scholarly journals NUDT7 Loss Promotes KrasG12D CRC Development

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 576
Author(s):  
Jinsoo Song ◽  
Sujeong Park ◽  
Jinjoo Oh ◽  
Deokha Kim ◽  
Ji Hyun Ryu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lipid Metabolism ◽  
Palmitic Acid ◽  
Wnt Signaling ◽  
Ingenuity Pathway Analysis ◽  
Pathway Analysis ◽  
Lipid Accumulation ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Expression Levels

Studies have suggested that dysregulation of peroxisomal lipid metabolism might play an important role in colorectal cancer (CRC) development. Here, we found that KrasG12D-driven CRC tumors demonstrate dysfunctional peroxisomal β-oxidation and identified Nudt7 (peroxisomal coenzyme A diphosphatase NUDT7) as one of responsible peroxisomal genes. In KrasG12D-driven CRC tumors, the expression level of Nudt7 was significantly decreased. Treatment of azoxymethane/dextran sulfate sodium (AOM/DSS) into Nudt7 knockout (Nudt7−/−) mice significantly induced lipid accumulation and the expression levels of CRC-related genes whereas xenografting of Nudt7-overexpressed LS-174T cells into mice significantly reduced lipid accumulation and the expression levels of CRC-related genes. Ingenuity pathway analysis of microarray using the colon of Nudt7−/− and Nudt7+/+ mice treated with AOM/DSS suggested Wnt signaling as one of activated signaling pathways in Nudt7−/− colons. Upregulated levels of β-catenin were observed in the colons of KrasG12D and AOM/DSS-treated Nudt7−/− mice and downstream targets of β-catenin such as Myc, Ccdn1, and Nos2, were also significantly increased in the colon of Nudt7−/− mice. We observed an increased level of palmitic acid in the colon of Nudt7−/− mice and attachment of palmitic acid-conjugated chitosan patch into the colon of mice induced the expression levels of β-catenin and CRC-related genes. Overall, our data reveal a novel role for peroxisomal NUDT7 in KrasG12D-driven CRC development.

GPR120 agonist ameliorated insulin resistance and improved ovarian function

Zygote ◽  
2021 ◽  
pp. 1-6
Author(s):  
Yang Liu ◽  
Jiayi Ding ◽  
Xiaofang Tan ◽  
Ya Shen ◽  
Li Xu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Rat Model ◽  
Lipid Accumulation ◽  
Ovarian Function ◽  
Polycystic Ovary ◽  
Vital Role ◽  
Expression Levels ◽  
Glucose And Lipid Metabolism

Summary GPR120 is implicated in the regulation of glucose and lipid metabolism, and insulin resistance. In the current study, we aimed to investigate the role of GPR120 in polycystic ovary syndrome (PCOS). With the adoption of dehydroepiandrosterone, a rat model was established to simulate PCOS in vitro. mRNA and protein expression levels of GPR120 were measured using RT-qPCR and western blot, respectively. In addition, expression levels of testosterone, estradiol, luteinizing hormone and follicle-stimulating hormone, serum total cholesterol and triglyceride were assessed using the corresponding kits. Moreover, haematoxylin and eosin staining was used to detect pathological changes in ovary or liver and oil red staining was utilized to evaluate lipid accumulation. In the present study, GPR120 was downregulated in plasma, liver and ovary in the PCOS rat model. In addition, the GPR120 agonist regulated lipid metabolism in the liver and weight in the PCOS rat model. Furthermore, the GPR120 agonist decreased insulin resistance in the PCOS rat model but improved the ovarian function. It is suggested that GPR120 plays a vital role in suppressing insulin resistance, regulating ovary function and decreasing lipid accumulation in the liver, demonstrating that targeting GPR120 could be an effective method for the improvement of PCOS.

scholarly journals Piperlongumine Alleviates Mouse Colitis and Colitis-Associated Colorectal Cancer

2020 ◽  
Vol 11 ◽  
Author(s):  
Jia-Rong Huang ◽  
Sheng-Te Wang ◽  
Meng-Ning Wei ◽  
Kun Liu ◽  
Jing-Wen Fu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Epithelial Mesenchymal Transition ◽  
Colonic Neoplasms ◽  
Causative Factor ◽  
Therapeutic Effects ◽  
Acute Colitis ◽  
Related Factors ◽  
Mesenchymal Transition

Colorectal cancer is one of the most common and lethal cancers in the world. An important causative factor of colorectal cancer is ulcerative colitis. In this study, we investigated the therapeutic effects of piperlongumine (PL) on the dextran sulfate sodium (DSS)-induced acute colitis and azoxymethane (AOM)/DSS-induced colorectal cancer mouse models. Our results showed that PL could inhibit the inflammation of DSS-induced mouse colitis and reduce the number of large neoplasms (diameter >2 mm) of AOM/DSS-induced mouse colorectal cancer by downregulation of proinflammatory cytokines cyclooxygenase-2 and interleukin-6 and epithelial-mesenchymal transition-related factors, β-catenin, and snail expressions, but fail to improve the colitis symptoms and to decrease the incidence of colonic neoplasms and the number of small neoplasms (diameter <2 mm). These data suggested that PL might be an effective agent in treating colitis and colorectal cancer.

scholarly journals 17β-Estradiol strongly inhibits azoxymethane/dextran sulfate sodium-induced colorectal cancer development in Nrf2 knockout male mice

2020 ◽  
Vol 182 ◽  
pp. 114279
Author(s):  
Chin-Hee Song ◽  
Nayoung Kim ◽  
Ryoung Hee Nam ◽  
Soo In Choi ◽  
Joo Hee Son ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Cancer Development ◽  
Male Mice ◽  
Nrf2 Knockout ◽  
17Β Estradiol

scholarly journals Colitis-induced IL11 promotes colon carcinogenesis

2020 ◽  
Author(s):  
Hong Wang ◽  
David H Wang ◽  
Xu Yang ◽  
Yuhai Sun ◽  
Chung S Yang
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Epithelial Cells ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Colon Carcinogenesis ◽  
Human Colorectal Cancer ◽  
Colon Crypt

Abstract Colitis increases the risk of colorectal cancer; however, the mechanism of the association between colitis and cancer remains largely unknown. To identify colitis-associated cancer promoting factors, we investigated gene expression changes caused by dextran sulfate sodium (DSS)-induced colitis in mice. By analyzing gene expression profiles, we found that IL11 was upregulated in DSS-induced colitis tissue and 2-amino-1-methyl-6-phenylimidazo[4,5-b]-pyridine (PhIP)/DSS-induced colon tumors in mice as well as in human colorectal cancer. By characterizing the activation/phosphorylation of STAT3 (pSTAT3), we found that pSTAT3 was induced transiently in colitis, but maintained at higher levels from hyper-proliferative dysplastic lesions to tumors. Using the IL11 receptor (IL11Rα1) knockout mice, we found that pSTAT3 in the newly regenerated crypt epithelial cells in colitis is abolished in IL11Rα1+/- and -/- mice, suggesting that colitis-induced IL11 activates STAT3 in colon crypt epithelial cells. Moreover, colitis-promoted colon carcinogenesis was significantly reduced in IL11Rα1+/- and -/- mice. To determine the roles of the IL11 in colitis, we found that the inhibition of IL11 signaling by recombinant IL11 antagonist mutein during colitis was sufficient to attenuate colitis-promoted carcinogenesis. Together, our results demonstrated that colitis-induced IL11 plays critical roles in creating cancer promoting microenvironment to facilitate the development of colon cancer from dormant premalignant cells.

scholarly journals Changes in the Pharmacokinetics of Phenytoin in Dextran Sulfate Sodium–Induced Ulcerative Colitis in Mice

2017 ◽  
Vol 36 (6) ◽  
pp. 485-491 ◽  
Author(s):  
Yoshiki Kusunoki ◽  
Yurika Kido ◽  
Yuichi Naito ◽  
Risako Kon ◽  
Nanaho Mizukami ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Protein Expression ◽  
Messenger Rna ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Plasma Concentrations ◽  
Control Group ◽  
Time Curve ◽  
Blood Concentrations ◽  
Expression Levels

We previously demonstrated that the expression levels of drug-metabolizing enzymes, cytochrome P450 (CYP) enzymes, in the liver are significantly decreased in a murine model of ulcerative colitis (UC). In this study, we investigated changes in the pharmacokinetics of phenytoin, a CYP2C substrate drug, in the presence of UC. Colitis was induced by feeding male mice 3.5% dextran sulfate sodium (DSS) dissolved in drinking water for 10 days. The messenger RNA (mRNA) expression of CYP2C29 and CYP2C37 and the protein expression of CYP2C in the liver were evaluated via real-time reverse transcription–polymerase chain reaction and Western blotting, respectively. In DSS-treated animals, both mRNA and protein expression levels of CYP2C in the liver were significantly reduced relative to those in control animals (by 20%-40%). Phenytoin (30 mg/kg) was administered orally in a single dose to mice, and plasma concentrations were measured. Plasma concentrations of phenytoin were higher in the DSS-treated group than in the control group at 12, 24, and 36 hours after administration. Animals given DSS also exhibited a higher area under the plasma concentration–time curve extrapolated to infinity (AUCinf, 315 μg·h/mL), a delayed elimination half-life ( T1/2, 8.1 hours), and a decreased body clearance (CL/F, 3.52 mL/h) compared with that of control animals (AUCinf, 215 μg·h/mL; T1/2, 3.6 h; CL/F, 5.58 mL/h). This study indicated that the presence of UC decreases CYP2C expression levels in the liver, thereby delaying the metabolism of CYP2C substrates, including phenytoin, and increasing blood concentrations of these substrates.

Mucosal permeability is an intrinsic factor in susceptibility to dextran sulfate sodium-induced colitis in rats

2012 ◽  
Vol 237 (4) ◽  
pp. 451-460 ◽  
Author(s):  
Hitoshi Iwaya ◽  
Koushi Maeta ◽  
Hiroshi Hara ◽  
Satoshi Ishizuka
Keyword(s):  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Clinical Symptoms ◽  
Intrinsic Factor ◽  
Dark Agouti ◽  
Colon Tissue ◽  
Mucosal Permeability ◽  
Expression Levels ◽  
Ussing Chambers ◽  
Inbred Rat

We investigated differences in the pathogenesis of dextran sulfate sodium (DSS)-induced colitis between two inbred rat strains, Wistar King A Hokkaido (WKAH) and Dark Agouti (DA) rats, to determine the intrinsic factors responsible for the development of colitis. DSS exposure exacerbated the clinical symptoms such as body weight loss, stool consistency and rectal bleeding in DA rats rather than that in WKAH rats. Additionally, the average survival was shorter in DA rats than in WKAH rats. The expression levels of tumor necrosis factor- α, interleukin (IL)-12 p35 and IL-23 p19 increased prominently in the DA rats that were administered DSS, accompanied by severe infiltration of leukocytes into the colon. We also found that colonic permeability was greater in the DA rats than in the WKAH rats. In Ussing chambers, exposure of the isolated colon tissue to DSS enhanced the colonic permeability of both strains. Immunoblot analysis revealed that the expression levels of tight junction (TJ) proteins were modulated during DSS administration. Higher expression levels of claudin-4 and junctional adhesion molecule-A proteins were observed in DA rats than in WKAH rats, even in intact conditions. These results indicated that the expression pattern of TJ proteins determines the colonic permeability of the rats. In conclusion, the intrinsic colonic permeability is one of critical factors responsible for the susceptibility of rats to colitis.

scholarly journals Four sesquiterpene glycosides from loquat (Eriobotrya japonica) leaf ameliorates palmitic acid-induced insulin resistance and lipid accumulation in HepG2 Cells via AMPK signaling pathway

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10413
Author(s):  
Jiawei Li ◽  
Xiaoqin Ding ◽  
Tunyu Jian ◽  
Han Lü ◽  
Lei Zhao ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Palmitic Acid ◽  
Signaling Pathway ◽  
Lipid Accumulation ◽  
Hepg2 Cells ◽  
Eriobotrya Japonica ◽  
Expression Levels ◽  
Ampk Signaling ◽  
Insulin Resistant ◽  
Compound C

Insulin resistance (IR), caused by impaired insulin signal and decreased insulin sensitivity, is generally responsible for the pathophysiology of type 2 diabetes mellitus (T2DM). Sesquiterpene glycosides (SGs), the exclusive natural products from loquat leaf, have been regarded as potential lead compounds owing to their high efficacy in hypoglycemia and hypolipidemia. Here, we evaluated the beneficial effects of four single SGs isolated from loquat leaf, including SG1, SG2, SG3 and one novel compound SG4 against palmitic acid-induced insulin resistance in HepG2 cells. SG1, SG3 and SG4 could significantly enhance glucose uptake of insulin-resistant HepG2 cells at non-cytotoxic concentration. Meanwhile, Oil Red O staining showed the decrease of both total cholesterol and triglyceride content, suggesting the amelioration of lipid accumulation by SGs in insulin-resistant HepG2 cells. Further investigations found that the expression levels of phosphorylated AMPK, ACC, IRS-1, and Akt were significantly up-regulated after SGs treatment, on the contrary, the expression levels of SREBP-1 and FAS were significantly down-regulated. Notably, AMPK inhibitor Compound C (CC) blocked the regulative effects, while AMPK activator AICAR mimicked the effects of SGs in PA-treated insulin-resistant HepG2 cells. In conclusion, SGs (SG4>SG1≈SG3>SG2) improved lipid accumulation in insulin-resistant HepG2 cells through the AMPK signaling pathway.

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