Activation of oxidative stress and inflammatory factors could account for histopathological progression of aflatoxin-B1 induced hepatocarcinogenesis in rat

Singh, Krishna B.; Maurya, Brajesh Kumar; Trigun, Surendra Kumar

doi:10.1007/s11010-014-2306-x

Cited by 51 publications

(44 citation statements)

References 54 publications

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“…Nrf2 antioxidant responses occur after exposure to other liver toxins including aflatoxin (Kensler et al 2014; Merrick et al 2012; Singh et al 2015) and carbon tetrachloride (Chen et al 2014), and are found in other organ toxicities including in the lung (Cho et al 2015) and nasal cavity (Dunnick et al 2015). …”

Section: Discussionmentioning

confidence: 99%

Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats

et al. 2016

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N,N-dimethyl-p-toluidine (DMPT), an accelerant for methyl methacrylate monomers in medical devices, was a liver carcinogen in male and female F344/N rats and B6C3F1 mice in a 2-year oral exposure study. p-Toluidine, a structurally-related chemical, was a liver carcinogen in mice but not in rats in an 18-month feed exposure study. In this current study, liver transcriptomic data was used to characterize mechanisms in DMPT and p-toluidine liver toxicity and for conducting benchmark dose (BMD) analysis. Male F344/N rats were exposed orally to DMPT or p-toluidine (0, 1, 6, 20, 60 or 120 mg/kg/day) for 5-days. The liver was examined for lesions and transcriptomic alterations. Both chemicals caused mild hepatic toxicity at 60 and 120 mg/kg and dose-related transcriptomic alterations in the liver. There were 511 liver transcripts differentially expressed for DMPT and 354 for p-toluidine at 120 mg/kg/day (false discovery rate threshold of 5%). The liver transcriptomic alterations were characteristic of an anti-oxidative damage response (activation of the Nrf2 pathway) and hepatic toxicity. The top cellular processes in gene ontology (GO) categories altered in livers exposed to DMPT or p-toluidine were used for BMD calculations. The lower confidence bound benchmark doses (BMDL) for these chemicals were 2 mg/kg/day for DMPT and 7 mg/kg/day for p-toluidine. These studies show the promise of using 5-day target organ transcriptomic data to identify chemical-induced molecular changes that can serve as markers for preliminary toxicity risk assessment.

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Section: Discussionmentioning

confidence: 99%

Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats

et al. 2016

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“…Moreover, inflammation and ROS generation are now evident to go hand to hand in a number of pathological manifestations, wherein, TNF-α has been found to play a regulatory role [35,36]. In case of brain disorders also, neuroinflammation and excitotoxicity have been found to be responsible for triggering neuro-excitotoxic disorders/diseases like; traumatic brain injury, Ischemia, Alzheimers disease, Parkinson's disease, etc [17,[37][38][39][40][41][42][43][44][45][46][47].…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Normalizes Hyperammonemia Induced Pro-Inflammatory and Pro-Apoptotic Conditions in Rat Brain

Khanna¹,

Trigun²

2016

IJCAM

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Research ArticleInt J Complement Alt Med 2016, 4(2): 00115 IntroductionAmmonia neurotoxicity is considered responsible for development of a serious nervous system disorder called hepatic encephalopathy (HE). This situation arises mainly due to liver dysfunction led hyperammonemia (HA). HE is characterized by the neuropsychiatric manifestations related to motor dysfunction, memory impairment, and deranged sleep-awake cycle [1,2]. Since HE affects the quality of life of the patients, it is important to develop effective therapeutic strategy against HE. This necessitates understanding the neuro-chemistry of HA pathogenesis.Since ammonia crosses the blood brain barrier easily, prolonged HA condition, a common situation during chronic liver failure (CLF), is likely to maintain increased ammonia concentration in brain [3,4]. The information, mainly derived from the cell culture system and from animal models with acute HE, suggest that the increased brain ammonia level mainly drives astrocytes to undergo significant morpho-pathological changes and also over activates glutamate-NMDA receptor (N-Methyl-D-Aspartate Receptor) pathway in the post-synaptic neurons [1,[5][6][7]. Moreover, NMDAR inhibition could not be translated into prevention of ammonia neurotoxicity, mainly because threshold glutamate-NMDAR activation is necessary for normal neurological functions including higher order brain functions and normal synaptic activity.During recent past, "TNF theory" (Tumor necrosis factor) of HE pathogenesis could draw much attention due to a close association between the level of TNF-α and ammonia in the brain of CLF patients with HE [8]. Later studies have also emphasized significant involvement of TNF-α and other cytokines in HE to the extent that these cytokines could be used as markers for encephalopathy grading [4,[9][10][11][12][13].It is now evident that the microglia and astroglia cells in brain synthesize TNF-α to regulate higher order brain functions and astrocyte induced synaptic strengthening [14][15][16][17]. However, when produced in higher amounts during neuropathology, they are known to potentiate glutamate induced cytotoxicity by inhibiting glutamate transport to the glial cells from the synaptic cleft [12,[16][17][18][19]. Even development of MHE has been described to be dependent more on enhanced inflammatory markers than the severity of CLF or HA in the CLF patients [20]. Moreover, some findings from in vitro studies suggest that resveratrol treatment could prevent ammonia toxicity in astroglial cells by normalizing ROS/RNS level [12,21,22]. Thus, hinting towards a significant role of resveratrol in ameliorating ammonia toxicity. However, the mechanism by which resveratrol does so is unclear.Resveratrol (3, 3, 4'-trihydroxy-Trans stilbene), a natural polyphenol, is found in a number of dietary sources such as grapes, berries, and red wine [23][24][25]. It acts as an effective cardioprotector, AbstractChronic liver failure (CLF) led hyperammonemia (HA) is known to develop a metabolic brain disorder known a...

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“…The anomers of the AFB 1 -FAPY-DNA adduct block DNA replication or cause mutations in Escherichia coli (Smela et al, 2002;Brown et al, 2006) and in vitro (Lin et al, 2014). Metabolically active AFB 1 can also indirectly damage DNA through oxidative stress (Shen et al, 1995;Bedard and Masey, 2006;Bernabucci et al, 2011;Singh et al, 2015). Identifying genes that repair AFB 1 -associated DNA damage could help identify which individuals are at elevated risk for HCC.…”

Section: Introductionmentioning

confidence: 99%

Genome Profiling for Aflatoxin B1 Resistance inSaccharomyces cerevisiaeReveals a Role for the CSM2/SHU Complex in Tolerance of Aflatoxin B₁-associated DNA Damage

Fasullo

John

Freedland

et al. 2019

Preprint

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Exposure to the mycotoxin aflatoxin B1 (AFB 1 ) strongly correlates with hepatocellular carcinoma. P450 enzymes convert AFB 1 into a highly reactive epoxide that forms unstable 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 (AFB 1 -N 7 -Gua) DNA adducts, which convert to stable mutagenic AFB 1 formamidopyrimidine (FAPY) DNA adducts. In CYP1A2-expressing budding yeast, AFB 1 is a weak mutagen but a potent recombinagen. However, few genes have been identified that confer AFB 1 resistance. Here, we profiled the yeast genome for AFB 1 resistance. We introduced the human CYP1A2 into ~90% of the diploid deletion library, and pooled samples from CYP1A2-expressing libraries and the original library were exposed to 50 M AFB 1 for 20 hs. By using next generation sequencing to count molecular barcodes, we identified 85 AFB 1 resistant genes from the CYP1A2-expressing libraries. While functionally diverse genes, including those that function in proteolysis, actin reorganization, and tRNA modification, were identified, those that function in post-replication DNA repair and encode proteins that bind to DNA damage were over-represented, compared to the yeast genome, at large. DNA metabolism genes included those functioning in DNA damage tolerance, checkpoint recovery and replication fork maintenance, emphasizing the potency of the mycotoxin to trigger replication stress. Among genes involved in error-free DNA damage tolerance, we observed that CSM2, a member of the CSM2(SHU) complex, functioned in AFB 1 -associated sister chromatid recombination while suppressing AFB 1 -associated mutations. These studies thus broaden the number of AFB 1 resistant genes and have elucidated a mechanism of error-free bypass of AFB 1associated DNA adducts.

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Activation of oxidative stress and inflammatory factors could account for histopathological progression of aflatoxin-B1 induced hepatocarcinogenesis in rat

Cited by 51 publications

References 54 publications

Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats

Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats

Resveratrol Normalizes Hyperammonemia Induced Pro-Inflammatory and Pro-Apoptotic Conditions in Rat Brain

Genome Profiling for Aflatoxin B1 Resistance inSaccharomyces cerevisiaeReveals a Role for the CSM2/SHU Complex in Tolerance of Aflatoxin B₁-associated DNA Damage

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Activation of oxidative stress and inflammatory factors could account for histopathological progression of aflatoxin-B1 induced hepatocarcinogenesis in rat

Cited by 51 publications

References 54 publications

Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats

Hepatic transcriptomic alterations for N,N-dimethyl-p-toluidine (DMPT) and p-toluidine after 5-day exposure in rats

Resveratrol Normalizes Hyperammonemia Induced Pro-Inflammatory and Pro-Apoptotic Conditions in Rat Brain

Genome Profiling for Aflatoxin B1 Resistance inSaccharomyces cerevisiaeReveals a Role for the CSM2/SHU Complex in Tolerance of Aflatoxin B1-associated DNA Damage

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Genome Profiling for Aflatoxin B1 Resistance inSaccharomyces cerevisiaeReveals a Role for the CSM2/SHU Complex in Tolerance of Aflatoxin B₁-associated DNA Damage