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Arquivos de Gastroenterologia 2023•In this review, we described different murine models of carcinogenesis: classic models, new transgenic and combined models, that reproduce the key points for HCC and... (Review)
Review
•In this review, we described different murine models of carcinogenesis: classic models, new transgenic and combined models, that reproduce the key points for HCC and CCA genesis allowing a better understanding of its genetic physiopathological, and environmental abnormalities. •Each model has its advantages, disadvantages, similarities, and differences with the corresponding human disease and should be chosen according to the specificity of the study. Ultimately, those models can also be used for testing new anticancer therapeutic approaches. •Cholangiocarcinoma has been highlighted, with an increase in prevalence. This review has an important role in understanding the pathophysiology and the development of new drugs. Background - This manuscript provides an overview of liver carcinogenesis in murine models of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Objective - A review through MEDLINE and EMBASE was performed to assess articles until August 2022.Methods - Search was conducted of the entire electronic databases and the keywords used was HCC, CCA, carcinogenesis, animal models and liver. Articles exclusion was based on the lack of close relation to the subject. Carcinogenesis models of HCC include HCC induced by senescence in transgenic animals, HCC diet-induced, HCC induced by chemotoxicagents, xenograft, oncogenes, and HCC in transgenic animals inoculated with B and C virus. The models of CCA include the use of dimethylnitrosamine (DMN), diethylnitrosamine (DEN), thioacetamide (TAA), and carbon tetrachloride (CCl4). CCA murine models may also be induced by: CCA cells, genetic manipulation, Smad4, PTEN and p53 knockout, xenograft, and DEN-left median bile duct ligation. Results - In this review, we described different murine models of carcinogenesis that reproduce the key points for HCC and CCA genesis allowing a better understanding of its genetic, physiopathological, and environmental abnormalities. Conclusion - Each model has its advantages, disadvantages, similarities, and differences with the corresponding human disease and should be chosen according to the specificity of the study. Ultimately, those models can also be used for testing new anticancer therapeutic approaches.
Topics: Animals; Mice; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinogenesis; Carcinoma, Hepatocellular; Cholangiocarcinoma; Disease Models, Animal; Liver Neoplasms
PubMed: 37792769
DOI: 10.1590/S0004-2803.230302023-58 -
Cell Reports Apr 2023Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) has been reported to play a role in tumorigenesis. However, its function in hepatocellular...
Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) has been reported to play a role in tumorigenesis. However, its function in hepatocellular carcinoma (HCC) remains poorly understood. In this study, we report that PPDPF is significantly downregulated in HCC and the decreased PPDPF expression indicates poor prognosis. In the dimethylnitrosamine (DEN)-induced HCC mouse model, hepatocyte-specific depletion of Ppdpf promotes hepatocarcinogenesis, and reintroduction of PPDPF into liver-specific Ppdpf knockout (LKO) mice inhibits the accelerated HCC development. Mechanistic study shows that PPDPF regulates nuclear factor κB (NF-κB) signaling through modulation of RIPK1 ubiquitination. PPDPF interacts with RIPK1 and facilitates K63-linked ubiquitination of RIPK1 via recruiting the E3 ligase TRIM21, which catalyzes K63-linked ubiquitination of RIPK1 at K140. In addition, liver-specific overexpression of PPDPF activates NF-κB signaling and attenuates apoptosis and compensatory proliferation in mice, which significantly suppresses HCC development. This work identifies PPDPF as a regulator of NF-κB signaling and provides a potential therapeutic candidate for HCC.
Topics: Animals; Mice; Carcinogenesis; Carcinoma, Hepatocellular; Liver Neoplasms; NF-kappa B; Ubiquitination
PubMed: 37027301
DOI: 10.1016/j.celrep.2023.112340 -
The Oncologist Jun 2020The FDA has ordered the withdrawal of all ranitidine products from the marketplace based on recent findings of increased and unacceptable levels of...
The FDA has ordered the withdrawal of all ranitidine products from the marketplace based on recent findings of increased and unacceptable levels of N‐nitrosodimethylamine (NDMA). This commentary reviews the sources and properties of NDMA, assesses the dangers it poses, and suggests measures to mitigate contamination.
Topics: Dimethylnitrosamine; Humans
PubMed: 32267983
DOI: 10.1634/theoncologist.2020-0142 -
Arhiv Za Higijenu Rada I Toksikologiju Mar 2021In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received... (Review)
Review
In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received particular attention: -nitrosodimethylamine (NDMA) and -nitrosodiethylamine (NDEA). These have since been confirmed in different types of medicinal products, including ranitidine and metformin. Consequently, the European Medicines Agency (EMA) started an investigation into the cause of contamination and an assessment of the risk to patients taking contaminated medicinal products. The main source of contamination were changes in production, which involves combinations of amines and nitrogen compounds and the use of specific catalysts and reagents. Withdrawals of medicinal products that took place in Croatia did not lead to a shortage of sartan- or metformin-containing medicines. Moreover, ranitidine had been preventively withdrawn all over the EU, including Croatia, creating shortages at the time, but was subsequently replaced with therapeutic alternatives.
Topics: Carcinogens; Diethylnitrosamine; Dimethylnitrosamine; Drug Contamination; Humans; Nitrosamines
PubMed: 33787187
DOI: 10.2478/aiht-2021-72-3491 -
JAMA Jul 2021
Topics: Dimethylnitrosamine; Ranitidine; Water Pollutants, Chemical
PubMed: 34180953
DOI: 10.1001/jama.2021.10043 -
The Annals of Pharmacotherapy Jun 2020-nitrosodimethylamine (NDMA) is a hepatotoxic agent and carcinogen contaminant in commonly used medications such as valsartan, losartan, irbesartan, and ranitidine. NDMA...
-nitrosodimethylamine (NDMA) is a hepatotoxic agent and carcinogen contaminant in commonly used medications such as valsartan, losartan, irbesartan, and ranitidine. NDMA can be produced during manufacture, introduced from contaminated ingredients procured elsewhere, or introduced from contaminated solvents and catalysts. The Food and Drug Administration has established a maximum dose of NDMA that is permissible per tablet and guidance for manufacturers. However, many unanswered questions about NDMA contamination need rigorous investigation.
Topics: Angiotensin Receptor Antagonists; Dimethylnitrosamine; Drug Contamination; Humans; Ranitidine; Tablets; United States; United States Food and Drug Administration
PubMed: 31771343
DOI: 10.1177/1060028019892222 -
Journal of Pharmaceutical Sciences Sep 2023Most N-Nitrosamine compounds are found to be genotoxic in several animal species. Some are classified as probable or possible human carcinogens and very low acceptable... (Review)
Review
Most N-Nitrosamine compounds are found to be genotoxic in several animal species. Some are classified as probable or possible human carcinogens and very low acceptable daily intake has been established such as 96 ng/day for N-nitrosodimethylamine (NDMA) and 26.5 ng/N-nitrosodiethylamine (NDEA). The pharmaceutical industry has considered all processing areas for potential formation or contamination of N-nitrosamine. One risk is the potential contamination of nitrosamine during drug product blister packaging using lidding foils containing nitrocellulose, and different approaches have been used by pharmaceutical companies to evaluate and mitigate this risk. Herein we share a perspective from IQ Consortium N-nitrosamine Working Group on some of the approaches and corresponding results. From these assessments, it was concluded that the risk of nitrosamine contamination during blister packaging is negligible. The approaches shared in this perspective can be incorporated into risk assessment for nitrosamine contamination during drug product packaging at other pharmaceutical companies.
Topics: Animals; Humans; Nitrosamines; Blister; Dimethylnitrosamine; Drug Contamination; Product Packaging; Pharmaceutical Preparations
PubMed: 37478970
DOI: 10.1016/j.xphs.2023.07.014 -
Life Sciences Jul 2022The liver, a component of the gastrointestinal tract, is one of the most important organs in the human body. The liver performs over 500 functions to promote... (Review)
Review
The liver, a component of the gastrointestinal tract, is one of the most important organs in the human body. The liver performs over 500 functions to promote physiological homeostasis. In addition, the liver acts as a screen, by metabolizing substances carried by blood coming from the digestive tract before they enter the systemic circulation. This vital function exposes the hepatic tissue to hepatotoxic agents, which can lead to liver damage if the organ's repair and regenerative capacity is insufficient. Several conditions such as persistent exposure to hepatitis C and B viruses, alcohol, and drugs can provoke this disbalance, eventually leading to liver cirrhosis, which is an irreversible and life-threatening condition. This paradigm of irreversibility began to be reconsidered when several studies showed that hepatic fibrosis is potentially reversible after cessation of exposure to the hepatotoxic agent or eradication of the primary disease. In the context of basic research in liver fibrosis and cirrhosis, it is essential to keep in mind that the capacity of the organ to recover spontaneously might be a significant limitation to long-term studies that use experimental models of liver cirrhosis. Here, we review animal models where liver cirrhosis is experimentally induced. We focus on a surgery-based model, i.e., bile duct ligation (BDL), and hepatotoxic drugs such as carbon tetrachloride (CCl), thioacetamide (TAA), and dimethylnitrosamine (DMN) administrated alone or in association with alcohol, the latter to potentialize the hepatotoxic effect of these agents. Also, we analyze the effects of these approaches, emphasizing the risks, spontaneous reversibility, and outcomes on animal health.
Topics: Animals; Carbon Tetrachloride; Disease Models, Animal; Liver; Liver Cirrhosis; Liver Cirrhosis, Experimental; Models, Theoretical; Rodentia; Thioacetamide
PubMed: 35526595
DOI: 10.1016/j.lfs.2022.120615 -
Molecular Biology Reports Nov 2021Previous study reports that fibroblast growth factor 21 (FGF21) could ameliorate hepatic fibrosis, but its mechanisms have not been fully investigated.
BACKGROUND
Previous study reports that fibroblast growth factor 21 (FGF21) could ameliorate hepatic fibrosis, but its mechanisms have not been fully investigated.
METHODS AND RESULTS
In this study, three models were used to investigate the mechanism by which FGF21 alleviates liver fibrosis. Hepatic fibrosis animal models were respectively induced by CCL and dimethylnitrosamine. Our results demonstrated that liver index and liver function were deteriorated in both models. Hematoxylin and eosin and Masson's staining showed that the damaged tissue architectonics were observed in the mice of both models. Treatment with FGF21 significantly ameliorated these changes. ELISA analysis showed that the serum levels of IL-1β, IL-6 and TNF-α were significantly elevated in both models. However, administration of FGF21 significantly reduced these inflammatory cytokines. Real-time PCR and Western blot analysis showed that treatment with FGF21 significantly decreased mRNA and protein expressions of collagenI, α-SMA and TGF-β. Platelet-derived growth factor-BB (PDGF-BB) stimulant was used to establish the experimental cell model in hepatic stellate cells (HSCs). Real-time PCR and Western blot analysis demonstrated that the expression of collagenI and α-SMA were significantly upregulated by this stimulant in model group. Interestingly, our results showed that mRNA and protein expressions of leptin were also significantly induced in PDGF-BB treated HSCs. Administration of FGF21 significantly reduced leptin expression in a dose dependent manner and these effects were reversed in siRNA (against β-klotho) transfected HSCs. Furthermore, the leptin signaling pathways related protein p-ERK/t-ERK, p-STAT3/STAT3 and TGF-β were significantly downregulated by FGF21 treatment in a dose dependent manner. The expressions of SOCS3 and Nrf-2 were enhanced by treatment with FGF21. The underlying mechanism may be that FGF21 regulates leptin-STAT3 axis via Nrf-2 and SOCS3 pathway in activated HSCs.
CONCLUSIONS
FGF21 ameliorates hepatic fibrosis by multiple mechanisms.
Topics: Animals; Carbon Tetrachloride Poisoning; Fibroblast Growth Factors; Gene Expression Regulation; Interleukin-1beta; Interleukin-6; Liver Cirrhosis; Male; Mice; Mice, Inbred ICR; Tumor Necrosis Factor-alpha
PubMed: 34536190
DOI: 10.1007/s11033-021-06707-0 -
The Science of the Total Environment Jun 2022This review summarizes major findings over the last decade related to N-nitrosodimethylamine (NDMA) formed upon ozonation, which was regarded as highly toxic and... (Review)
Review
This review summarizes major findings over the last decade related to N-nitrosodimethylamine (NDMA) formed upon ozonation, which was regarded as highly toxic and carcinogenic disinfection by-products. The reaction kinetics, chemical yields and mechanisms were assessed for the ozonation of potential precursors including dimethylamine (DMA), N,N-dimethylsulfamide, hydrazines, N-containing water and wastewater polymers, dyes containing a dimethylamino function, N-functionalized carbon nanotubes, guanidine, and phenylurea. The effects of bromide on the NDMA formation during ozonation of different types of precursors were also discussed. The mechanism for NDMA formation during ozonation of DMA was re-summarized and new perspectives were proposed to assess on this mechanism. Effect of hydroxyl radicals (•OH) on NDMA formation during ozonation was also discussed due to the noticeable oxidation of NDMA by •OH. Surrogate parameters including nitrate formation and UV after ozonation may be useful parameters to estimate NDMA formation for practical application. The strategies for NDMA formation control were proposed through improving the ozonation process such as ozone/hydrogen peroxide, ozone/peroxymonosulfate and catalytic ozonation process based on membrane pores aeration (MEMBROX).
Topics: Dimethylnitrosamine; Nanotubes, Carbon; Ozone; Wastewater; Water Pollutants, Chemical; Water Purification
PubMed: 35131246
DOI: 10.1016/j.scitotenv.2022.153679