3-Aminobenzamide Prevents Concanavalin A-Induced Acute Hepatitis by an Anti-inflammatory and Anti-oxidative Mechanism

Wardi, Joram; Ernst, Orna; Lilja, Anna M.; Aeed, Hussein; Katz, S.; Ben-Nachum, Idan; Ben-Dror, Iris; Katz, D. H.; Bernadsky, Olga; Kandhikonda, Rajendar; Avni, Yona; Fraser, Iain D. C.; Weinstain, Roy; Biro, Alexander; Zor, Tsaffrir

doi:10.1007/s10620-018-5267-1

Cited by 10 publications

(5 citation statements)

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“…5C), consistent with the lack of early ROS production in the absence of NDPK-D. It has been suggested that antioxidants can diminish LPS-induced inflammatory gene activation ( 50 – 52 ). We therefore tested whether mitochondrial ROS induction contributes to the early transcriptional response.…”

Section: Resultssupporting

confidence: 73%

A genome-wide screen uncovers multiple roles for mitochondrial nucleoside diphosphate kinase D in inflammasome activation

et al. 2021

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Noncanonical inflammasome activation by cytosolic lipopolysaccharide (LPS) is a critical component of the host response to Gram-negative bacteria. Cytosolic LPS recognition in macrophages is preceded by a Toll-like receptor (TLR) priming signal required to induce transcription of inflammasome components and facilitate the metabolic reprograming that fuels the inflammatory response. Using a genome-scale arrayed siRNA screen to find inflammasome regulators in mouse macrophages, we identified the mitochondrial enzyme nucleoside diphosphate kinase D (NDPK-D) as a regulator of both noncanonical and canonical inflammasomes. NDPK-D was required for both mitochondrial DNA synthesis and cardiolipin exposure on the mitochondrial surface in response to inflammasome priming signals mediated by TLRs, and macrophages deficient in NDPK-D had multiple defects in LPS-induced inflammasome activation. In addition, NDPK-D was required for the recruitment of TNF receptor–associated factor 6 (TRAF6) to mitochondria, which was critical for reactive oxygen species (ROS) production and the metabolic reprogramming that supported the TLR-induced gene program. NDPK-D knockout mice were protected from LPS-induced shock, consistent with decreased ROS production and attenuated glycolytic commitment during priming. Our findings suggest that, in response to microbial challenge, NDPK-D–dependent TRAF6 mitochondrial recruitment triggers an energetic fitness checkpoint required to engage and maintain the transcriptional program necessary for inflammasome activation.

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Section: Resultssupporting

confidence: 73%

A genome-wide screen uncovers multiple roles for mitochondrial nucleoside diphosphate kinase D in inflammasome activation

et al. 2021

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“…Experimental Animals. Male wild-type (WT) C57BL/6 mice (purchased from Animal Feeding Center of Xi'an Jiaotong University Health Science Center, Xi'an, China) and male mice with TPH1 (critical rate-limiting enzyme for the synthesis of peripheral serotonin) knockout (TPH1−/−, which originated from C57BL/6 mice, kindly presented by Max Planck Institute for Molecular Genetics, Berlin, Germany, and the genotype was tested by PCR) were used (6)(7)(8) weeks old, 20-25 g). As previously described, the lack of peripheral serotonin is the only difference between TPH1 −/− and WT mice [26].…”

Section: Methodsmentioning

confidence: 99%

“…This model is accompanied by massive liver tissue necrosis, extensive inflammatory response, and prominent hepatocyte apoptosis [5]. In addition, remarkable oxidative stress injury, characterized by significant upregulation in contents of oxidative markers and significant downregulation in activities of antioxidative markers, is closely related to inflammation and Con A-mediated hepatocyte damage [5][6][7][8]. As easy operation, low cost, well repeatability, and close to the pathological process of human viral hepatitis, Con A-induced ALI is regarded as the best experimental model for ALI research [9,10].…”

Section: Introductionmentioning

confidence: 99%

“…In Con A-induced liver injury, one of the important characteristics is the imbalance of oxidative stress [36]. He et al showed elevated oxidative products (MDA and 8-hydroxy-2′-deoxyguanosine) and reduced activities of SOD and cata-lase in Con A-treated mice [7]. El-Agamy reported that the administration of Con A markedly increased hepatic MDA content and decreased hepatic levels of GSH and SOD compared to the control group [8].…”

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confidence: 99%

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The Role of Serotonin in Concanavalin A-Induced Liver Injury in Mice

Pang

Jin

et al. 2020

Oxidative Medicine and Cellular Longevity

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Serotonin is involved in the pathological processes of several liver diseases via the regulation of inflammatory response and oxidative stress. We aimed to investigate the role of serotonin in Concanavalin A- (Con A-) induced acute liver injury (ALI). ALI was induced in C57B/6 wild-type (WT) mice and tryptophan hydroxylase 1 (TPH1) knockout mice through tail vein injection of Con A (15 mg/kg body weight). Another group of TPH1 knockout ALI mice was supplied with 5-hydroxytryptophan (5-HTP) in advance to recover serotonin. The blood and liver tissues of mice were collected in all groups. Markedly increased serum levels of serotonin were identified after the injection of Con A. Increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and stronger hepatic tissue pathology were detected, suggesting that serotonin could mediate Con A-induced liver damage. Serotonin significantly facilitated the release of serum and intrahepatic inflammatory cytokines, including interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-17A (IL-17A), interferon-gamma (IFN-γ), and tumor necrosis-alpha (TNF-α), after the administration of Con A. In addition, serotonin significantly increased the intrahepatic levels of oxidative stress markers malonaldehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) and decreased antioxidant stress indicator glutathione (GSH) in Con A-treated mice. Additionally, serotonin promoted hepatocyte apoptosis and autophagy based on B-cell lymphoma-2 (Bcl-2), Bcl-2-asociated X protein (Bax), and Beclin-1 levels and TUNEL staining. More importantly, serotonin activated nuclear factor kappa B (NF-κB) and upregulated the hepatic expressions of high mobility group protein B1 (HMGB1), toll-like receptor-4 (TLR4), and downstream molecules in Con A-mediated liver injury. Serotonin 2A receptor was upregulated in liver tissue after Con A injection, and serotonin 2A receptor antagonist Ketanserin protected against Con A-induced hepatitis. These results indicated that serotonin has the potential to aggravate Con A-induced ALI via the promotion of inflammatory response, oxidative stress injury, and hepatocyte apoptosis and the activation of hepatic HMGB1-TLR signaling pathway and serotonin 2A receptor.

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“…221). Since these initial findings, multiple studies demonstrated the involvement of PARP activation in inflammatory reactions (for detailed review see in (Refs 222, 223, 224)), as much as the protective effect of PARP inhibition in acute and chronic inflammation (Refs 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245). As the majority of cellular PARP activity in mammals is attributed to PARP1, most of the available data in the context of inflammatory regulation focuses on the role of PARP1.…”

Section: Immunomodulatory Roles Of Parp2mentioning

confidence: 99%

Specific and shared biological functions of PARP2 – is PARP2 really a lil’ brother of PARP1?

Szántó,

Yélamos,

Bai

2024

Expert Rev. Mol. Med.

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PARP2, that belongs to the family of ADP-ribosyl transferase enzymes (ART), is a discovery of the millennium, as it was identified in 1999. Although PARP2 was described initially as a DNA repair factor, it is now evident that PARP2 partakes in the regulation or execution of multiple biological processes as inflammation, carcinogenesis and cancer progression, metabolism or oxidative stress-related diseases. Hereby, we review the involvement of PARP2 in these processes with the aim of understanding which processes are specific for PARP2, but not for other members of the ART family. A better understanding of the specific functions of PARP2 in all of these biological processes is crucial for the development of new PARP-centred selective therapies.

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3-Aminobenzamide Prevents Concanavalin A-Induced Acute Hepatitis by an Anti-inflammatory and Anti-oxidative Mechanism

Abstract: Our results suggest that 3-AB has a therapeutic effect on concanavalin A-induced liver injury by inhibiting expression of the key pro-inflammatory cytokine TNFα, via PARP-1-independent NFκB suppression and via an NFκB-independent anti-oxidative mechanism.

Cited by 10 publications

References 65 publications

A genome-wide screen uncovers multiple roles for mitochondrial nucleoside diphosphate kinase D in inflammasome activation

A genome-wide screen uncovers multiple roles for mitochondrial nucleoside diphosphate kinase D in inflammasome activation

The Role of Serotonin in Concanavalin A-Induced Liver Injury in Mice

Specific and shared biological functions of PARP2 – is PARP2 really a lil’ brother of PARP1?

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