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Impaired insulin signaling in the B10.D2--/oSnJ mouse model of complement factor 5 deficiency.
Peterson KR, Gutierrez DA, Kikuchi T, Anderson-Baucum EK, Winn NC, Shuey MM, Bolus WR, McGuinness OP, Hasty AH
(2019) Am J Physiol Endocrinol Metab 317: E200-E211
MeSH Terms: Adenoviridae, Animals, Complement C5, Disease Models, Animal, Energy Metabolism, Glucose Intolerance, Hereditary Complement Deficiency Diseases, Insulin Resistance, Mice, Mice, Inbred AKR, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Inbred DBA, Mice, Inbred NOD, Mice, Transgenic, Signal Transduction, Transduction, Genetic
Show Abstract · Added March 3, 2020
Given the chemoattractant potential of complement factor 5 (C5) and its increased expression in adipose tissue (AT) of obese mice, we determined whether this protein of the innate immune system impacts insulin action. C5 control (C5) and spontaneously C5-deficient (C5, B10.D2--/oSnJ) mice were placed on low- and high-fat diets to investigate their inflammatory and metabolic phenotypes. Adenoviral delivery was used to evaluate the effects of exogenous C5 on systemic metabolism. C5 mice gained less weight than controls while fed a high-fat diet, accompanied by reduced AT inflammation, liver mass, and liver triglyceride content. Despite these beneficial metabolic effects, C5 mice demonstrated severe glucose intolerance and systemic insulin resistance, as well as impaired insulin signaling in liver and AT. C5 mice also exhibited decreased expression of insulin receptor (INSR) gene and protein, as well as improper processing of pro-INSR. These changes were not due to the C5 deficiency alone as other C5-deficient models did not recapitulate the INSR processing defect; rather, in addition to the mutation in the gene, whole genome sequencing revealed an intronic 31-bp deletion in the gene in the B10.D2--/oSnJ model. Irrespective of the genetic defect, adenoviral delivery of C5 improved insulin sensitivity in both C5 and C5 mice, indicating an insulin-sensitizing function of C5.
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A mouse model for glucocorticoid-induced osteonecrosis: effect of a steroid holiday.
Yang L, Boyd K, Kaste SC, Kamdem Kamdem L, Rahija RJ, Relling MV
(2009) J Orthop Res 27: 169-75
MeSH Terms: Animals, Antineoplastic Agents, Asparaginase, Dexamethasone, Disease Models, Animal, Dose-Response Relationship, Drug, Glucocorticoids, Male, Mice, Mice, Inbred A, Mice, Inbred AKR, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred DBA, Osteonecrosis, Phenotype, Species Specificity
Show Abstract · Added March 5, 2014
Glucocorticoid-induced osteonecrosis is a common and dose-limiting adverse event. The goal of this study was to establish a mouse model of glucocorticoid-induced osteonecrosis suitable for testing the effects of different treatment strategies on its frequency. Fourteen murine strains were screened using various glucocorticoids, routes of administration, and diets. Four-week-old male BALB/cJ mice were treated with oral dexamethasone for up to 12 weeks either by continuous dosing or by discontinuous dosing, with or without asparaginase. Histopathological features of the distal femurs were examined by light microscopy. Osteonecrotic lesions were characterized by empty lacunae and osteocyte ghosts in trabecular bone surrounded by necrotic marrow and edema. The incidence of dexamethasone induced osteonecrosis in BALB/cJ mice was 40-45% (4/10 or 5/11) at 12 weeks. The frequency of osteonecrosis trended lower after discontinuous compared to continuous dosing for 12 weeks (8 vs. 45%) (p = 0.06) despite comparable cumulative plasma exposure. Asparaginase hastened the occurrence of osteonecrosis, which was observed as early as 4 weeks and the incidence was 50% after 6 weeks. A mouse model of glucocorticoid-induced osteonecrosis was established. Discontinuous was less osteonecrotic than continuous dexamethasone treatment, consistent with the possible benefits of a "steroid holiday" seen in clinical settings. Moreover, asparaginase hastened osteonecrosis, indicating that drugs may interact with glucocorticoids to affect osteonecrosis risk.
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18 MeSH Terms
Concurrent overexpression of cyclin D1 and cyclin-dependent kinase 4 (Cdk4) in intestinal adenomas from multiple intestinal neoplasia (Min) mice and human familial adenomatous polyposis patients.
Zhang T, Nanney LB, Luongo C, Lamps L, Heppner KJ, DuBois RN, Beauchamp RD
(1997) Cancer Res 57: 169-75
MeSH Terms: Adenomatous Polyposis Coli, Animals, Cell Division, Cyclin D1, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinases, Cyclins, Humans, Intestinal Neoplasms, Mice, Mice, Inbred AKR, Neoplasm Proteins, Neoplasms, Experimental, Neoplasms, Multiple Primary, Oncogene Proteins, Proliferating Cell Nuclear Antigen, Proto-Oncogene Proteins
Show Abstract · Added June 14, 2013
We postulated that increased expression of the cell cycle regulators cyclin D1 and cyclin-dependent kinase (Cdk) 4 may be involved in the development of intestinal adenomas associated with familial adenomatous polyposis (FAP). In the present study of multiple intestinal neoplasia (Min) mice and human FAP patients, the expression and distribution of cyclin D1, Cdk4, and cell proliferative activity (5-bromo-2'-deoxyuridine incorporation) in normal and adenomatous intestinal epithelium were investigated. Immunohistochemical analysis of Min mouse intestine revealed that cyclin D1 immunoreactivity in the intestinal epithelium was restricted to the adenomatous areas, with a significantly higher percentage of positively staining nuclei in high-grade dysplasia versus low-grade dysplasia (54.8 +/- 18.4% versus 34.6 +/- 16.9%, P = 0.016). Morphologically normal areas of intestinal epithelia were uniformly negative for cyclin D1 immunoreactivity. Cdk4 nuclear immunoreactivity was restricted to the crypt areas in morphologically normal small intestine and colon. Conversely, Cdk4 immunoreactivity was uniformly abundant in adenomatous areas regardless of the degree of dysplasia. Increased expression of cyclin D1 and Cdk4 in adenomas was accompanied by a significantly increased 5-bromo-2'-deoxyuridine incorporation rate in the same areas. Immunoblot analysis of lysates from surgical specimens revealed increased levels of cyclin D1 and Cdk4 in the majority of intestinal adenomas from human FAP patients in comparison to the adjacent grossly normal colonic mucosa. Our results indicate that overexpression of cyclin D1 and Cdk4 occurs in intestinal adenomas and is associated with increased cell proliferative activity in premalignant neoplastic cells. Increased cyclin D1 immunoreactivity is associated with more severe dysplasia. These data suggest that abnormal up-regulation of these important G1 cell cycle proteins is a relatively early event in intestinal carcinogenesis and that these changes may contribute to malignant progression within those lesions.
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17 MeSH Terms
Complex regulation of transforming growth factor beta 1, beta 2, and beta 3 mRNA expression in mouse fibroblasts and keratinocytes by transforming growth factors beta 1 and beta 2.
Bascom CC, Wolfshohl JR, Coffey RJ, Madisen L, Webb NR, Purchio AR, Derynck R, Moses HL
(1989) Mol Cell Biol 9: 5508-15
MeSH Terms: Animals, Cell Nucleus, Cells, Cultured, Cycloheximide, Dactinomycin, Fibroblasts, Gene Expression Regulation, Genes, Keratinocytes, Mice, Mice, Inbred AKR, Mice, Inbred BALB C, RNA, Messenger, Transcription, Genetic, Transforming Growth Factors
Show Abstract · Added February 17, 2014
Regulation of transforming growth factor beta 1 (TGF beta 1), TGF beta 2, and TGF beta 3 mRNAs in murine fibroblasts and keratinocytes by TGF beta 1 and TGF beta 2 was studied. In quiescent AKR-2B fibroblasts, in which TGF beta induces delayed stimulation of DNA synthesis, TGF beta 1 autoregulation of TGF beta 1 expression was observed as early as 1 h, with maximal induction (25-fold) after 6 to 12 h. Increased expression of TGF beta 1 mRNA was accompanied by increased TGF beta protein production into conditioned medium of AKR-2B cells. Neither TGF beta 2 nor TGF beta 3 mRNA, however, was significantly induced, but both were apparently down regulated at later times by TGF beta 1. Protein synthesis was not required for autoinduction of TGF beta 1 mRNA in AKR-2B cells. Nuclear run-on analyses and dactinomycin experiments indicated that autoregulation of TGF beta 1 expression is complex, involving both increased transcription and message stabilization. In contrast to TGF beta 1, TGF beta 2 treatment of quiescent AKR-2B cells increased expression of TGF beta 1, TGF beta 2, and TGF beta 3 mRNAs, but with different kinetics. Autoinduction of TGF beta 2 mRNA occurred rapidly with maximal induction at 1 to 3 h, enhanced TGF beta 3 mRNA levels were observed after 3 h, and increased expression of TGF beta 1 occurred later, with maximal mRNA levels obtained after 12 to 24 h. Nuclear run-on analyses indicated that TGF beta 2 regulation of TGF beta 2 and TGF beta 3 mRNA levels is transcriptional, while TGF beta 2 induction of TGF beta 1 expression most likely involves both transcriptional and posttranscriptional controls. In BALB/MK mouse keratinocytes, minimal autoinduction of TGF beta 1 occurred at only the 12- and 24-h time points and protein synthesis was required for this autoinduction. The results of this study provide an example in which TGF beta 1 and TGF beta 2 elicit different responses and demonstrate that expression of TGF beta 1, and TGF beta 3 are regulated differently. The physiological relevance of TGF beta 1 autoinduction in the context of wound healing is discussed.
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15 MeSH Terms