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BMC Gastroenterology Nov 2015Liver sinusoidal endothelial cells (SECs), hepatic stellate cells (HSCs) and Kupffer cells (KCs) are involved in the development of liver fibrosis and represent a...
BACKGROUND/AIMS
Liver sinusoidal endothelial cells (SECs), hepatic stellate cells (HSCs) and Kupffer cells (KCs) are involved in the development of liver fibrosis and represent a potential therapeutic target. The therapeutic effects on liver fibrosis of sorafenib, a multiple tyrosine kinase inhibitor, and gadolinium chloride (GdCl3), which depletes KCs, were evaluated in rats.
METHODS
Liver fibrosis was induced in rats with dimethylnitrosamine, and the effects of sorafenib and/or GdCl3 in these rats were monitored. Interactions among ECs, HSCs and KCs were assessed by laser confocal microscopy.
RESULTS
The combination of sorafenib and GdCl3, but not each agent alone, attenuated liver fibrosis and significantly reduced liver function and hydroxyproline (Hyp). Sorafenib significantly inhibited the expression of angiogenesis-associated cell markers and cytokines, including CD31, von Willebrand factor (vWF), and vascular endothelial growth factor, whereas GdCl3 suppressed macrophage-related cell markers and cytokines, including CD68, tumor necrosis factor-α, interleukin-1β, and CCL2. Laser confocal microscopy showed that sorafenib inhibited vWF expression and GdCl3 reduced CD68 staining. Sorafenib plus GdCl3 suppressed the interactions of HSCs, ECs and KCs.
CONCLUSION
Sorafenib plus GdCl3 can suppress collagen accumulation, suggesting that this combination may be a potential therapeutic strategy in the treatment of liver fibrosis.
Topics: Angiogenic Proteins; Animals; Anti-Inflammatory Agents; Cytokines; Dimethylnitrosamine; Drug Therapy, Combination; Gadolinium; Hepatic Stellate Cells; Hepatocytes; Hydroxyproline; Kupffer Cells; Liver; Liver Cirrhosis; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Rats; Rats, Wistar; Sorafenib
PubMed: 26572488
DOI: 10.1186/s12876-015-0380-5 -
Chinese Journal of Integrative Medicine Sep 2018To evaluate the preventive effect of salvianolate (Sal B) on glucose metabolism disorders of dimethylnitrosamine (DMN)-induced cirrhotic rats.
OBJECTIVE
To evaluate the preventive effect of salvianolate (Sal B) on glucose metabolism disorders of dimethylnitrosamine (DMN)-induced cirrhotic rats.
METHODS
Fifty-five Wistar rats were randomly divided into a control group (n=10) and a cirrhotic group (n=45) according to a random number table. Liver cirrhosis was induced by intraperitoneal administration of DMN. The cirrhotic rats were divided into model, Sal B and metformin groups (n=15), respectively. Rats in the model group were given saline, two treatment groups were given Sal B (50 mg/kg), metformin (150 mg/kg) respectively for 28 consecutive days, while rats in the control group were injected 0.9% saline with same volume of vehicle. Body weight was measured everyday. Insulin sensitivity was determined by euglycemic hyperinsulinemic clamp. Organ index, glucose tolerance test (OGTT), and fasting plasma glucose (FPG), fasting insulin (FINS), hepatic glycogen, hydroxyproline (HYP) and liver function were detected at the end of the treatment. Area under the curve (AUC) for OGTT was calculated. Liver and pancreas histology were determined by histopathological examination with hematoxylin and eosin staining (HE), Sirius Red staining and Masson's trichrome staining, respectively. Hepatic expression of α-smooth muscle actin (α-SMA) and collagen (Col I) were evaluated by immunohistochemical staining.
RESULTS
Compared with the model group, Sal B significantly increased body and liver weight, liver-body ratio, glucose infusion rate (GIR), FPG, FINS levels and hepatic glycogen at the end of administration (P<0.05 or P<0.01). Meanwhile, Sal B significantly decreased AUC for OGTT, spleen weight, spleen-body ratio, aminotransferase and HYP level (P<0.05 or P<0.01). Sal B was also effective in alleviating necrosis of liver tissue, suppressing fibrosis progression and inhibiting the expression of α-SMA and Col I in liver. Compared with the metformin group, Sal B had advantages in ameliorating FPG, hepatic glycogen, spleen weight, organ index, liver function and cirrhosis (P<0.05). Metformin increased insulin sensitivity more potently than Sal B (P<0.05).
CONCLUSIONS
Sal B could improve glucose metabolism in cirrhotic rats by protecting hepatic glycogen reserve, increasing insulin sensitivity, and alleviating pancreatic morphology abnormalities. Sal B was clinically potential in preventing glucose metabolism anomalies accompanied with cirrhosis.
Topics: Animals; Dimethylnitrosamine; Glucose; Glucose Tolerance Test; Insulin Resistance; Liver; Liver Cirrhosis, Experimental; Liver Glycogen; Male; Metformin; Plant Extracts; Rats; Rats, Wistar
PubMed: 29209957
DOI: 10.1007/s11655-017-2773-5 -
Phytomedicine : International Journal... Feb 2024Hepatic fibrosis is the pivotal determinant in the progression of chronic liver diseases towards cirrhosis or advanced stages. Studies have shown that Schisantherin A...
BACKGROUND
Hepatic fibrosis is the pivotal determinant in the progression of chronic liver diseases towards cirrhosis or advanced stages. Studies have shown that Schisantherin A (Sin A), the primary active compound from Schizandra chinensis (Turcz.) Baill., exhibits anti-hepatic fibrosis effects. However, the mechanism of Sin A in liver fibrosis remain unclear.
PURPOSE
To examine the effects and underlying mechanism of Sin A on hepatic fibrosis.
STUDY DESIGN AND METHODS
The effects and mechanism of Sin A were investigated using liver fibrosis mouse models induced by carbon tetrachloride (CCl) or dimethylnitrosamine (DMN), as well as HO-induced hepatocyte injury in vitro.
RESULTS
Sin A treatment ameliorated hepatocyte injury, inflammation, hepatic sinusoidal capillarization, and hepatic fibrosis in both CCl-induced and DMN-induced mice. Sin A effectively reversed the reduction of DDAH1 expression, the p-eNOS/eNOS ratio and NO generation and attenuated the elevation of hepatic ADMA level induced by CCl and DMN. Knockdown of DDAH1 in hepatocytes not only triggered hepatocyte damage, but it also counteracted the effect of Sin A on protecting hepatocytes in vitro.
CONCLUSION
Our findings indicate that Sin A ameliorates liver fibrosis by upregulating DDAH1 to protect against hepatocyte injury. These results provide compelling evidence for Sin A treatment in liver fibrosis.
Topics: Mice; Animals; Hydrogen Peroxide; Liver Cirrhosis; Hepatocytes; Liver; Liver Diseases; Carbon Tetrachloride; Dioxoles; Lignans; Cyclooctanes
PubMed: 38185067
DOI: 10.1016/j.phymed.2023.155330 -
FEBS Open Bio Nov 2019RNA-sequencing (RNA-Seq) is a useful method to explore the molecular events in cells and tissues at the transcriptional level. However, comprehensive transcriptome...
RNA-sequencing (RNA-Seq) is a useful method to explore the molecular events in cells and tissues at the transcriptional level. However, comprehensive transcriptome analysis of hepatocarcinogenesis and progression is lacking. In this study, we aimed to characterize a dimethylnitrosamine (DEN) and carbon tetrachloride (CCl ; DEN+CCl )-induced hepatocellular carcinoma (HCC) mouse model by RNA-Seq. In total, 2033 genes were up-regulated and 841 genes were down-regulated after DEN and CCl stimulation. The differentially expressed genes were highly enriched for the Gene Ontology terms oxoacid metabolic process, carboxylic acid metabolic process, and organic acid metabolic process. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the top five significantly overrepresented pathways were metabolic pathways, chemical carcinogenesis, steroid hormone biosynthesis, retinol metabolism and metabolism of xenobiotics by cytochrome P450. Moreover, a protein-protein interaction network analysis indicated that Rous sarcoma oncogene (Src) may play a key role in DEN+CCl -induced HCC. These results provide a comprehensive overview of transcriptome events in DEN+CCl -induced HCC.
Topics: Animals; Carcinoma, Hepatocellular; Diethylnitrosamine; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Injections, Intraperitoneal; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Sequence Analysis, RNA
PubMed: 31433574
DOI: 10.1002/2211-5463.12724 -
Journal of Food Protection May 2023This study aimed to investigate the effects of tea polyphenol (TP), epigallocatechin gallate (EGCG), and their palmitic acid-modified derivatives palmitoyl-TP (pTP) and...
Changes in N-nitrosamines, Residual Nitrites, Lipid Oxidation, Biogenic Amines, and Microbiota in Chinese Sausages Following Treatment with Tea Polyphenols and Their Palmitic Acid-modified Derivatives.
This study aimed to investigate the effects of tea polyphenol (TP), epigallocatechin gallate (EGCG), and their palmitic acid-modified derivatives palmitoyl-TP (pTP) and palmitoyl-EGCG (pEGCG) on the accumulation of N-nitrosamine and biogenic amines (BAs), residual nitrites, and lipid oxidation in Chinese sausages. The microorganisms, color, and texture properties of sausages were evaluated. TP, EGCG, pTP, or pEGCG significantly inhibited the accumulation of N-nitrosodimethylamine (NDMA) and BAs, residual nitrites, and lipid oxidation, but enhanced the redness, hardness, and chewiness of sausages. The concentration of NDMA in sausages was reduced by 58.11%, 63.51%, 36.49%, and 44.59%, respectively, after treatment with TP, EGCG, pTP, and pEGCG. Both EGCG and pEGCG exhibited excellent inhibitory effects on the predominant BAs, including putrescine, tyramine, cadaverine, histamine, and 2-phenylethylamine. Palmitoyl-EGCG was found to be the strongest inhibitor of lipid oxidation. Besides, the four antioxidants weakly affected the population of total aerobic bacteria and lactic acid bacteria but totally suppressed the growth of undesirable Enterobacteriaceae. The principal component and correlation analyses proved that BAs, nitrites, lipid oxidation, and microbiota were responsible for the formation of NDMA. The results indicated that palmitic acid-modified TPs and similar derivatives might serve as potential preservatives to improve the safety and quality of fermented meat products.
Topics: Biogenic Amines; Dimethylnitrosamine; Fermentation; Meat Products; Microbiota; Nitrites; Nitrosamines; Palmitic Acid; Polyphenols; Tea
PubMed: 37001484
DOI: 10.1016/j.jfp.2023.100072 -
Cancer Letters Apr 2024Rat model of N-nitrosomethylbenzylamine (NMBzA)-induced esophageal squamous cell carcinoma (ESCC) is routinely used to study ESCC initiation, progression and new...
Rat model of N-nitrosomethylbenzylamine (NMBzA)-induced esophageal squamous cell carcinoma (ESCC) is routinely used to study ESCC initiation, progression and new therapeutic strategies. However, the model is time-consuming and malignant tumor incidences are low. Here, we report the usage of multi-kinase inhibitor sorafenib as a tumor promoter to establish an efficient two-stage NMBzA-induced rat ESCC carcinogenesis model, resulting in increments of tumor incidences and shortened tumor formation times. By establishing the model and applying whole-genome sequencing, we discover that benign papillomas and malignant ESCCs harbor most of the "driver" events found in rat ESCCs (e.g. recurrent mutations in Ras family, the Hippo and Notch pathways and histone modifier genes) and the mutational landscapes of rat and human ESCCs overlap extensively. We generate tumor cell lines derived from NMBzA-induced papillomas and ESCCs, showing that papilloma cells retain more characteristics of normal epithelial cells than carcinoma cells, especially their exhibitions of normal rat cell karyotypes and inabilities of forming tumors in immunodeficient mice. Three-dimensional (3-D) organoid cultures and single cell RNA sequencing (scRNA-seq) indicate that, when compared to control- and papilloma-organoids, ESCC-organoids display salient abnormalities at tissue and single-cell levels. Multi-omic analyses indicate that NMBzA-induced rat ESCCs are accompanied by progressive hyperactivations of the FAT-Hippo-YAP1 axis and siRNA or inhibitors of YAP1 block the growth of rat ESCCs. Taken together, these studies provide a framework of using an effective rat ESCC model to investigate multilevel functional genomics of ESCC carcinogenesis, which justify targeting YAP1 as a therapeutic strategy for ESCC.
Topics: Humans; Rats; Mice; Animals; Esophageal Squamous Cell Carcinoma; Esophageal Neoplasms; Carcinoma, Squamous Cell; Cell Line, Tumor; Carcinogenesis; Papilloma; Dimethylnitrosamine
PubMed: 38499266
DOI: 10.1016/j.canlet.2024.216813 -
Journal of Molecular Graphics &... Dec 2023N-Nitrosodimethylamine (NDMA, ONN(CH)) is a highly potent carcinogenic investigated by health authorities in some countries. In this manuscript, density functional...
N-Nitrosodimethylamine (NDMA, ONN(CH)) is a highly potent carcinogenic investigated by health authorities in some countries. In this manuscript, density functional theory (DFT) is applied to study the NDMA molecular and dissociative adsorption on a Ni nanocluster. Molecular adsorption is two times stronger than the NDMA adsorption on the Ni{111} surface. NDMA dissociative adsorption is found more stable than molecular adsorption by ≈1 eV. To dissociate the NDMA molecule into O and NN(CH) fragments, an activation energy is calculated in 0.954 and 0.810 eV from the two most stable molecular configurations. However, to dissociate the NDMA molecule into ON and N(CH) fragments, a smaller activation energy of 0.654 eV is calculated. With the inclusion of the London dispersion forces (optB88-vdW functional), NDMA molecular interactions are a bit stronger. However, the activation energies are slightly smaller. Meta-GGA functional SCAN has also, been applied. The inclusion of the implicit solvation model displays a NDMA weaker interaction with the Ni nanocluster. Dissociative adsorption is more stable than molecular adsorption, but the energy difference is a bit smaller, ≈0.850 eV. Present results show that the Ni nanoclusters are promising catalysts to NDMA elimination from water.
Topics: Dimethylnitrosamine; Adsorption; Water; Water Pollutants, Chemical
PubMed: 37552910
DOI: 10.1016/j.jmgm.2023.108578 -
JAMA Nov 2021
Topics: Dimethylnitrosamine; Ranitidine; Water Pollutants, Chemical
PubMed: 34812875
DOI: 10.1001/jama.2021.16261 -
Archiv Der Pharmazie Feb 2023Various drug samples (N = 249; drug substances, tablets, capsules, solutions, crèmes, and more) from the European pharmaceutical market were collected since 2019...
Various drug samples (N = 249; drug substances, tablets, capsules, solutions, crèmes, and more) from the European pharmaceutical market were collected since 2019 and analyzed for 16 nitrosamines (NAs). In 2.0% of the cases, NAs were detected. These findings included four active pharmaceutical ingredients already known for potential NA contamination: losartan (N-nitrosodimethylamine [NDMA] and N-nitrosodiethylamine, simultaneously), valsartan (NDMA), metformin (NDMA) and ranitidine (NDMA). The fifth new finding, which has not been reported yet, discovered contamination of a molsidomine tablet sample with N-nitrosomorpholine (NMor). The tablet contained 144% of the toxicological allowable intake for NMor. NMor was included in our screening from the beginning and is currently the focus of regulatory authorities, but was added to the guidelines only last year. Thus, it may not have been the focus of regulatory investigations for too long. Our results indicate that the majority of drug products in the market are nonhazardous in terms of patient safety and drug purity. Unfortunately, the list of individual affected products keeps growing constantly and new NA cases, such as molsidomine or nitrosated drug substances (nitrosamine drug substance-related impurities [NDSRI]), continue to emerge. We therefore expect nitrosamine screenings to remain a high priority.
Topics: Humans; Molsidomine; Prevalence; Structure-Activity Relationship; Nitrosamines; Dimethylnitrosamine; Tablets
PubMed: 36461687
DOI: 10.1002/ardp.202200484 -
Food Chemistry Jun 2022Several epidemiological studies emphasize the consumption of processed meat products as a risk factor of colorectal cancer, linking N-nitrosamines (NAs) formed during...
Several epidemiological studies emphasize the consumption of processed meat products as a risk factor of colorectal cancer, linking N-nitrosamines (NAs) formed during nitrite curing to this cancer risk. The occurrence of volatile N-nitrosamines (VNAs) has over the years been intensively studied while the knowledge on the occurrence and toxicity of non-volatile N-nitrosamines (NVNAs) is still limited. Therefore, this study focuses on quantification of both VNAs and NVNAs in a large selection of processed meat products. For this purpose, a robust, specific and sensitive method allowing analysis of seven VNAs and two NVNAs was optimized and validated using kassler, sausage, and salami. The limit of quantification achieved was 0.1-0.5 ng·g for most of the VNA, and 2.3-4.2 ng·g for the NVNA. In one hundred commercial samples N-nitroso-thiazolidine-4-carboxylic acid (NTCA) was the most frequently detected (97 samples) among all target NAs and it was found at concentrations ranging from 3.1 ng·g to 1660 ng·g. The samples contained relatively low mean levels of the individual VNAs (≤1 ng·g). The levels of N-nitrosodimethylamine (NDMA), N-nitrosopyrrolidine (NPYR), and N-nitrosopiperidine (NPIP) ranged from non-detectable to 3.8, 10.8 and 2.9 ng·g, respectively. A correlation between the detected residual levels of nitrite and/or nitrate and concentrations of individual NAs could not be demonstrated. Based on principle component analysis (PCA) some correlations between salami, sausage and bacon and NAs could be shown.
Topics: Denmark; Dimethylnitrosamine; Meat; Meat Products; Nitrites; Nitrosamines
PubMed: 35026484
DOI: 10.1016/j.foodchem.2022.132046