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Biochemical Pharmacology

Anna Zimdahl Kahlin, Sara Helander, Karin Skoglund, Peter Söderkvist, Lars-Göran Mårtensson, Malin Lindqvist Appell
Thiopurines are widely used in the treatment of leukemia and inflammatory bowel diseases. Thiopurine metabolism varies among individuals because of differences in the polymorphic enzyme thiopurine methyltransferase (TPMT, EC, and to avoid severe adverse reactions caused by incorrect dosing it is recommended that the patient's TPMT status be determined before the start of thiopurine treatment. This study describes the concordance between genotyping for common TPMT alleles and phenotyping in a Swedish cohort of 12,663 patients sampled before or during thiopurine treatment...
April 18, 2019: Biochemical Pharmacology
Iman Alqarni, Yieldez A Bassiouni, Amira M Badr, Rehab A Ali
Renin-angiotensin-aldosterone system (RAS) has been implicated in non-alcoholic fatty liver disease (NAFLD); the most common cause of chronic liver diseases. There is accumulating evidence that altered TLR4 and Sphingosine kinase 1(SphK1)/sphingosine1phosphate (S1P) signaling pathways are key players in the pathogenesis of NAFLD. Cross talk of the sphingosine signaling pathway, toll-4 (TLR4) receptors ,and angiotensin II was reported in various tissues. Therefore, the aim of this study was to define the contribution of these two pathways to the hepatoprotective effects of telmisartan and/or chlorogenic acid (CGA) in NAFLD...
April 17, 2019: Biochemical Pharmacology
Taizhen Liang, Xuanxuan Zhang, Fangyuan Lai, Jian Lin, Chenliang Zhou, Xinfeng Xu, Xinghua Tan, Shuwen Liu, Lin Li
The persistence of latent human immunodeficiency virus type 1 (HIV-1) reservoirs remains a major hurdle for HIV-1 eradication. The "shock and kill" strategy relies on the drug-mediated reversion of HIV-1 latency and the subsequent death of HIV-producing cells. Unfortunately, none of the agents currently in use possess a sufficient potency to reactivate latent virus or eliminate the latent HIV-1 reservoir in vivo. Here, we demonstrated that a promising specific bromodomain and extraterminal domain inhibitor, CPI-203, could potently reactivate latent HIV-1 in different latently infected cell lines with minimal cytotoxicity by activating the positive transcription elongation factor b signaling pathway...
April 13, 2019: Biochemical Pharmacology
You-Cheng Hseu, Yi-Geng Ho, Dony Chacko Mathew, Hung-Rong Yen, Xuan-Zao Chen, Hsin-Ling Yang
Coenzyme CoQ10 (CoQ10), a ubiquinone compound, has been reported to inhibit tyrosinase activity and melanin production in melanoma B16F10 cells. However, the molecular mechanism underlying this inhibitory effect is poorly understood. In this paper we aimed to investigate the molecular mechanisms involved in the anti-melanogenic activity of CoQ10 (1-2 μM) in UVA (5 J/cm2 )-irradiated keratinocyte HaCaT cells and α-MSH stimulated B16-F10 cells. It was observed that CoQ10 suppressed p53/POMC, α-MSH production as well as inhibited ROS generation in UVA-irradiated keratinocyte HaCaT cells...
April 13, 2019: Biochemical Pharmacology
Harika Sabbineni, Arti Verma, Sandeep Artham, Daniel Anderson, Oge Amaka, Fang Liu, Subhadra P Narayanan, Payaningal R Somanath
Endothelial to mesenchymal transition (EndMT), where endothelial cells acquire mesenchymal characteristics has been implicated in several cardiopulmonary, vascular and fibrotic diseases. The most commonly studied molecular mechanisms involved in EndMT include TGFβ, Notch, interleukin, and interferon-γ signaling. As of today, the contributions of Akt1, an important mediator of TGFβ signaling and a key regulator of endothelial barrier function to EndMT remains unclear. By using the ShRNA based gene silencing approach and endothelial-specific inducible Akt1 knockdown (ECKOAkt1 ) mice, we studied the role of Akt1 in EndMT in vitro and pathological vascular remodeling in vivo...
April 13, 2019: Biochemical Pharmacology
Takao Hirai, Yuhei Mitani, Karen Kurumisawa, Kohei Nomura, Wei Wang, Ken-Ichi Nakashima, Makoto Inoue
Fibroblast growth factor 21 (FGF21), a member of the FGF subfamily that acts through the FGF receptor 1 with the co-receptor β-Klotho, functions as an important metabolic regulator of peripheral glucose tolerance and lipid homeostasis in an endocrine or autocrine and/or paracrine manner. Previous studies showed that FGF21 ameliorated and prevented the development of metabolic disorders, such as obesity and diabetes mellitus. In the present study, we demonstrated that berberine, a naturally occurring compound, stimulated FGF21 expression in brown adipose tissue (BAT)...
April 13, 2019: Biochemical Pharmacology
Chin-Hee Song, Nayoung Kim, Sun Min Lee, Ryoung Hee Nam, Soo In Choi, So Ra Kang, Eun Shin, Dong Ho Lee, Ha-Na Lee, Young-Joon Surh
Estrogen is known to have a protective effect in colorectal cancer (CRC) development. Previously, we reported the anti-inflammatory and antitumorigenic effects of 17β-estradiol (E2) in azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated male mice. The aim of this study was to investigate whether ovariectomy in a female AOM/DSS mouse model increases colorectal tumorigenesis and whether tumorigenesis is reduced by estrogen supplementation after ovariectomy. Clinical symptoms and histological severity of colitis and the levels of inflammatory mediators were evaluated in the colon of AOM/DSS-treated ovariectomized (OVX) mice...
April 11, 2019: Biochemical Pharmacology
Pedro Buc Calderon, Raphaël Beck, Christophe Glorieux
A crucial process in biology is the conversion of the genetic information into functional proteins that carry out the genetic program. However, a supplementary step is required to obtain functional proteins: the folding of the newly translated polypeptides into well-defined, three-dimensional conformations. Proteins chaperones are crucial for this final step in the readout of genetic information, which results in the formation of functional proteins. In this review, a special attention will be given to the strategies targeting hsp90 family members in order to increase cancer cell death...
April 11, 2019: Biochemical Pharmacology
Olivier Malaise, Dominique de Seny
No abstract text is available yet for this article.
April 11, 2019: Biochemical Pharmacology
Daniel Villalobos-García, Rolando Hernández-Muñoz
Liver slices from starved rats and incubated without other substrates oxidized ethanol at a rate of 4.1 µmols • h-1 • g-1 . Addition of 10 mmols • L-1 lactate increased this rate 2-fold. 4-methylpyrazole (4-MP), an alcohol dehydrogenase (ADH) inhibitor, drastically decreased the rate of ethanol oxidation, but did not inhibit the stimulation due to lactate. In the same context, liver acetaldehyde production, as the main by-product of ethanol oxidation, appeared to be much less inhibited by 4-MP in the presence of lactate...
April 11, 2019: Biochemical Pharmacology
Dino Luethi, Marius C Hoener, Stephan Krähenbühl, Matthias E Liechti, Urs Duthaler
In recent years, experimental research on lysergic acid diethylamide (LSD) in humans has gained new momentum. In humans, LSD is metabolized rapidly into several metabolites but knowledge of the involved metabolizing enzymes is limited. The aim of the current study was to identify the cytochrome P450 (CYP) isoforms involved in the metabolism of LSD to 6-norlysergic acid diethylamide (nor-LSD) and 2-oxo-3-hydroxy-LSD (O-H-LSD) in vitro, in order to evaluate potential effects of enzyme polymorphisms or prescription drugs on LSD pharmacokinetics...
April 11, 2019: Biochemical Pharmacology
Han Gyung Kim, Woo Seok Yang, Yo Han Hong, Dae-Hyuk Kweon, Jongsung Lee, Sunggyu Kim, Jae Youl Cho
This study presents BN82002 as an anti-inflammatory drug candidate. It was found that BN82002 inhibited the production of nitric oxide (NO) and prostaglandin E2 (PGE2 ) in RAW 264.7 cells and peritoneal macrophages that were activated by toll-like receptor (TLR) 4 ligand, lipopolysaccharide (LPS). BN82002 dose-dependently down-regulated mRNA levels of nitric oxide synthase, tumor necrosis factor-α, and cyclooxygenase-2. The nuclear translocation of nuclear factor (NF)-κB (p65 and p50) was also blocked by BN82002 in RAW265...
April 10, 2019: Biochemical Pharmacology
Mao-Xu Ge, Rong-Guang Shao, Hong-Wei He
The conversion of cholesterol to bile acids (BAs) contributes to the elimination of total cholesterol from the body. In addition, manipulating BA homeostasis by modulating cholesterol 7α-hydroxylase (CYP7A1) may affect the metabolic processing of cholesterol, exerting therapeutic effects on hypercholesterolemia and cardiovascular diseases. Multiple mechanisms (such as various nuclear receptors and regulatory factors) are involved in CYP7A1 modulation. Recently, microRNAs, protein degradation pathways, and the gut microbiota have been identified to participate in these sophisticated networks...
April 9, 2019: Biochemical Pharmacology
Ioanna Petta, Isabelle Peene, Dirk Elewaut, Lars Vereecke, Karolien De Bosscher
Glucocorticoids (GCs) constitute a first line treatment for many autoimmune and inflammatory diseases. Due to their potent anti-inflammatory and immunosuppressive actions, GCs are added frequently to disease modifying antirheumatic drugs (DMARDs) in various arthritic diseases, such as rheumatoid arthritis. However, their prolonged administration or administration at high doses is associated with adverse effects that may be (quality of) life-threatening, including osteoporosis, metabolic, gastrointestinal and cardiovascular side effects...
April 9, 2019: Biochemical Pharmacology
Brice Korkmaz, Adam Lesner, Magdalena Wysocka, Artur Gieldon, Maria Håkansson, Francis Gauthier, Derek T Logan, Dieter Jenne, Conni Lauritzen, John Pedersen
Cathepsin C (CatC) is a dipeptidyl-exopeptidase which activates neutrophil serine protease precursors (elastase, proteinase 3, cathepsin G and NSP4) by removing their N-terminal propeptide in bone marrow cells at the promyelocytic stage of neutrophil differentiation. The resulting active proteases are implicated in chronic inflammatory and autoimmune diseases. Hence, inhibition of CatC represents a therapeutic strategy to suppress excessive protease activities in various neutrophil mediated diseases. We designed and synthesized a series of dipeptidyl cyclopropyl nitrile compounds as putative CatC inhibitors...
April 9, 2019: Biochemical Pharmacology
Elise R Orellana, Mihai Covasa, Andras Hajnal
Currently, the only available effective treatment option for obesity and its comorbidities is weight loss surgery (WLS). Long-term maintenance of weight loss after surgery cannot be explained by caloric restriction or malabsorption alone and has been attributed to unexplained changes in eating behavior. Whether these behavioral changes are related to altered taste or reward functions, or both, are subject to debate. In contrast to reduced food cravings and food addiction following WLS, recent clinical studies have revealed that bariatric surgery patients are prone to an increased risk for substance use disorder (SUD), especially alcohol use disorder (AUD)...
April 4, 2019: Biochemical Pharmacology
Elisabet Vila, Montse Solé, Núria Masip, Lídia Puertas-Umbert, Sergi Amaro, Ana Paula Dantas, Mercedes Unzeta, Pilar D'Ocon, Anna Maria Planas, Ángel Chamorro, Francesc Jiménez-Altayó
Uric acid (UA) is a promising protective treatment in ischaemic stroke, but the precise molecular targets underlying its in vivo beneficial actions remain unclear. High concentrations of UA inhibit angiogenesis of cultured endothelial cells via Krüppel-like factor 2 (KLF)-induced downregulation of vascular endothelial growth factor (VEGF), a pro-angiogenic mediator that is able to increase blood-brain barrier (BBB) permeability in acute stroke. Here, we investigated whether UA treatment after ischaemic stroke protects brain endothelial cell functions and modulates the KLF2-VEGF-A axis...
April 4, 2019: Biochemical Pharmacology
Teresa Di Desidero, Paola Orlandi, Anna Fioravanti, Greta Alì, Chiara Cremolini, Fotios Loupakis, Daniela Gentile, Marta Banchi, Federico Cucchiara, Carlotta Antoniotti, Gianluca Masi, Gabriella Fontanini, Alfredo Falcone, Guido Bocci
The aim of the study was to evaluate the effects and the related pharmacological mechanisms of switched schedules of antiangiogenic and chemotherapeutic drugs beyond progression after a first line treatment in a colorectal cancer preclinical model. In vivo studies were performed in nude mice subcutaneously transplanted with colon cancer cells. The treatments included drug combinations with a switch between chemotherapeutic (i.e., irinotecan and 5-fluoruracil) and/or antiangiogenic drugs (i.e., anti-VEGF antibodies and sunitinib) at the time of tumor progression...
April 3, 2019: Biochemical Pharmacology
Andres J P Klein-Szanto, Daniel Bassi
Hypercholesterolemia represents a leading cause in the development of atherosclerotic plaques, increasing the risk for ACVS. It actually counts as a major cause of cardiovascular disease etiopathogenesis. The causes of hypercholesterolemia are multifactorial, spanning from genetic constitution, age, sex, to sedentary lifestyle and diets rich in sugars and lipids. Although dietary restriction in saturated fats, increased exercise, and other modification in lifestyle represent a first-line approach to treat very initial stages in hypercholesterolemia, most patients will require the addition of pharmacological agents...
April 3, 2019: Biochemical Pharmacology
Christian Henninger, Stephanie Pohlmann, Verena Ziegler, Jan Ohlig, Joachim Schmitt, Gerhard Fritz
Cardiotoxicity is the dose limiting adverse effect of anthracycline-based anticancer therapy. Inhibitor studies point to Rac1 as therapeutic target to prevent anthracycline-induced cardiotoxicity. Yet, supporting genetic evidence is still missing and the pathophysiological relevance of different cardiac cell types is unclear. Here, we employed a tamoxifen-inducible cardiomyocyte-specific rac1 knock-out mouse model (Rac1flox/flox/MHC-MerCreMer ) to investigate the impact of Rac1 expression in cardiomyocytes on cardiac injury following doxorubicin treatment...
March 29, 2019: Biochemical Pharmacology
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