 0.001). HNL (pab/765) (p = 0.01) and EDN (p = 0.004) increased in IBS patients after mesalazine treatment. Colo-rectal mucosa showed strong staining of HPLBII-P and western blotting of fecal extracts showed the presence of mainly monomeric, epithelial-associated HNL. CONCLUSIONS The absence of signs of involvement of neutrophils and eosinophils in IBS suggests that activity of local epithelial cells rather than inflammation may be a major determinant of the disease. The measurements of EDN, HNL (pab/765), and HPLBII-P may serve as potential fecal biomarkers in the study and monitoring of IBS.
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Affiliation(s)
- Per Venge
- Department of Medical SciencesUppsala University and Diagnostics DevelopmentUppsalaSweden
- Diagnostics DevelopmentUppsalaSweden
| | - Valeria Castro Tejera
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
| | - Christer Petersson
- Department of Medical SciencesUppsala University and Diagnostics DevelopmentUppsalaSweden
| | - Shengyuan Xu
- Department of Medical SciencesUppsala University and Diagnostics DevelopmentUppsalaSweden
| | - Anders Larsson
- Department of Medical SciencesUppsala University and Diagnostics DevelopmentUppsalaSweden
| | - Magnus Simrén
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
- Center for Functional GI and Motility DisordersUniversity of North Carolina‐Chapel HillChapel HillNorth CarolinaUSA
| | - Lena Öhman
- Department of Microbiology and Immunology, Institute of BiomedicineUniversity of GothenburgGothenburgSweden
| | - Hans Törnblom
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
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3
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Okafor EN, Ebede SO, Agbo EO. Recent Advances in Nephrology: The Research Gaps and the Need for Greater Emphasis on Incorporating Hard Clinical Endpoints. Niger J Clin Pract 2025; 28:137-144. [PMID: 40326892 DOI: 10.4103/njcp.njcp_867_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 12/14/2024] [Indexed: 05/07/2025]
Abstract
Current limitations exist in the availability of specific therapies for preventing acute kidney injury (AKI). Managing AKI poses challenges, particularly as interventions are often initiated only after a substantial increase in serum creatinine or a gradual decline in urine output. However, relying on these parameters raises concerns due to their insensitivity to acute changes. The timely detection of patients at risk of kidney disease through the diagnostic utility of biomarkers is essential for the prompt implementation of active interventions. Despite the initial optimism surrounding the discovery of AKI biomarkers, their integration into the routine care of at-risk patients lags behind and is underutilized, even after validations. Therefore, the utilization of biomarkers holds promise in promptly diagnosing AKI and improving patient outcomes. Despite notable technological advancements in various medical subspecialties, survival rates among acute and chronic kidney disease (CKD) patients have not witnessed significant improvement compared to other disciplines. While HIV infection and AIDS were once considered a death sentence, advancements in HIV treatment have allowed for control and longer-acting management. However, a definitive cure for CKD remains elusive. Nephrology research faces challenges, including the imperative to enhance both the quality and quantity of research. The number of randomized controlled trials in nephrology is notably lower compared to other subspecialties, with many yielding negative results. Studies evaluating hard clinical endpoints are also limited. This review provides an overview of recent advances in nephrology and the need for greater emphasis on incorporating hard clinical endpoints that could impact clinical practice.
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Affiliation(s)
- E N Okafor
- Department of Medical Laboratory Sciences, College of Medicine, University of Nigeria, Enugu Campus, Nigeria
| | - S O Ebede
- Department of Medical Microbiology, College of Medicine, University of Nigeria, Ituku-Ozalla, Enugu State, Nigeria
| | - E O Agbo
- Department of Chemical Pathology, Faculty of Basic Clinical Sciences, College of Medicine and Health Sciences, Baze University, Abuja, Nigeria
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4
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Qiao G, Sheng J. Lipocalin-2 Determination on Multiwalled Carbon Nanotube Integrated Circular Electrodes for Diagnosing Ulcerative Colitis. Biotechnol Appl Biochem 2025. [PMID: 39834132 DOI: 10.1002/bab.2715] [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: 05/16/2024] [Accepted: 12/23/2024] [Indexed: 01/22/2025]
Abstract
Ulcerative colitis affects the inner lining of the large intestine, causing discomfort, pain, and digestion issues, and sometimes leading to life-threatening complications. With proper medication, symptoms and inflammation can be reduced, improving the condition. In this research, a multiwalled carbon nanotube (MWCN)-modified circular interdigitated electrode (circular-IDE) biosensor was developed to detect the ulcerative colitis biomarker lipocalin-2 and measured at 0-2 V. A dual probing strategy with aptamer and antibody on gold nanoparticles was employed for the detection of lipocalin-2. Probe immobilization was optimized on MWCN-modified circular-IDE, and saturation of 800 nM of aptamer on the GNP-antibody facilitated the identification of lipocalin-2 at concentrations as low as 1 pg/mL, with an R2 value of 0.9716 [y = 2.1058x - 2.7351]. Furthermore, lipocalin-2 spiking in serum increased the current responses in correlation with the concentrations of lipocalin-2, indicating selective identification without interference. In addition, nonimmune antibody and GNP-conjugated complementary aptamer did not increase the current responses, affirming the specific detection of lipocalin-2. This MWCN-modified circular-IDE biosensor, utilizing aptamer-antibody interactions, aids in identifying the condition of ulcerative colitis.
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Affiliation(s)
- Guangchao Qiao
- Department of Gastrointestinal Surgery, The Fifth People's Hospital of Jinan, Jinan, Shandong, China
| | - Jijian Sheng
- Department of Gastrointestinal Surgery, The Fifth People's Hospital of Jinan, Jinan, Shandong, China
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Sanchez-Garrido J, Baghshomali YN, Kaushal P, Kozik Z, Perry RW, Williams HRT, Choudhary J, Frankel G. Impaired neutrophil migration underpins host susceptibility to infectious colitis. Mucosal Immunol 2024; 17:939-957. [PMID: 38936619 DOI: 10.1016/j.mucimm.2024.06.008] [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: 02/29/2024] [Revised: 06/07/2024] [Accepted: 06/19/2024] [Indexed: 06/29/2024]
Abstract
Citrobacter rodentium models infection with enteropathogenic Escherichia coli and ulcerative colitis (UC). While C57BL/6 (C57) mice recover, C3H/HeN (C3H) mice succumb to infection, partially due to increased colonic neutrophil elastase activity, also seen in UC patients; however, the underlying cause was unknown. Here, we found that bone marrow, blood, and colonic C57 neutrophils expressed (CD)11bHi and reached the infected colonic lumen, where they underwent productive NETosis. In contrast, while the number of C3H neutrophils increased in the bone marrow, blood, and colon, they remained CD11bLo and got trapped in the submucosa, away from C. rodentium, where they underwent harmful NETosis. CD11bLo neutrophils in C3H mice infected with CRi9, which triggers expression of neutrophil chemoattractants, reached the colonization site, resulting in host survival. UC patient neutrophils also displayed decreased levels of the activation/differentiation markers CD16/CXCR4. These results, suggesting that neutrophil malfunction contributes to exacerbated colitis, provide insight for future therapeutic prospects.
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Affiliation(s)
| | | | - Prashant Kaushal
- Functional Proteomics Group, Chester Beatty Laboratories, Institute of Cancer Research, London, United Kingdom
| | - Zuza Kozik
- Functional Proteomics Group, Chester Beatty Laboratories, Institute of Cancer Research, London, United Kingdom
| | - Robert W Perry
- Department of Metabolism, Digestion and Reproduction, Imperial College, London, United Kingdom
| | - Horace R T Williams
- Department of Metabolism, Digestion and Reproduction, Imperial College, London, United Kingdom
| | - Jyoti Choudhary
- Functional Proteomics Group, Chester Beatty Laboratories, Institute of Cancer Research, London, United Kingdom
| | - Gad Frankel
- Department of Life Sciences, Imperial College, London, United Kingdom
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Abdul Kalam Saleena L, Chang SK, Simarani K, Arunachalam KD, Thammakulkrajang R, How YH, Pui LP. A comprehensive review of Bifidobacterium spp: as a probiotic, application in the food and therapeutic, and forthcoming trends. Crit Rev Microbiol 2024; 50:581-597. [PMID: 37551693 DOI: 10.1080/1040841x.2023.2243617] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 07/03/2023] [Accepted: 07/26/2023] [Indexed: 08/09/2023]
Abstract
Recently, more consumers are interested in purchasing probiotic food and beverage products that may improve their immune health. The market for functional foods and beverages that include Bifidobacterium is expanding because of their potential uses in both food and therapeutic applications. However, maintaining Bifidobacterium's viability during food processing and storage remains a challenge. Microencapsulation technique has been explored to improve the viability of Bifidobacterium. Despite the technical, microbiological, and economic challenges, the market potential for immune-supporting functional foods and beverages is significant. Additionally, there is a shift toward postbiotics as a solution for product innovation, a promising postbiotic product that can be incorporated into various food and beverage formats is also introduced in this review. As consumers become more health-conscious, future developments in the functional food and beverage market discussed in this review could serve as a reference for researchers and industrialist.
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Affiliation(s)
| | - Sui Kiat Chang
- Department of Allied Health Sciences, Faculty of Science, Universiti Tunku Abdul Rahman Kampar, Perak, Malaysia
| | - Khanom Simarani
- Faculty of Science, Institute Biological Sciences, University of Malaya, Kuala Lumpur, Malaysia
| | - Kantha Deivi Arunachalam
- Directorate of Research, Center For Environmental Nuclear Research, SRM Institute of Science and Technology, SRM Nagar, Chennai, India
- Faculty of Sciences, Marwadi University, Rajkot, India
| | | | - Yu Hsuan How
- Department of Food Science and Nutrition, Faculty of Applied Sciences, UCSI University, Kuala Lumpur, Malaysia
| | - Liew Phing Pui
- Department of Food Science and Nutrition, Faculty of Applied Sciences, UCSI University, Kuala Lumpur, Malaysia
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Dong K, Zhang Y, Ji HR, Guan ZL, Wang DY, Guo ZY, Deng SJ, He BY, Xing JF, You CY. Dexamethasone-Loaded Lipid Calcium Phosphate Nanoparticles Treat Experimental Colitis by Regulating Macrophage Polarization in Inflammatory Sites. Int J Nanomedicine 2024; 19:993-1016. [PMID: 38299194 PMCID: PMC10829593 DOI: 10.2147/ijn.s442369] [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] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 01/20/2024] [Indexed: 02/02/2024] Open
Abstract
Background The M1/M2 polarization of intestinal macrophages exerts an essential function in the pathogenesis of ulcerative colitis (UC), which can be adjusted to alleviate the UC symptoms. Purpose A kind of pH-sensitive lipid calcium phosphate core-shell nanoparticles (NPs), co-loading with dexamethasone (Dex) and its water-soluble salts, dexamethasone sodium phosphate (Dsp), was constructed to comprehensively regulate macrophages in different states towards the M2 phenotype to promote anti-inflammatory effects. Methods Dex and Dsp were loaded in the outer lipid shell and inner lipid calcium phosphate (Cap) core of the LdCaPd NPs, respectively. Then, the morphology of NPs and methods for determining drug concentration were investigated, followed by in vitro protein adsorption, stability, and release tests. Cell experiments evaluated the cytotoxicity, cellular uptake, and macrophage polarization induction ability of NPs. The in vivo distribution and anti-inflammatory effect of NPs were evaluated through a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced BALB/c mice ulcerative colitis model. Results The LdCaPd NPs showed a particle size of about 200 nm and achieved considerable loading amounts of Dex and Dsp. The in vitro and in vivo studies revealed that in the acidic UC microenvironment, the cationic lipid shell of LdCaPd underwent protonated dissociation to release Dex first for creating a microenvironment conducive to M2 polarization. Then, the exposed CaP core was further engulfed by M1 macrophages to release Dsp to restrict the pro-inflammatory cytokines production by inhibiting the activation and function of the nuclear factor kappa-B (NF-κB) through activating the GC receptor and the NF kappa B inhibitor α (I-κBα), respectively, ultimately reversing the M1 polarization to promote the anti-inflammatory therapy. Conclusion The LdCaPd NPs accomplished the sequential release of Dex and Dsp to the UC site and the inflammatory M1 macrophages at this site, promoting the regulation of macrophage polarization to accelerate the remission of UC symptoms.
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Affiliation(s)
- Kai Dong
- Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
- School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Ying Zhang
- School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Hong Rui Ji
- School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Ze Lin Guan
- School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Dan Yang Wang
- School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Zi Yang Guo
- School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Shu Jing Deng
- School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Bin Yang He
- School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Jian Feng Xing
- School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
| | - Cui Yu You
- Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China
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Hong S, Wang H, Chan S, Zhang J, Chen B, Ma X, Chen X. Identifying Macrophage-Related Genes in Ulcerative Colitis Using Weighted Coexpression Network Analysis and Machine Learning. Mediators Inflamm 2023; 2023:4373840. [PMID: 38633005 PMCID: PMC11023725 DOI: 10.1155/2023/4373840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 08/23/2023] [Accepted: 09/27/2023] [Indexed: 04/19/2024] Open
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease of unknown cause that typically affects the colon and rectum. Innate intestinal immunity, including macrophages, plays a significant role in the pathological development of UC. Using the CIBERSORT algorithm, we observed elevated levels of 22 types of immune cell infiltrates, as well as increased M1 and decreased M2 macrophages in UC compared to normal colonic mucosa. Weighted gene coexpression network analysis (WGCNA) was used to identify modules associated with macrophages and UC, resulting in the identification of 52 macrophage-related genes (MRGs) that were enriched in macrophages at single-cell resolution. Consensus clustering based on these 52 MRGs divided the integrated UC cohorts into three subtypes. Machine learning algorithms were used to identify ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), sodium- and chloride-dependent neutral and basic amino acid transporter B(0+) (SLC6A14), and 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) in the training set, and their diagnostic value was validated in independent validation sets. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) revealed the main biological effects, and that interleukin-17 was one of several signaling pathways enriched by the three genes. We also constructed a competitive endogenous RNA (CeRNA) network reflecting a potential posttranscriptional regulatory mechanism. Expression of diagnostic markers was validated in vivo and in biospecimens, and our immunohistochemistry (IHC) results confirmed that HMGCS2 gradually decreased during the transformation of UC to colorectal cancer. In conclusion, ENPP1, SLC6A14, and HMGCS2 are associated with macrophages and the progression of UC pathogenesis and have good diagnostic value for patients with UC.
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Affiliation(s)
- Shaocheng Hong
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
- Anhui Provincial Key Laboratory of Digestive Diseases, Hefei, China
| | - Hongqian Wang
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
- Anhui Provincial Key Laboratory of Digestive Diseases, Hefei, China
| | - Shixin Chan
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Jiayi Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
- Anhui Provincial Key Laboratory of Digestive Diseases, Hefei, China
| | - Bangjie Chen
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Xiaohan Ma
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
- Anhui Provincial Key Laboratory of Digestive Diseases, Hefei, China
| | - Xi Chen
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
- Anhui Provincial Key Laboratory of Digestive Diseases, Hefei, China
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9
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Costa-Fujishima M, Yazdanpanah A, Horne S, Lamont A, Lopez P, Farr Zuend C, Birse K, Taverner M, Greenslade R, Abou M, Noel-Romas L, Abrenica B, Ajibola O, Ikeogu N, Su RC, McKinnon LR, Pymar H, Poliquin V, Berard AR, Burgener AD, Murooka TT. Nonoptimal bacteria species induce neutrophil-driven inflammation and barrier disruption in the female genital tract. Mucosal Immunol 2023; 16:341-356. [PMID: 37121385 DOI: 10.1016/j.mucimm.2023.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/27/2023] [Accepted: 04/02/2023] [Indexed: 05/02/2023]
Abstract
Neutrophil recruitment and activation within the female genital tract are often associated with tissue inflammation, loss of vaginal epithelial barrier integrity, and increased risk for sexually transmitted infections, such as HIV-1. However, the direct role of neutrophils on vaginal epithelial barrier function during genital inflammation in vivo remains unclear. Using complementary proteome and immunological analyses, we show high neutrophil influx into the lower female genital tract in response to physiological surges in progesterone, stimulating distinct stromal, immunological, and metabolic signaling pathways. However, despite the release of extracellular matrix-modifying proteases and inflammatory mediators, neutrophils contributed little to physiological mucosal remodeling events such as epithelial shedding or re-epithelialization during transition from diestrus to estrus phase. In contrast, the presence of bacterial vaginosis-associated bacteria resulted in a rapid and sustained neutrophil recruitment, resulting in vaginal epithelial barrier leakage and decreased cell-cell junction protein expression in vivo. Thus, neutrophils are important mucosal sentinels that rapidly respond to various biological cues within the female genital tract, dictating the magnitude and duration of the ensuing inflammatory response at steady state and during disease processes.
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Affiliation(s)
- Marina Costa-Fujishima
- University of Manitoba, Rady Faculty of Health Sciences, Department of Immunology, Winnipeg, Canada
| | - Atta Yazdanpanah
- University of Manitoba, Rady Faculty of Health Sciences, Department of Immunology, Winnipeg, Canada
| | - Samantha Horne
- Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, USA; University of Manitoba, Department of Obstetrics, Gynecology, and Reproductive Sciences, Winnipeg, Canada
| | - Alana Lamont
- University of Manitoba, Rady Faculty of Health Sciences, Department of Medical Microbiology and Infectious Diseases, Winnipeg, Canada; National HIV and Retrovirology Labs, JC Wilt Infectious Disease Research Centre, Public Health Agency of Canada, Winnipeg, Canada
| | - Paul Lopez
- University of Manitoba, Rady Faculty of Health Sciences, Department of Immunology, Winnipeg, Canada
| | - Christina Farr Zuend
- Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, USA
| | - Kenzie Birse
- Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, USA; University of Manitoba, Department of Obstetrics, Gynecology, and Reproductive Sciences, Winnipeg, Canada
| | - Morgan Taverner
- University of Manitoba, Rady Faculty of Health Sciences, Department of Medical Microbiology and Infectious Diseases, Winnipeg, Canada
| | - Riley Greenslade
- University of Manitoba, Rady Faculty of Health Sciences, Department of Immunology, Winnipeg, Canada
| | - Max Abou
- National HIV and Retrovirology Labs, JC Wilt Infectious Disease Research Centre, Public Health Agency of Canada, Winnipeg, Canada
| | - Laura Noel-Romas
- Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, USA; University of Manitoba, Department of Obstetrics, Gynecology, and Reproductive Sciences, Winnipeg, Canada
| | - Bernard Abrenica
- National HIV and Retrovirology Labs, JC Wilt Infectious Disease Research Centre, Public Health Agency of Canada, Winnipeg, Canada
| | - Oluwaseun Ajibola
- University of Manitoba, Rady Faculty of Health Sciences, Department of Immunology, Winnipeg, Canada
| | - Nnamdi Ikeogu
- University of Manitoba, Rady Faculty of Health Sciences, Department of Immunology, Winnipeg, Canada
| | - Ruey-Chyi Su
- University of Manitoba, Rady Faculty of Health Sciences, Department of Medical Microbiology and Infectious Diseases, Winnipeg, Canada; National HIV and Retrovirology Labs, JC Wilt Infectious Disease Research Centre, Public Health Agency of Canada, Winnipeg, Canada
| | - Lyle R McKinnon
- University of Manitoba, Rady Faculty of Health Sciences, Department of Medical Microbiology and Infectious Diseases, Winnipeg, Canada; Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa; Department of Medical Microbiology and Immunology, University of Nairobi, Nairobi, Kenya
| | - Helen Pymar
- University of Manitoba, Department of Obstetrics, Gynecology, and Reproductive Sciences, Winnipeg, Canada
| | - Vanessa Poliquin
- University of Manitoba, Department of Obstetrics, Gynecology, and Reproductive Sciences, Winnipeg, Canada
| | - Alicia R Berard
- Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, USA; University of Manitoba, Department of Obstetrics, Gynecology, and Reproductive Sciences, Winnipeg, Canada
| | - Adam D Burgener
- Center for Global Health and Diseases, Department of Pathology, Case Western Reserve University, Cleveland, USA; University of Manitoba, Department of Obstetrics, Gynecology, and Reproductive Sciences, Winnipeg, Canada; Unit of Infectious Diseases, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Thomas T Murooka
- University of Manitoba, Rady Faculty of Health Sciences, Department of Immunology, Winnipeg, Canada; University of Manitoba, Rady Faculty of Health Sciences, Department of Medical Microbiology and Infectious Diseases, Winnipeg, Canada.
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10
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Liu X, Zhou M, Dai Z, Luo S, Shi Y, He Z, Chen Y. Salidroside alleviates ulcerative colitis via inhibiting macrophage pyroptosis and repairing the dysbacteriosis-associated Th17/Treg imbalance. Phytother Res 2023; 37:367-382. [PMID: 36331009 DOI: 10.1002/ptr.7636] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 09/03/2022] [Accepted: 09/14/2022] [Indexed: 11/06/2022]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by flora disequilibrium and mucosal immunity disorder. Here, we report that salidroside effectively restricts experimental colitis from two aspects of intestinal macrophage pyroptosis and dysbacteriosis-derived colonic Th17/Treg imbalance. In innate immunity, the upregulated TREM1 and pyroptosis-related proteins in inflamed colons were inhibited by salidroside administration and further experiments in vitro showed that salidroside suppressed LPS/ATP-induced bone marrow-derived macrophages (BMDMs) pyroptosis evident by the decline of LDH and IL-1β release as well as the protein level of NLRP3, caspase-1, and GSDMD p30. Moreover, the TREM1 inhibitor weakened the effect of salidroside on BMDMs pyroptosis, whereas salidroside still could downregulate TREM1 when NLRP3 was inhibited. In adaptive immunity, salidroside improved the gut microflora diversity and Th17/Treg ratio in DSS-induced mice, especially promoting the abundance of Firmicutes. Clearance of the gut flora blocked the benefit of salidroside on colonic inflammation and Th17/Treg adaptive immunity, but transplanting salidroside-treated foecal bacterium into flora-depleted wild mice reproduced the resistance of salidroside to gut inflammation. Taken together, our data demonstrated that salidroside protected experimental colitis via skewing macrophage pyroptosis and Th17/Treg balance, indicating its potential effect on UC and other immune disorders.
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Affiliation(s)
- Xiaoman Liu
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Mingxia Zhou
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Zhenzhen Dai
- Shanghai Institute for Pediatric Research, Shanghai, China
| | - Shangjian Luo
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Yingying Shi
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Zhenjuan He
- Department of Neonatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Yingwei Chen
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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11
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Yadav SK, Ito N, Mindur JE, Kumar H, Youssef M, Suresh S, Kulkarni R, Rosario Y, Balashov KE, Dhib-Jalbut S, Ito K. Fecal Lcn-2 level is a sensitive biological indicator for gut dysbiosis and intestinal inflammation in multiple sclerosis. Front Immunol 2022; 13:1015372. [PMID: 36341389 PMCID: PMC9634083 DOI: 10.3389/fimmu.2022.1015372] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 10/04/2022] [Indexed: 07/30/2023] Open
Abstract
Multiple Sclerosis (MS) has been reported to be associated with intestinal inflammation and gut dysbiosis. To elucidate the underlying biology of MS-linked gut inflammation, we investigated gut infiltration of immune cells during the development of spontaneous experimental autoimmune encephalomyelitis (EAE) in humanized transgenic (Tg) mice expressing HLA-DR2a and human T cell receptor (TCR) specific for myelin basic protein peptide (MBP87-99)/HLA-DR2a complexes. Strikingly, we noted the simultaneous development of EAE and colitis, suggesting a link between autoimmune diseases of the central nervous system (CNS) and intestinal inflammation. Examination of the colon in these mice revealed the infiltration of MBP-specific Th17 cells as well as recruitment of neutrophils. Furthermore, we observed that fecal Lipocalin-2 (Lcn-2), a biomarker of intestinal inflammation, was significantly elevated and predominantly produced by the gut-infiltrating neutrophils. We then extended our findings to MS patients and demonstrate that their fecal Lcn-2 levels are significantly elevated compared to healthy donors (HDs). The elevation of fecal Lcn-2 levels correlated with reduced bacterial diversity and increased levels of other intestinal inflammation markers including neutrophil elastase and calprotectin. Of interest, bacteria thought to be beneficial for inflammatory bowel disease (IBD) such as Anaerobutyricum, Blautia, and Roseburia, were reduced in fecal Lcn-2-high MS patients. We also observed a decreasing trend in serum acetate (a short-chain fatty acid) levels in MS Lcn-2-high patients compared to HDs. Furthermore, a decrease in the relative abundance of Blautia massiliensis was significantly associated with a reduction of acetate in the serum of MS patients. This study suggests that gut infiltration of Th17 cells and recruitment of neutrophils are associated with the development of gut dysbiosis and intestinal inflammation, and that fecal Lcn-2 level is a sensitive biological indicator for gut dysbiosis in multiple sclerosis.
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Affiliation(s)
- Sudhir K. Yadav
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, United States
| | - Naoko Ito
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, United States
| | - John E. Mindur
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, United States
| | - Hetal Kumar
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, United States
| | - Mysra Youssef
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, United States
- Department of Clinical and Chemical Pathology, National Research Centre, Dokki, Egypt
| | - Shradha Suresh
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, United States
| | - Ratuja Kulkarni
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, United States
| | - Yaritza Rosario
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, United States
| | - Konstantin E. Balashov
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, United States
| | - Suhayl Dhib-Jalbut
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, United States
- Department of Neurology, Rutgers-New Jersey Medical School, Newark, NJ, United States
| | - Kouichi Ito
- Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, United States
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12
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Li C, Wang L, Zhao J, Wei Y, Zhai S, Tan M, Guan K, Huang Z, Chen C. Lonicera rupicola Hook.f.et Thoms flavonoids ameliorated dysregulated inflammatory responses, intestinal barrier, and gut microbiome in ulcerative colitis via PI3K/AKT pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 104:154284. [PMID: 35777121 DOI: 10.1016/j.phymed.2022.154284] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 06/13/2022] [Accepted: 06/17/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Lonicera rupicola Hook.f.et Thoms (LRH) is used as a customary medicinal herb in Tibetans. And LRH flavonoids have excellent anti-inflammatory and antioxidant pharmacological activities. However, the specific effects of LRH and its mechanism remain unknown, and there is a deficiency of systematic research, leading to the waste of LRH as a medicinal resource. PURPOSE In this study, in an attempt to rationalize the development and utilization of Tibetan herbal resources, the therapeutic efficacy and the underlying molecular mechanisms of LRH flavonoids on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) were investigated, establishing the favorable basis for the pharmacodynamic material basis of LRH and providing a scientific basis for the discovery of new drugs for the treatment of UC. METHODS Firstly, ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was used for identification and detection of the flavonoid components of LRH. Meanwhile, their potential targets, biological functions and signaling pathways were predicted with the assistance of network pharmacology analysis. Subsequently, pharmacological efficacy of LRH were evaluated by body weight loss, colon length, disease activity index (DAI), histology observation and the expression levels of inflammatory mediators, messenger RNA (mRNA) and tight junction proteins. Moreover, in the present investigation, we also profiled the gut microbiome via high-throughput sequencing of the V3-V4 region of 16S ribosomal DNA (rDNA) for bacterial community composition and diversity by Illumina MiSeq platforms. Finally, the key regulatory proteins in the PI3K/AKT pathways were measured to investigate their underlying molecular mechanisms. RESULTS A total of 37 LRH flavonoid components were identified and detected by UPLC-MS/MS, and 12 potential active components were obtained after screening. 137 of their common targets with UC were further predicted. GO and KEGG pathway enrichment analysis and molecular docking experiments demonstrated that LRH flavonoids could interfere with UC through "multi-component-multi-target-multi-pathway". In the animal experiments, LRH flavonoids could significantly attenuate UC as demonstrated by reducing the body weight loss and DAI, restoring colon length, decreasing oxidative stress, and improving the intestinal epithelial cell barrier. The mRNA and proteins expression levels of inflammatory mediators were returned to dynamic balance following LRH flavonoids treatment. 16S rDNA sequence analysis indicated that LRH flavonoids promoted the recovery of gut microbiome. And the PI3K/AKT pathway was significantly suppressed by LRH flavonoids. CONCLUSIONS LRH flavonoids exhibited multifaceted protective effects against DSS-induced UC in mice through mitigating colon inflammation and oxidative stress, restoring epithelial barrier function, and improving the gut microenvironment potentially through modulation of the PI3K/AKT pathway. This finding demonstrated that LRH flavonoids possessed great potential for becoming an excellent drug for the treatment of UC.
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Affiliation(s)
- Congcong Li
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
| | - Lu Wang
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China; Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Southwest Minzu University, Chengdu 610041, China
| | - Juebo Zhao
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
| | - Yucai Wei
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
| | - Shuo Zhai
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
| | - Min Tan
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
| | - Kuikui Guan
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China
| | - Zhihong Huang
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China.
| | - Chaoxi Chen
- College of Animal & Veterinary Sciences, Southwest Minzu University, Chengdu 610041, China; Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Southwest Minzu University, Chengdu 610041, China.
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13
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Winther MF, Haugaard SL, Pihl TH, Jacobsen S. Concentrations of Neutrophil Gelatinase-Associated Lipocalin are increased in serum and peritoneal fluid from horses with inflammatory abdominal disease and non-strangulating intestinal infarctions. Equine Vet J 2022; 55:426-434. [PMID: 35642326 DOI: 10.1111/evj.13603] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 05/12/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Neutrophil gelatinase-associated lipocalin (NGAL) is produced in response to inflammation in horses, but it has not yet been investigated as a biomarker in horses with abdominal disease. OBJECTIVES To investigate NGAL in serum and peritoneal fluid in horses with abdominal disease. STUDY DESIGN Retrospective clinical study. METHODS Data from medical records of 270 horses admitted with acute abdominal disease (simple obstructions [n=43], strangulating obstructions [n=104], inflammatory abdominal disease [n=99], non-strangulating intestinal infarction [NSII, n=24]) and 9 healthy control horses were reviewed, and serum and peritoneal fluid samples were retrieved from a biobank. NGAL was measured in serum and peritoneal fluid by ELISA. Differences in NGAL concentrations between groups were assessed. RESULTS Healthy horses had low serum and peritoneal fluid concentrations of NGAL (median = 21.0 and 9.5 μg/L, respectively). Neither serum nor peritoneal fluid NGAL concentrations (median serum, peritoneal fluid) differed between healthy horses and horses with simple (28.1 μg/L, 13.0 μg/L) and strangulating intestinal obstructions (34.7 μg/L, 38.4 μg/L). Horses with NSII (308.0 μg/L, 2163.0 μg/L) and inflammatory abdominal disease (171.1 μg/L, 314.1 μg/L) had higher serum and peritoneal fluid concentrations of NGAL than the other groups (P<0.001). Peritoneal fluid NGAL concentrations in horses with NSII were higher than in horses with inflammatory abdominal disease (P=0.03). MAIN LIMITATIONS Retrospective study design; small group of control horses. CONCLUSIONS NGAL is a marker of inflammation in horses with abdominal disease. The high peritoneal fluid concentration of NGAL in horses with NSII compared to all other groups may render NGAL useful for identifying this condition, which is otherwise difficult to differentiate from other types of peritonitis. Thereby, NGAL may potentially facilitate timely surgical intervention in this group of patients. The results of this study must be evaluated in larger, and preferably prospective, studies to obtain a more comprehensive evaluation of the diagnostic utility of NGAL. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Malou F Winther
- University of Copenhagen, Department of Veterinary Clinical Sciences, Copenhagen, Denmark
| | - Simon L Haugaard
- University of Copenhagen, Department of Veterinary Clinical Sciences, Copenhagen, Denmark
| | - Tina H Pihl
- University of Copenhagen, Department of Veterinary Clinical Sciences, Copenhagen, Denmark
| | - Stine Jacobsen
- University of Copenhagen, Department of Veterinary Clinical Sciences, Copenhagen, Denmark
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14
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Liu H, Yu Y, Niu Y. Utility of Human Neutrophil Lipocalin as a Diagnosing Biomarker of Prosthetic Joint Infection: A Clinical Pilot Study. Infect Drug Resist 2022; 15:2393-2400. [PMID: 35528185 PMCID: PMC9075898 DOI: 10.2147/idr.s355180] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 04/29/2022] [Indexed: 12/12/2022] Open
Abstract
Purpose The discrimination of prosthetic joint infection (PJI) from aseptic failure is regarded as a major clinical challenge. The key function of human neutrophil lipocalin (HNL) in regulating bacterial infection rationalizes its potential as a biomarker to diagnose PJI. This work evaluated the accuracy of serum human neutrophil lipocalin as a biomarker to diagnose PJI. Methods This prospective cohort study enrolled altogether 58 patients suffering from miserable knee or hip arthroplasty and receiving revision surgery from 2018 to 2020. Related laboratory and clinical information of these patients were retrieved. Following the Musculoskeletal Infection Society (MSIS) criteria, the diagnosis of PJI was conducted. Collecting preoperative blood samples, we measured HNL by the standard assay. Thereafter, plotting the receiver-operating characteristic curve (ROC), the area under the curve (AUC) values were calculated to analyze the diagnosis accuracy. Results According to the MSIS criteria, 38 cases (65.5%) were classified into the PJI group, while 20 (34.5%) into the aseptic loosening group, with age ranging from 38 to 87 (median, 66.9) years. The median serum HNL level of the PJI patients was 199.01 (range, 85.34–357.79) ng/mL, significantly higher as compared with that of 64.81 (range, 20.73–157.89) ng/mL of the aseptic loosening group. Using the Youden index, the optimal threshold value was 105.1ng/mL, while the specificity, sensitivity, and AUC were 85.0%, 81.6%, and 0.919, respectively. Conclusion Serum HNL is the creditable test that can be employed as the laboratory biomarker to screen PJI. The threshold HNL level is 105.1 ng/mL, which may distinguish PJI from aseptic failure.
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Affiliation(s)
- Hanjiang Liu
- Department of Clinical Laboratory, Zhengzhou Orthopaedics Hospital, Zhengzhou, Henan, 450000, People’s Republic of China
| | - Yali Yu
- Department of Clinical Laboratory, Zhengzhou Orthopaedics Hospital, Zhengzhou, Henan, 450000, People’s Republic of China
| | - Yanli Niu
- School of Basic Medical Science, Henan University, Kaifeng, Henan, 475004, People’s Republic of China
- Correspondence: Yanli Niu, School of Basic Medical Science, Henan University, Kaifeng, Henan, 475004, People’s Republic of China, Email
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15
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Hsu CF, Huang CC, Liu TT, Yang UC, Liu CW, Huang SF, Yang YY, Huang YH, Hou MC, Lin HC. Deletion of intestinal SIRT1 exacerbated muscle wasting in cirrhotic mice by decreasing the intestinal concentration of short-chain fatty acids and inflammation. J Pharmacol Sci 2021; 147:376-385. [PMID: 34663520 DOI: 10.1016/j.jphs.2021.09.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 08/28/2021] [Accepted: 09/06/2021] [Indexed: 11/20/2022] Open
Abstract
Systemic sirtuin 1 (SIRT1) activation alleviates muscle wasting and improves muscle function by downregulation of myotropic and proteolytic markers. In this study, we evaluated the effects of the intestinal Sirt1 deletion on the dysregulated gutmuscle axis in cirrhotic mice. Cirrhosis-related muscle wasting was induced by common bile duct ligated (BDL) in either wild-type (WT) or intestine-specific Sirt1-deleted (Sirt1IEC-KO) mice, including WT-BDL, WT-sham, Sirt1IEC-KO-BDL and Sirt1IEC-KO-sham mice. Compared with WT-BDL mice, Sirt1IEC-KO-BDL mice showed worsened low lean mass, exacerbated muscle wasting, increased expression of myotropic markers, increased muscular protein degradation, and decreased expression of myogenic markers through aggravation of intestinal inflammation (as evidenced by increased fecal calprotectin/lipocalin-2 levels, increased intestinal macrophage infiltration, and increased intestinal TNFα/IL-6 levels), decrease in abundance of short-chain fatty acid (SCFA)-producing bacteria, decrease in levels of intestinal SCFAs (with anti-inflammatory effects), and downregulation of SCFA receptor GPR43. In biliary cirrhotic mice, a decrease in the abundance of SCFA-producing bacteria and an increase in the levels of intestinal/muscular inflammatory markers are involved in the pathogenesis of dysregulated gut-muscle axis-related muscle wasting, and intestinal deletion of Sirt1 exacerbated these changes.
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Affiliation(s)
- Chien-Fu Hsu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chia-Chang Huang
- Division of Clinical Skills Training Center, Department of Medical Education, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Tze-Tze Liu
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ueng-Cheng Yang
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Wei Liu
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Shiang-Fen Huang
- Division of Infection, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ying-Ying Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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16
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Li Y, Li C, Tu Y, Tao J, Liu P, Xu H, Tang Y, Gu Y. In vivo assessing colitis severity by topical administration of fluorescent probe against neutrophils. Talanta 2021; 233:122519. [PMID: 34215134 DOI: 10.1016/j.talanta.2021.122519] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease has become a global burden given its high incidence and refractory to medical treatment. Improved diagnostic strategies to monitor disease activity more accurately are necessary to conduct and evaluate medical treatment. High level of neutrophil infiltration in colon is associated with poor prognosis and enhanced risk of developing colitis-associated cancer. Herein, to accurately monitor neutrophil levels in colitis condition, we designed and constructed a specific probe (CPM), consisting of a neutrophil formyl peptide receptor targeting group (cFLFLFK), a short PEG linker and a near-infrared fluorescent dye. CPM selectively identified neutrophils in vitro and preferentially recognized neutrophils in vivo with enhanced targeting ability and biodistribution property. After verified the ability to target activated neutrophils, CPM was used to detect neutrophils in experimental colitis by systemic and topical administration. Compared to systemic administration, topical administration of CPM allows lower dosage, higher target-to-background ratio and longer duration of effective monitoring. More importantly, we used CPM to assess neutrophil levels in the course of colitis development. The fluorescence intensity of CPM increased along with colitis progression. Additionally, CPM was used to detected neutrophil levels in colitis-associated cancer and enhanced neutrophil infiltration in the tumor sites was detected. In conclusion, the probe CPM is a promising tool for in vivo improved diagnosis of colitis severity by monitoring the extent of neutrophil infiltration.
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Affiliation(s)
- Yi Li
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China
| | - Chang Li
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China
| | - Yuanbiao Tu
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China; Jiangzhong Cancer Research Center, Jiangxi University of Traditional Chinese Medicine, No.1688 Meiling Road, Wanli District, Nanchang, 330004, China
| | - Ji Tao
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China
| | - Peifei Liu
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China
| | - Haoran Xu
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China
| | - Yongjia Tang
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China
| | - Yueqing Gu
- State Key Laboratory of Natural Medicine, Department of Biomedical Engineering, School of Engineering, China Pharmaceutical University, No. 24 Tongjia Lane, Gulou District, Nanjing, 210009, China.
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17
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Riffelmacher T, Giles DA, Zahner S, Dicker M, Andreyev AY, McArdle S, Perez-Jeldres T, van der Gracht E, Murray MP, Hartmann N, Tumanov AV, Kronenberg M. Metabolic activation and colitis pathogenesis is prevented by lymphotoxin β receptor expression in neutrophils. Mucosal Immunol 2021; 14:679-690. [PMID: 33568785 PMCID: PMC8075978 DOI: 10.1038/s41385-021-00378-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 12/09/2020] [Accepted: 12/30/2020] [Indexed: 02/04/2023]
Abstract
Inflammatory bowel disease is characterized by an exacerbated intestinal immune response, but the critical mechanisms regulating immune activation remain incompletely understood. We previously reported that the TNF-superfamily molecule TNFSF14 (LIGHT) is required for preventing severe disease in mouse models of colitis. In addition, deletion of lymphotoxin beta receptor (LTβR), which binds LIGHT, also led to aggravated colitis pathogenesis. Here, we aimed to determine the cell type(s) requiring LTβR and the mechanism critical for exacerbation of colitis. Specific deletion of LTβR in neutrophils (LTβRΔN), but not in several other cell types, was sufficient to induce aggravated colitis and colonic neutrophil accumulation. Mechanistically, RNA-Seq analysis revealed LIGHT-induced suppression of cellular metabolism, and mitochondrial function, that was dependent on LTβR. Functional studies confirmed increased mitochondrial mass and activity, associated with excessive mitochondrial ROS production and elevated glycolysis at steady-state and during colitis. Targeting these metabolic changes rescued exacerbated disease severity. Our results demonstrate that LIGHT signals to LTβR on neutrophils to suppress metabolic activation and thereby prevents exacerbated immune pathogenesis during colitis.
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Affiliation(s)
- Thomas Riffelmacher
- La Jolla Institute for Immunology, La Jolla, CA, USA
- Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK
| | | | - Sonja Zahner
- La Jolla Institute for Immunology, La Jolla, CA, USA
| | | | - Alexander Y Andreyev
- Department of Pharmacology, University of California San Diego, La Jolla, CA, USA
| | - Sara McArdle
- La Jolla Institute for Immunology, La Jolla, CA, USA
| | | | | | | | | | - Alexei V Tumanov
- Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health Science Center San Antonio, San Antonio, USA
| | - Mitchell Kronenberg
- La Jolla Institute for Immunology, La Jolla, CA, USA.
- Division of Biological Sciences, University of California San Diego, La Jolla, CA, USA.
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Glutamine Administration Attenuates Kidney Inflammation in Obese Mice Complicated with Polymicrobial Sepsis. Mediators Inflamm 2021; 2021:5597118. [PMID: 33859538 PMCID: PMC8024070 DOI: 10.1155/2021/5597118] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 03/04/2021] [Accepted: 03/12/2021] [Indexed: 11/17/2022] Open
Abstract
Obesity is a well-known public health issue around the world. Sepsis is a lethal clinical syndrome that causes multiorgan failure. Obesity may aggravate inflammation in septic patients. Glutamine (GLN) is a nutrient with immune regulatory and anti-inflammatory properties. Since sepsis is a common contributing factor for acute kidney injury (AKI), this study investigated the effects of GLN administration on sepsis-induced inflammation and AKI in obese mice. A high-fat diet which consists of 60% of calories from fat was provided for 10 weeks to induce obesity in the mice. Then, the obese mice were subdivided into sepsis with saline (SS) or GLN (SG) groups. Cecal ligation and puncture (CLP) was performed to produce sepsis. The SS group was intravenously injected with saline while the SG group was administered GLN one or two doses after CLP. Obese mice with sepsis were sacrificed at 12, 24, or 48 h post-CLP. Results revealed that sepsis resulted in upregulated high-mobility group box protein-1 pathway-associated gene expression in obese mice. Also, expressions of macrophage/neutrophil infiltration markers and inflammatory cytokines in kidneys were elevated. Obese mice treated with GLN after sepsis reversed the depletion of plasma GLN, reduced production of lipid peroxides, and downregulated macrophage/neutrophil infiltration and the inflammatory-associated pathway whereas tight junction gene expression increased in the kidneys. These findings suggest that intravenously administered GLN to obese mice after sepsis alleviated inflammation and attenuated AKI. This model may have clinical application to obese patients with a risk for infection in abdominal surgery.
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19
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Brassica oleracea Prevents HCl/Ethanol-Induced Gastric Damages in Mice. APPLIED SCIENCES-BASEL 2020. [DOI: 10.3390/app11010016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Brassica oleracea var. capitata L. (cabbage) is a popular vegetable with a wide range of pharmacological activities that help to promote human health. The present study investigated the beneficial effects of B. oleracea var. capitata L. extract (BOE) on HCl/ethanol (H/E)-induced gastric damages in mice. Pre-administration of BOE (25–100 mg/kg) for 7 consecutive days significantly decreased macroscopically visible lesion on the gastric mucosa induced by H/E. In addition, results from hematoxylin and eosin-stained gastric tissue showed that BOE inhibited invaded percentage of lesion and prevented the reduction in mucosal thickness in peri-ulcerative region. BOE significantly alleviated the H/E-mediated decreases in Alcian blue binding, total hexose, sialic acid, and collagen in the gastric tissue, suggesting BOE attenuates the gastric damage via preserving the integrity of gastric mucus. Moreover, BOE significantly decreased histamine level in the plasma and reduced mRNA levels associated with secreting gastric acid. Furthermore, BOE inhibited myeloperoxidase activity and suppressed nuclear factor-κB mRNA and its dependent inflammatory genes expression induced by H/E. BOE also strengthened antioxidant enzyme activity, with a mitigating H/E-mediated increase in malondialdehyde level of the gastric tissue. Thus, these results suggest that BOE has the potential to protect the gastric tissue via inhibiting gastric acid secretion, inflammation, and oxidative stress.
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20
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Augustijns P, Vertzoni M, Reppas C, Langguth P, Lennernäs H, Abrahamsson B, Hasler WL, Baker JR, Vanuytsel T, Tack J, Corsetti M, Bermejo M, Paixão P, Amidon GL, Hens B. Unraveling the behavior of oral drug products inside the human gastrointestinal tract using the aspiration technique: History, methodology and applications. Eur J Pharm Sci 2020; 155:105517. [DOI: 10.1016/j.ejps.2020.105517] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 08/12/2020] [Accepted: 08/16/2020] [Indexed: 02/08/2023]
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21
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Lin A, Inman RD, Streutker CJ, Zhang Z, Pritzker KPH, Tsui HW, Tsui FWL. Lipocalin 2 links inflammation and ankylosis in the clinical overlap of inflammatory bowel disease (IBD) and ankylosing spondylitis (AS). Arthritis Res Ther 2020; 22:51. [PMID: 32188494 PMCID: PMC7081573 DOI: 10.1186/s13075-020-02149-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 03/09/2020] [Indexed: 12/16/2022] Open
Abstract
Background Little is known about the mechanisms underlying the clinical overlap between gut inflammation and joint ankylosis, as exemplified by the concurrence of inflammatory bowel diseases (IBD) and ankylosing spondylitis (AS). As dysbiosis may serve as a common contributor, the anti-microbial pleiotropic factor lipocalin 2 could be a potential mediator due to its roles in inflammation and bone homeostasis. Methods Baseline colonic pathology was conducted in the ank/ank mouse model. Serum lipocalin 2 was analyzed by ELISA, in ank/ank mutants versus C3FeB6-A/Aw-jwt/wt, in patients with concurrent AS-IBD, AS alone, IBD alone, or mechanical back pain, and in healthy controls. In the ank/ank mouse model, the expression of nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) was examined by real-time PCR. Intraperitoneal injection was done with the PPARγ agonist rosiglitazone or antagonist bisphenol A diglycidyl ether for four consecutive days. Serum levels of lipocalin 2 were examined on the sixth day. Results This study showed that the ank/ank mice with fully fused spines had concurrent colonic inflammation. By first using the ank/ank mouse model with progressive ankylosis and subclinical colonic inflammation, confirmed in patients with concurrent AS and IBD, elevated circulating lipocalin 2 levels were associated with the coexisting ankylosis and gut inflammation. The intracellular pathway of lipocalin 2 was further investigated with the ank/ank mouse model involving PPARγ. Colonic expression of PPARγ was negatively associated with the degree of gut inflammation. The PPARγ agonist rosiglitazone treatment significantly upregulated the serum levels of lipocalin 2, suggesting a potential regulatory role of PPARγ in the aberrant expression of lipocalin 2. Conclusions In summary, lipocalin 2 modulated by PPARγ could be a potential pathway involved in concurrent inflammation and ankylosis in AS and IBD.
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Affiliation(s)
- Aifeng Lin
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. .,Krembil Research Institute, University Health Network, Toronto, Ontario, Canada. .,KeyIntel Medical Inc, Toronto, Ontario, Canada.
| | - Robert D Inman
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.,Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.,Department of Immunology and Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Catherine J Streutker
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Li Ka Shing Institute, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Zhenbo Zhang
- Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Kenneth P H Pritzker
- KeyIntel Medical Inc, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Hing Wo Tsui
- Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Florence W L Tsui
- KeyIntel Medical Inc, Toronto, Ontario, Canada.,Department of Immunology and Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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22
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Kirov S, Sasson A, Zhang C, Chasalow S, Dongre A, Steen H, Stensballe A, Andersen V, Birkelund S, Bennike TB. Degradation of the extracellular matrix is part of the pathology of ulcerative colitis. Mol Omics 2019; 15:67-76. [PMID: 30702115 DOI: 10.1039/c8mo00239h] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The scientific value of re-analyzing existing datasets is often proportional to the complexity of the data. Proteomics data are inherently complex and can be analyzed at many levels, including proteins, peptides, and post-translational modifications to verify and/or develop new hypotheses. In this paper, we present our re-analysis of a previously published study comparing colon biopsy samples from ulcerative colitis (UC) patients to non-affected controls. We used a different statistical approach, employing a linear mixed-effects regression model and analyzed the data both on the protein and peptide level. In addition to confirming and reinforcing the original finding of upregulation of neutrophil extracellular traps (NETs), we report novel findings, including that Extracellular Matrix (ECM) degradation and neutrophil maturation are involved in the pathology of UC. The pharmaceutically most relevant differential protein expressions were confirmed using immunohistochemistry as an orthogonal method. As part of this study, we also compared proteomics data to previously published mRNA expression data. These comparisons indicated compensatory regulation at transcription levels of the ECM proteins we identified and open possible new avenues for drug discovery.
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Affiliation(s)
- Stefan Kirov
- Translational Bioinformatics, Bristol Myers Squib, Pennington, NJ, USA.
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23
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Liu Z, Cominelli F, Di Martino L, Liu R, Devireddy N, Devireddy LR, Wald DN. Lipocalin 24p3 Induction in Colitis Adversely Affects Inflammation and Contributes to Mortality. Front Immunol 2019; 10:812. [PMID: 31057545 PMCID: PMC6478753 DOI: 10.3389/fimmu.2019.00812] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2019] [Accepted: 03/27/2019] [Indexed: 12/12/2022] Open
Abstract
Recognition of microorganism associated molecular patterns by epithelial cells elicits signaling cascades resulting in the production of host defense proteins. Lipocalin 24p3 is purported to be one such protein. 24p3 binds prokaryotic and eukaryotic siderophores and by sequestering iron laden bacterial siderophores it was believed to restrict bacterial replication. As such mice deficient for 24p3 are susceptible to systemic infections. However, it is not clear whether deficiency of 24p3 on the gut mucosa contributes to inflammation. In line with 24p3's function as a bacteriostat, it would be reasonable to assume that deficiencies in the control of intestinal flora from 24p3 absence play a role in inflammatory intestinal diseases. Surprisingly, we show 24p3 is a contributor of inflammation and 24p3 deficiency protects mice from dextran sodium sulfate (DSS)-induced colitis. 24p3 was found to be a negative regulator of platelet-derived growth factor (PDGF), which helps maintain the integrity of the gut mucosa. Neutralization of PDGF-BB abrogated resistance of 24p3 null mice to DSS confirming the direct link between 24p3 and PDGF-BB. Finally, iron handling in wild-type and 24p3-null mice upon DSS treatment also differed. In summary, differential iron levels and enhanced expression of PDGF-BB in 24p3 null mice confers resistance to DSS.
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Affiliation(s)
- Zhuoming Liu
- Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
| | - Fabio Cominelli
- Department of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Luca Di Martino
- Department of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Ruifu Liu
- Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
| | | | - Lax R Devireddy
- Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
| | - David N Wald
- Department of Pathology, Case Western Reserve University, Cleveland, OH, United States.,Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
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24
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Chung LK, Raffatellu M. G.I. pros: Antimicrobial defense in the gastrointestinal tract. Semin Cell Dev Biol 2019; 88:129-137. [PMID: 29432952 PMCID: PMC6087682 DOI: 10.1016/j.semcdb.2018.02.001] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 02/06/2018] [Accepted: 02/06/2018] [Indexed: 01/11/2023]
Abstract
The gastrointestinal tract is a complex environment in which the host immune system interacts with a diverse array of microorganisms, both symbiotic and pathogenic. As such, mobilizing a rapid and appropriate antimicrobial response depending on the nature of each stimulus is crucial for maintaining the balance between homeostasis and inflammation in the gut. Here we focus on the mechanisms by which intestinal antimicrobial peptides regulate microbial communities during dysbiosis and infection. We also discuss classes of bacterial peptides that contribute to reducing enteric pathogen outgrowth. This review aims to provide a comprehensive overview on the interplay of diverse antimicrobial responses with enteric pathogens and the gut microbiota.
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Affiliation(s)
- Lawton K Chung
- Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics, University of California, San Diego, La Jolla, CA, 92093-0704, United States
| | - Manuela Raffatellu
- Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics, University of California, San Diego, La Jolla, CA, 92093-0704, United States; Chiba University-UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines (CU-UCSD cMAV), La Jolla CA, United States.
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25
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Yu LM, Zhao KJ, Wang SS, Wang X, Lu B. Corticotropin-releasing factor induces inflammatory cytokines via the NLRP6-inflammatory cytokine axis in a murine model of irritable bowel syndrome. J Dig Dis 2019; 20:143-151. [PMID: 30663229 DOI: 10.1111/1751-2980.12704] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 01/15/2019] [Accepted: 01/15/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVE This study aimed to determine the effect of corticotropin-releasing factor (CRF) on regulating the NOD-like receptor pyrin domain-containing protein 6 (NLRP6)-inflammatory cytokine axis in a murine model of irritable bowel syndrome (IBS). METHODS C57BL/6 mice were subjected to water avoidance stress (WAS) for 1 h per day for 10 days, and the abdominal withdrawal reflex (AWR) and colonic inflammation were assessed. We also measured the levels of CRF, NLRP6 inflammasome components, myeloperoxidase, D-lactate, interleukin (IL)-1β, and IL-18. In vitro experiments with Caco-2 cell line were also performed. In addition, we assessed the effect of Clostridium butyricum (C. butyricum) on IBS mice. RESULTS IBS mice exhibited visceral hypersensitivity and inflammation, accompanied by increases in CRF, myeloperoxidase, D-lactate, IL-1β, and IL-18 levels, but a decrease in NLRP6 expression. In vitro data showed that CRF suppressed NLRP6, but induced IL-1β and IL-18 levels, in Caco-2 cells. C. butyricum restored CRF levels and maintained the NLRP6-inflammatory cytokine axis in IBS mice. CONCLUSIONS CRF induces the NLRP6-inflammatory cytokine axis in IBS mice. C. butyricum could be beneficial in controlling IBS.
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Affiliation(s)
- Lei Min Yu
- Department of Gastroenterology, Hangzhou Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang Province, China.,Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Ke Jia Zhao
- Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Shuang Shuang Wang
- Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Xi Wang
- The Key Laboratory of Digestive Pathophysiology of Zhejiang Province, The First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
| | - Bin Lu
- Department of Gastroenterology, First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, China
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26
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The human olfactory cleft mucus proteome and its age-related changes. Sci Rep 2018; 8:17170. [PMID: 30464187 PMCID: PMC6249231 DOI: 10.1038/s41598-018-35102-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 10/22/2018] [Indexed: 12/14/2022] Open
Abstract
Age-related decreases in olfactory sensitivity are often accompanied by a decrease in the quality of life. However, the molecular mechanisms underlying these changes are not well described. Inhaled substances including odorants are detected by sensory neurons in the olfactory cleft covered with a layer of mucus. This olfactory mucus is the first molecular machinery responsible for tissue protection and for detection of environmental odorants. Yet, little is known about the molecular identities of the actors because of the lack of information on the mucus proteome and its age-related changes. Here, we sampled human mucus from different nasal locations and from young and elderly subjects. The composition of the mucus was extensively analyzed by shotgun proteomic analysis for a vast array of proteins. We also explored correlations between the levels of each mucus proteins with the olfactory sensitivity of subjects. This analysis revealed previously unrecognized proteins with potentially important functions in olfaction. Taken together, this report describes the most comprehensive catalogue of the nasal mucus proteins to date, their positional and age-related differences, and candidate proteins associated with olfaction. This catalogue will provide fundamental information useful for future studies, such as identification of olfactory auxiliary proteins, causes of age-related declines in olfaction, and biomarkers for neurodegenerative disorders.
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27
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Bozzi Cionci N, Baffoni L, Gaggìa F, Di Gioia D. Therapeutic Microbiology: The Role of Bifidobacterium breve as Food Supplement for the Prevention/Treatment of Paediatric Diseases. Nutrients 2018; 10:E1723. [PMID: 30423810 PMCID: PMC6265827 DOI: 10.3390/nu10111723] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Revised: 11/05/2018] [Accepted: 11/08/2018] [Indexed: 02/07/2023] Open
Abstract
The human intestinal microbiota, establishing a symbiotic relationship with the host, plays a significant role for human health. It is also well known that a disease status is frequently characterized by a dysbiotic condition of the gut microbiota. A probiotic treatment can represent an alternative therapy for enteric disorders and human pathologies not apparently linked to the gastrointestinal tract. Among bifidobacteria, strains of the species Bifidobacterium breve are widely used in paediatrics. B. breve is the dominant species in the gut of breast-fed infants and it has also been isolated from human milk. It has antimicrobial activity against human pathogens, it does not possess transmissible antibiotic resistance traits, it is not cytotoxic and it has immuno-stimulating abilities. This review describes the applications of B. breve strains mainly for the prevention/treatment of paediatric pathologies. The target pathologies range from widespread gut diseases, including diarrhoea and infant colics, to celiac disease, obesity, allergic and neurological disorders. Moreover, B. breve strains are used for the prevention of side infections in preterm newborns and during antibiotic treatments or chemotherapy. With this documentation, we hope to increase knowledge on this species to boost the interest in the emerging discipline known as "therapeutic microbiology".
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Affiliation(s)
- Nicole Bozzi Cionci
- Department of Agricultural and Food Sciences (DISTAL), Alma Mater Studiorum-Università di Bologna, Viale Fanin 42, 40127 Bologna, Italy.
| | - Loredana Baffoni
- Department of Agricultural and Food Sciences (DISTAL), Alma Mater Studiorum-Università di Bologna, Viale Fanin 42, 40127 Bologna, Italy.
| | - Francesca Gaggìa
- Department of Agricultural and Food Sciences (DISTAL), Alma Mater Studiorum-Università di Bologna, Viale Fanin 42, 40127 Bologna, Italy.
| | - Diana Di Gioia
- Department of Agricultural and Food Sciences (DISTAL), Alma Mater Studiorum-Università di Bologna, Viale Fanin 42, 40127 Bologna, Italy.
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28
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Mortaz E, Alipoor SD, Adcock IM, Mumby S, Koenderman L. Update on Neutrophil Function in Severe Inflammation. Front Immunol 2018; 9:2171. [PMID: 30356867 PMCID: PMC6190891 DOI: 10.3389/fimmu.2018.02171] [Citation(s) in RCA: 270] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Accepted: 09/03/2018] [Indexed: 12/17/2022] Open
Abstract
Neutrophils are main players in the effector phase of the host defense against micro-organisms and have a major role in the innate immune response. Neutrophils show phenotypic heterogeneity and functional flexibility, which highlight their importance in regulation of immune function. However, neutrophils can play a dual role and besides their antimicrobial function, deregulation of neutrophils and their hyperactivity can lead to tissue damage in severe inflammation or trauma. Neutrophils also have an important role in the modulation of the immune system in response to severe injury and trauma. In this review we will provide an overview of the current understanding of neutrophil subpopulations and their function during and post-infection and discuss the possible mechanisms of immune modulation by neutrophils in severe inflammation.
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Affiliation(s)
- Esmaeil Mortaz
- Department of Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shamila D Alipoor
- Molecular Medicine Department, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Ian M Adcock
- Priority Research Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.,Airways Disease Section, Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Sharon Mumby
- Airways Disease Section, Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Leo Koenderman
- Laboratory of Translational Immunology, Department of Respiratory Medicine, University Medical Centre Utrecht, Utrecht, Netherlands
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29
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Gao W, Zhang L, Wang X, Yu L, Wang C, Gong Y. The combination of indirubin and isatin attenuates dextran sodium sulfate induced ulcerative colitis in mice. Biochem Cell Biol 2018; 96:636-645. [PMID: 29671340 DOI: 10.1139/bcb-2018-0041] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Indirubin and isatin have been used in the treatment of inflammatory diseases due to their anti-inflammatory properties. This study aimed to evaluate the combined effect of indirubin and isatin on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). UC was induced by the administration of 3% (w/v) DSS solution, and then the model mice were administered indirubin (10 mg/kg body mass) and (or) isatin (10 mg/kg body mass) by gavage once daily for 7 days. The results showed that indirubin and isatin, individually or combined, significantly inhibited weight loss, lowered disease activity index (DAI), ameliorated pathological changes, decreased the levels of pro-inflammatory mediators and myeloperoxidase (MPO) activity, increased the expression of anti-inflammatory cytokines and Foxp3, suppressed CD4+ T cell infiltration, and inhibited oxidative stress and epithelial cell apoptosis. Additionally, indirubin and isatin, both individually and combined, can also inhibit activation of the NF-κB and MAPK pathways induced by DSS. The protective effect of combination therapy against UC was superior to that of single-agent treatment. These results suggest that indirubin combined with isatin attenuates DSS-induced UC, and changes to the NF-κB and MAPK signaling pathways may mediate the protective effects of indirubin and isatin in UC.
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Affiliation(s)
- Wenyan Gao
- a Department of Traditional Chinese Medicine, The General Hospital of Shenyang Military Area Command, Shenyang 110016, People's Republic of China
| | - Luding Zhang
- b Graduate School, Liaoning University of Traditional Chinese Medicine, Shenyang 110847, People's Republic of China
| | - Xiaoqian Wang
- a Department of Traditional Chinese Medicine, The General Hospital of Shenyang Military Area Command, Shenyang 110016, People's Republic of China
| | - Li Yu
- a Department of Traditional Chinese Medicine, The General Hospital of Shenyang Military Area Command, Shenyang 110016, People's Republic of China
| | - Changhong Wang
- a Department of Traditional Chinese Medicine, The General Hospital of Shenyang Military Area Command, Shenyang 110016, People's Republic of China
| | - Yang Gong
- a Department of Traditional Chinese Medicine, The General Hospital of Shenyang Military Area Command, Shenyang 110016, People's Republic of China
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30
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Zhang S, Huang G, Yuan K, Zhu Q, Sheng H, Yu R, Luo G, Xu A. Tanshinone IIA ameliorates chronic arthritis in mice by modulating neutrophil activities. Clin Exp Immunol 2017; 190:29-39. [PMID: 28542869 DOI: 10.1111/cei.12993] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2017] [Indexed: 01/13/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic immune inflammatory disease mediated by the influx of immune cells into the synovial joint space. As Tanshinone IIA (TIIA) has potent anti-oxidant and anti-inflammatory activities, we used the adjuvant-induced arthritis (AA) murine model of RA to investigate the impact of TIIA on RA and immune cell activation. The anti-arthritic activity of TIIA was investigated in an adjuvant-induced arthritis model of RA in mice. Myeloperoxidase and neutrophil elastase expression levels were assessed in ankle joints by immunohistochemistry analysis. Immune cell infiltration was evaluated in air pouch experiments. Proinflammatory cytokines expression levels were determined by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assays. Neutrophil extracellular traps (NETs) were assessed by immunostaining and confocal microscopy. Treatment with TIIA alleviated cartilage erosion and neutrophil infiltration in the ankle joints of AA mice and reduced proinflammatory cytokine expression levels in sera. TIIA suppressed interleukin-6 and tumour necrosis factor-α expression and release in neutrophils and promoted neutrophil apoptosis. TIIA also inhibited the NET formation of neutrophils. Our findings demonstrated that TIIA can ameliorate RA effectively by targeting neutrophils, indicating that TIIA may act as a potential therapeutic for RA.
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Affiliation(s)
- S Zhang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - G Huang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - K Yuan
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - Q Zhu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - H Sheng
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - R Yu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - G Luo
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
| | - A Xu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China.,State Key Laboratory of Biocontrol, Department of Biochemistry, School of Life Sciences, Sun Yat-Sen (Zhongshan) University, Guangzhou, Guangdong, China
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31
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Hallison DNS, Suzana VR, Tamara CD, Fernanda GDSO, Roxana BDAT, Juliane CS, Mariana GES, Henrique DMC, Irwin RADM, Jackson RGDSA. Antinociceptive and anti-inflammatory activities of ethanolic extract from atemoya (Annona cherimola Mill x Annona squamosa L.). ACTA ACUST UNITED AC 2017. [DOI: 10.5897/ajpp2017.4778] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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32
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Beber AP, de Souza P, Boeing T, Somensi LB, Mariano LNB, Cury BJ, Burci LM, da Silva CB, Simionatto E, de Andrade SF, da Silva LM. Constituents of leaves from Bauhinia curvula Benth. exert gastroprotective activity in rodents: role of quercitrin and kaempferol. Inflammopharmacology 2017; 26:539-550. [PMID: 28176198 DOI: 10.1007/s10787-017-0313-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 01/21/2017] [Indexed: 12/29/2022]
Abstract
The Bauhinia genus is known as "Pata-de-Vaca" and a wide variety of these species are used in Brazilian folk medicine due to their gastroprotective properties. This study aimed to investigate the antiulcer efficacy of the hydroalcoholic extract from B. curvula (HEBC) leaves, as well as its semi-purified fraction (SPFr) and the contribution of their phytochemicals constituents for this effect. For that, ethanol 60%/HCl 0.3 M- and indomethacin-induced gastric ulcer were performed in rodents. Gastric ulcerated tissues were processed for histological, histochemical and biochemical analysis. The oral treatment with HEBC and SPFr decreased the gastric ulcer induced by ethanol/HCl in mice and by indomethacin (only HEBC) in rats. The gastroprotective effect of HEBC was abolished in mice pretreated with Nω-Nitro-L-arginine methyl ester, N-Ethylmaleimide, glibenclamide or indomethacin. Both HEBC and SPFr reduced myeloperoxidase activity in parallel with a decrease of lipoperoxides content at the site of the lesion. On the other hand, HEBC did not alter volume, pH, total acidity or pepsin activity of acid gastric secretion in rats, and neither inhibited the in vitro H(+),K(+)-ATPase activity. Additionally, the compounds identified and isolated from the SPFr, the flavonoids quercitrin (65%) and kaempferol (35%), were able to diminish the extent of ulcerated area induced by both ethanol/HCl and indomethacin. Taking together, these findings show that B. curvula extracts present gastroprotective effect, mainly explained by the presence of flavonoids quercitrin and kaempferol, which may possibly improve the defensive factors of gastric mucosa.
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Affiliation(s)
- Ana Paula Beber
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí-UNIVALI, Rua Uruguai, 458, 88302-901, Itajaí, SC, Brazil
| | - Priscila de Souza
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí-UNIVALI, Rua Uruguai, 458, 88302-901, Itajaí, SC, Brazil.
| | - Thaise Boeing
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí-UNIVALI, Rua Uruguai, 458, 88302-901, Itajaí, SC, Brazil
| | - Lincon Bordignon Somensi
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí-UNIVALI, Rua Uruguai, 458, 88302-901, Itajaí, SC, Brazil
| | - Luísa Nathália Bolda Mariano
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí-UNIVALI, Rua Uruguai, 458, 88302-901, Itajaí, SC, Brazil
| | - Benhur Judah Cury
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí-UNIVALI, Rua Uruguai, 458, 88302-901, Itajaí, SC, Brazil
| | - Ligia Moura Burci
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Estadual do Paraná, Curitiba, Brazil
| | | | - Euclésio Simionatto
- Programa de Pós-Graduação em Química, Universidade Estadual do Mato Grosso do Sul, Campo Grande, Brazil
| | - Sérgio Faloni de Andrade
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí-UNIVALI, Rua Uruguai, 458, 88302-901, Itajaí, SC, Brazil
| | - Luísa Mota da Silva
- Programa de Pós-Graduação em Ciências Farmacêuticas, Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí-UNIVALI, Rua Uruguai, 458, 88302-901, Itajaí, SC, Brazil
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Abstract
Despite advances in our understanding of the pathophysiology underlying inflammatory bowel disease, there remains a significant need for biomarkers that can differentiate between Crohn's disease and ulcerative colitis with high sensitivity and specificity, in a cost-efficient manner. As the focus on personalized approaches to the delivery of medical treatment increases, new biomarkers are being developed to predict an individual's response to therapy and their overall disease course. In this review, we will outline many of the existing and recently developed biomarkers, detailing their role in the assessment of patients with inflammatory bowel disease. We will identify opportunities for improvement in our biomarkers, including better differentiation between the subtypes of inflammatory bowel disease. We will also discuss new targets and strategies in biomarker development, including combining modalities to create biomarker signatures to improve the ability to predict disease courses and response to therapy among individual patients.
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Ribeiro ARS, do Nascimento Valença JD, da Silva Santos J, Boeing T, da Silva LM, de Andrade SF, Albuquerque-Júnior RLC, Thomazzi SM. The effects of baicalein on gastric mucosal ulcerations in mice: Protective pathways and anti-secretory mechanisms. Chem Biol Interact 2016; 260:33-41. [PMID: 27780710 DOI: 10.1016/j.cbi.2016.10.016] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 10/10/2016] [Accepted: 10/21/2016] [Indexed: 01/15/2023]
Abstract
Many flavonoids have been shown to present good results for the treatment of gastric ulcers. Baicalein, a bioactive flavonoid derived from the Scutellaria baicalensis Georgi root, possesses several biological effects, such as anti-inflammatory and antioxidant. This study was conducted to assess the gastroprotective properties of baicalein. Anti-ulcerogenic assay was performed using the protocol of ulcer induced by ethanol/HCl in mice; then, the role of presynaptic α2-receptors, sulfhydryl (SH) compounds, nitric oxide (NO), prostaglandin (PG) and ATP-sensitive K+ (KATP) channels in gastroprotection of baicalein was investigated. The levels of reduced glutathione (GSH) and the myeloperoxidase (MPO) activity were measured in the gastric mucosa. Parameters of gastric secretion (volume, [H+] and pH) were determined with or without the presence of the secretagogue agent histamine, as well as mucus in gastric contents, by the pylorus ligation model. In vitro H+,K+-ATPase activity was also determined. Baicalein (10, 30 and 100 mg/kg) exhibited a dose related gastroprotective effect (P < 0.001) against acidified ethanol-induced lesions. The intraperitoneal treatment of mice with a α2-adrenoreceptor antagonist (yohimbine; 2 mg/kg), a SH compounds blocker (N-ethylmaleimide, NEM; 10 mg/kg), a non-selective inhibitor of NO synthase (Nw-nitro-L-arginine methyl ester hydrochloride, L-NAME; 10 mg/kg), a non-selective inhibitor of cyclo-oxygenase (indomethacin; 10 mg/kg) or a KATP channel blocker (glibenclamide; 10 mg/kg) was able to reverse (P < 0.001) the gastroprotective response caused by baicalein (30 mg/kg). Baicalein (30 mg/kg; P < 0.05) was able to increase GSH levels and decreasing MPO activity. The intraduodenal treatment with baicalein (30 and 100 mg/kg) significantly increased (P < 0.05) the gastric mucus secretion. Additionally, the treatment with baicalein reduced (30 and 100 mg/kg; P < 0.05) the secretion volume and total acid secretion, and also increased (10, 30 and 100 mg/kg; P < 0.001) the pH value, after pylorus ligature. Baicalein (30 mg/kg) was also effective in inhibiting the effects of histamine on gastric secretion (volume, [H+] and pH; P < 0.001). Baicalein at 10 and 30 μg/mL showed anti-H+,K+-ATPase activity. In conclusion, the present results provide convincing evidence that baicalein could be used as a cytoprotective (preventive effect) and anti-ulcerogenic (anti-secretory effect) agent in the gastric ulcers.
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Affiliation(s)
- Ana Roseli S Ribeiro
- Departamento de Fisiologia, Universidade Federal de Sergipe, Av. Marechal Rondon, Cidade Universitária, CEP 49100-000 São Cristóvão, Sergipe, Brazil
| | - José Diego do Nascimento Valença
- Departamento de Fisiologia, Universidade Federal de Sergipe, Av. Marechal Rondon, Cidade Universitária, CEP 49100-000 São Cristóvão, Sergipe, Brazil
| | - Jeferson da Silva Santos
- Departamento de Fisiologia, Universidade Federal de Sergipe, Av. Marechal Rondon, Cidade Universitária, CEP 49100-000 São Cristóvão, Sergipe, Brazil
| | - Thaise Boeing
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, Rua Uruguai, 458, CEP 88302-202 Itajaí, Santa Catarina, Brazil
| | - Luisa Mota da Silva
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, Rua Uruguai, 458, CEP 88302-202 Itajaí, Santa Catarina, Brazil
| | - Sérgio Faloni de Andrade
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade do Vale do Itajaí, Rua Uruguai, 458, CEP 88302-202 Itajaí, Santa Catarina, Brazil
| | - Ricardo L C Albuquerque-Júnior
- Instituto de Tecnologia e Pesquisa-ITP, Universidade Tiradentes, Av. Murilo Dantas, 300, CEP 49032-490 Aracaju, Sergipe, Brazil
| | - Sara Maria Thomazzi
- Departamento de Fisiologia, Universidade Federal de Sergipe, Av. Marechal Rondon, Cidade Universitária, CEP 49100-000 São Cristóvão, Sergipe, Brazil.
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Mariano LNB, da Silva LM, de Souza P, Boeing T, Somensi LB, Bonomini TJ, Delle Monache F, Cechinel Filho V, de Andrade SF, Niero R. Gastroprotective xanthones isolated from Garcinia achachairu: Study on mucosal defensive factors and H(+), K(+)-ATPase activity. Chem Biol Interact 2016; 258:30-9. [PMID: 27545833 DOI: 10.1016/j.cbi.2016.08.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 08/01/2016] [Accepted: 08/15/2016] [Indexed: 11/24/2022]
Abstract
The present study was designed to investigate the gastroprotective effect of xanthones 7-preniljacareubin (PJB), 1,3,5,6-tetrahydroxy xanthone (THX), 3-demethyl-2-geranyl-4-prenylbellidypholine (DGP) and 1,5,8-trihydroxy-4', 5'-dimethyl-2H-pyrane (2,3:3,2)-4-(3-methylbut-2-enyl) xanthone (TDP) isolated of branches from G. achachairu. Their structures were identified through the spectroscopic analysis in comparison with previously reported data. The xanthones were tested at dose of 10 mg/kg against ethanol 60%/HCl 0.3 N-induced gastric ulcer in female swiss mice. The xanthones PJB, THX, DGP and TDP exhibit gastroprotective effect after intraperitoneal treatment, but only the first two displayed anti-ulcer activity after oral administration. Both PJB and THX augmented the antioxidative capacity of tissue by an increase in glutathione levels, as well as were able to prevent an increase in myeloperoxidase activity and tumor necrosis factor level. On the other hand, only THX showed an in vitro free radical scavenger activity, and only PJB avoided mucus depletion on gastric mucosa, which was not associated with an increase in mucin production at glandular level. In addition, PJB and THX inhibited the in vitro H(+)K(+)-ATPase activity at similar range as omeprazole. Together, these results demonstrate the anti-ulcer efficacy of xanthones isolated from G. achachairu, which can contribute for future directions in the development of effective strategies to improve gastric diseases.
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Affiliation(s)
- Luísa Nathália Bolda Mariano
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-901, Itajaí, SC, Brazil
| | - Luisa Mota da Silva
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-901, Itajaí, SC, Brazil
| | - Priscila de Souza
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-901, Itajaí, SC, Brazil
| | - Thaise Boeing
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-901, Itajaí, SC, Brazil
| | - Lincon Bordignon Somensi
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-901, Itajaí, SC, Brazil
| | - Tiago José Bonomini
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-901, Itajaí, SC, Brazil
| | - Franco Delle Monache
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-901, Itajaí, SC, Brazil
| | - Valdir Cechinel Filho
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-901, Itajaí, SC, Brazil
| | - Sérgio Faloni de Andrade
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-901, Itajaí, SC, Brazil.
| | - Rivaldo Niero
- Programa de Pós-Graduação em Ciências Farmacêuticas (PPGCF), Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Rua Uruguai, 458, Centro, 88302-901, Itajaí, SC, Brazil
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Abnormal cannabidiol attenuates experimental colitis in mice, promotes wound healing and inhibits neutrophil recruitment. JOURNAL OF INFLAMMATION-LONDON 2016; 13:21. [PMID: 27418880 PMCID: PMC4944257 DOI: 10.1186/s12950-016-0129-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 06/15/2016] [Indexed: 12/30/2022]
Abstract
Background Non-psychotropic atypical cannabinoids have therapeutic potential in a variety of inflammatory conditions including those of the gastrointestinal tract. Here we examined the effects of the atypical cannabinoid abnormal cannabidiol (Abn-CBD) on wound healing, inflammatory cell recruitment and colitis in mice. Methods Colitis was induced in CD1 mice by a single intrarectal administration of trinitrobenzene sulfonic acid (TNBS, 4 mg/100 μl in 30 % ethanol) and Abn-CBD and/or the antagonists O-1918 (Abd-CBD), AM251 (CB1 receptor) and AM630 (CB2 receptor), were administered intraperitoneally (all 5 mg/kg, twice daily for 3 days). The degree of colitis was assessed macro- and microscopically and tissue myeloperoxidase activity was determined. The effects of Abn-CBD on wound healing of endothelial and epithelial cells (LoVo) were assessed in a scratch injury assay. Human neutrophils were employed in Transwell assays or perfused over human umbilical vein endothelial cells (HUVEC) to study the effect of Abn-CBD on neutrophil accumulation and transmigration. Results TNBS-induced colitis was attenuated by treatment with Abn-CBD. Histological, macroscopic colitis scores and tissue myeloperoxidase activity were significantly reduced. These effects were inhibited by O-1918, but not by AM630, and only in part by AM251. Wound healing of both HUVEC and LoVo cells was enhanced by Abn-CBD. Abn-CBD inhibited neutrophil migration towards IL-8, and dose-dependently inhibited accumulation of neutrophils on HUVEC. Conclusions Abn-CBD is protective against TNBS-induced colitis, promotes wound healing of endothelial and epithelial cells and inhibits neutrophil accumulation on HUVEC monolayers. Thus, the atypical cannabinoid Abn-CBD represents a novel potential therapeutic in the treatment of intestinal inflammatory diseases. Electronic supplementary material The online version of this article (doi:10.1186/s12950-016-0129-0) contains supplementary material, which is available to authorized users.
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Peterson CGB, Lampinen M, Hansson T, Lidén M, Hällgren R, Carlson M. Evaluation of biomarkers for ulcerative colitis comparing two sampling methods: fecal markers reflect colorectal inflammation both macroscopically and on a cellular level. Scandinavian Journal of Clinical and Laboratory Investigation 2016; 76:393-401. [PMID: 27223407 DOI: 10.1080/00365513.2016.1185145] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Simple, objective and inexpensive tools for the assessment of mucosal inflammation in ulcerative colitis (UC) are highly desirable. The aim of this study was to evaluate a broad spectrum of activity markers comparing two sampling methods: fecal samples and the mucosal patch technique. METHODS Twenty patients with active UC and 14 healthy controls were characterized by means of clinical indices and endoscopy together with histology and immunohistochemistry on colorectal sections. Neutrophil myeloperoxidase (MPO), calprotectin, eosinophil cationic protein (ECP), eosinophil protein X (EPX/EDN) and IL-1β were analyzed in fecal samples and rectal fluid collected by the patch technique. Nitric oxide (NO) was analyzed in rectal gas samples. Expression of activity markers on colorectal neutrophils and eosinophils were analyzed by flow cytometry. RESULTS All fecal and patch markers were increased in UC patients compared with healthy controls. Fecal markers and the level of neutrophil activation correlated to disease activity, whereas patch markers did not. The best markers in terms of discriminative power were fecal MPO and IL-1β. Fecal marker levels were related to sigmoidal histology scores and to neutrophil number and activation. Patch markers were related to rectal inflammation only. CONCLUSIONS The levels of inflammation markers in feces and patch fluid distinctly reflected active inflammation in UC. The degree of disease activity was however best assessed by fecal markers, particularly MPO and IL-1β. Fecal markers reflect colorectal inflammation both macroscopically and on a cellular level, and may be useful for the evaluation of subclinical inflammation. The applicability of patch markers is restricted to rectal inflammation.
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Affiliation(s)
- Christer G B Peterson
- a Department of Medical Sciences , Clinical Chemistry, University Hospital , Uppsala , Sweden
| | - Maria Lampinen
- b Department of Medical Sciences , Gastroenterology Research Group, University Hospital , Uppsala , Sweden
| | - Tony Hansson
- c Department of Women's and Children's Health , University Hospital , Uppsala , Sweden
| | - Maria Lidén
- d Department of Medical Sciences , Clinic of Rheumatology, University Hospital , Uppsala , Sweden
| | - Roger Hällgren
- d Department of Medical Sciences , Clinic of Rheumatology, University Hospital , Uppsala , Sweden
| | - Marie Carlson
- b Department of Medical Sciences , Gastroenterology Research Group, University Hospital , Uppsala , Sweden
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Prata MDMG, Havt A, Bolick DT, Pinkerton R, Lima A, Guerrant RL. Comparisons between myeloperoxidase, lactoferrin, calprotectin and lipocalin-2, as fecal biomarkers of intestinal inflammation in malnourished children. ACTA ACUST UNITED AC 2016; 2:134-139. [PMID: 27746954 PMCID: PMC5061054 DOI: 10.15761/jts.1000130] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Fecal biomarkers have emerged as important tools to assess intestinal inflammation and enteropathy. The aim of this study was to investigate the correlations between the fecal markers, myeloperoxidase (MPO), lactoferrin (FL), calprotectin (FC) and lipocalin-2 (Lcn-2), and to compare differences by breastfeeding status as well as normalization by fecal protein or by fecal weight. Simultaneous, quantitative MPO, FL, FC and Lcn-2, levels were determined in frozen fecal specimens collected from 78 children (mean age 15.2 ± 5.3 months) in a case-control study of childhood malnutrition in Brazil. The biomarker concentrations were measured by enzymelinked immunosorbent assay. The correlations among all biomarkers were significant (P<0.01). There were stronger correlations of fecal MPO with fecal lactoferrin and calprotectin, with lower, but still highly significant correlations of all 3 inflammatory biomarkers with Lcn-2 likely because the latter may also reflect enterocyte damage as well as neutrophil presence. Furthermore, the biomarker results with protein normalized compared to simple fecal weight normalized values showed only a slightly better correlation suggesting that the added cost and time for protein normalization added little to carefully measured fecal weights as denominators. In conclusion, fecal MPO correlates tightly with fecal lactoferrin and calprotectin irrespective of breastfeeding status and provides a common, available biomarker for comparison of human and animal model studies.
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Affiliation(s)
- Mara de Moura Gondim Prata
- Department of Physiology and Pharmacology and INCT-Biomedicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - A Havt
- Department of Physiology and Pharmacology and INCT-Biomedicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - D T Bolick
- Center for Global Health, Division of Infectious Diseases and International Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - R Pinkerton
- Department of Physiology and Pharmacology and INCT-Biomedicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Aam Lima
- Department of Physiology and Pharmacology and INCT-Biomedicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - R L Guerrant
- Center for Global Health, Division of Infectious Diseases and International Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA; Department of Physiology and Pharmacology and INCT-Biomedicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
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Singh V, Yeoh BS, Chassaing B, Zhang B, Saha P, Xiao X, Awasthi D, Shashidharamurthy R, Dikshit M, Gewirtz A, Vijay-Kumar M. Microbiota-inducible Innate Immune, Siderophore Binding Protein Lipocalin 2 is Critical for Intestinal Homeostasis. Cell Mol Gastroenterol Hepatol 2016; 2:482-498.e6. [PMID: 27458605 PMCID: PMC4957954 DOI: 10.1016/j.jcmgh.2016.03.007] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Lipocalin 2 (Lcn2) is a multifunctional innate immune protein whose expression closely correlates with extent of intestinal inflammation. However, whether Lcn2 plays a role in the pathogenesis of gut inflammation is unknown. Herein, we investigated the extent to which Lcn2 regulates inflammation and gut bacterial dysbiosis in mouse models of IBD. METHODS Lcn2 expression was monitored in murine colitis models and upon microbiota ablation/restoration. WT and Lcn2 knockout (Lcn2KO) mice were analyzed for gut bacterial load, composition by 16S rRNA gene pyrosequencing and, their colitogenic potential by co-housing with Il-10KO mice. Acute (dextran sodium sulfate) and chronic (IL-10R neutralization and T-cell adoptive transfer) colitis was induced in WT and Lcn2KO mice with or without antibiotics. RESULTS Lcn2 expression was dramatically induced upon inflammation and was dependent upon presence of a gut microbiota and MyD88 signaling. Use of bone-marrow chimeric mice revealed non-immune cells are the major contributors of circulating Lcn2. Lcn2KO mice exhibited elevated levels of entA-expressing gut bacteria burden and, moreover, a broadly distinct bacterial community relative to WT littermates. Lcn2KO mice developed highly colitogenic T-cells and exhibited exacerbated colitis upon exposure to DSS or neutralization of IL-10. Such exacerbated colitis could be prevented by antibiotic treatment. Moreover, exposure to the microbiota of Lcn2KO mice, via cohousing, resulted in severe colitis in Il-10KO mice. CONCLUSION Lcn2 is a bacterially-induced, MyD88-dependent, protein that play an important role in gut homeostasis and a pivotal role upon challenge. Hence, therapeutic manipulation of Lcn2 levels may provide a strategy to help manage diseases driven by alteration of the gut microbiota.
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Affiliation(s)
- Vishal Singh
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania
| | - Beng San Yeoh
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania
| | - Benoit Chassaing
- Center for Inflammation, Immunity and Infection, Institute of Biomedical Sciences, Georgia State University, Atlanta, Georgia
| | - Benyue Zhang
- Center for Inflammation, Immunity and Infection, Institute of Biomedical Sciences, Georgia State University, Atlanta, Georgia
| | - Piu Saha
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania
| | - Xia Xiao
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania
| | - Deepika Awasthi
- Pharmacology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India
| | | | - Madhu Dikshit
- Pharmacology Division, Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow, India
| | - Andrew Gewirtz
- Center for Inflammation, Immunity and Infection, Institute of Biomedical Sciences, Georgia State University, Atlanta, Georgia
| | - Matam Vijay-Kumar
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, Pennsylvania,Department of Medicine, The Pennsylvania State University Medical Center, Hershey, Pennsylvania,Correspondence Address correspondence to: Matam Vijay-Kumar, PhD, Department of Nutritional Sciences 222, Chandlee Laboratory, The Pennsylvania State University, University Park, Pennsylvania 16802. fax: (814) 863-6103.Department of Nutritional Sciences 222Chandlee LaboratoryThe Pennsylvania State UniversityUniversity ParkPennsylvania 16802
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Fish Oil-Based Fat Emulsion Reduces Acute Kidney Injury and Inflammatory Response in Antibiotic-Treated Polymicrobial Septic Mice. Nutrients 2016; 8:165. [PMID: 26999192 PMCID: PMC4808893 DOI: 10.3390/nu8030165] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 03/04/2016] [Accepted: 03/07/2016] [Indexed: 12/24/2022] Open
Abstract
Acute kidney injury (AKI) is a common complication in sepsis. This study compared the effects of a fish oil-based with a mixed oil fat emulsion on remote renal injury in an antibiotic-treated septic murine model. Mice were randomly assigned to a normal control (NC) group and three septic groups. Sepsis was induced by cecal ligation and puncture (CLP). The antibiotic was injected intraperitoneally (IP) after CLP and then daily till the time of sacrifice. Three hours after antibiotic treatment, one of the septic groups was injected IP with a fish oil-based emulsion (FO), while the other two groups were given either a mixed oil emulsion (MO) or saline (SC). The septic groups were further divided into two separate time groups, with blood and kidneys samples collected at 24 h or 72 h post-CLP. The results showed that sepsis leads to the activation of neutrophils, T helper (Th)1/Th-2/Th-17 and Treg cells (p < 0.05). Plasma NGAL and mRNA expressions of renal MyD88 and TLR4 were also enhanced (p < 0.05). Compared to the SC group, the group given the fish oil-based emulsion had decreased plasma NGAL by 22% and Treg by 33%. Furthermore, renal gene expressions of MyD88 and TLR4 reduced by 46% and 62%, respectively, whereas heat shock protein 70 and peroxisome proliferator-activated receptor-γ increased by 158% and 69%, respectively (p < 0.05), at Day 3 after CLP. These results suggest that administration of a fish oil-based emulsion has favorable effects, maintaining blood T cell percentage, downregulating Treg expression, attenuating systemic and local inflammation and offering renal protection under conditions of antibiotic-treated polymicrobial sepsis.
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Tanshinone IIA Protects against Dextran Sulfate Sodium- (DSS-) Induced Colitis in Mice by Modulation of Neutrophil Infiltration and Activation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:7916763. [PMID: 26881040 PMCID: PMC4735939 DOI: 10.1155/2016/7916763] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2015] [Revised: 10/09/2015] [Accepted: 10/13/2015] [Indexed: 12/19/2022]
Abstract
Neutrophils play a critical role in the initiation and maintenance of intestinal inflammation. However, conventional neutrophil-targeted therapies can impair normal host defense. Tanshinone IIA has been recently revealed to act directly on neutrophils. Hence, we aimed at investigating whether Tanshinone IIA can protect against experimental colitis through modulation of neutrophils. We induced colitis in C57BL/6 mice by giving 3% dextran sulfate sodium (DSS) orally, and meanwhile, we treated mice daily with Tanshinone IIA intraperitoneally. The severity of colitis was evaluated by calculating disease activity index (DAI) and histological parameters. Neutrophil infiltration and activation in the colons of mice were measured. Moreover, whether Tanshinone IIA has direct effects on neutrophil migration and activation was determined in vitro. Our data showed that Tanshinone IIA significantly ameliorated the severity of DSS-induced colitis in mice, evidenced by the reduced DAI and improved colonic inflammation. In addition, Tanshinone IIA decreased neutrophil infiltration of intestinal mucosa and activation and reduced colonic inflammatory cytokines in DSS-treated mice. Furthermore, Tanshinone IIA was demonstrated to significantly suppress neutrophil migration and activation. These results provide compelling evidence that Tanshinone IIA has a therapeutic potential for alleviating inflammatory colitis in mice, which is possibly mediated by the immunomodulation of neutrophils.
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Garcia-Alvarez M, Glassford NJ, Betbese AJ, Ordoñez J, Baños V, Argilaga M, Martínez A, Suzuki S, Schneider AG, Eastwood GM, Victoria Moral M, Bellomo R. Urinary Neutrophil Gelatinase-Associated Lipocalin as Predictor of Short- or Long-Term Outcomes in Cardiac Surgery Patients. J Cardiothorac Vasc Anesth 2015; 29:1480-8. [DOI: 10.1053/j.jvca.2015.05.060] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Indexed: 11/11/2022]
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Abstract
Diagnostics of inflammatory bowel diseases (IBDs) currently relies on a combination of biological and morphological tests. The current method of diagnostic remains a critical challenge for physicians in part due to their invasiveness and also for their limitations in term of diagnosis, prognosis, disease activity and severity assessment, and therapeutic outcomes. Laboratory biomarkers can be used in the diagnosis and management of IBD, but none of them has been proven to be ideal. Increasing efforts are being made to discover new biomarkers that can discriminate between the types of IBD, predict future responses to treatment, and aid in differential diagnosis, treatment planning, and prognosis prediction. This review addresses the potential for current biomarkers and the emergence of the concept of biomarker signatures in IBD diagnostic and personalized medicine.
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Neutrophil-Derived MMP-8 Drives AMPK-Dependent Matrix Destruction in Human Pulmonary Tuberculosis. PLoS Pathog 2015; 11:e1004917. [PMID: 25996154 PMCID: PMC4440706 DOI: 10.1371/journal.ppat.1004917] [Citation(s) in RCA: 154] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2015] [Accepted: 04/27/2015] [Indexed: 02/07/2023] Open
Abstract
Pulmonary cavities, the hallmark of tuberculosis (TB), are characterized by high mycobacterial load and perpetuate the spread of M. tuberculosis. The mechanism of matrix destruction resulting in cavitation is not well defined. Neutrophils are emerging as key mediators of TB immunopathology and their influx are associated with poor outcomes. We investigated neutrophil-dependent mechanisms involved in TB-associated matrix destruction using a cellular model, a cohort of 108 patients, and in separate patient lung biopsies. Neutrophil-derived NF-kB-dependent matrix metalloproteinase-8 (MMP-8) secretion was up-regulated in TB and caused matrix destruction both in vitro and in respiratory samples of TB patients. Collagen destruction induced by TB infection was abolished by doxycycline, a licensed MMP inhibitor. Neutrophil extracellular traps (NETs) contain MMP-8 and are increased in samples from TB patients. Neutrophils lined the circumference of human pulmonary TB cavities and sputum MMP-8 concentrations reflected TB radiological and clinical disease severity. AMPK, a central regulator of catabolism, drove neutrophil MMP-8 secretion and neutrophils from AMPK-deficient patients secrete lower MMP-8 concentrations. AMPK-expressing neutrophils are present in human TB lung biopsies with phospho-AMPK detected in nuclei. These data demonstrate that neutrophil-derived MMP-8 has a key role in the immunopathology of TB and is a potential target for host-directed therapy in this infectious disease.
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Kishida K, Kohyama M, Kurashima Y, Kogure Y, Wang J, Hirayasu K, Suenaga T, Kiyono H, Kunisawa J, Arase H. Negative regulation of DSS-induced experimental colitis by PILRα. Int Immunol 2015; 27:307-14. [DOI: 10.1093/intimm/dxv004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 01/23/2015] [Indexed: 12/16/2022] Open
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Visnagri A, Kandhare AD, Bodhankar SL. Renoprotective effect of berberine via intonation on apoptosis and mitochondrial-dependent pathway in renal ischemia reperfusion-induced mutilation. Ren Fail 2015; 37:482-93. [PMID: 25598236 DOI: 10.3109/0886022x.2014.996843] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
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Lipocalin-2 test in distinguishing acute lung injury cases from septic mice without acute lung injury. ACTA ACUST UNITED AC 2014; 29:65-77. [PMID: 24998227 DOI: 10.1016/s1001-9294(14)60031-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVE To explore whether the amount of lipocalin-2 in the biofluid could reflect the onset of sepsis-induced acute lung injury (ALI) in mice. METHODS Lipopolysaccharide (LPS, 10 mg/kg) injection or cecal ligation and puncture (CLP) was performed to induce severe sepsis and ALI in C57 BL/6 male mice randomly divided into 5 groups (n=10 in each group): group A (intraperitoneal LPS injection), group B (intravenous LPS injection via tail vein), group C (CLP with 25% of the cecum ligated), group D (CLP with 75% of the cecum ligated), and the control group (6 sham-operation controls plus 4 saline controls). All the mice received volume resuscitation. Measurements of pulmonary morphological and functional alterations were used to identify the presence of experimental ALI. The expressions of lipocalin-2 and interleukin (IL)-6 in serum, bronchoalveolar lavage fluid (BALF), and lung tissue were quantified at both protein and mRNA levels. The overall abilities of lipocalin-2 and IL-6 tests to diagnose sepsis-induced ALI were evaluated by generating receiver operator characteristic curves (ROC) and computing area under curve (AUC). RESULTS In both group B and group D, most of the main features of experimental ALI were reproduced in mice, while group A and group C showed septic syndrome without definite evidence for the presence of ALI. Compared with septic mice without ALI (group A+group C), lipocalin-2 protein expression in septic mice with ALI (group B+group D) was significantly up-regulated in BALF (P<0.01) and in serum (P<0.01), and mRNA expression boosted in lung tissues (all P<0.05). Lipocalin-2 tests performed better than IL-6 tests in recognizing sepsis-induced ALI cases, evidenced by the larger AUC of the former (BALF tests, 0.8800 versus 0.6625; serum tests, 0.8500 versus 0.7000). Using a dual cutoff system to diagnose sepsis-induced ALI, BALF lipocalin-2 test exhibited the highest positive likelihood ratio (13.000) and the lowest negative likelihood ratio (0.077) among the tests of lipocalin-2 and IL-6 in blood and BALF. A statistically significant correlation was found between lipocalin-2 concentration in BALF and that in serum (Spearman r=0.8803, P<0.0001). CONCLUSIONS Lipocalin-2 expression is significantly up-regulated in septic ALI mice compared with those without ALI. Lipocalin-2 tests with a dual cutoff system could be an effective tool in distinguishing experimental ALI cases.
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Blázquez-Medela AM, García-Sánchez O, Blanco-Gozalo V, Quiros Y, Montero MJ, Martínez-Salgado C, López-Novoa JM, López-Hernández FJ. Hypertension and hyperglycemia synergize to cause incipient renal tubular alterations resulting in increased NGAL urinary excretion in rats. PLoS One 2014; 9:e105988. [PMID: 25148248 PMCID: PMC4141836 DOI: 10.1371/journal.pone.0105988] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 07/25/2014] [Indexed: 01/12/2023] Open
Abstract
Background Hypertension and diabetes are the two leading causes of chronic kidney disease (CKD) eventually leading to end stage renal disease (ESRD) and the need of renal replacement therapy. Mortality among CKD and ESRD patients is high, mostly due to cardiovascular events. New early markers of risk are necessary to better anticipate the course of the disease, to detect the renal affection of additive risk factors, and to appropriately handle patients in a pre-emptive and personalized manner. Methods Renal function and NGAL urinary excretion was monitored in rats with spontaneous (SHR) or L-NAME induced hypertension rendered hyperglycemic (or not as controls). Results Combination of hypertension and hyperglycemia (but not each of these factors independently) causes an increased urinary excretion of neutrophil gelatinase-associated lipocalin (NGAL) in the rat, in the absence of signs of renal damage. Increased NGAL excretion is observed in diabetic animals with two independent models of hypertension. Elevated urinary NGAL results from a specific alteration in its tubular handling, rather than from an increase in its renal expression. In fact, when kidneys of hyperglycaemic-hypertensive rats are perfused in situ with Krebs-dextran solution containing exogenous NGAL, they excrete more NGAL in the urine than hypertensive rats. We also show that albuminuria is not capable of detecting the additive effect posed by the coexistence of these two risk factors. Conclusions Our results suggest that accumulation of hypertension and hyperglycemia induces an incipient and quite specific alteration in the tubular handling of NGAL resulting in its increased urinary excretion.
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Affiliation(s)
- Ana M. Blázquez-Medela
- Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain
- Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain
| | - Omar García-Sánchez
- Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain
- Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain
| | - Víctor Blanco-Gozalo
- Instituto de Estudios de Ciencias de la Salud de Castilla y León-Instituto de Investigación Biomédica de Salamanca (IECSCYL-IBSAL), Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain
- Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain
- Bio-inRen, S.L., Salamanca, Spain
| | - Yaremi Quiros
- Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain
- Bio-inRen, S.L., Salamanca, Spain
| | - María J. Montero
- Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain
| | - Carlos Martínez-Salgado
- Instituto de Estudios de Ciencias de la Salud de Castilla y León-Instituto de Investigación Biomédica de Salamanca (IECSCYL-IBSAL), Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain
- Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain
- Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain
| | - José M. López-Novoa
- Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain
- Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain
| | - Francisco J. López-Hernández
- Instituto de Estudios de Ciencias de la Salud de Castilla y León-Instituto de Investigación Biomédica de Salamanca (IECSCYL-IBSAL), Unidad de Investigación, Hospital Universitario de Salamanca, Salamanca, Spain
- Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Spain
- Instituto Reina Sofía de Investigación Nefrológica, Fundación Iñigo Álvarez de Toledo, Madrid, Spain
- * E-mail:
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Nascimento Santos MDS, de M Magalhães JE, Castro LSEPW, de Sousa Pinheiro T, Sabry DA, Nobre LTDB, Lima JPMS, Baseia IG, Leite EL. Effect of glucans from Caripia montagnei mushroom on TNBS-induced colitis. Int J Mol Sci 2014; 15:2368-85. [PMID: 24518681 PMCID: PMC3958856 DOI: 10.3390/ijms15022368] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2013] [Revised: 01/13/2014] [Accepted: 01/19/2014] [Indexed: 12/22/2022] Open
Abstract
In this study, we evaluated the effect of different doses of polysaccharides extracted from Caripia montagnei mushroom at different intervals of treatment on colonic injury in the model of colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). The FT-IR analysis and NMR showed that the polysaccharides from this species of mushroom are composed of α- and β-glucans. The colonic damage was evaluated by macroscopic, histological, biochemical and immunologic analyses. The results showed the reduction of colonic lesions in all groups treated with the glucans. Such glucans significantly reduced the levels of IL-6 (50 and 75 mg/kg, p < 0.05), a major inflammatory cytokine. Biochemical analyses showed that the glucans from C. montagnei acted on reducing levels of alkaline phosphatase (75 mg/kg, p < 0.01) and myeloperoxidase (p < 0.001), a result confirmed by the reduction of cellular infiltration observed microscopically. The increase of catalase activity possibly indicates a protective effect of these glucans on colonic tissue, confirming their anti-inflammatory potential.
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Affiliation(s)
- Marilia da S Nascimento Santos
- Laboratory of Glycobiology, Department of Biochemistry, Federal University of Rio Grande do Norte, Av. Salgado Filho, 3000, Bairro L. Nova, CEP 59078-970, Natal, RN, Brazil.
| | - Joedyson Emmanuel de M Magalhães
- Laboratory of Glycobiology, Department of Biochemistry, Federal University of Rio Grande do Norte, Av. Salgado Filho, 3000, Bairro L. Nova, CEP 59078-970, Natal, RN, Brazil.
| | - Luiza Sheyla Evenni P Will Castro
- Laboratory of Glycobiology, Department of Biochemistry, Federal University of Rio Grande do Norte, Av. Salgado Filho, 3000, Bairro L. Nova, CEP 59078-970, Natal, RN, Brazil.
| | - Thuane de Sousa Pinheiro
- Laboratory of Glycobiology, Department of Biochemistry, Federal University of Rio Grande do Norte, Av. Salgado Filho, 3000, Bairro L. Nova, CEP 59078-970, Natal, RN, Brazil.
| | - Diego Araujo Sabry
- Department of Biochemistry, Federal University of Paraná, UFPR, Curitiba CEP 81531-980, PR, Brazil.
| | - Leonardo Thiago Duarte B Nobre
- Laboratory of Glycobiology, Department of Biochemistry, Federal University of Rio Grande do Norte, Av. Salgado Filho, 3000, Bairro L. Nova, CEP 59078-970, Natal, RN, Brazil.
| | - João Paulo Matos Santos Lima
- Laboratory of Glycobiology, Department of Biochemistry, Federal University of Rio Grande do Norte, Av. Salgado Filho, 3000, Bairro L. Nova, CEP 59078-970, Natal, RN, Brazil.
| | - Iuri Goulart Baseia
- Laboratory of Mycology, Department of Botany, Zoology and Ecology, Federal University of Rio Grande do Norte, Av. Salgado Filho, 3000, Bairro L. Nova 59078-970, Natal, RN, Brazil.
| | - Edda Lisboa Leite
- Laboratory of Glycobiology, Department of Biochemistry, Federal University of Rio Grande do Norte, Av. Salgado Filho, 3000, Bairro L. Nova, CEP 59078-970, Natal, RN, Brazil.
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Graphene-based immunoassay for human lipocalin-2. Anal Biochem 2014; 446:96-101. [DOI: 10.1016/j.ab.2013.10.022] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 09/09/2013] [Accepted: 10/15/2013] [Indexed: 02/02/2023]
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