tbuckley/cabot-search huggingface dataset:
Metabolic Remodeling Induced by Mitochondrial Aldehyde Stress Stimulates Tolerance to Oxidative Stress in the Heart
Authors: Jin Endo, Motoaki Sano, Takaharu Katayama, Takako Hishiki, Ken Shinmura, Shintaro Morizane, Tomohiro Matsuhashi, Yoshinori Katsumata, Yan Zhang, Hideyuki Ito, Yoshiko Nagahata, Satori Marchitti, Kiyomi Nishimaki, Alexander Martin Wolf, Hiroki Nakanishi, Fumiyuki Hattori, Vasilis Vasiliou, Takeshi Adachi, Ikuroh Ohsawa, Ryo Taguchi, Yoshio Hirabayashi, Shigeo Ohta, Makoto Suematsu, Satoshi Ogawa, Keiichi Fukuda
Journal: Circulation Research (2009)

Aldehyde accumulation is regarded as a pathognomonic feature of oxidative stress-associated cardiovascular disease.We investigated how the heart compensates for the accelerated accumulation of aldehydes.Aldehyde dehydrogenase 2 (ALDH2) has a major role in aldehyde detoxification in the mitochondria, a major source of aldehydes. Transgenic (Tg) mice carrying an Aldh2 gene with a single nucleotide polymorphism (Aldh2*2) were developed. This polymorphism has a dominant-negative effect and the Tg mice exhibited impaired ALDH activity against a broad range of aldehydes. Despite a shift toward the oxidative state in mitochondrial matrices, Aldh2*2 Tg hearts displayed normal left ventricular function by echocardiography and, because of metabolic remodeling, an unexpected tolerance to oxidative stress induced by ischemia/reperfusion injury. Mitochondrial aldehyde stress stimulated eukaryotic translation initiation factor 2alpha phosphorylation. Subsequent translational and transcriptional activation of activating transcription factor-4 promoted the expression of enzymes involved in amino acid biosynthesis and transport, ultimately providing precursor amino acids for glutathione biosynthesis. Intracellular glutathione levels were increased 1.37-fold in Aldh2*2 Tg hearts compared with wild-type controls. Heterozygous knockout of Atf4 blunted the increase in intracellular glutathione levels in Aldh2*2 Tg hearts, thereby attenuating the oxidative stress-resistant phenotype. Furthermore, glycolysis and NADPH generation via the pentose phosphate pathway were activated in Aldh2*2 Tg hearts. (NADPH is required for the recycling of oxidized glutathione.)The findings of the present study indicate that mitochondrial aldehyde stress in the heart induces metabolic remodeling, leading to activation of the glutathione-redox cycle, which confers resistance against acute oxidative stress induced by ischemia/reperfusion.
All-or-None Measurement of Health Care Quality
Authors: Joseph G. Van Matre
Journal: JAMA (2006)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Diabetes Induces Endothelial Dysfunction but Does Not Increase Neointimal Formation in High-Fat Diet Fed C57BL/6J Mice
Authors: Judit Molnar, Shuiqing Yu, Nino Mzhavia, Clara Pau, Igor Chereshnev, Hayes M. Dansky
Journal: Circulation Research (2005)

Studies of diabetic vascular disease have traditionally used murine models of type 1 diabetes and genetic models of type 2 diabetes. Because the majority of patients with type 2 diabetes have diet induced obesity, we sought to study the effect of diabetes on arterial disease in a mouse model of diet induced obesity/diabetes. C57Bl/6 mice fed a high-fat diet for 9 weeks developed type 2 diabetes characterized by elevated body weight, hyperglycemia, and hyperinsulinemia. Arteries from diabetic mice exhibited a marked decrease in endothelium-dependent vasodilation, a modest decrease in endothelium independent vasodilation, and an increase in sensitivity to adrenergic vasoconstricting agents. Insulin stimulated protein kinase B (akt) and endothelial nitric oxide synthase (eNOS) phosphorylation were preserved in arteries from diabetic mice; however, eNOS protein dimers were markedly diminished. Arterial nitrotyrosine staining indicated that increased levels of peroxynitrite contributed to eNOS dimer disruption in the diabetic mice. The abnormal vasomotion was not an acute response to the high-fat diet, as short term high-fat diet feeding had no effect on endothelium dependent dilation. A trend toward smaller neointimal lesions was noted in high-fat diet fed mice after femoral artery wire denudation injury. In summary, disrupted eNOS dimer formation rather than impaired insulin mediated eNOS phosphorylation contributed to the endothelial dysfunction in diet induced obese/diabetic mice. The lack of an increase in neointimal formation indicates that additional diabetes associated parameters (such as hyperlipidemia and atherosclerotic vascular disease) may need to be present to increase neointimal formation in this model.
Physical Exercise and Reduced Risk of Breast Cancer in Young Women
Authors: L. Bernstein, B. E. Henderson, R. Hanisch, J. Sullivan-Halley, R. K. Ross
Journal: JNCI Journal of the National Cancer Institute (1994)

Background: Epidemiologic evidence strongly suggests that cumulative exposure to ovarian hormones is a determinant of breast cancer risk. Because physical activity can modify menstrual cycle patterns and alter the production of ovarian hormones, it may reduce breast cancer risk; yet few epidemiologic studies have assessed this relationship. Purpose: The major ob-jective of this study was to determine whether young women (aged 40 and younger) who regularly participated in physical exercise activities during their reproductive years had a reduced risk of breast cancer. Methods: Using a case-control design, we conducted personal interviews of a total of 545 women (aged 40 and younger at diagnosis) who had been newly diagnosed with in situ or invasive breast cancer between July 1, 1983, and January 1, 1989, and a total of 545 control subjects. Case patients and control subjects were individually matched on date of birth (within 36 months), race (white), parity (nulliparous versus parous), and neighborhood of resi-dence. Lifetime histories of participa-tion in physical exercise activities on a regular basis were obtained during the personal interview. Results: After ad-justment for potential confounding fac-tors, we found that the average number of hours spent in physical exercise ac-tivities per week from menarche to 1 year prior to the case patient‘s diag-nosis was a significant predictor of reduced breast cancer risk (two-sided P for trend <.0001). The odds ratio (OR) of breast cancer among women who, on average, spent 3.8 or more hours per week participating in physical exercise activities was 0.42 (95%confidence limits [CLs] = 0.27, 0.64) relative to inactive women. The effect was stronger among women who had had a full-term pregnancy. Comparing most active (>3.8 hours/wk of exercise) women to inactive women, the ORs were 0.28 (95% CL = 0.16, 0.50) for parous and 0.73 (95% CL = 038, 1.41) for nulliparous women. Conclusions: Most previously identified risk factors for breast cancer are reproductive and menstrual events that cannot be readily altered. The protective effect of exer-cise on breast cancer risk in the women whom we studied suggests that physical activity offers one modifiable lifestyle characteristic that may substantially reduce a woman’s lifetime risk of breast cancer. Implications: Whether the protective effects of exercise on breast cancer risk are due to alterations in ovarian function and whether they extend into women‘s menopausal years need to be established. Our results suggest that implementation of regular physical exercise programs as a critical component of a healthy lifestyle should be a high priority for adolescent and adult women. [J Natl Cancer Inst 86: 1403–1408, 1994]
Differential Regulation of Murine T Lymphocyte Subsets
Authors: F W Fitch, M D McKisic, D W Lancki, T F Gajewski
Journal: Annual Review of Immunology (1993)

Signaling pathways in T lymphocytes have been incompletely characterized. It is evident that differences exist among the T cell subsets. We have defined several distinct mechanisms that affect differentially the activities of murine T lymphocyte clones representing various CD4+ and CD8+ subsets: Interferon-gamma (IFN-gamma) inhibits proliferation of but not lymphokine production by TH2 cells. IL-10 inhibits antigen-presenting cell (APC)-induced lymphokine production by TH1 cells but not by TH2 cells. Murine TH1 and TH2 clones proliferate optimally in response to distinct APC populations. TH1 and TH2 clones utilize different TCR-associated signaling pathways. High concentrations of antigen (or anti-TCR mAb) inhibit IL-2-induced proliferation (but not lymphokine production) by TH1 and cytolytic T lymphocyte (CTL) clones only. Exposure of TH1 clones (but not TH2 clones or CD8+ CTL clones) to IL-2 induces unresponsiveness to antigen. TH1 and TH2 clones as well as CD8+ clones can be cytolytic, but not all T cells use the same cytolytic mechanisms. CD4+ clones from some mouse strains are not cytolytic if they do not secrete IFN-gamma. Understanding the mechanisms that differentially regulate the various kinds of T cells, in addition to providing insights into the molecular events associated with activation of those subsets, should facilitate modulation of their activities in vivo, making it possible to influence favorably the outcome of disease processes.
Mesenchymal Stem Cells Induce Resistance to Chemotherapy through the Release of Platinum-Induced Fatty Acids
Authors: Jeanine M.L. Roodhart, Laura G.M. Daenen, Edwin C.A. Stigter, Henk-Jan Prins, Johan Gerrits, Julia M. Houthuijzen, Marije G. Gerritsen, Henk S. Schipper, Marieke J.G. Backer, Miranda van Amersfoort, Joost S.P. Vermaat, Petra Moerer, Kenji Ishihara, Eric Kalkhoven, Jos H. Beijnen, Patrick W.B. Derksen, Rene H. Medema, Anton C. Martens, Arjan B. Brenkman, Emile E. Voest
Journal: Cancer Cell (2011)
Downregulation of Interleukin-12 (IL-12) Responsiveness in Human T Cells by Transforming Growth Factor-β: Relationship With IL-12 Signaling
Authors: Cécile Pardoux, Xiaojing Ma, Stéphanie Gobert, Sandra Pellegrini, Patrick Mayeux, Françoise Gay, Giorgio Trinchieri, Salem Chouaib
Journal: Blood (1999)
Truncated active matrix metalloproteinase-8 gene expression in HepG2 cells is active against native type I collagen
Authors: Fernando Siller-López, Jesus García-Bañuelos, Karen A Hasty, Jorge Segura, Martha Ramos-Márquez, M Walid Qoronfleh, Estuardo Aguilar-Cordova, Juan Armendáriz-Borunda
Journal: Journal of Hepatology (2000)
Tumor Necrosis Factor-α–Induced Protein 3 As a Putative Regulator of Nuclear Factor-κB–Mediated Resistance to O<sup>6</sup>-Alkylating Agents in Human Glioblastomas
Authors: Markus Bredel, Claudia Bredel, Dejan Juric, George E. Duran, Ron X. Yu, Griffith R. Harsh, Hannes Vogel, Lawrence D. Recht, Adrienne C. Scheck, Branimir I. Sikic
Journal: Journal of Clinical Oncology (2005)

Pre-existing and acquired drug resistance are major obstacles to the successful treatment of glioblastomas.We used an integrated resistance model and genomics tools to globally explore molecular factors and cellular pathways mediating resistance to O6-alkylating agents in glioblastoma cells.We identified a transcriptomic signature that predicts a common in vitro and in vivo resistance phenotype to these agents, a proportion of which is imprinted recurrently by gene dosage changes in the resistant glioblastoma genome. This signature was highly enriched for genes with functions in cell death, compromise, and survival. Modularity was a predominant organizational principle of the signature, with functions being carried out by groups of interacting molecules in overlapping networks. A highly significant network was built around nuclear factor-kappaB (NF-kappaB), which included the persistent alterations of various NF-kappaB pathway elements. Tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) was identified as a new regulatory component of a putative cytoplasmic signaling cascade that mediates NF-kappaB activation in response to DNA damage caused by O6-alkylating agents. Expression of the corresponding zinc finger protein A20 closely mirrored the expression of the TNFAIP3 transcript, and was inversely related to NF-kappaB activation status in the resistant cells. A prediction model based on the resistance signature enabled the subclassification of an independent, validation cohort of 31 glioblastomas into two outcome groups (P = .037) and revealed TNFAIP3 as part of an optimized four-gene predictor associated significantly with patient survival (P = .022).Our results offer strong evidence for TNFAIP3 as a key regulator of the cytoplasmic signaling to activate NF-kappaB en route to O6-alkylating agent resistance in glioblastoma cells. This pathway may be an attractive target for therapeutic modulation of glioblastomas.
Enhanced alpha 1-adrenergic responsiveness in cardiomyopathic hamster cardiac myocytes. Relation to the expression of pertussis toxin-sensitive G protein and alpha 1-adrenergic receptors.
Authors: L Sen, B T Liang, W S Colucci, T W Smith
Journal: Circulation Research (1990)

The pathogenesis of the myopathy occurring in the heart of the cardiomyopathic strain of the Syrian hamster is not well understood but is believed to be associated with abnormal calcium handling by myopathic cells. The purpose of this study was to determine whether the cardiomyopathy occurring in strain BIO 14.6 animals is associated with an enhanced alpha 1-adrenergic receptor-mediated rise in cytosolic calcium, whether a pertussis toxin-sensitive G protein is involved in coupling the alpha 1-adrenergic receptor to changes in intracellular calcium and whether enhanced alpha 1 responsiveness is associated with an increase in the level of expression of the alpha 1-adrenergic receptor or in the pertussis toxin-sensitive G protein or proteins. To test the hypothesis that the cardiomyopathic state is associated with a greater alpha 1-receptor-mediated rise in cytosolic calcium, we studied the effect of phenylephrine (in the presence of propranolol) on time-averaged cytosolic calcium concentration ([Ca2+]i) in isolated cardiac myocytes from cardiomyopathic and age-matched control hamsters. Phenylephrine caused a greater increase both in time-averaged [Ca2+]i (an increase of 48 +/- 8% versus 12 +/- 3%, p less than 0.01) and in contractility (+181 +/- 22% versus +35 +/- 9%, p less than 0.01) in cardiomyopathic than in normal cardiac myocytes. Exposure to pertussis toxin (200 ng/ml for 3 hours) attenuated the alpha 1-adrenergic receptor-mediated increase in contractility and time-averaged [Ca2+]i in both cardiomyopathic and normal cells. The level of pertussis toxin-sensitive G protein, as determined by pertussis toxin-mediated [32P]ADP-ribosylation, was 1.6-fold higher in cardiomyopathic versus normal hamster hearts. The density of alpha 1-adrenergic receptors, as measured by the antagonist radioligand [3H]prazosin and the affinity of the receptor for agonist and antagonist were similar in myopathic and normal heart membranes. Thus, in cardiac myocytes from hamsters, the alpha 1-adrenergic receptor-mediated effects on [Ca2+]i and contractility appear to be mediated by a pertussis toxin-sensitive G protein or proteins. In myocytes from cardiomyopathic hamsters, these alpha 1-adrenergic effects were increased in magnitude, as was the level of pertussis toxin-sensitive G protein, but there was no measurable alteration in the density or ligand binding properties of alpha 1-adrenergic receptors.
Genomic Gigantism: DNA Loss Is Slow in Mountain Grasshoppers
Authors: Douda Bensasson, Dmitri A. Petrov, De-Xing Zhang, Daniel L. Hartl, Godfrey M. Hewitt
Journal: Molecular Biology and Evolution (2001)

Several studies have shown DNA loss to be inversely correlated with genome size in animals. These studies include a comparison between Drosophila and the cricket, Laupala, but there has been no assessment of DNA loss in insects with very large genomes. Podisma pedestris, the brown mountain grasshopper, has a genome over 100 times as large as that of Drosophila and 10 times as large as that of Laupala. We used 58 paralogous nuclear pseudogenes of mitochondrial origin to study the characteristics of insertion, deletion, and point substitution in P. pedestris and Italopodisma. In animals, these pseudogenes are "dead on arrival"; they are abundant in many different eukaryotes, and their mitochondrial origin simplifies the identification of point substitutions accumulated in nuclear pseudogene lineages. There appears to be a mononucleotide repeat within the 643-bp pseudogene sequence studied that acts as a strong hot spot for insertions or deletions (indels). Because the data for other insect species did not contain such an unusual region, hot spots were excluded from species comparisons. The rate of DNA loss relative to point substitution appears to be considerably and significantly lower in the grasshoppers studied than in Drosophila or Laupala. This suggests that the inverse correlation between genome size and the rate of DNA loss can be extended to comparisons between insects with large or gigantic genomes (i.e., Laupala and Podisma). The low rate of DNA loss implies that in grasshoppers, the accumulation of point mutations is a more potent force for obscuring ancient pseudogenes than their loss through indel accumulation, whereas the reverse is true for Drosophila. The main factor contributing to the difference in the rates of DNA loss estimated for grasshoppers, crickets, and Drosophila appears to be deletion size. Large deletions are relatively rare in Podisma and Italopodisma.
Constitutive and Inducible Expression of <i>Cyp1a1</i> and <i>Cyp1b1</i> in Vascular Smooth Muscle Cells
Authors: J. Kevin Kerzee, Kenneth S. Ramos
Journal: Circulation Research (2001)

Abstract— Ahr is a ligand-activated bHLH/PAS transcription factor involved in cytochrome P450 (CYP) gene regulation and murine susceptibility to atherogenic stimuli. The present studies were conducted to examine constitutive and inducible expression of Cyp1a1 and Cyp1b1 in vascular smooth muscle cells (VSMCs) from Ahr +/+ and Ahr −/− mice. Cyp1a1 mRNA was not expressed constitutively in VSMCs irrespective of Ahr phenotype. Although Cyp1a1 was inducible in Ahr +/+ by 3 μmol/L benzo(a)pyrene, a known hydrocarbon inducer, the protein was uninducible. In contrast, Cyp1b1 mRNA and protein were expressed under constitutive and inducible conditions irrespective of Ahr phenotype or growth status. CYP-encoded aryl hydrocarbon hydroxylase activity was higher in Ahr −/− VSMCs under constitutive conditions and induced by benzo(a)pyrene in Ahr +/+ and Ahr −/− VSMCs. CYP expression was influenced by mitogenic status, because randomly cycling cells consistently exhibited higher levels than growth-arrested counterparts. Actinomycin D (2 μg/mL) or cycloheximide (10 μmol/L) did not inhibit constitutive or hydrocarbon-inducible aryl hydrocarbon hydroxylase activity in VSMCs. These data indicate that in murine VSMCs, expression of Cyp1al and Cyp1b1 is differentially influenced by Ahr phenotype and mitogenic status, with patterns that may dictate inherent susceptibility to atherogenic stimuli.
Internalization of Monomeric Lipopolysaccharide Occurs after Transfer Out of Cell Surface Cd14
Authors: Thierry Vasselon, Eric Hailman, Rolf Thieringer, Patricia A. Detmers
Journal: The Journal of Experimental Medicine (1999)

Lipopolysaccharide (LPS) fluorescently labeled with boron dipyrromethane (BODIPY) first binds to the plasma membrane of CD14-expressing cells and is subsequently internalized. Intracellular LPS appears in small vesicles near the cell surface and later in larger, punctate structures identified as the Golgi apparatus. To determine if membrane (m)CD14 directs the movement of LPS to the Golgi apparatus, an mCD14 chimera containing enhanced green fluorescent protein (mCD14-EGFP) was used to follow trafficking of mCD14 and BODIPY-LPS in stable transfectants. The chimera was expressed strongly on the cell surface and also in a Golgi complex-like structure. mCD14-EGFP was functional in mediating binding of and responses to LPS. BODIPY-LPS presented to the transfectants as complexes with soluble CD14 first colocalized with mCD14-EGFP on the cell surface. However, within 5-10 min, the BODIPY-LPS distributed to intracellular vesicles that did not contain mCD14-EGFP, indicating that mCD14 did not accompany LPS during endocytic movement. These results suggest that monomeric LPS is transferred out of mCD14 at the plasma membrane and traffics within the cell independently of mCD14. In contrast, aggregates of LPS were internalized in association with mCD14, suggesting that LPS clearance occurs via a pathway distinct from that which leads to signaling via monomeric LPS.
Single Copies of Mutant <i>KRAS</i> and Mutant <i>PIK3CA</i> Cooperate in Immortalized Human Epithelial Cells to Induce Tumor Formation
Authors: Grace M. Wang, Hong Yuen Wong, Hiroyuki Konishi, Brian G. Blair, Abde M. Abukhdeir, John P. Gustin, D. Marc Rosen, Samuel Ray Denmeade, Zeshaan Rasheed, William Matsui, Joseph P. Garay, Morassa Mohseni, Michaela J. Higgins, Justin Cidado, Danijela Jelovac, Sarah Croessmann, Rory L. Cochran, Sivasundaram Karnan, Yuko Konishi, Akinobu Ota, Yoshitaka Hosokawa, Pedram Argani, Josh Lauring, Ben Ho Park
Journal: Cancer Research (2013)

Abstract The selective pressures leading to cancers with mutations in both KRAS and PIK3CA are unclear. Here, we show that somatic cell knockin of both KRAS G12V and oncogenic PIK3CA mutations in human breast epithelial cells results in cooperative activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in vitro, and leads to tumor formation in immunocompromised mice. Xenografts from double-knockin cells retain single copies of mutant KRAS and PIK3CA, suggesting that tumor formation does not require increased copy number of either oncogene, and these results were also observed in human colorectal cancer specimens. Mechanistically, the cooperativity between mutant KRAS and PIK3CA is mediated in part by Ras/p110α binding, as inactivating point mutations within the Ras-binding domain of PIK3CA significantly abates pathway signaling. In addition, Pdk1 activation of the downstream effector p90RSK is also increased by the combined presence of mutant KRAS and PIK3CA. These results provide new insights into mutant KRAS function and its role in carcinogenesis. Cancer Res; 73(11); 3248–61. ©2013 AACR.
Simple method of diagnostic screening for amyloidosis.
Authors: B Stenkvist, P Westermark, L Wibell
Journal: Annals of the Rheumatic Diseases (1974)

Thediagnosis ofamyloid disease usually rests on attempts toobtain adequate specimens forthestudy ofhistological sections fromtherectal mucosa or internal organs.Suchprocedures are notsuitable forthescreening oflarge groupsofpatients. Fineneedle biopsy ofthesubcutaneous fat(Westermark andStenkvist, 1971) would, however, besimple and safe enough for useinclinical practice orinsurveysof patient populations. A pilot study was therefore performed ina groupofsubjects liable toinclude a fewcases ofhitherto undetected secondary amyloidosis.