3bb717e5ba6af2a934b358f4632bf31a pmc_10094987.pdf a97fdd06225b60f1f8d04944d3bbd1df6fa63f19 pmc_10094987.pdf 513d125318f92f608bb21dbe489c8d2089eb8f2c26161c760dde09b6d0bfbccd pmc_10094987.pdf Title: Response Variability to Drug Testing in Two Models of Chemically Induced Colitis Subject: The lack of knowledge regarding the pathogenesis of IBD is a challenge for the development of more effective and safer therapies. Although in vivo preclinical approaches are critical for drug testing, none of the existing models accurately reproduce human IBD. Factors that influence the intra-individual response to drugs have barely been described. With this in mind, our aim was to compare the anti-inflammatory efficacy of a new molecule (MTADV) to that of corticosteroids in TNBS and DSS-induced colitis mice of both sexes in order to clarify further the response mechanism involved and the variability between sexes. The drugs were administered preventively and therapeutically, and real-time bioluminescence was performed for the in vivo time-course colitis monitoring. Morphometric data were also collected, and colonic cytokines and acute plasma phase proteins were analyzed by qRT-PCR and ELISA, respectively—bioluminescence images correlated with inflammatory markers. In the TNBS model, dexamethasone worked better in females, while MTADV improved inflammation in males. In DSS-colitis, both therapies worked similarly. Based on the molecular profiles, interaction networks were constructed to pinpoint the drivers of therapeutic response that were highly dependent on the sex. In conclusion, our results suggest the importance of considering sex in IBD preclinical drug screening. Keywords: inflammatory bowel disease; Crohn’s disease; ulcerative colitis; TNBS-induced colitis; DSS-induced colitis; bioluminescence; sex; inflammation Author: Roger Suau, Anna Garcia, Carla Bernal, Mariona Llaves, Katharina Schiering, Eva Jou-Ollé, Alex Pertegaz, Arce Garcia-Jaraquemada, Ramon Bartolí, Violeta Lorén, Patri Vergara, Míriam Mañosa, Eugeni Domènech and Josep Manyé Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Mar 29 12:24:44 2023 CEST ModDate: Wed Mar 29 12:52:55 2023 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 21 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 9142030 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- YFNERV+VnURWPalladioL Type 1 Custom yes yes no 10 0 AOHWGS+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 METNOS+URWPalladioL-Roma Type 1 Custom 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AOGJPD+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 773 0 AOGJPE+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 779 0 AOGJPF+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 785 0 AOGKAF+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 788 0 AOGKAG+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 791 0 MPUDFL+PazoMath Type 1 Builtin yes yes no 799 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-05-25 02:25:24 CEST RepresentationInformation: pmc_10094987.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-05-05 02:20:42 CEST Size: 9142030 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 1091 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Bioluminescence Natural Time-Course in TNBS or DSS Colitis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Bioluminescence Intensity Correlated with Intestinal Immune-Inflammatory mRNA Expression and Plasmatic Acute Phase Proteins Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Therapeutic Monitoring Response by Bioluminescence and Macroscopic Evaluations Shows Differences between Colitis Models, Experimental Trials, and Mouse Sex Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Immune-Inflammatory Signatures in Experimental Colitis Drug Response Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Mechanism of Action Based on Co-Expression Interactive Networks Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: Mice Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Chemically Induced IBD Models Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Experimental Groups Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Real-Time In Vivo ROS Quantification by Bioluminescent Imaging Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Sampling and Macroscopic Colitis Evaluation Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Quantitative Real-Time Polymerase Chain Reaction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Item: Title: Enzyme-Linked Immunosorbent Assay Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Statistics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Info: Title: Response Variability to Drug Testing in Two Models of Chemically Induced Colitis Author: Roger Suau, Anna Garcia, Carla Bernal, Mariona Llaves, Katharina Schiering, Eva Jou-Ollé, Alex Pertegaz, Arce Garcia-Jaraquemada, Ramon Bartolí, Violeta Lorén, Patri Vergara, Míriam Mañosa, Eugeni Domènech and Josep Manyé Subject: The lack of knowledge regarding the pathogenesis of IBD is a challenge for the development of more effective and safer therapies. Although in vivo preclinical approaches are critical for drug testing, none of the existing models accurately reproduce human IBD. Factors that influence the intra-individual response to drugs have barely been described. With this in mind, our aim was to compare the anti-inflammatory efficacy of a new molecule (MTADV) to that of corticosteroids in TNBS and DSS-induced colitis mice of both sexes in order to clarify further the response mechanism involved and the variability between sexes. The drugs were administered preventively and therapeutically, and real-time bioluminescence was performed for the in vivo time-course colitis monitoring. Morphometric data were also collected, and colonic cytokines and acute plasma phase proteins were analyzed by qRT-PCR and ELISA, respectively bioluminescence images correlated with inflammatory markers. In the TNBS model, dexamethasone worked better in females, while MTADV improved inflammation in males. In DSS-colitis, both therapies worked similarly. Based on the molecular profiles, interaction networks were constructed to pinpoint the drivers of therapeutic response that were highly dependent on the sex. In conclusion, our results suggest the importance of considering sex in IBD preclinical drug screening. 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