Jamie McClellan - Academia.edu (original) (raw)
Papers by Jamie McClellan
The FASEB Journal
PURPOSE: Adipose tissue macrophages are thought to be a major player in the dysregulation of meta... more PURPOSE: Adipose tissue macrophages are thought to be a major player in the dysregulation of metabolic and inflammatory processes associated with high fat diet (HFD)-induced obesity. Monocyte chemo...
Leakiness in SCID mouse models refers to the occasionally productive VDJ rearrangement leading to... more Leakiness in SCID mouse models refers to the occasionally productive VDJ rearrangement leading to clonal expansion of these limited B and T cell clones. The rate and extent of leakiness in immunode...
Biochemical and biophysical research communications, Jan 25, 2017
Skeletal muscle atrophy is associated with a disruption in protein turnover involving increased p... more Skeletal muscle atrophy is associated with a disruption in protein turnover involving increased protein degradation and suppressed protein synthesis. Although it has been well studied that the IGF-1/PI3K/Akt pathway plays an essential role in the regulation of the protein turnover, molecule(s) that triggers the change in protein turnover still remains to be elucidated. TRB3 has been shown to inhibit Akt through direct binding. In this study, we hypothesized that TRB3 in mouse skeletal muscle negatively regulates protein turnover via the disruption of Akt and its downstream molecules. Muscle-specific TRB3 transgenic (TRB3TG) mice had decreased muscle mass and fiber size, resulting in impaired muscle function. We also found that protein synthesis rate and signaling molecules, mTOR and S6K1, were significantly reduced in TRB3TG mice, whereas the protein breakdown pathway was significantly activated. In contrast, TRB3 knockout mice showed increased muscle mass and had an increase in pro...
Cancer Research
The “R2G2” (B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd) knockout mouse is the latest advancement to pro... more The “R2G2” (B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd) knockout mouse is the latest advancement to provide an alternative option in the highly immunodeficient mouse model category for the oncology, immunology and other biomedical research communities. This model was generated by backcrossing an IL2rg (common gamma) knockout model to a RAG2 (recombinase activating gene) knockout model. The resulting mouse lacks various cytokines including IL-2, IL-4, IL-7, IL-9 and IL-15. In addition, this model lacks B cells, T cells, NK cells and has a deficit in lymphocyte development. The R2G2 model is not only ultra immunodeficient, but provides a model that is less leaky and more tolerant to gamma radiation than traditional SCID models. This model is particularly useful for both tumor transplantation and humanization studies. Herein we describe the development and characterization of the R2G2 model, which includes breeding history, growth curve, CBC/Chemistry, flow cytometry and both huHSC and huPMBC humanization studies. Citation Format: Sheryl J. Wildt, Jamie McClellan, Mandy Horn. Development and characterization of the ultra immunodeficient B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd (R2G2) mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2812. doi:10.1158/1538-7445.AM2017-2812
PloS one, 2016
The purpose of this study was to examine the effect of a 40% high-fat diet (HFD) supplemented wit... more The purpose of this study was to examine the effect of a 40% high-fat diet (HFD) supplemented with a dietary attainable level of quercetin (0.02%) on body composition, adipose tissue (AT) inflammation, Non-Alcoholic Fatty-Liver Disease (NAFLD), and metabolic outcomes. Diets were administered for 16 weeks to C57BL/6J mice (n = 10/group) beginning at 4 weeks of age. Body composition and fasting blood glucose, insulin, and total cholesterol concentrations were examined intermittently. AT and liver mRNA expression (RT-PCR) of inflammatory mediators (F4/80, CD206 (AT only), CD11c (AT only) TLR-2 (AT only), TLR-4 (AT only), MCP-1, TNF-α, IL-6 (AT only), and IL-10 (AT only)) were measured along with activation of NFκB-p65, and JNK (western blot). Hepatic lipid accumulation, gene expression (RT-PCR) of hepatic metabolic markers (ACAC1, SREBP-1, PPAR-γ), protein content of Endoplasmic Reticulum (ER) Stress markers (BiP, phosphorylated and total EIF2α, phosphorylated and total IRE1α, CHOP), a...
The Faseb Journal, Apr 1, 2013
The etiology of colon cancer is a complex phenomenon that involves both genetic and environmental... more The etiology of colon cancer is a complex phenomenon that involves both genetic and environmental factors. However, only about 20% have a familial basis with the largest fraction being attributed to environmental causes that can lead to chronic inflammation. Tumors associated macrophages drive the pro-inflammatory response in the tumor micro-environment and are associated with poor prognosis in certain cancers. Monocyte chemoattractant protein 1 (MCP-1) is thought to be the most important chemokine for recruitment of macrophages to the tumor microenvironment. In chapter 1, we examined the timing and magnitude of the intestinal inflammatory cytokine response in relation to tumorigenesis in the Apc Min/+ mouse. Then, in chapter 2, we examined the role of MCP-1 on tumor associated macrophages, inflammation, and intestinal tumorigenesis in Apc Min/+ mice. In chapter 3, we examined the effects of exercise on markers associated with macrophages and select T cell populations in Apc Min/+ mice and related this to polyp characteristics. The results in chapter 1 show that the increase in polyp burden with age is positively correlated with the increase in intestinal inflammatory cytokine expression (mRNA and protein) of MCP-1, IL-1β, IL-6 and TNF-α, with MCP-1 showing the highest association. Similarly, circulating MCP-1 was increased at 12 wks (P<0.05) and then again at 20 wks (P<0.05). MCP-1 deficiency decreased overall polyp number by 20% and specifically large polyp number by 45% (P<0.05). In chapter 2, we show that MCP-1 deficiency decreased F4/80 positive cells in both the polyp tissue and surrounding intestinal tissue (P<0.05) as well as expression of vi markers associated with M1 (IL-12 & IL-23) and M2 macrophages (IL-13, CD206, TGFβ & CCL17) (P<0.05). MCP-1 knockout was also associated with increased CTLs and decreased Tregs (P<0.05). In chapter 3, we show that while there was no significant difference in overall polyp number between the groups (Sed: 23.3 ± 4.3 and Ex: 16.5 ± 4.3), Ex did have a reduction in the number of large polyps (Sed:6.1 ± 1.1 and Ex: 3.0 ± 0.6) (P<0.05). Similarly, Ex reduced mRNA expression of overall macrophages (F4/80) as well as markers associated with both M1 (IL-12) and M2 (CD206, CCL22, & Arg-1) subtypes (P<0.05). CD8 expression was increased while Foxp3 expression was decreased with Ex (P<0.05). We demonstrate that MCP-1 is an important mediator of tumor growth and immune regulation that may serve as an important biomarker and/or therapeutic target in colon cancer. This data also provides important new information on immune regulation as a possible mechanism for the documented benefits of exercise training on reducing colon cancer progression. vii
American Journal of Physiology - Gastrointestinal and Liver Physiology, 2016
High-fat-diet (HFD) consumption is associated with colon cancer risk. However, little is known ab... more High-fat-diet (HFD) consumption is associated with colon cancer risk. However, little is known about how the lipid composition of a HFD can influence prooncogenic processes. We examined the effects of three HFDs differing in the percentage of total calories from saturated fat (SF) (6, 12, and 24% of total caloric intake), but identical in total fat (40%), and a commercially available Western diet (26 and 41% saturated and total fat, respectively) on colon cancer development using the azoxymethane (AOM)/dextran sulfate sodium (DSS) murine model. A second dose-response experiment was performed using diets supplemented with the saturated-fatty-acid (SFA)-rich coconut oil. In experiment 1, we found an inverse association between SF content and tumor burden. Furthermore, increased SF content was associated with reduced inflammation, increased apoptosis, and decreased proliferation. The second dose-response experiment was performed to test whether this effect may be attributed to the SF c...
The Faseb Journal, Apr 1, 2010
Biochemical and Biophysical Research Communications, 2016
Recent studies have demonstrated that adult humans have substantial amounts of functioning brown ... more Recent studies have demonstrated that adult humans have substantial amounts of functioning brown adipose tissue (BAT). Since BAT has been implicated as an anti-obese and anti-diabetic tissue, it is important to understand the signaling molecules that regulate BAT function. There has been a link between insulin signaling and BAT metabolism as deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function. Tribbles 3 (TRB3) is a pseudo kinase that has been shown to regulate metabolism and insulin signaling in multiple tissues but the role of TRB3 in BAT has not been studied. In this study, we found that TRB3 expression was present in BAT and overexpression of TRB3 in brown preadipocytes impaired differentiation and decreased expression of BAT markers. Furthermore, TRB3 overexpression resulted in significantly lower oxygen consumption rates for basal and proton leakage, indicating decreased BAT activity. Based on previous studies showing that deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function, we assessed insulin signaling in brown preadipocytes and BAT in vivo. Overexpression of TRB3 in cells impaired insulin-stimulated IRS1 and Akt phosphorylation, whereas TRB3KO mice displayed improved IRS1 and Akt phosphorylation. Finally, deletion of IRS1 abolished the function of TRB3 to regulate BAT differentiation and metabolism. These data demonstrate that TRB3 inhibits insulin signaling in BAT, resulting in impaired differentiation and function.
American Journal of Physiology - Gastrointestinal and Liver Physiology, 2016
Clinical studies have linked microRNA-155 (miR-155) expression in the tumor microenvironment to p... more Clinical studies have linked microRNA-155 (miR-155) expression in the tumor microenvironment to poor prognosis. However, whether miR-155 upregulation is predictive of a pro- or antitumorigenic response is unclear, as the limited preclinical data available remain controversial. We examined miR-155 expression in tumor tissue from colon cancer patients. Furthermore, we investigated the role of this microRNA in proliferation and apoptosis, inflammatory processes, immune cell populations, and transforming growth factor-β/SMAD signaling in a chemically induced (azoxymethane-dextran sulfate sodium) mouse model of colitis-associated colon cancer. We found a higher expression of miR-155 in the tumor region than in nontumor colon tissue of patients with colon cancer. Deletion of miR-155 in mice resulted in a greater number of polyps/adenomas, an increased symptom severity score, a higher grade of epithelial dysplasia, and a decrease in survival. Surprisingly, these findings were associated wi...
Nutrition research (New York, N.Y.), Jan 11, 2015
It is hypothesized that a high dietary n-6:n-3 (eg, 10-20:1) is partly responsible for the rise i... more It is hypothesized that a high dietary n-6:n-3 (eg, 10-20:1) is partly responsible for the rise in obesity and related health ailments. However, no tightly controlled studies using high-fat diets differing in the n-6:n-3 have tested this hypothesis. The aim of the study was to determine the role that the dietary n-6:n-3 plays in non-alcoholic fatty-liver disease (NAFLD) and colitis development. We hypothesized that reducing the dietary n-6:n-3 would hinder the development of NAFLD and colitis. Male C57BL/6 J mice were fed high-fat diets, differing in the n-6:n-3 (1:1, 5:1, 10:1, 20:1), for 20 weeks. Gas chromatography-mass spectrometry was used to analyze the hepatic phospholipid arachidonic acid (AA):eicosapentaenoic acid and AA:docosahexaenoic acid. Hepatic metabolism, inflammatory signaling, macrophage polarization, gene expression of inflammatory mediators, oxidative and endoplasmic reticulum stress, and oxidative capacity were assessed as well as colonic inflammatory signaling,...
Cancer Biology & Therapy, 2014
Breast cancer is the leading cause of cancer related death in women. Quercetin is a flavonol show... more Breast cancer is the leading cause of cancer related death in women. Quercetin is a flavonol shown to have anticarcinogenic actions. However, few studies have investigated the dose-dependent effects of quercetin on tumorigenesis and none have used the C3(1)/SV40 Tag breast cancer mouse model. At 4 weeks of age female C3(1)/ SV40 Tag mice were randomized to one of four dietary treatments (n D 15-16/group): control (no quercetin), low-dose quercetin (0.02% diet), moderate-dose quercetin (0.2% diet), or high-dose quercetin (2% diet). Tumor number and volume was assessed twice a week and at sacrifice (20 wks). Results showed an inverted 'U' dose-dependent effect of dietary quercetin on tumor number and volume; at sacrifice the moderate dose was most efficacious and reduced tumor number 20% and tumor volume 78% compared to control mice (C3-Con: 9.0 § 0.9; C3-0.2%: 7.3 § 0.9) and (C3-Con: 2061.8 § 977.0 mm 3 ; and C3-0.2%: 462.9 § 75.9 mm 3). Tumor volume at sacrifice was also reduced by the moderate dose compared to the high and low doses (C3-2%: 1163.2 § 305.9 mm 3 ; C3-0.02%: 1401.5 § 555.6 mm 3), as was tumor number (C3-2%: 10.7 § 1.3 mm 3 ; C3-0.02%: 8.1 § 1.1 mm 3). Gene expression microarray analysis performed on mammary glands from C3-Con and C3-0.2% mice determined that 31 genes were down-regulated and 9 genes were up-regulated more than 2-fold (P < 0.05) by quercetin treatment. We report the novel finding that there is a distinct dose-dependent effect of quercetin on tumor number and volume in a transgenic mouse model of human breast cancer, which is associated with a specific gene expression signature related to quercetin treatment.
We examined the possible negative interaction of the combined use of the NSAID indomethacin (IND)... more We examined the possible negative interaction of the combined use of the NSAID indomethacin (IND) and exercise in mice. Mice were assigned to one of 4 groups: Exercise 2.5 mg/kg IND (Ex-2.5), Sedentary 2.5 mg/kg IND (Sed-2.5), Exercise 5.0 mg/kg IND (Ex-5.0) and Sedentary 5.0 mg/kg IND (Sed-5.0). Mice were given IND (gavage) 1 h prior to exercise (treadmill run at 30 m/min, 8% grade for 90 min) or rest for 14 consecutive days. Run times, body weight and mortality were recorded daily. Sed-5.0 was highly toxic and caused 70% mortality compared to Sed-2.5, which was well tolerated (0% mortality) (P&amp;lt;0.05). While the addition of exercise had no greater effect on mortality in Ex-5.0, it increased it in the 2.5 group (52% vs. 0%; P&amp;lt;0.05). Run time was reduced from baseline beginning on day 2 (Ex-5.0), or day 3 (Ex-2.5) (P&amp;lt;0.05). Body weight (recorded in the 2.5 mg/kg groups only) was decreased from baseline in Ex-2.5 and Sed-2.5 (P&amp;lt;0.05), but this effect occurred earlier and was of greater magnitude in Ex-2.5. Exercise combined with IND use can lead to serious side effects in mice. Future research is needed to test the hypothesis that this effect is due to increased GI permeability and whether humans are also at risk.
The FASEB Journal
PURPOSE: Adipose tissue macrophages are thought to be a major player in the dysregulation of meta... more PURPOSE: Adipose tissue macrophages are thought to be a major player in the dysregulation of metabolic and inflammatory processes associated with high fat diet (HFD)-induced obesity. Monocyte chemo...
Leakiness in SCID mouse models refers to the occasionally productive VDJ rearrangement leading to... more Leakiness in SCID mouse models refers to the occasionally productive VDJ rearrangement leading to clonal expansion of these limited B and T cell clones. The rate and extent of leakiness in immunode...
Biochemical and biophysical research communications, Jan 25, 2017
Skeletal muscle atrophy is associated with a disruption in protein turnover involving increased p... more Skeletal muscle atrophy is associated with a disruption in protein turnover involving increased protein degradation and suppressed protein synthesis. Although it has been well studied that the IGF-1/PI3K/Akt pathway plays an essential role in the regulation of the protein turnover, molecule(s) that triggers the change in protein turnover still remains to be elucidated. TRB3 has been shown to inhibit Akt through direct binding. In this study, we hypothesized that TRB3 in mouse skeletal muscle negatively regulates protein turnover via the disruption of Akt and its downstream molecules. Muscle-specific TRB3 transgenic (TRB3TG) mice had decreased muscle mass and fiber size, resulting in impaired muscle function. We also found that protein synthesis rate and signaling molecules, mTOR and S6K1, were significantly reduced in TRB3TG mice, whereas the protein breakdown pathway was significantly activated. In contrast, TRB3 knockout mice showed increased muscle mass and had an increase in pro...
Cancer Research
The “R2G2” (B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd) knockout mouse is the latest advancement to pro... more The “R2G2” (B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd) knockout mouse is the latest advancement to provide an alternative option in the highly immunodeficient mouse model category for the oncology, immunology and other biomedical research communities. This model was generated by backcrossing an IL2rg (common gamma) knockout model to a RAG2 (recombinase activating gene) knockout model. The resulting mouse lacks various cytokines including IL-2, IL-4, IL-7, IL-9 and IL-15. In addition, this model lacks B cells, T cells, NK cells and has a deficit in lymphocyte development. The R2G2 model is not only ultra immunodeficient, but provides a model that is less leaky and more tolerant to gamma radiation than traditional SCID models. This model is particularly useful for both tumor transplantation and humanization studies. Herein we describe the development and characterization of the R2G2 model, which includes breeding history, growth curve, CBC/Chemistry, flow cytometry and both huHSC and huPMBC humanization studies. Citation Format: Sheryl J. Wildt, Jamie McClellan, Mandy Horn. Development and characterization of the ultra immunodeficient B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd (R2G2) mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2812. doi:10.1158/1538-7445.AM2017-2812
PloS one, 2016
The purpose of this study was to examine the effect of a 40% high-fat diet (HFD) supplemented wit... more The purpose of this study was to examine the effect of a 40% high-fat diet (HFD) supplemented with a dietary attainable level of quercetin (0.02%) on body composition, adipose tissue (AT) inflammation, Non-Alcoholic Fatty-Liver Disease (NAFLD), and metabolic outcomes. Diets were administered for 16 weeks to C57BL/6J mice (n = 10/group) beginning at 4 weeks of age. Body composition and fasting blood glucose, insulin, and total cholesterol concentrations were examined intermittently. AT and liver mRNA expression (RT-PCR) of inflammatory mediators (F4/80, CD206 (AT only), CD11c (AT only) TLR-2 (AT only), TLR-4 (AT only), MCP-1, TNF-α, IL-6 (AT only), and IL-10 (AT only)) were measured along with activation of NFκB-p65, and JNK (western blot). Hepatic lipid accumulation, gene expression (RT-PCR) of hepatic metabolic markers (ACAC1, SREBP-1, PPAR-γ), protein content of Endoplasmic Reticulum (ER) Stress markers (BiP, phosphorylated and total EIF2α, phosphorylated and total IRE1α, CHOP), a...
The Faseb Journal, Apr 1, 2013
The etiology of colon cancer is a complex phenomenon that involves both genetic and environmental... more The etiology of colon cancer is a complex phenomenon that involves both genetic and environmental factors. However, only about 20% have a familial basis with the largest fraction being attributed to environmental causes that can lead to chronic inflammation. Tumors associated macrophages drive the pro-inflammatory response in the tumor micro-environment and are associated with poor prognosis in certain cancers. Monocyte chemoattractant protein 1 (MCP-1) is thought to be the most important chemokine for recruitment of macrophages to the tumor microenvironment. In chapter 1, we examined the timing and magnitude of the intestinal inflammatory cytokine response in relation to tumorigenesis in the Apc Min/+ mouse. Then, in chapter 2, we examined the role of MCP-1 on tumor associated macrophages, inflammation, and intestinal tumorigenesis in Apc Min/+ mice. In chapter 3, we examined the effects of exercise on markers associated with macrophages and select T cell populations in Apc Min/+ mice and related this to polyp characteristics. The results in chapter 1 show that the increase in polyp burden with age is positively correlated with the increase in intestinal inflammatory cytokine expression (mRNA and protein) of MCP-1, IL-1β, IL-6 and TNF-α, with MCP-1 showing the highest association. Similarly, circulating MCP-1 was increased at 12 wks (P<0.05) and then again at 20 wks (P<0.05). MCP-1 deficiency decreased overall polyp number by 20% and specifically large polyp number by 45% (P<0.05). In chapter 2, we show that MCP-1 deficiency decreased F4/80 positive cells in both the polyp tissue and surrounding intestinal tissue (P<0.05) as well as expression of vi markers associated with M1 (IL-12 & IL-23) and M2 macrophages (IL-13, CD206, TGFβ & CCL17) (P<0.05). MCP-1 knockout was also associated with increased CTLs and decreased Tregs (P<0.05). In chapter 3, we show that while there was no significant difference in overall polyp number between the groups (Sed: 23.3 ± 4.3 and Ex: 16.5 ± 4.3), Ex did have a reduction in the number of large polyps (Sed:6.1 ± 1.1 and Ex: 3.0 ± 0.6) (P<0.05). Similarly, Ex reduced mRNA expression of overall macrophages (F4/80) as well as markers associated with both M1 (IL-12) and M2 (CD206, CCL22, & Arg-1) subtypes (P<0.05). CD8 expression was increased while Foxp3 expression was decreased with Ex (P<0.05). We demonstrate that MCP-1 is an important mediator of tumor growth and immune regulation that may serve as an important biomarker and/or therapeutic target in colon cancer. This data also provides important new information on immune regulation as a possible mechanism for the documented benefits of exercise training on reducing colon cancer progression. vii
American Journal of Physiology - Gastrointestinal and Liver Physiology, 2016
High-fat-diet (HFD) consumption is associated with colon cancer risk. However, little is known ab... more High-fat-diet (HFD) consumption is associated with colon cancer risk. However, little is known about how the lipid composition of a HFD can influence prooncogenic processes. We examined the effects of three HFDs differing in the percentage of total calories from saturated fat (SF) (6, 12, and 24% of total caloric intake), but identical in total fat (40%), and a commercially available Western diet (26 and 41% saturated and total fat, respectively) on colon cancer development using the azoxymethane (AOM)/dextran sulfate sodium (DSS) murine model. A second dose-response experiment was performed using diets supplemented with the saturated-fatty-acid (SFA)-rich coconut oil. In experiment 1, we found an inverse association between SF content and tumor burden. Furthermore, increased SF content was associated with reduced inflammation, increased apoptosis, and decreased proliferation. The second dose-response experiment was performed to test whether this effect may be attributed to the SF c...
The Faseb Journal, Apr 1, 2010
Biochemical and Biophysical Research Communications, 2016
Recent studies have demonstrated that adult humans have substantial amounts of functioning brown ... more Recent studies have demonstrated that adult humans have substantial amounts of functioning brown adipose tissue (BAT). Since BAT has been implicated as an anti-obese and anti-diabetic tissue, it is important to understand the signaling molecules that regulate BAT function. There has been a link between insulin signaling and BAT metabolism as deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function. Tribbles 3 (TRB3) is a pseudo kinase that has been shown to regulate metabolism and insulin signaling in multiple tissues but the role of TRB3 in BAT has not been studied. In this study, we found that TRB3 expression was present in BAT and overexpression of TRB3 in brown preadipocytes impaired differentiation and decreased expression of BAT markers. Furthermore, TRB3 overexpression resulted in significantly lower oxygen consumption rates for basal and proton leakage, indicating decreased BAT activity. Based on previous studies showing that deletion or pharmaceutical inhibition of insulin signaling impairs BAT differentiation and function, we assessed insulin signaling in brown preadipocytes and BAT in vivo. Overexpression of TRB3 in cells impaired insulin-stimulated IRS1 and Akt phosphorylation, whereas TRB3KO mice displayed improved IRS1 and Akt phosphorylation. Finally, deletion of IRS1 abolished the function of TRB3 to regulate BAT differentiation and metabolism. These data demonstrate that TRB3 inhibits insulin signaling in BAT, resulting in impaired differentiation and function.
American Journal of Physiology - Gastrointestinal and Liver Physiology, 2016
Clinical studies have linked microRNA-155 (miR-155) expression in the tumor microenvironment to p... more Clinical studies have linked microRNA-155 (miR-155) expression in the tumor microenvironment to poor prognosis. However, whether miR-155 upregulation is predictive of a pro- or antitumorigenic response is unclear, as the limited preclinical data available remain controversial. We examined miR-155 expression in tumor tissue from colon cancer patients. Furthermore, we investigated the role of this microRNA in proliferation and apoptosis, inflammatory processes, immune cell populations, and transforming growth factor-β/SMAD signaling in a chemically induced (azoxymethane-dextran sulfate sodium) mouse model of colitis-associated colon cancer. We found a higher expression of miR-155 in the tumor region than in nontumor colon tissue of patients with colon cancer. Deletion of miR-155 in mice resulted in a greater number of polyps/adenomas, an increased symptom severity score, a higher grade of epithelial dysplasia, and a decrease in survival. Surprisingly, these findings were associated wi...
Nutrition research (New York, N.Y.), Jan 11, 2015
It is hypothesized that a high dietary n-6:n-3 (eg, 10-20:1) is partly responsible for the rise i... more It is hypothesized that a high dietary n-6:n-3 (eg, 10-20:1) is partly responsible for the rise in obesity and related health ailments. However, no tightly controlled studies using high-fat diets differing in the n-6:n-3 have tested this hypothesis. The aim of the study was to determine the role that the dietary n-6:n-3 plays in non-alcoholic fatty-liver disease (NAFLD) and colitis development. We hypothesized that reducing the dietary n-6:n-3 would hinder the development of NAFLD and colitis. Male C57BL/6 J mice were fed high-fat diets, differing in the n-6:n-3 (1:1, 5:1, 10:1, 20:1), for 20 weeks. Gas chromatography-mass spectrometry was used to analyze the hepatic phospholipid arachidonic acid (AA):eicosapentaenoic acid and AA:docosahexaenoic acid. Hepatic metabolism, inflammatory signaling, macrophage polarization, gene expression of inflammatory mediators, oxidative and endoplasmic reticulum stress, and oxidative capacity were assessed as well as colonic inflammatory signaling,...
Cancer Biology & Therapy, 2014
Breast cancer is the leading cause of cancer related death in women. Quercetin is a flavonol show... more Breast cancer is the leading cause of cancer related death in women. Quercetin is a flavonol shown to have anticarcinogenic actions. However, few studies have investigated the dose-dependent effects of quercetin on tumorigenesis and none have used the C3(1)/SV40 Tag breast cancer mouse model. At 4 weeks of age female C3(1)/ SV40 Tag mice were randomized to one of four dietary treatments (n D 15-16/group): control (no quercetin), low-dose quercetin (0.02% diet), moderate-dose quercetin (0.2% diet), or high-dose quercetin (2% diet). Tumor number and volume was assessed twice a week and at sacrifice (20 wks). Results showed an inverted 'U' dose-dependent effect of dietary quercetin on tumor number and volume; at sacrifice the moderate dose was most efficacious and reduced tumor number 20% and tumor volume 78% compared to control mice (C3-Con: 9.0 § 0.9; C3-0.2%: 7.3 § 0.9) and (C3-Con: 2061.8 § 977.0 mm 3 ; and C3-0.2%: 462.9 § 75.9 mm 3). Tumor volume at sacrifice was also reduced by the moderate dose compared to the high and low doses (C3-2%: 1163.2 § 305.9 mm 3 ; C3-0.02%: 1401.5 § 555.6 mm 3), as was tumor number (C3-2%: 10.7 § 1.3 mm 3 ; C3-0.02%: 8.1 § 1.1 mm 3). Gene expression microarray analysis performed on mammary glands from C3-Con and C3-0.2% mice determined that 31 genes were down-regulated and 9 genes were up-regulated more than 2-fold (P < 0.05) by quercetin treatment. We report the novel finding that there is a distinct dose-dependent effect of quercetin on tumor number and volume in a transgenic mouse model of human breast cancer, which is associated with a specific gene expression signature related to quercetin treatment.
We examined the possible negative interaction of the combined use of the NSAID indomethacin (IND)... more We examined the possible negative interaction of the combined use of the NSAID indomethacin (IND) and exercise in mice. Mice were assigned to one of 4 groups: Exercise 2.5 mg/kg IND (Ex-2.5), Sedentary 2.5 mg/kg IND (Sed-2.5), Exercise 5.0 mg/kg IND (Ex-5.0) and Sedentary 5.0 mg/kg IND (Sed-5.0). Mice were given IND (gavage) 1 h prior to exercise (treadmill run at 30 m/min, 8% grade for 90 min) or rest for 14 consecutive days. Run times, body weight and mortality were recorded daily. Sed-5.0 was highly toxic and caused 70% mortality compared to Sed-2.5, which was well tolerated (0% mortality) (P&amp;lt;0.05). While the addition of exercise had no greater effect on mortality in Ex-5.0, it increased it in the 2.5 group (52% vs. 0%; P&amp;lt;0.05). Run time was reduced from baseline beginning on day 2 (Ex-5.0), or day 3 (Ex-2.5) (P&amp;lt;0.05). Body weight (recorded in the 2.5 mg/kg groups only) was decreased from baseline in Ex-2.5 and Sed-2.5 (P&amp;lt;0.05), but this effect occurred earlier and was of greater magnitude in Ex-2.5. Exercise combined with IND use can lead to serious side effects in mice. Future research is needed to test the hypothesis that this effect is due to increased GI permeability and whether humans are also at risk.