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International Journal of Environmental... Sep 2021Many nitrosamines are potent carcinogens, with more than 30 listed under California's Proposition 65. Recently, nitrosamine contamination of commonly used drugs for...
Many nitrosamines are potent carcinogens, with more than 30 listed under California's Proposition 65. Recently, nitrosamine contamination of commonly used drugs for treatment of hypertension, heartburn, and type 2 diabetes has prompted numerous Food and Drug Administration (FDA) recalls in the US. These contaminants include the carcinogens NDMA (N-nitrosodimethylamine) and NDEA (N-nitrosodiethylamine) and the animal tumorigen NMBA (N-nitroso-N-methyl-4-aminobutyric acid). NMBA and NDEA are metabolically and/or structurally related to NDMA, an N-nitrosomethyl--alkylamine (NMA), and 12 other carcinogenic NMAs. These nitrosamines exhibit common genotoxic and tumorigenic activities, with shared target tumor sites amongst chemicals and within a given laboratory animal species. We use the drug valsartan as a case study to estimate the additional cancer risks associated with NDMA and NDEA contamination, based on nitrosamine levels reported by the US FDA, cancer potencies developed by California's Proposition 65 program and the US Environmental Protection Agency (EPA), and specific exposure scenarios. These estimates suggest that nitrosamine contamination in drugs that are used long-term can increase cancer risks and pose a serious concern to public health.
Topics: Animals; Carcinogens; Diabetes Mellitus, Type 2; Diethylnitrosamine; Dimethylnitrosamine; Neoplasms; Nitrosamines
PubMed: 34574388
DOI: 10.3390/ijerph18189465 -
Natural Product Research Mar 2023Hepatocellular carcinoma (HCC) is one of the most fatal cancers around the world and remain asymptomatic in early stage. An alcoholic extract prepared from leaves of L....
Hepatocellular carcinoma (HCC) is one of the most fatal cancers around the world and remain asymptomatic in early stage. An alcoholic extract prepared from leaves of L. (Tropaeolaceae) was assessed for its potential activity against diethylnitrosamine-induced liver carcinoma . Oral administration of the extract significantly decreased the inflammatory marker translation NF-kB and supressed HCC progression in combination with 0.5 Gy gamma radiation via EGF-HER-2 pathway. Histopathological and immunohistopathological features also showed the recovery of a hepatic architecture. Immunohistochemical study showed the and LDR enhancement effect on proapoptotic markers (caspase-3 and Bax) and inhibition of anti-apoptotic factor (BCl2). HPLC-DAD-MS analysis of the extract revealed the annotation of twelve compounds. could mediate a defensive influence against diethylnitrosamine-induced hepatocarcinogenesis and serve as a respectable option in amelioration of the hepatocellular carcinoma development in combination with low dose of gamma radiation.
Topics: Tropaeolum; Carcinoma, Hepatocellular; Plant Extracts; Diethylnitrosamine; Gamma Rays; Liver Neoplasms; Signal Transduction; Liver; ErbB Receptors; Apoptosis
PubMed: 35834717
DOI: 10.1080/14786419.2022.2098958 -
Cancer Chemotherapy and Pharmacology Feb 2020One promising strategy for minimizing chemotherapeutic resistance in hepatocellular carcinoma (HCC) is the use of effective chemosensitizers. We studied the...
Novel complementary antitumour effects of celastrol and metformin by targeting IκBκB, apoptosis and NLRP3 inflammasome activation in diethylnitrosamine-induced murine hepatocarcinogenesis.
One promising strategy for minimizing chemotherapeutic resistance in hepatocellular carcinoma (HCC) is the use of effective chemosensitizers. We studied the complementary multi-targeted molecular mechanisms of metformin and celastrol in mice with diethylnitrosamine-induced HCC to investigate whether metformin could augment the sensitivity of HCC tissue to the effect of celastrol. Simultaneous administration of celastrol (2 mg/kg) and metformin (200 mg/kg) improved liver function, enhanced the histological picture and prolonged survival. Additionally, combination therapy exerted anti-inflammatory activity, as indicated by the decreased levels of TNF-α and IL-6. This protective role could be attributed to inhibition of inflammasome activation. Herein, our data revealed downregulated NLRP3 gene expression, suppressed caspase-1 activity and reduced levels of the active forms of IL-1β and IL-18. Under this condition, pyroptotic activity was suppressed. In contrast, in the celastrol and celastrol + metformin groups, the apoptotic potential was amplified, as revealed by the increase in the caspase-9 and caspase-3 levels and Bax:BCL-2 ratio. In addition to their repressive effect on the gene expression of NFκBp65, TNFR and TLR4, metformin and celastrol inhibited phosphorylation-induced activation of IκBκB and NFκBp65 and decreased IκBα degradation. Combination therapy with metformin and celastrol repressed markers of angiogenesis, metastasis and tumour proliferation, as revealed by the decreased hepatic levels of VEGF, MMP-2/9 and cyclin D1 mRNA, respectively. In conclusion, by inhibiting NLRP3 inflammasome and its prerequisite NFκB signalling, simultaneous administration of metformin and celastrol appears to have additive benefits in the treatment of HCC compared to cela monotherapy. This effect warrants further clinical investigation.
Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinogenesis; Carcinoma, Hepatocellular; Diethylnitrosamine; I-kappa B Kinase; Inflammasomes; Liver Neoplasms; Male; Metformin; Mice; Mice, Inbred BALB C; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Pentacyclic Triterpenes; Signal Transduction; Triterpenes
PubMed: 31989218
DOI: 10.1007/s00280-020-04033-z -
Scientific Reports Aug 2019Acute liver failure (ALF) is characterized by loss of liver function in response to sustained augmentation of the acute-phase response (APR) in the liver, which can...
Acute liver failure (ALF) is characterized by loss of liver function in response to sustained augmentation of the acute-phase response (APR) in the liver, which can progress even to death. Although the inflammatory interleukin-6 (IL-6)-axis is a crucial factor that drives the hepatic APR by releasing diverse acute-phase proteins (APPs), therapeutic strategies to block the IL-6-STAT3-mediated APR are not well developed. Here, we show that the nuclear receptor retinoic acid-related orphan receptor α (RORα) limits APR-mediated liver injury by inhibiting the hepatic IL-6-STAT3 signaling pathway. Administration of JC1-40, an RORα activator, diminished diethylnitrosamine-induced acute liver injury and repressed transcriptional expression of APPs such as CXCL1 and LCN2 in mice. IL-6-mediated activation of STAT3 was repressed after RORα activation by either adenoviral infusion of RORα or JC1-40 treatment in primary hepatocytes. Activation of RORα decreased transcriptional expression of IL-6 receptor α, an upstream activator of STAT3, both in vitro and in vivo. This may be one mechanism underlying the RORα-mediated inhibition of STAT3. Taken together, our results suggest that RORα is a regulator of the hepatic IL-6-STAT3 signaling pathway and may be a new therapeutic target for treating APR-associated inflammatory ALF.
Topics: Acute-Phase Reaction; Adenoviridae; Animals; Chemical and Drug Induced Liver Injury; Chemokine CXCL1; Deoxyuracil Nucleotides; Diethylnitrosamine; Disease Models, Animal; Gene Expression Regulation; Hepatocytes; Humans; Hydroxycholesterols; Interleukin-6; Liver; Liver Failure, Acute; Mice; Nuclear Receptor Subfamily 1, Group F, Member 1; Primary Cell Culture; STAT3 Transcription Factor; Signal Transduction
PubMed: 31409825
DOI: 10.1038/s41598-019-48171-8 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Aug 2020To study the inhibitory effect of pills (BJJ) agaisnt diethylnitrosamine (DEN)-induced hepatocarcinogenesis and explore the relation between this effect and the...
OBJECTIVE
To study the inhibitory effect of pills (BJJ) agaisnt diethylnitrosamine (DEN)-induced hepatocarcinogenesis and explore the relation between this effect and the inflammasome signaling pathway.
METHODS
Sixty-five male SD rats were randomly divided into control group, DEN model group, and 3 BJJ treatment groups at low, medium and high dose (with daily dose of 0.55, 1.1 and 2.2 g/kg, respectively, for 12 consecutive weeks starting from the 5th week after modeling). The pathological changes of the liver tissue were observed with HE and Masson staining, and serum levels of alanine transaminase (ALT), glutamic oxaloacetic transaminase (AST), alkaline phosphatase (ALP) and total bilirubin (TBIL) of the rats were detected using ELISA. Oxidation stress in the liver tissue was assessed with ELISA, and Western blotting and ELISA were used to detect the molecular expressions of inflammasome-related pathway.
RESULTS
BJJ significantly inhibited tumor growth in the liver of the rats. HE and Masson staining showed that BJJ treatment obviously ameliorated liver fibrosis and reduced cancer cell and inflammatory cell infiltration in the liver. BJJ significantly reduced elevations of serum ALT, AST, ALP and TBIL levels, increased the contents of superoxide dismutase, catalase and glutathione peroxidase in the liver and suppressed malondialdehyde in Den-treated rats. BJJ also dose-dependently decreased the expressions of NLRP3, apoptosis-associated speck-like protein (ASC), caspase-1, pro-IL-1β, pro-IL-18, IL-1β and IL-18 in the liver of Den-treated rats.
CONCLUSIONS
BJJ treatment can dose-dependently inhibit DEN-induced hepatocarcinogenesis by enhancing antioxidant capacity and down-regulating inflammatory-related pathways in rats.
Topics: Animals; Aspartate Aminotransferases; Diethylnitrosamine; Liver; Liver Neoplasms; Male; Rats; Rats, Sprague-Dawley
PubMed: 32895174
DOI: 10.12122/j.issn.1673-4254.2020.08.12 -
Lipids in Health and Disease Oct 2021Dysregulated lipid metabolism is critically involved in the development of hepatocellular carcinoma (HCC). The respective metabolic pathways affected in HCC can be...
BACKGROUND
Dysregulated lipid metabolism is critically involved in the development of hepatocellular carcinoma (HCC). The respective metabolic pathways affected in HCC can be identified using suitable experimental models. Mice injected with diethylnitrosamine (DEN) and fed a normal chow develop HCC. For the analysis of the pathophysiology of HCC in this model a comprehensive lipidomic analysis was performed.
METHODS
Lipids were measured in tumor and non-tumorous tissues by direct flow injection analysis. Proteins with a role in lipid metabolism were analysed by immunoblot. Mann-Whitney U-test or paired Student´s t-test were used for data analysis.
RESULTS
Intra-tumor lipid deposition is a characteristic of HCCs, and di- and triglycerides accumulated in the tumor tissues of the mice. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha, lipoprotein lipase and hepatic lipase protein were low in the tumors whereas proteins involved in de novo lipogenesis were not changed. Higher rates of de novo lipogenesis cause a shift towards saturated acyl chains, which did not occur in the murine HCC model. Besides, LDL-receptor protein and cholesteryl ester levels were higher in the murine HCC tissues. Ceramides are cytotoxic lipids and are low in human HCCs. Notably, ceramide levels increased in the murine tumors, and the simultaneous decline of sphingomyelins suggests that sphingomyelinases were involved herein. DEN is well described to induce the tumor suppressor protein p53 in the liver, and p53 was additionally upregulated in the tumors.
CONCLUSIONS
Ceramides mediate the anti-cancer effects of different chemotherapeutic drugs and restoration of ceramide levels was effective against HCC. High ceramide levels in the tumors makes the DEN injected mice an unsuitable model to study therapies targeting ceramide metabolism. This model is useful for investigating how tumors evade the cytotoxic effects of ceramides.
Topics: Animals; Carcinoma, Hepatocellular; Ceramides; Cholesterol; Diethylnitrosamine; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Lipidomics; Lipogenesis; Male; Mice; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Triglycerides; Tumor Suppressor Protein p53
PubMed: 34629057
DOI: 10.1186/s12944-021-01567-w -
Acta Biochimica Polonica Sep 2022The tumour suppressive role of miRNA320a is observed in many cancer types like in colon, lung, breast, and osteosarcoma but it is inversely reported in prostate cancer...
The tumour suppressive role of miRNA320a is observed in many cancer types like in colon, lung, breast, and osteosarcoma but it is inversely reported in prostate cancer and in MPM cell lines. miRNA320a targets programmed death ligand 1 (PDL1) negatively in many cancer types and recently in Malignant pleural mesothelioma. In this background it is important to understand the regulatory mechanism of miRNA320a in determining PDL1 expression in different pathological stages of lung cancer. Histology was used to grade the initial and advanced stage of lung cancer following carcinogenic injection. Immunohistochemistry and Western blotting technique were used to analyse PDL1 protein expression. In-situ hybridization was used to determine miRNA320a signals. Initially, using the chemical carcinogen Diethylnitrosamine (25 μg/g), we successfully initiate initial and advanced stage of lung cancer following 6 months and 9 months of carcinogenic injection. The formation of initial and advanced stage of lung cancer is confirmed through histopathological changes which show neoplastic appearance in initial lung cancer and appearance of more mitotic cells along with tissue hardness in the advanced lung cancer stages. In miRNA320a blocked tissue the cancer condition becomes worse with decreased tissue elasticity along with more proliferative cells. Immunohistochemistry and Western blotting studies show that PDL1 is overexpressed in the advanced stages rather than in initial lung cancer because the expression of miRNA320a is overexpressed in initial stages but restricted in advanced stages of lung cancer. miRNA32a blocking studies confirm that miRNA320a expression act as a tumour suppressor that directly controls PDL1 expression that lack of miRNA320a enhances PDL1 expression as well as it triggers lung cancer advances. In summary, miRNA320a possess tumour suppressor function that limits PDL1 expression in initial lung cancer but its control over PDL1 suppression is lost once miRNA320a is downregulated in advanced stage of lung cancer.
Topics: Animals; B7-H1 Antigen; Biomarkers, Tumor; Carcinogens; Diethylnitrosamine; Lung Neoplasms; Male; Mice; MicroRNAs; Prognosis
PubMed: 36099512
DOI: 10.18388/abp.2020_5867 -
Mitochondrion May 2021Targeting mitochondrial oxidative stress during initial stages of hepatocarcinogenesis can be an effective and promising strategy to prevent hepatocellular carcinoma...
Targeting mitochondrial oxidative stress during initial stages of hepatocarcinogenesis can be an effective and promising strategy to prevent hepatocellular carcinoma (HCC). In the present study, mitochondria targeted antioxidant, mito-TEMPO was administered to male BALB/c mice at a dosage 0.1 mg/kg b.w. (intraperitoneal) twice a week, followed by single N-Nitrosodiethylamine (NDEA) intraperitoneal injection (10 mg/kg b.w.). After 24 h of NDEA administration, animals were sacrificed, blood and liver tissue were collected. Liver injury markers, histoarchitecture, antioxidant defence status, mitochondrial reactive oxygen species (ROS), lipid peroxidation (LPO), mitochondrial dysfunction analysis, and mitochondrial membrane potential were investigated. Mito-TEMPO pre-treatment protected animals from the damaging effects of NDEA as observed by normalization of liver injury markers. NDEA metabolism resulted in a significantly increased intracellular and mitochondrial ROS generation with concomitant increase in LPO formation. The activity of mitochondrial complex I, complex II, malate dehydrogenase were significantly reduced and mitochondrial membrane potential was increased. Mito-TEMPO effectively scavenged NDEA-induced ROS generation and reduced LPO formation. A significant improvement was also observed in the activity of mitochondrial complex I, complex II, malate dehydrogenase and normalisation of mitochondrial membrane potential. Results suggested that mito-TEMPO had significant impact on the initiation phase of hepatocarcinogensis which could be one of the reason for its reported chemopreventive effect.
Topics: Animals; Antioxidants; Carcinogens; Diethylnitrosamine; Lipid Peroxidation; Liver; Liver Neoplasms; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mitochondria; Organophosphorus Compounds; Piperidines; Reactive Oxygen Species
PubMed: 33711502
DOI: 10.1016/j.mito.2021.03.001 -
Toxicology and Applied Pharmacology Oct 2022Cancer chemoprevention is an approach that offers huge potential for preventing/retarding carcinogenesis. MitoQ is well-known and extensively studied...
Cancer chemoprevention is an approach that offers huge potential for preventing/retarding carcinogenesis. MitoQ is well-known and extensively studied mitochondria-targeted antioxidants for its applications in diseases linked with oxidative stress. In the present study chemopreventive potential of mitoQ was studied with a focus on the role of gap-junctions and p53 at an advanced stage of HCC. BALB/c mice model of hepatocarcinogenesis was established using N-nitrosodiethylamine as a carcinogen (200 mg/kg b. w., cumulative dose, intraperitoneally). The chemopreventive effect of mitoQ was studied by pre-protecting animals with mitoQ (0.125 mg/kg b. w., orally once a week) till the termination of the study. The tumors developed in the course of the study were histopathologically analyzed and statistically evaluated. The mechanistic role of mitoQ was investigated in terms of mitochondrial oxidative stress, expression of 8-OHdG, Cx26, Cx32, p53 and status of gap-junctional intercellular communication (GJIC) in tumors. Chemopreventive activity of mitoQ was evident from improved survival of animals, significantly (p ≤ 0.05) lower tumor multiplicity, tumor incidence and a total number of tumors. MitoQ treatment significantly (p ≤ 0.05) decreased mitochondrial oxidative stress as indicated by reduced mtROS and mtLPO. Increased staining intensity of 8-OHdG and internalization of Cx26, Cx32 which was observed in hepatic tumors was reduced upon mitoQ treatment. Furthermore, the expression of Cx26, Cx32 and p53 was significantly increased along with improvement in GJIC in mitoQ treatment group. MitoQ demonstrated its chemopreventive potential probably by regulating mtROS, connexins and p53 in hepatocarcinogenesis.
Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; Chemoprevention; Connexins; Diethylnitrosamine; Liver Neoplasms; Mice; Rodentia; Tumor Suppressor Protein p53
PubMed: 36037915
DOI: 10.1016/j.taap.2022.116211 -
Oncology 2018Large animal models are important tools for hepatocellular carcinoma (HCC) research, especially in studies of hepatic vasculature, interventional techniques, and...
Large animal models are important tools for hepatocellular carcinoma (HCC) research, especially in studies of hepatic vasculature, interventional techniques, and radiofrequency or microwave hyperthermia. Currently, diethylnitrosamine (DENA)-induced HCC in pigs is the only large animal model for in situ HCC with a tumor latency of 10-26 months. While phenobarbital (PB) is often used to accelerate DENA-induced HCC in rodents, it has not been previously studied in the porcine model. Therefore, we hypothesize that the addition of PB in the DENA-induced HCC porcine model will accelerate tumor latency compared to DENA alone. HCC and benign lesions were seen on serial MRI and confirmed on histopathology. Liver and tumors were further characterized by CT angiography, vascular corrosion casting, and permittivity measurements.
Topics: Animals; Carcinogens; Diethylnitrosamine; Disease Models, Animal; Drug Synergism; Female; Injections, Intraperitoneal; Liver Neoplasms, Experimental; Phenobarbital; Swine; Swine, Miniature
PubMed: 30269135
DOI: 10.1159/000491092