4d468d643e7a12932bcd11418c179786 301299.pdf 1293156370447488fca5a6851baf992845b09a65 301299.pdf 8654d13f2a987ffc0e349bd65c4e3234f68588e55d2c6a0176abe289fbce07ae 301299.pdf Title: Nicotinamide Prevents Diabetic Brain Inflammation via NAD+-Dependent Deacetylation Mechanisms Subject: This study investigated the effect of nicotinamide (NAM) supplementation on the development of brain inflammation and microglial activation in a mouse model of type 1 diabetes mellitus. C57BL/6J male mice, which were made diabetic with five consecutive, low-dose (55 mg/kg i.p.) streptozotocin (STZ) injections. Diabetic mice were randomly distributed in different experimental groups and challenged to different doses of NAM (untreated, NAM low-dose, LD, 0.1%; NAM high-dose, HD, 0.25%) for 25 days. A control, non-diabetic group of mice was used as a reference. The NAD+ content was increased in the brains of NAM-treated mice compared with untreated diabetic mice (NAM LD: 3-fold; NAM HD: 3-fold, p-value < 0.05). Immunohistochemical staining revealed that markers of inflammation (TNF: NAM LD: -35%; NAM HD: -46%; p-value < 0.05) and microglial activation (IBA-1: NAM LD: -29%; NAM HD: -50%; p-value < 0.05; BDKRB1: NAM LD: -36%; NAM HD: -37%; p-value < 0.05) in brains from NAM-treated diabetic mice were significantly decreased compared with non-treated T1D mice. This finding was accompanied by a concomitant alleviation of nuclear NFB (p65) signaling in treated diabetic mice (NFB (p65): NAM LD: -38%; NAM HD: -53%, p-value < 0.05). Notably, the acetylated form of the nuclear NFB (p65) was significantly decreased in the brains of NAM-treated, diabetic mice (NAM LD: -48%; NAM HD: -63%, p-value < 0.05) and inversely correlated with NAD+ content (r = -0.50, p-value = 0.03), suggesting increased activity of NAD+-dependent deacetylases in the brains of treated mice. Thus, dietary NAM supplementation in diabetic T1D mice prevented brain inflammation via NAD+-dependent deacetylation mechanisms, suggesting an increased action of sirtuin signaling. Keywords: type 1 diabetes mellitus; macrophage; sirtuin; activated microglia; neurological disease; neuropathy; neuroinflammation Author: Jeimy Katherine Torres-Méndez, Julia Niño-Narvión, Patricia Martinez-Santos, Elena María Goretti Diarte-Añazco, Karen Alejandra Méndez-Lara, Tania Vázquez del Olmo, Noemi Rotllan, Maria Teresa Julián, Núria Alonso, Didac Mauricio, Mercedes Camacho, Juan Pablo Muñoz, Joana Rossell and Josep Julve Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sun Jul 9 10:51:11 2023 CEST ModDate: Sun Jul 9 11:06:42 2023 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 15 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 4934285 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- DGBDNV+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 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RepresentationInformation: 301299.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-10-04 10:46:43 CEST Size: 4934285 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 521 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Mice and Treatments Destination: subsection.2.1 Item: Title: Assessment of NAM on Diabetic Brain Inflammation Induced with STZ Destination: subsection.2.2 Item: Title: Laboratory Analysis Destination: subsection.2.3 Item: Title: Immunohistochemistry Analysis Destination: subsection.2.4 Item: Title: Western Blotting Destination: subsection.2.5 Item: Title: Quantitative Real-Time RT-PCR Analysis Destination: subsection.2.6 Item: Title: Statistical Analysis Destination: subsection.2.7 Item: Title: Results Destination: section.3 Children: Item: Title: NAM Effects on Gross and Biochemical Parameters of Diabetic Mice Destination: subsection.3.1 Item: Title: NAM Attenuated NFB Signaling and Microglial Activation in Diabetic Mice Destination: subsection.3.2 Item: Title: NAM Enhanced NAD+-Dependent Deacetylation of NFB to Ameliorate Brain Inflammation of Diabetic Mice Destination: subsection.3.3 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.A. Info: Title: Nicotinamide Prevents Diabetic Brain Inflammation via NAD+-Dependent Deacetylation Mechanisms Author: Jeimy Katherine Torres-Méndez, Julia Niño-Narvión, Patricia Martinez-Santos, Elena María Goretti Diarte-Añazco, Karen Alejandra Méndez-Lara, Tania Vázquez del Olmo, Noemi Rotllan, Maria Teresa Julián, Núria Alonso, Didac Mauricio, Mercedes Camacho, Juan Pablo Muñoz, Joana Rossell and Josep Julve Subject: This study investigated the effect of nicotinamide (NAM) supplementation on the development of brain inflammation and microglial activation in a mouse model of type 1 diabetes mellitus. C57BL/6J male mice, which were made diabetic with five consecutive, low-dose (55 mg/kg i.p.) streptozotocin (STZ) injections. Diabetic mice were randomly distributed in different experimental groups and challenged to different doses of NAM (untreated, NAM low-dose, LD, 0.1%; NAM high-dose, HD, 0.25%) for 25 days. A control, non-diabetic group of mice was used as a reference. The NAD+ content was increased in the brains of NAM-treated mice compared with untreated diabetic mice (NAM LD: 3-fold; NAM HD: 3-fold, p-value < 0.05). Immunohistochemical staining revealed that markers of inflammation (TNF: NAM LD: -35%; NAM HD: -46%; p-value < 0.05) and microglial activation (IBA-1: NAM LD: -29%; NAM HD: -50%; p-value < 0.05; BDKRB1: NAM LD: -36%; NAM HD: -37%; p-value < 0.05) in brains from NAM-treated diabetic mice were significantly decreased compared with non-treated T1D mice. This finding was accompanied by a concomitant alleviation of nuclear NFB (p65) signaling in treated diabetic mice (NFB (p65): NAM LD: -38%; NAM HD: -53%, p-value < 0.05). Notably, the acetylated form of the nuclear NFB (p65) was significantly decreased in the brains of NAM-treated, diabetic mice (NAM LD: -48%; NAM HD: -63%, p-value < 0.05) and inversely correlated with NAD+ content (r = -0.50, p-value = 0.03), suggesting increased activity of NAD+-dependent deacetylases in the brains of treated mice. Thus, dietary NAM supplementation in diabetic T1D mice prevented brain inflammation via NAD+-dependent deacetylation mechanisms, suggesting an increased action of sirtuin signaling. 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