Metabolomic credentialing of murine carcinogen-induced urothelial cancer

Afify, Hesham; Ghoneum, Alia; Almousa, Sameh; Abdulfattah, Ammar Yasser; Warren, Bailey; Langsten, Kendall; Gonzalez, Daniela; Casals, Randy; Bharadwaj, Manish S.; Kridel, Steven J.; Said, Neveen

doi:10.1038/s41598-021-99746-3

Cited by 3 publications

(2 citation statements)

References 69 publications

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“…We first tested the hypothesis that FASN promotes Tgf-β-driven activation of human stellate cells in vitro. To investigate the role of palmitate production in stellate cell activation, LX2 human stellate cells were treated with a validated, potent, and specific small molecule inhibitor of FASN, TVB-3664 36,44,45 , at a final concentration of either 1nM or 100nM for 4 hours. Cells were then subjected to 5ng/ml Tgf-β, a strong stimulator of stellate cell activation 46 .…”

Section: Resultsmentioning

confidence: 99%

Dual targeting of hepatocyte DGAT2 and stellate cell FASN alleviates nonalcoholic steatohepatitis in mice

Yenilmez

DiMarzio

Kelly

et al. 2023

Preprint

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Nonalcoholic steatohepatitis (NASH) is a malady of multiple cell types associated with hepatocyte triglyceride (TG) accumulation, macrophage inflammation, and stellate cell-induced fibrosis, with no approved therapeutics yet available. Here, we report that stellate cell fatty acid synthase (FASN) in de novo lipogenesis drives the autophagic flux that is required for stellate cell activation and fibrotic collagen production. Further, we employ a dual targeting approach to NASH that selectively depletes collagen through selective stellate cell knockout of FASN (using AAV9-LRAT Cre in FASNfl/fl mice), while lowering hepatocyte triglyceride by depleting DGAT2 with a GalNac-conjugated, fully chemically modified siRNA. DGAT2 silencing in hepatocytes alone or in combination with stellate cell FASNKO reduced liver TG accumulation in a choline-deficient NASH mouse model, while FASNKO in hepatocytes alone (using AAV8-TBG Cre in FASNfl/fl mice) did not. Neither hepatocyte DGAT2 silencing alone nor FASNKO in stellate cells alone decreased fibrosis (total collagen), while loss of both DGAT2 plus FASN caused a highly significant attenuation of NASH. These data establish proof of concept that dual targeting of DGAT2 plus FASN alleviates NASH progression in mice far greater than targeting either gene product alone.

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Section: Resultsmentioning

confidence: 99%

Dual targeting of hepatocyte DGAT2 and stellate cell FASN alleviates nonalcoholic steatohepatitis in mice

Yenilmez

DiMarzio

Kelly

et al. 2023

Preprint

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“…Current intravesical murine models of BCa include carcinogen-induced, orthotopic, transgenic, or humanized mice [ 12 , 13 , 14 , 15 ]. Carcinogenic models are developed by the oral administration of chemical carcinogens, which have been reported to recapitulate the progression of human BCa [ 16 , 17 , 18 ]. However, tumors make take as long as several months to develop using this method [ 19 , 20 ].…”

Section: Murine Models Of Bcamentioning

confidence: 99%

Non-Invasive Imaging Modalities in Intravesical Murine Models of Bladder Cancer

Relouw

Dugbartey

Şener

2023

Cancers

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Bladder cancer (BCa) is the sixth most prevalent cancer in men and seventeenth most prevalent cancer in women worldwide. Current treatment paradigms have limited therapeutic impact, suggesting an urgent need for the investigation of novel therapies. To best emulate the progression of human BCa, a pre-clinical intravesical murine model is required in conjunction with existing non-invasive imaging modalities to detect and evaluate cancer progression. Non-invasive imaging modalities reduce the number of required experimental models while allowing for longitudinal studies of novel therapies to investigate long-term efficacy. In this review, we discuss the individual and multi-modal use of non-invasive imaging modalities; bioluminescence imaging (BLI), micro-ultrasound imaging (MUI), magnetic resonance imaging (MRI), and positron emission tomography (PET) in BCa evaluation. We also provide an update on the potential and the future directions of imaging modalities in relation to intravesical murine models of BCa.

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A critical review of advances in tumor metabolism abnormalities induced by nitrosamine disinfection by-products in drinking water

Sun,

Shen,

Guo

et al. 2024

Toxicological Sciences

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Intensified sanitation practices amid the recent SARS-CoV-2 outbreak might result in the increased release of chloramine disinfectants into surface water, significantly promoting the formation of nitrosamine disinfection by-products (DBPs) in drinking water. Unfortunately, these nitrosamine DBPs exhibit significant genotoxic, carcinogenic, and mutagenic properties, while chlorinating disinfectants remain in global practice. The current review provides valuable insights into the occurrence, identification, contamination status, exposure limits, and toxicity of the new unregulated disinfection by-products (nitrosamine DBPs) in drinking water. As a result, concentrations of nitrosamine DBPs far exceed allowable limits in drinking water, and prolonged exposure has the potential to cause metabolic disorders, a critical step in tumor initiation and progression. Importantly, based on recent research, we have concluded the role of nitrosamines DBPs in different metabolic pathways. Remarkably, nitrosamine DBPs can induce chronic inflammation and initiate tumors by activating sphingolipid and polyunsaturated fatty acid metabolism. Regarding amino acid and nucleotide metabolism, nitrosamine DBPs can inhibit tryptophan (TRP) metabolism and de novo nucleotide synthesis. Moreover, inhibition of de novo nucleotide synthesis fails to repair DNA damage induced by nitrosamines. Additionally, the accumulation of lactate induced by nitrosamine DBPs may act as a pivotal signaling molecule in communication within the tumor microenvironment. However, with the advancement of tumor metabolomics, understanding the role of nitrosamine DBPs in causing cancer by inducing metabolic abnormalities significantly lags behind, and specific mechanisms of toxic effects are not clearly defined. Urgently, further studies exploring this promising area are needed.

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Metabolomic credentialing of murine carcinogen-induced urothelial cancer

Cited by 3 publications

References 69 publications

Dual targeting of hepatocyte DGAT2 and stellate cell FASN alleviates nonalcoholic steatohepatitis in mice

Dual targeting of hepatocyte DGAT2 and stellate cell FASN alleviates nonalcoholic steatohepatitis in mice

Non-Invasive Imaging Modalities in Intravesical Murine Models of Bladder Cancer

A critical review of advances in tumor metabolism abnormalities induced by nitrosamine disinfection by-products in drinking water

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