Succinylsulfathiazole modulates the mTOR signaling pathway in the liver of c57BL/6 mice via a folate independent mechanism

Beydoun, Safa; Fardous, Ali M.; Saruna, Michael M.; Beydoun, Ali G.; Sorge, Johnathan A.; Aoun, Ghada; Unnikrishnan, Archana; Cabelof, Diane C.; Heydari, Ahmad R.

doi:10.1016/j.exger.2021.111387

Cited by 3 publications

(4 citation statements)

References 82 publications

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“…Secondly, there was concern that the stress of 4NQO treatment in animals void of dietary folate might compromise successful completion of the 23‐week protocol. Succinyl‐sulfathiazole, a common antibiotic targeting the folate biosynthetic pathway, has been shown to regulate the hepatic mTOR signaling pathway in C57Bl/6 mice via a mechanism independent of folate, which would have confounded conclusions in this model (Beydoun et al, 2021). It remains possible that we might have observed more significant changes in some of our parameters had we employed a more stringent folate deficiency.…”

Section: Discussionmentioning

confidence: 99%

Effects of folate deficiency and sex on carcinogenesis in a mouse model of oral cancer

Pitstick,

Goral,

Ciancio

et al. 2023

Oral Diseases

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ObjectivesTo investigate the effects of dietary folate and sex on histopathology of oral squamous cell carcinoma in mice.Materials and MethodsMice (C57Bl/6, 30/sex) were fed either a deficient folate or sufficient folate diet. Vehicle or 4‐nitroquinoline1‐oxide (50 μg/mL) in vehicle were administered in drinking water for 20 weeks, followed by 6 weeks of regular drinking water. Oral lesions were observed weekly. Tongues were studied for histopathologic changes. Immunohistochemical techniques were used to measure cell proliferation (Ki67+), and to quantify expression of folate receptor, reduced folate carrier, and proton‐coupled folate transporter. T cells, macrophages, and neutrophils were counted and normalized to area.ResultsAll 4NQO‐treated mice developed oral tumors. Dietary folate level did not affect tumor burden. More tumors were observed on the ventral aspect of the tongue than in other locations within the oral cavity. 4‐nitroquinoline‐1‐oxide‐treated mice displayed 27%–46% significantly lower expression of all three folate transport proteins; diet and sex had no effect on folate transporter expression. T‐cell and neutrophil infiltration in tongues were 9.1‐fold and 18.1‐fold increased in the 4‐nitroquinoline‐1‐oxide‐treated mouse tongues than in controls.ConclusionTreatment with 4NQO was the primary factor in determining cancer development, decreased folate transport expression, and lymphoid cell infiltration.

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Section: Discussionmentioning

confidence: 99%

Effects of folate deficiency and sex on carcinogenesis in a mouse model of oral cancer

Pitstick,

Goral,

Ciancio

et al. 2023

Oral Diseases

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“…A group schematic is presented in Supplementary Figure S2a . The colon form SST treated mice were used for ACF scoring, but liver tissues from the same animals were omitted from the mechanistic analysis of this paper due to the confounding effect of the microbiome perturbation on analyzed pathways, as discussed earlier [ 32 ].…”

Section: Methodsmentioning

confidence: 99%

“…Another important consideration is that coprophagy and bacterial gut fermentation can supplement the animals with significant folate, even in the absence of dietary sources [ 31 ]. The use of sulfonamide antibiotics such as succinyl sulfathiazole (SST) to limit host folate production leads to large shifts in the gut microbiota, further complicating mechanistic analyses by impacting major nutrient sensing, metabolic pathways, and growth pathways [ 32 ]. SST reduces folate intake by inhibiting folate-producing bacteria in the gut, thus inducing a severe depletion.…”

Section: Introductionmentioning

confidence: 99%

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The Timing and Duration of Folate Restriction Differentially Impacts Colon Carcinogenesis

et al. 2021

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Diet plays a crucial role in the development of colorectal cancer (CRC). Of particular importance, folate, present in foods and supplements, is a crucial modulator of CRC risk. The role of folate, and, specifically, the synthetic variant, folic acid, in the primary prevention of CRC has not been fully elucidated. Animal studies varied considerably in the timing, duration, and supplementation of folates, leading to equivocal results. Our work attempts to isolate these variables to ascertain the role of folic acid in CRC initiation, as we previously demonstrated that folate restriction conferred protection against CRC initiation in a β-pol haploinsufficient mouse model. Here we demonstrated that prior adaptation to folate restriction altered the response to carcinogen exposure in wild-type C57BL/6 mice. Mice adapted to folate restriction for 8 weeks were protected from CRC initiation compared to mice placed on folate restriction for 1 week, irrespective of antibiotic supplementation. Through analyses of mTOR signaling, DNA methyltransferase, and DNA repair, we have identified factors that may play a critical role in the differential responses to folate restriction. Furthermore, the timing and duration of folate restriction altered these pathways differently in the absence of carcinogenic insult. These results represent novel findings, as we were able to show that, in the same model and under controlled conditions, folate restriction produced contrasting results depending on the timing and duration of the intervention.

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Synthesis and antibacterial activity of FST and its effects on inflammatory response and intestinal barrier function in mice infected with Escherichia coli O78

Ge,

Li,

Yang

et al. 2024

International Immunopharmacology

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Succinylsulfathiazole modulates the mTOR signaling pathway in the liver of c57BL/6 mice via a folate independent mechanism

Cited by 3 publications

References 82 publications

Effects of folate deficiency and sex on carcinogenesis in a mouse model of oral cancer

Effects of folate deficiency and sex on carcinogenesis in a mouse model of oral cancer

The Timing and Duration of Folate Restriction Differentially Impacts Colon Carcinogenesis

Synthesis and antibacterial activity of FST and its effects on inflammatory response and intestinal barrier function in mice infected with Escherichia coli O78

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