29a0e5493ddd4f4e6f750b4e79ab5f2e antioxidants-12-01794-v3.pdf b326726a903ebe4cf4125fc47ae556faffb06051 antioxidants-12-01794-v3.pdf 1c8c68712800160d1fe061785c29bb7efb85f4564d35f81af0a1c3101b474e56 antioxidants-12-01794-v3.pdf Title: Novel Heme Oxygenase-1 Inducers Palliate Inflammatory Pain and Emotional Disorders by Regulating NLRP3 Inflammasome and Activating the Antioxidant Pathway Subject: Chronic pain caused by persistent inflammation is current in multiple diseases and has a strong negative impact on society. It is commonly associated with several mental illnesses, which can exert a negative influence on pain perception, and needs to be eradicated. Nevertheless, actual therapies are not sufficiently safe and effective. Recent reports demonstrate that the induction of heme oxygenase-1 (HO-1) enzyme produces analgesic effects in animals with osteoarthritis pain and reverses the grip strength loss caused by sciatic nerve crush. In this research, we evaluated the potential use of three new HO-1 inducers, 1m, 1a, and 1b, as well as dimethyl fumarate (DMF), for treating persistent inflammatory pain induced by the subplantar injection of complete Freud’s adjuvant and the functional deficits and emotional sickness associated. The modulator role of these treatments on the inflammatory and antioxidant pathways were also assessed. Our findings revealed that repeated treatment, for four days, with 1m, 1a, 1b, or DMF inhibited inflammatory pain, reversed grip strength deficits, and reversed the linked anxious- and depressive-like behaviors, with 1m being the most effective. These treatments also suppressed the up-regulation of the inflammasome NLRP3 and activated the expression of the Nrf2 transcription factor and the HO-1 and superoxide dismutase 1 enzymes in the paw and/or amygdala, thus revealing the anti-inflammatory and antioxidant capacity of these compounds during inflammatory pain. Results suggest the use of 1m, 1a, 1b, and DMF, particularly 1m, as promising therapies for inflammatory pain and the accompanying functional disabilities and emotional diseases. Keywords: analgesia; anxiety; depression; heme oxygenase-1; inflammasome; inflammatory pain; Nrf2 transcription factor; oxidative stress Author: Montse Pérez-Fernández, Irene Suárez-Rojas, Xue Bai, Ignacio Martínez-Martel, Valeria Ciaffaglione, Valeria Pittalà, Loredana Salerno and Olga Pol Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Sep 28 03:18:23 2023 CEST ModDate: Thu Sep 28 03:21:44 2023 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2527430 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- VJNASK+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 OHKNFJ+VnURWPalladioL Type 1 Custom yes yes no 15 0 FWPNAM+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 XEZHHC+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 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0 BDJNOG+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 172 0 BDJNNC+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 186 0 BDJNOE+PalatinoLinotype TrueType WinAnsi yes yes no 189 0 BDJNOG+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 192 0 BDJNNC+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 207 0 BDJNOE+PalatinoLinotype TrueType WinAnsi yes yes no 210 0 BDJNOG+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 213 0 BDJPMM+PalatinoLinotype,BoldItalic TrueType WinAnsi yes yes no 216 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-11-21 02:32:29 CET RepresentationInformation: antioxidants-12-01794-v3.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-11-20 13:45:34 CET Size: 2527430 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 446 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Materials and Method Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Children: Item: Title: Animals Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: Generation of Inflammatory Pain Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Allodynia, Hyperalgesia, and Grip Strength Measurements Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Emotional-like Behaviors Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Item: Title: Western Blot Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Item: Title: Drugs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Item: Title: Experimental Design Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Item: Title: Statistical Analyses Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@11758f2a Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@e720b71 Children: Item: Title: Effects of the Treatment with DMF, 1m, 1a, and 1b on the Mechanical Allodynia, Thermal Hyperalgesia, and Grip Strength Loss Caused by CFA Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1b26f7b2 Item: Title: Effects of Treatment with DMF, 1m, 1a, and 1b on the Anxiety-like Behaviours Associated with Inflammatory Pain Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@491cc5c9 Item: Title: Effects of Treatment with DMF, 1m, 1a, and 1b on the Depressive-like Behaviours Linked with Inflammatory Pain Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@74ad1f1f Item: Title: Effects of DMF, 1m, 1a, and 1b Treatments on the Expression of NLRP3, Nrf2, HO-1, SOD-1, NQO1, and GSTM1 in the Paw and Amygdala from CFA-Injected Mice Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6a1aab78 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@462d5aee Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@69b0fd6f Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@757942a1 Info: Title: Novel Heme Oxygenase-1 Inducers Palliate Inflammatory Pain and Emotional Disorders by Regulating NLRP3 Inflammasome and Activating the Antioxidant Pathway Author: Montse Pérez-Fernández, Irene Suárez-Rojas, Xue Bai, Ignacio Martínez-Martel, Valeria Ciaffaglione, Valeria Pittalà, Loredana Salerno and Olga Pol Subject: Chronic pain caused by persistent inflammation is current in multiple diseases and has a strong negative impact on society. It is commonly associated with several mental illnesses, which can exert a negative influence on pain perception, and needs to be eradicated. Nevertheless, actual therapies are not sufficiently safe and effective. Recent reports demonstrate that the induction of heme oxygenase-1 (HO-1) enzyme produces analgesic effects in animals with osteoarthritis pain and reverses the grip strength loss caused by sciatic nerve crush. In this research, we evaluated the potential use of three new HO-1 inducers, 1m, 1a, and 1b, as well as dimethyl fumarate (DMF), for treating persistent inflammatory pain induced by the subplantar injection of complete Freud’s adjuvant and the functional deficits and emotional sickness associated. The modulator role of these treatments on the inflammatory and antioxidant pathways were also assessed. Our findings revealed that repeated treatment, for four days, with 1m, 1a, 1b, or DMF inhibited inflammatory pain, reversed grip strength deficits, and reversed the linked anxious- and depressive-like behaviors, with 1m being the most effective. These treatments also suppressed the up-regulation of the inflammasome NLRP3 and activated the expression of the Nrf2 transcription factor and the HO-1 and superoxide dismutase 1 enzymes in the paw and/or amygdala, thus revealing the anti-inflammatory and antioxidant capacity of these compounds during inflammatory pain. Results suggest the use of 1m, 1a, 1b, and DMF, particularly 1m, as promising therapies for inflammatory pain and the accompanying functional disabilities and emotional diseases. 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