Interaction of Angiotensin with Exogenous and Neurally Released Norepinephrine on the Cat Nictitating Membrane in Vitro. PETER CERVONI AND ERNEST REIT 1 The Activity of Tyrosine Hydroxylase in Intact Adrenergic Neurons of the Mouse Vas Deferens. RICHARD A. BJUR AND NORMAN WEINER 9 Postnatal Elevation of Brain Tyrosine Hydroxylase Activity, without Concurrent Increases in Steady-State Catecholamine Levels, Resulting from dl-a-Methylparatyrosine Administrat ion during Embryonic Development. R. B. LYDIARD, L. H. FossoM AND S. B. SPARHER 27 Effect of Thioridazine, Clozapine and Other Antipsychotics on the Kinetic State of Tyrosine Hydroxylase and on the Turnover Rate of Dopamine in Striatum and Nucleus Accumbens. B. ZIvKovIc, A. GulDorrI. A. REVUELTA AND E. COSTA 37 Amphetamine: Evaluation of dand 1-Isomers as Releasing Agents and Uptake Inhibitors for 3H-Dopamine and 3H-Norepinephrine in Slices of Rat Neostriatum and Cerebral Cortex. RICHARD E. HEIKKILA, HERBERT ORLANSKY, CATHERINE MYTILINEOU AND GERALD COHEN 47 Application of Principles of Steady-State Kinetics to the Estimation of Brain Acetyicholine Turnover Rate: Effects of Oxotremorine and Physostigmine. M. TRABUCCHI. D. L. CHENEY, I. HANIN AND E. COSTA 57 Brain Acetyicholine and Choline following Acute and Chronic Morphine Treatment and during Withdrawal. HEMENDRA N. BHARGAVA AND E. LEONG WAY 65 Cannabinoids: Influence on Neurotransmitter Uptake in Rat Brain Synaptosomes. SHAILESH P. BANERJEE, SOLOMON H. SNYDER AND RAPHAEL MECHOULAM 74 The Transport of Gentamicin in the Choroid Plexus and Cerebrospinal Fluid. REYNOLD SPECTOR 82 Permeability of Selected Drugs and Chemicals across the Blood-Testis Barrier of the Rat. KATSUHIKO OKUMURA, INsu P. LEE AND ROBERT L. DIXON 89 The Absence of Renal Bicarbonate Reabsorption Maxima during Carbonic Anhydrase Inhibition. LAL C. GARG 96 Influence of Tetrahydrouridine on the Phosphorylation of l-$-o-Arabinofuranosylcytosine (ara-C) by Enzymes from Solid Tumors in Vitro. R. L. FURNER, L. B. MELLETT ANDT. C. HERREN 103 Pentobarbital Pharmacokinetics in the Normal and in the Hepatectomized Rat. FRIEDRICH-WILHELM OSSENBERG, MICHkLE PEIGNOUX, DENISE BOURDIAU AND JEAN-PIERRE BENHAMOU 111 Study of the Hepatic Metabolism of Primidone by Improved Methodology. JOHN ALVIN, EDWARD GOH AND MILTON T. BUSH 117 A Study of Absorption of Compounds from the Rat Biliary Tree by Retrograde Intrabiliary Injection (Ru). RICHARD E. PETERSON AND JAMES M. FUJIMOTO 126 The Relationship between Nitro Group Reduction and the Intestinal Microflora. LARRY A. WHEELER, FRANCES B. SODERBERG AND PETER GOLDMAN 135 Immunopharmacological Studies Using 5-Hydroxytryptamine Antibody. R. A. O’BRIEN, M. BOUBLIK AND S. SPECTOR 145 Mechanism of Action of Colchicine. I. Effects of Coichicine and Its Analogs on the Reversed Passive Arthus Reaction and the Carrageenan-Induced Hindpaw Edema in the Rat. YI-HAN C HANG 154 Mechanism of Action of Colchicine. II. Effects of Colchicine and Its Analogs on Phagocytosis and Chemotaxis in Vitro. YI-HAN C HANG 159 Effects of Sodium Acetylsalicylate on Body Temperature of Monkeys under Heat Exposure M. T. LIN ANDC.Y.CHAI 165 Effects of Mercury on Spermatogenesis Studied by Velocity of Sedimentation Cell Separation and Serial Mating. I. P. LEE AND R. L. DIXON 171 Intestinal Smooth Muscle Contraction and the Effects of Cadmium and A23187. C. R. TRIGC.LE, W. F. GRANT AND D. J. TRIGGLE 182

The journal of pharmacology and experimental therapeutics

Endogenous non-enzymatic antioxidants in the human body.

Nutrition, metabolism, and cardiovascular diseases : NMCD.

The upregulation of heme oxygenase-1 (HO-1) is one of the most important mechanisms of cell adaptation to stress. Indeed, the redox sensitive transcription factor Nrf2 is the pivotal regulator of HO-1 induction. Through the antioxidant, antiapoptotic, and antinflammatory properties of its metabolic products, HO-1 plays a key role in healthy cells in maintaining redox homeostasis and in preventing carcinogenesis. Nevertheless, several lines of evidence have highlighted the role of HO-1 in cancer progression and its expression correlates with tumor growth, aggressiveness, metastatic and angiogenetic potential, resistance to therapy, tumor escape, and poor prognosis, even though a tumor- and tissue-specific activity has been observed. In this review, we summarize the current literature regarding the pro-tumorigenic role of HO-1 dependent tumor progression as a promising target in anticancer strategy.

https://www.mdpi.com/2076-3921/6/2/29/pdf

HO-1 Induction in Cancer Progression: A Matter of Cell Adaptation.

Bilirubin is a component of the heme catabolic pathway that is essential for liver function and has been shown to reduce hepatic fat accumulation. High plasma bilirubin levels are reflective of liver disease due to an injurious effect on hepatocytes. In healthy liver, bilirubin is conjugated and excreted to the intestine and converted by microbes to urobilinoids, which are reduced to the predominant pigment in feces, stercobilin, or reabsorbed. The function of urobilinoids in the gut or their physiological relevance of reabsorption is not well understood. In this review, we discuss the relationship of hepatic bilirubin signaling to the intestinal microbiota and its regulation of the liver–gut axis, as well as its capacity to mediate these processes.

Bilirubin in the Liver-Gut Signaling Axis.

The biliverdin reductase (BVR) isozymes BVRA and BVRB are cell surface membrane receptors with pleiotropic functions. This review compares, for the first time, the structural and functional differences between the isozymes. They reduce biliverdin, a byproduct of heme catabolism, to bilirubin, display kinase activity, and BVRA, but not BVRB, can act as a transcription factor. The binding motifs present in the BVR isozymes allow a wide range of interactions with components of metabolically important signaling pathways such as the insulin receptor kinase cascades, protein kinases (PKs), and inflammatory mediators. In addition, serum bilirubin levels have been negatively associated with abdominal obesity and hypertriglyceridemia. We discuss the roles of the BVR isozymes in metabolism and their potential as therapeutic targets.

/pdf/biliverdin-reductase-isozymes-in-metabolism-19y3wp3mjo.pdf

Biliverdin Reductase Isozymes in Metabolism

Glucocorticoid hormones (GCs) are important regulators of lipid metabolism, promoting lipolysis with acute treatment but lipogenesis with chronic exposure. Conventional wisdom posits that these disparate outcomes are mediated by the classical glucocorticoid receptor GRα. There is insufficient knowledge of the GC receptors (GRα and GRβ) in metabolic conditions such as obesity and diabetes. We present acute models of GC exposure that induce lipolysis, such as exercise, as well as chronic-excess models that cause obesity and lipid accumulation in the liver, such as hepatic steatosis. Alternative mechanisms are then proposed for the lipogenic actions of GCs, including induction of GC resistance by the GRβ isoform, and promotion of lipogenesis by GC activation of the mineralocorticoid receptor (MR). Finally, the potential involvement of chaperone proteins in the regulation of adipogenesis is considered. This reevaluation may prove useful to future studies on the steroidal basis of adipogenesis and obesity.

/pdf/the-glucocorticoid-receptor-cause-of-or-cure-for-obesity-ykveiaixm5.pdf

The glucocorticoid receptor: cause of or cure for obesity?

Nutrient overload and genetic factors have led to a worldwide epidemic of obesity that is the underlying cause of diabetes, atherosclerosis, and cardiovascular disease. In this study, we used macrolide drugs such as FK506, rapamycin, and macrolide derived, timcodar (VX-853), to determine their effects on lipid accumulation during adipogenesis. Rapamycin and FK506 bind to FK506-binding proteins (FKBPs), such as FKBP12, which causes suppression of the immune system and inhibition of mTOR. Rapamycin has been previously reported to inhibit the adipogenic process and lipid accumulation. However, rapamycin treatment in rodents caused immune suppression and glucose resistance, even though the mice lost weight. Here we show that timcodar (1 μM), a non-FKBP12-binding drug, significantly () inhibited lipid accumulation during adipogenesis. A comparison of the same concentration of timcodar (1 μM) and rapamycin (1 μM) showed that both are inhibitors of lipid accumulation during adipogenesis. Importantly, timcodar potently () suppressed transcriptional regulators of adipogenesis, PPARγ and C/EBPα, resulting in the inhibition of genes involved in lipid accumulation. These studies set the stage for timcodar as a possible antiobesity therapy, which is rapidly emerging as a pandemic.

/pdf/timcodar-vx-853-is-a-non-fkbp12-binding-macrolide-derivative-4ko7jjpr5l.pdf

Timcodar (VX-853) Is a Non-FKBP12 Binding Macrolide Derivative That Inhibits PPARγ and Suppresses Adipogenesis

Numerous clinical and population studies have demonstrated that increased serum bilirubin levels protect against cardiovascular and metabolic diseases such as obesity and diabetes. Bilirubin is a potent antioxidant, and the beneficial actions of moderate increases in plasma bilirubin have been thought to be due to the antioxidant effects of this bile pigment. In the present study, we found that bilirubin has a new function as a ligand for PPARα. We show that bilirubin can bind directly to PPARα and increase transcriptional activity. When we compared biliverdin, the precursor to bilirubin, on PPARα transcriptional activation to known PPARα ligands, WY 14,643 and fenofibrate, it showed that fenofibrate and biliverdin have similar activation properties. Treatment of 3T3-L1 adipocytes with biliverdin suppressed lipid accumulation and upregulated PPARα target genes. We treated wild-type and PPARα KO mice on a high fat diet with fenofibrate or bilirubin for seven days and found that both signal through PPARα dependent mechanisms. Furthermore, the effect of bilirubin on lowering glucose and reducing body fat percentage was blunted in PPARα KO mice. These data demonstrate a new function for bilirubin as an agonist of PPARα, which mediates the protection from adiposity afforded by moderate increases in bilirubin.

/pdf/bilirubin-binding-to-ppara-inhibits-lipid-accumulation-37q5y1psjo.pdf

Bilirubin Binding to PPARα Inhibits Lipid Accumulation

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Biliverdin Reductase Isozymes in Metabolism

The glucocorticoid receptor: cause of or cure for obesity?

Timcodar (VX-853) Is a Non-FKBP12 Binding Macrolide Derivative That Inhibits PPARγ and Suppresses Adipogenesis

Bilirubin Binding to PPARα Inhibits Lipid Accumulation