Last update 21 Mar 2024
DEFA5
defensin alpha 5
Last update 21 Mar 2024
Basic Info
Synonyms DEF5, DEFA5, defensin alpha 5 + [8] |
Introduction Host-defense peptide that maintains sterility in the urogenital system (PubMed:12021776, PubMed:12660734, PubMed:15616305, PubMed:22359618, PubMed:25354318, PubMed:30808760, PubMed:19589339, PubMed:22573326, PubMed:25782105). Has antimicrobial activity against a wide range of bacteria, including Gram-negative E.coli, P.aeruginosa and S.typhimurium, and Gram-positive E.aerogenes, S.aureus, B.cereus, E.faecium and L.monocytogenes (PubMed:12021776, PubMed:15616305, PubMed:22359618, PubMed:25354318, PubMed:30808760, PubMed:19589339, PubMed:22573326). Confers resistance to intestinal infection by S.typhimurium (PubMed:12660734). Exhibits antimicrobial activity against enteric commensal bacteria such as B.adolescentis, L.acidophilus, B.breve, L.fermentum, B.longum and S.thermophilus (PubMed:25354318). Binds to bacterial membranes and causes membrane disintegration (PubMed:25782105). Induces the secretion of the chemokine IL-8 by intestinal epithelial cells (PubMed:19589339). Binds to B.antracis lef/lethal factor, a major virulence factor from B.anthracis, and neutralizes its enzymatic activity (PubMed:22573326).
(Microbial infection) Acts as a target for S.flexneri infection by binding to the bacterium, possibly via bacterial surface proteins, and thereby augmenting infectivity via enhanced bacterial adhesion and invasion of epithelial cells and tissues. |
Related
Target |
Mechanism |
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Active Indication |
Inactive Indication |
Drug Highest Phase |
First Approval Ctry. / Loc. |
First Approval Date |
100 Clinical Results associated with DEFA5
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100 Translational Medicine associated with DEFA5
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08 Feb 2024Hepatology international
FXR-FGF19 signaling in the gut-liver axis is dysregulated in patients with cirrhosis and correlates with impaired intestinal defence.
Article
Author: Benedikt Simbrunner ; Benedikt S Hofer ; Philipp Schwabl ; Kerstin Zinober ; Oleksandr Petrenko ; Claudia Fuchs ; Georg Semmler ; Rodrig Marculescu ; Mattias Mandorfer ; Christian Datz ; Michael Trauner ; Thomas Reiberger
BACKGROUND AND AIMS:
Experimental studies linked dysfunctional Farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling to liver disease. This study investigated key intersections of the FXR-FGF19 pathway along the gut-liver axis and their link to disease severity in patients with cirrhosis.
METHODS:
Patients with cirrhosis undergoing hepatic venous pressure gradient measurement (cohort-I n = 107, including n = 53 with concomitant liver biopsy; n = 5 healthy controls) or colonoscopy with ileum biopsy (cohort-II n = 37; n = 6 controls) were included. Hepatic and intestinal gene expression reflecting FXR activation and intestinal barrier integrity was assessed. Systemic bile acid (BA) and FGF19 levels were measured.
RESULTS:
Systemic BA and FGF19 levels correlated significantly (r = 0.461; p < 0.001) and increased with cirrhosis severity. Hepatic SHP expression decreased in patients with cirrhosis (vs. controls; p < 0.001), indicating reduced FXR activation in the liver. Systemic FGF19 (r = -0.512, p < 0.001) and BA (r = -0.487, p < 0.001) levels correlated negatively with hepatic CYP7A1, but not SHP or CYP8B1 expression, suggesting impaired feedback signaling in the liver. In the ileum, expression of FXR, SHP and FGF19 decreased in patients with cirrhosis, and interestingly, intestinal FGF19 expression was not linked to systemic FGF19 levels. Intestinal zonula occludens-1, occludin, and alpha-5-defensin expression in the ileum correlated with SHP and decreased in patients with decompensated cirrhosis as compared to controls.
CONCLUSIONS:
FXR-FGF19 signaling is dysregulated at essential molecular intersections along the gut-liver axis in patients with cirrhosis. Decreased FXR activation in the ileum mucosa was linked to reduced expression of intestinal barrier proteins. These human data call for further mechanistic research on interventions targeting the FXR-FGF19 pathway in patients with cirrhosis.
CLINICAL TRIAL NUMBER:
NCT03267615.
07 Feb 2024Archives of medical research
Human Intestinal Defensin 5 Ameliorates the Sensitization of Colonic Cancer Cells to 5-Fluorouracil.
Article
Author: Anshul Panjeta ; Khushpreet Kaur ; Rinkle Sharma ; Indu Verma ; Simran Preet
BACKGROUND AND AIM:
The increasing dilemma of multidrug-resistant cancer cells in response to currently available chemotherapeutic drugs and their associated side effect(s), calls for the investigation of alternative anticancer advances and molecules. Therefore, the present study aimed to elucidate the combinatorial potential against colon cancer of human defensin 5 in combination with 5-fluorouracil (5-FU), and against 5-FU resistant colon tumor cells.
METHODS:
The in vivo combinatorial potential of HD-5 with 5-FU was elucidated in terms of tumor morphometrics, apoptosis assay, surface morphology histology of the colon(s), and transcriptional alterations. Changes in membrane dynamics with mucin expression were evaluated by fluorescence microscopy and histochemistry. The in vitro activity of the peptide/drug conjunction was explored by phase contrast microscopy, MTT, LDH assay, and AO/EtBr staining. Chemoresistance to 5-FU was determined by phase contrast microscopy, MTT assay, annexin V-FITC/PI flow cytometry, and MDR-1, Bak, and Bax expression.
RESULTS:
In vivo decreases in tumor parameters, with a marked increase in apoptosis and neutrophil infiltrations indicated restoration of normal architecture with improved mucin content in the treated colons. This happened with substantial changes in key molecular markers of the intrinsic apoptotic cascade. Membrane dynamics revealed that peptides and chemotherapeutic drugs could bind to cancerous cells by taking advantage of altered levels of membrane fluidity.
CONCLUSION:
Peptide treatment of drug-resistant Caco-2 cells promotes enhanced 5-FU uptake, in contrast to when cells were treated with 5-FU alone. Hence, HD-5 as an adjunct to 5-FU, exhibited strong cancer cell killing even against 5-FU-resistant tumorigenic cells.
06 Feb 2024Diseases of the colon and rectum
Innate Immunity Activation in Newly Diagnosed Ileocolonic Crohn's Disease: A Cohort Study.
Article
Author: Imerio Angriman ; Giovanni Bordignon ; Andromachi Kotsafti ; Claudia Mescoli ; Melania Scarpa ; Cesare Ruffolo ; Matteo Fassan ; Angelo Paolo Dei Tos ; Renata D'Incà ; Edoardo Savarino ; Fabiana Zingone ; Salvatore Pucciarelli ; Romeo Bardini ; Ignazio Castagliuolo ; Marco Scarpa
BACKGROUND:
Recent studies showed that early surgery for Crohn's disease leads to a lower recurrence rate. However, the underlying mechanism is unknown.
OBJECTIVE:
The study aims to analyze the innate immunity microenvironment in ileal mucosa according to Crohn's disease duration.
DESIGN:
A prospective cohort study.
SETTINGS:
Tertiary referral center for IBD surgery.
PATIENTS:
A total of 88 consecutive Crohn's disease patients undergoing ileocolonic resection were prospectively enrolled. Mucosal samples were obtained from both healthy and inflamed ileum. Data from a public dataset were analyzed as an external validation cohort.
MAIN OUTCOME MEASURES:
Neutrophil infiltration was evaluated at histology and macrophage subpopulation at immunohistochemistry. Expression of TLR2, TLR4, TLR5, DEFB1, DEFB4A, DEFB103, DEFA5 and DEFA6 was quantified by Real-Time qPCR. Concentrations of BDNF, CCL11, ICAM1, IL1A, IL1B, IL1RN, IL12 p40, IL12 p70, IL15, IL17A, IL23A, MMP3, CCL3, KITLG, VEGFA were determined with immunometric assay.
RESULTS:
Neutrophil infiltration is inversely correlated with disease duration. DEFB4A mRNA expression tended to be higher in late-stage Crohn's disease (p = 0.07). A higher number of macrophages expressed CD163 at low intensity in the late stage (p = 0.04). The concentration of IL15 (p = 0.02) and IL23A (p = 0.05) was higher in healthy ileal mucosa of early-stage patients. In the external cohort, expression of DEFB1 (p = 0.03) and DEFB4A (p = 0.01), IL2 (p = 0.04), and IL3 (p = 0.03) increased in late-stage patients.
LIMITATIONS:
A relatively small number of patients, especially in the newly diagnosed group.
CONCLUSIONS:
In newly diagnosed Crohn's disease, high levels of IL-15 and IL-23 in healthy mucosa suggest that innate immunity is the starter of acute inflammation. Moreover, M2 macrophages increase in healthy mucosa of late-stage Crohn's disease patients suggesting that reparative and profibrotic processes are predominant in the long term and in this phase, anti-inflammatory therapy may be less efficient. See Video Abstract.
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