tbuckley/cabot-search huggingface dataset:
The gut-brain-liver axis: A new option to treat obesity and diabetes?
Authors: Naiara Beraza
Journal: Hepatology (2008)

Wang PY, Caspi L, Lam CK, Chari M, Li X, Light PE, et al. Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature 2008;452:1012–1016. www.nature.com (Reprinted with permission.) Abstract Energy and glucose homeostasis are regulated by food intake and liver glucose production, respectively. The upper intestine has a critical role in nutrient digestion and absorption. However, studies indicate that upper intestinal lipids inhibit food intake as well in rodents and humans by the activation of an intestine–brain axis. In parallel, a brain–liver axis has recently been proposed to detect blood lipids to inhibit glucose production in rodents. Thus, we tested the hypothesis that upper intestinal lipids activate an intestine–brain–liver neural axis to regulate glucose homeostasis. Here we demonstrate that direct administration of lipids into the upper intestine increased upper intestinal long-chain fatty acyl-coenzyme A (LCFA-CoA) levels and suppressed glucose production. Co-infusion of the acyl-CoA synthase inhibitor triacsin C or the anaesthetic tetracaine with duodenal lipids abolished the inhibition of glucose production, indicating that upper intestinal LCFA-CoAs regulate glucose production in the preabsorptive state. Subdiaphragmatic vagotomy or gut vagal deafferentation interrupts the neural connection between the gut and the brain, and blocks the ability of upper intestinal lipids to inhibit glucose production. Direct administration of the N -methyl-d-aspartate ion channel blocker MK-801 into the fourth ventricle or the nucleus of the solitary tract where gut sensory fibres terminate abolished the upper-intestinal-lipid-induced inhibition of glucose production. Finally, hepatic vagotomy negated the inhibitory effects of upper intestinal lipids on glucose production. These findings indicate that upper intestinal lipids activate an intestine–brain–liver neural axis to inhibit glucose production, and thereby reveal a previously unappreciated pathway that regulates glucose homeostasis.
Thyrotropin-releasing hormone in the dorsal vagal complex stimulates hepatic blood flow in rats
Authors: Masashi Yoneda, Takashi Hashimoto, Kimihide Nakamura, Keisuke Tamori, Shiro Yokohama, Toru Kono, Hajime Watanobe, Akira Terano
Journal: Hepatology (2003)

Central administration of thyrotropin-releasing hormone (TRH) enhances hepatic blood flow in animal models. TRH nerve fibers and receptors are localized in the dorsal vagal complex (DVC), and retrograde tracing techniques have shown that hepatic vagal nerves arise mainly from the left DVC. However, nothing is known about the central sites of action for TRH to elicit the stimulation of hepatic blood flow. The effect of microinjection of a TRH analogue into the DVC on hepatic blood flow was investigated in urethane-anesthetized rats. After measuring basal flow, a stable TRH analogue (RX-77368) was microinjected into the DVC and hepatic blood flow response was observed for 120 minutes by laser Doppler flowmetry. Either left or right cervical vagotomy or hepatic branch vagotomy was performed 2 hours before the peptide. Microinjection of RX-77368 (0.5-5 ng) into the left DVC dose-dependently increased hepatic blood flow. The stimulation of hepatic blood flow by RX-77368 microinjection into the left DVC was eliminated by left cervical and hepatic branch vagotomy but not by right cervical vagotomy. By contrast, microinjection of RX-77368 into the right DVC did not significantly alter hepatic blood flow. These results suggest that TRH acts in the left DVC to stimulate hepatic blood flow through the left cervical and hepatic vagus, indicating that neuropeptides may act in the specific brain nuclei to regulate hepatic function.
GENDER-RELATED DIFFERENCES IN SHORT-TERM REFERRAL RATES TO CATHETERIZATION AFTER NON-INVASIVE CARDIAC IMAGING IN PATIENTS WITHOUT KNOWN CAD: RESULTS FROM THE STUDY OF MYOCARDIAL PERFUSION AND CORONARY ANATOMY IMAGING ROLES IN CAD (SPARC)
Authors: Marcelo F. Di Carli, James R. Johnson, Leslee J. Shaw, Mark A. Hlatky, Rob Beanlands, Benjamin Chow, Elizabeth Branscomb, Michael L. Ridner, John Lesser, Panithaya Chareonthaitawee, Subha Raman, Szilard Voros, Daniel S. Berman, Barbara H. Johnson, Mariya Gaber, Julie Williams, Rory Hachamovitch
Journal: Journal of the American College of Cardiology (2010)
Genome‐wide molecular profiles of HCV‐induced dysplasia and hepatocellular carcinoma†
Authors: Elisa Wurmbach, Ying‐bei Chen, Greg Khitrov, Weijia Zhang, Sasan Roayaie, Myron Schwartz, Isabel Fiel, Swan Thung, Vincenzo Mazzaferro, Jordi Bruix, Erwin Bottinger, Scott Friedman, Samuel Waxman, Josep M. Llovet
Journal: Hepatology (2007)

Although HCC is the third-leading cause of cancer-related deaths worldwide, there is only an elemental understanding of its molecular pathogenesis. In western countries, HCV infection is the main etiology underlying this cancer's accelerating incidence. To characterize the molecular events of the hepatocarcinogenic process, and to identify new biomarkers for early HCC, the gene expression profiles of 75 tissue samples were analyzed representing the stepwise carcinogenic process from preneoplastic lesions (cirrhosis and dysplasia) to HCC, including 4 neoplastic stages (very early HCC to metastatic tumors) from patients with HCV infection. We identified gene signatures that accurately reflect the pathological progression of disease at each stage. Eight genes distinguish between control and cirrhosis, 24 between cirrhosis and dysplasia, 93 between dysplasia and early HCC, and 9 between early and advanced HCC. Using quantitative real-time reverse-transcription PCR, we validated several novel molecular tissue markers for early HCC diagnosis, specifically induction of abnormal spindle-like, microcephaly-associated protein, hyaluronan-mediated motility receptor, primase 1, erythropoietin, and neuregulin 1. In addition, pathway analysis revealed dysregulation of the Notch and Toll-like receptor pathways in cirrhosis, followed by deregulation of several components of the Jak/STAT pathway in early carcinogenesis, then upregulation of genes involved in DNA replication and repair and cell cycle in late cancerous stages.These findings provide a comprehensive molecular portrait of genomic changes in progressive HCV-related HCC.
Abstract 1266: Oncogenic stress induced by Bcr-Abl over-activation leads to cell death mediated by a massively enhanced aerobic glycolysis
Authors: Michael A. Dengler, Annette Staiger, Matthias Gutekunst, Ute Hofmann, Walter E. Aulitzky, Heiko van der Kuip
Journal: Cancer Research (2011)

Abstract It is well established that normal cells respond to over-activation of oncogenes by induction of genetically encoded programs such as apoptosis or senescence. Therefore, too much activity of a growth promoting oncogene seems to disturb the cellular homeostasis, a phenomenon which is known as oncogenic stress. To investigate the molecular mechanisms behind this phenomenon we used cell clones overexpressing the oncogene Bcr-Abl and cultivated them continuously in the presence of the Bcr-Abl inhibitor Imatinib. Removal of Imatinib led to a robust induction of Bcr-Abl autophosphorylation and concomitant overstimulation of the Bcr-Abl downstream pathways PI3K/AKT-, RAS/MAPK-, and JAK/STAT. Importantly, this acute over-activation of Bcr-Abl resulted in a delayed non-apoptotic cell death starting not before 48 hours after Imatinib withdrawal. This cell death was preceded by a massively enhanced aerobic glycolysis and glutaminolysis (Warburg effect) and amino acid metabolism leading to an elevated cellular ATP and protein content. During the first 30 hours after Imatinib deprivation the enhanced metabolism had no effect on proliferation but resulted in cellular swelling, cytoplasmic vacuolization, and massive induction of ER stress markers indicating that Bcr-Abl over-activation induces ER stress response. However, cell death upon Bcr-Abl over-activation was not dependent on this severe ER stress since siRNA mediated knockdown of CHOP and BIM had no effect on cell viability. In contrast, both inhibition of aerobic glycolysis by 2-deoxy-glucose as well as reduction of glutamine concentration in the medium were sufficient to block Imatinib deprivation induced cell death. These data demonstrate that the Bcr-Abl over-activation mediated enhanced metabolism is responsible for oncogenic stress induced cell death. Interestingly, screening of 1200 marketed small molecule inhibitors (Prestwick chemical library) for their potential effects on oncogenic stress response uncovered selectively steroids to effectively antagonize both ER stress and cell death upon Bcr-Abl over-activation. These agents were also able to normalize cellular metabolism upon Imatinib withdrawal, supporting the view that “overshooting” metabolism upon oncogenic over-activation leads to cell death. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1266. doi:10.1158/1538-7445.AM2011-1266
THE EFFECT OF PODOPHYLLOTOXIN ON TISSUE METABOLISM AND ENZYME SYSTEMS
Authors: Zelma Baker Miller, Clarke Davison, Paul K. Smith
Journal: The Journal of Experimental Medicine (1949)

Podophyllotoxin, 10(-3) (M), inhibits the respiration in vitro of rat lymph nodes, thymus, kidney, tumor, spleen, liver, brain, testis, and chicken embryo. Lymph node and spleen respiration are most sensitive, and the degree of inhibition increases with time. The injection of podophyllotoxin into tumor-bearing mice (20 mg. per kg.) causes a dramatic reduction in the respiration of tumor slices. Within 6 hours, the respiration approaches zero. Inhibition is evident 2 hours after injection of the drug. Spleen respiration is reduced 50 per cent within 6 hours. Kidney and liver respirations remain within normal limits. Marked reductions in the respiration of spleen, lymph nodes, and thymus glands of normal rats are produced by the injection of 15 mg. per kg. Thymus gland is the most sensitive of these three tissues, and its respiration is reduced 66 per cent 24 hours after injection of the drug. The injection of 0.8 microgram podophyllotoxin into the yolk sac of chicken eggs bearing 5 day embryos has no effect on the respiration of the embryo within 8 hours, although this is a sufficiently toxic dose to kill 80 per cent of the embryos (within 24 hours). Kidney respiration in the presence of acetate, glucose, alanine, and glutamate is inhibited to approximately the same degree as in the absence of added substrate. Succinate and pyruvate oxidation by rat kidney slices appear to be less sensitive. Oxidation of acetate and butyrate by rabbit kidney homogenate is more sensitive to podophyllotoxin than oxidation by rabbit kidney homogenate without added substrate. Glucose oxidation by this preparation is not inhibited by 10(-3)M podophyllotoxin. The anaerobic glycolysis of chicken embryo, rat brain, and rat testis is stimulated by 10(-5) and 10(-6)M podophyllotoxin, and is inhibited by 10(-3)M. The following enzymes are not inhibited by 10(-3)M podophyllotoxin: succinoxidase from pigeon breast muscle, choline, xanthine and tyrosine oxidase from rat liver homogenate, and leucine oxidase from Proteus vulgaris; alkaline and acid phosphatase from dog serum; adenosine triphosphatase from rat liver; choline esterase from rat brain homogenate; ribonucleodepolymerase from spleen mince and thymonucleodepolymerase from dog serum. High concentrations of podophyllotoxin do not influence the viscosity and degree of polymerization of thymonucleic acid.
Abstract 3375: The epithelial to endotheliod transition (EET): A cellular modulation that promotes the head and neck squamous cell carcinoma tumorigenic phenotype
Authors: Meng Tong, Lingli He, Byungdo Han, Andrew Holpuch, Ping Pei, Susan R. Mallery
Journal: Cancer Research (2011)

Abstract The presence of the EMT (epithelial-mesenchymal transition) and EndMT (endothelial-mesenchymal transition) demonstrates the extent of phenotypic plasticity in cancers. Previous findings in head and neck squamous cell carcinoma (HNSCC) cells, i.e., VEGF's autocrine-paracrine function and their responsiveness to endostatin, imply that HNSCC cells share some functional characteristics with endothelial cells and suggest the potential for an “epithelial-to-endotheliod transition (EET)”. Such a transition would facilitate HNSCC tumorigenesis by augmenting release of proangiogenic factors and facilitating tumor cell migration and invasion. Consequently, these studies elucidated whether or not an EET occurs in HNSCC cells and tumors, and evaluated cellular parameters to uniquely characterize this epithelial-endotheliod transition. Our results demonstrate that cultured HNSCC cells express a variety of endothelial-specific markers, and assumption of the endotheliod phenotype has functional consequences including uptake of acetylated low density lipoprotein and enhanced invasion and migration. Selective HNSCC cells were also highly responsive to transforming growth factor-β1 and express its auxiliary receptor, endoglin. Furthermore, the EET is not restricted to cultured HNSCC cells per se as tumor cells in resected human HNSCC tumors and proliferating epithelia at the margins of ulcers demonstrate a similar phenotype. These data suggest that, similar to EMT, the EET enhances epithelial cell migration. Also, the regulation of this transition-transient (wound healing) versus sustained (invasive cancers)-impacts clinical outcome. Finally, recognition of the EET as a distinct entity provides impetus for future clinical trials to concurrently assess the antitumorigenic as well as the angiostatic properties of therapeutic agents formally regarded as exclusively angiostatic in scope. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3375. doi:10.1158/1538-7445.AM2011-3375
In vitro lymphocyte proliferation in the diagnosis of allergy to phenoxymethylpenicillin
Authors: K. Cederbrant, V. Steiskal, P. Broman, L. Lindkvist, K. Sundell
Journal: Allergy (1998)

Background The aim of this study was to investigate in vitro lymphocyte proliferation in the diagnosis of allergy to phenoxymethylpenicillin (PcV), comparing chemically reactive PcV, added to cell cultures in unconjugated form, to a PcV‐PLL (poly‐L‐lysine) conjugate as antigens. Side‐chain specificity of lymphoproliferative responses was investigated with reactive benzylf)enicillin (PcG) and bacampicillin. Methods Seventeen patients with a history of hypersensitivity reactions in connection with PcV treatment were studied by means of the lymphocyte transformation test (LTT), the radioallergosorbent test (RAST). skin tests (prick and intracutaneous), and oral challenge with PcV. LTT was also performed in 20 control subjects exposed to PcV therapeutically, and in eight subjects with occupational exposure to this penicillin. Results Nine patients had a positive in vivo test to PcV (five by oral challenge, three by intracutaneous test, and one by both tests), and six were challenge‐negative. When reactive PcV was used as antigen in LTT, positive LTT responses were observed in five of the nine patients with a positive in vivo test, and two of them were also side‐chain specific. Positive LTT responses with reactive PcV also correlated with a positive RAST infiveof seven subjects. None of the six patients with a negative challenge test, and only one of the 28 controls showed a positive LTT result with reactive PcV. Thus, the specificity of LTT with reactive PcV was 96%. In contrast, when PLL‐conjugated PcV served as antigen, four challenge‐negative subjects and 11 controls were LTT‐positive. Conclusions The results of this study indicate that LTT with chemically reactive PcV could be useful as an in vitro complement in the diagnosis of PcV allergy and as a tool to reveal the side‐chain specificity of peripheral blood lymphocytes. A positive LTT to PLL‐conjugated PcV may be an indicator of immunization, but not necessarily allergy, to the penicilloyl structure.
Bone histomorphometry before and after long-term treatment with cinacalcet in dialysis patients with secondary hyperparathyroidism
Authors: Geert J. Behets, Goce Spasovski, Lulu R. Sterling, William G. Goodman, David M. Spiegel, Marc E. De Broe, Patrick C. D'Haese
Journal: Kidney International (2014)

The multicenter, single-arm BONAFIDE study characterized the skeletal response to cinacalcet in adult dialysis patients with plasma parathyroid hormone (PTH) levels of 300 pg/ml or more, serum calcium of 8.4 mg/dl or more, bone-specific alkaline phosphatase over 20.9 ng/ml and biopsy-proven high-turnover bone disease. Of 110 enrolled patients, 77 underwent a second bone biopsy with quantitative histomorphometry after 6-12 months of cinacalcet treatment. The median PTH decreased from 985 pg/ml at baseline to 480 pg/ml at the end of study (weeks 44-52). Bone formation rate/tissue area decreased from 728 to 336 μm(2)/mm(2)/day, osteoblast perimeter/osteoid perimeter decreased from 17.4 to 13.9%, and eroded perimeter/bone perimeter decreased from 12.7 to 8.3%. The number of patients with normal bone histology increased from none at baseline to 20 at 12 months. Two patients had adynamic bone at the end of study with a PTH under 150 pg/ml, and one patient with overt hypophosphatemia at baseline that reoccurred during follow-up developed osteomalacia. Thus, long-term treatment with cinacalcet substantially reduced PTH, diminished the elevated bone formation rate/tissue area, lowered several biochemical markers of high-turnover bone disease toward normal, and generally improved bone histology. Twenty patients had normal bone histology at follow-up, whereas most had mild hyperparathyroidism or mixed uremic osteodystrophy.
Branch Vein Occlusion
Authors: Daniel Finkelstein, John Clarkson, Kenneth Diddie, Argye Hillis, Allyn Kimball, David Orth, Clement Trempe, George Blankenship, Victor Curtin, Stuart L. Fine, Timothy Flood, Harry Flynn, MacKenzie Freeman, Donald Gass, Morton Goldberg, Wallace McMeel, Edward Norton, Richard Ober, Arnall Patz, Thomas Rice, Stephen Ryan, Charles Schepens, Ronald Smith, Mark T’so
Journal: Ophthalmology (1982)
A regiospecific monooxygenase with novel stereopreference is the major pathway for arachidonic acid oxygenation in isolated epidermal cells.
Authors: M J Holtzman, J Turk, A Pentland
Journal: Journal of Clinical Investigation (1989)

We investigated the enzymatic mechanisms responsible for AA oxygenation in homogenous cell suspensions obtained by trypsinization of epidermis from healthy subjects. Cell incubation with AA (0.3-150 microM) invariably resulted in the predominant generation of a compound identified as 12-hydroxyeicosatetraenoic acid (12-HETE) by HPLC and by both negative-ion chemical ionization and electron-impact mass spectrometry. Maximal amounts of 12-HETE were 126 +/- 21 pmol/10(6) cells (+/- SE), and concentration-response curves yielded half-maximal levels for 12-HETE similar to PGE2 at 2 microM AA. Two epoxyeicosatrienoic acids derived from AA were also identified. Stereochemical analysis by chiral-phase chromatography demonstrated that the epidermal cell 12-HETE was a mixture of the 12S- and 12R-hydroxy isomers in a molar ratio varying from 2:1 to 8:1 among subjects. Subcellular fractionation into 12,000 g pellet (containing mitochondria) and 100,000 g supernatant (cytosol) and pellet (microsome) demonstrated that greater than 99% of the 12-HETE was generated by enzymatic activity distributed equally in the two pellets. Both mitochondrial and microsomal activities were increased upon addition of NADPH and were inhibited by carbon monoxide, but the molar ratio of 12S/12R-HETE was threefold greater in microsomal than in mitochondrial fractions. The results demonstrate that human epidermis contains active membrane-bound monooxygenase(s) which preferentially generates 12-HETE from AA, exhibits a 12S stereopreference of hydroxylation, and suggests the presence of distinct mitochondrial and microsomal enzyme systems in epidermal cells.
Geographic Differences in the Risk of Insulin-dependent Diabetes Mellitus: The Importance of Registries
Authors: Ronald E LaPorte, Naoko Tajima, Hans K Åkerblom, Nina Berlin, James Brosseau, Morten Christy, Allan L Drash, Howard Fishbein, Anders Green, Richard Hamman, Maureen Harris, Hilary King, Zvi Laron, Andrew Neil
Journal: Diabetes Care (1985)

There are marked geographic differences in the incidence of insulin-dependent diabetes mellitus (IDDM); for example, children in countries such as Finland are over 35 times more likely to develop IDDM than children in Japan. An understanding of the reasons for the geographic differences is likely to be important for understanding and, hopefully, preventing IDDM. There are problems, however, because of the lack of registries with adequate standardization. The major needs for the future studies include (1) to clarify the definition of IDDM for epidemiologic study, (2) to establish a standardized approach for IDDM registries, (3) to use registries to evaluate viral, immunologic, and genetic differences in order to explain differential risks across populations, and (4) to encourage the development of new population-based registries worldwide.
Intrarenal Hemodynamics in Glycerol-Induced Myohemoglobinuric Acute Renal Failure in the Rat
Authors: G. Ayer, A. Grandchamp, T. Wyler, B. Truniger
Journal: Circulation Research (1971)

A modified 138 Xe washout technique was used to study changes in intrarenal hemodynamics during glycerol-induced acute renal failure in the rat. Within 10 minutes after glycerol injection, the flow fraction supplied to component 1 of the washout curve ("cortex A") decreases, reaching minimum values 24 hours afer glycerol (31% of control conditions). Seven days thereafter five of the rats, still uremic, showed cortical flow fractions less than 50% of control values. Nine others had recovered. Twenty-four hours after glycerol, renal blood flow was 27% and increased to 86% of control conditions in the recovered rats 7 days after glycerol. 85 Kr autoradiographs and silicone rubber casts of the renal vasculature demonstrated a severe cortical hypoperfusion at the height of oliguria that gradually disappeared in parallel with the functional recovery of the kidney. These observations, in good agreement with micropuncture data, suggest that oliguria and renal insufficiency in this experimental model are the result of a primary decrease in glomerular filtration rate due to an increased preglomerular resistance.
Nanofibrous scaffolds releasing a small molecule BDNF-mimetic for the re-direction of endogenous neuroblast migration in the brain
Authors: Deniece Fon, Kun Zhou, Francesca Ercole, Friederike Fehr, Silvia Marchesan, Myles R. Minter, Peter J. Crack, David I. Finkelstein, John S. Forsythe
Journal: Biomaterials (2014)
Claim of human reproductive cloning provokes calls for international ban
Authors: S. Mayor
Journal: BMJ (2004)

An international ban on reproductive cloning is urgently needed, say embryologists and organisations working in the field, after a claim last week that a fertilised egg produced by reproductive cloning had been implanted into a woman's uterus.

Panos Zavos, professor emeritus of reproductive physiology-andrology at the University of Kentucky, in the United States, claimed at a press conference held in London last week that he had implanted a cloned embryo into a woman's womb. He said that the embryo had been produced from the immature egg of an infertile 35 year old woman …