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Biochemical Pharmacology

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https://www.readbyqxmd.com/read/29158149/the-role-of-hydrogen-sulfide-in-cyclic-nucleotide-signaling
#1
REVIEW
Xu Cao, Zhiyuan Wu, Siping Xiong, Lei Cao, Gautam Sethi, Jin-Song Bian
Hydrogen sulfide (H2S) is recognized as an endogenous gaseous transmitter alongside nitric oxide (NO) and carbon monoxide (CO). By integrating into multiple signaling pathways, H2S elicits biological functions in various mammalian systems. Among these pathways, cyclic nucleotide signaling has gradually gained attention in the past decade. Based on current evidence, it seems that H2S may differentially affect the activity of resting adenylyl cyclases (ACs) and activated ACs, therefore playing a dual role in the regulation of cyclic adenosine monophosphate (cAMP) mediated signaling...
November 17, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29155058/foxo-1-contributes-to-the-efficacy-of-the-combination-of-the-xpo1-inhibitor-selinexor-and-cisplatin-in-ovarian-carcinoma-preclinical-models
#2
Cristina Corno, Simone Stucchi, Michelandrea De Cesare, Nives Carenini, Serena Stamatakos, Emilio Ciusani, Lucia Minoli, Eugenio Scanziani, Christian Argueta, Yosef Landesman, Nadia Zaffaroni, Laura Gatti, Paola Perego
The XPO1/CRM1 inhibitor selinexor (KPT-330), is currently being evaluated in multiple clinical trials as an anticancer agent. XPO1 participates in the nuclear export of FoxO-1, which we previously found to be decreased in platinum-resistant ovarian carcinoma. The aim of this study was to determine whether enriching FoxO-1 nuclear localization using selinexor would increase ovarian cancer cell sensitivity to cisplatin. Selinexor, as a single agent, displayed a striking antiproliferative effect in different ovarian carcinoma cell lines...
November 16, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29155148/functional-properties-and-mechanism-of-action-of-pptq-an-allosteric-agonist-and-low-nanomolar-positive-allosteric-modulator-at-gabaa-receptors
#3
Nawid Madjroh, Emma Rie Olander, Christoffer Bundgaard, Pella Cecilia Söderhielm, Anders A Jensen
The former sedative-hypnotic and recreational drug methaqualone (Quaalude) is a moderately potent, non-selective positive allosteric modulator (PAM) at GABAA receptors (GABAARs) (Hammer et al., 2015). In the present study, we have identified a novel methaqualone analog, 2-phenyl-3-(p-tolyl)quinazolin-4(3H)-one (PPTQ), in a screening of 67 analogs at five αβ2γ2S GABAAR subtypes and delineated its functional properties and mechanism of action at wild-type and mutant GABAARs expressed in Xenopus oocytes by two-electrode voltage clamp electrophysiology...
November 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29155147/selective-and-membrane-permeable-small-molecule-inhibitors-of-nicotinamide-n-methyltransferase-reverse-high-fat-diet-induced-obesity-in-mice
#4
Harshini Neelakantan, Virginia Vance, Michael D Wetzel, Hua-Yu Leo Wang, Stanton F McHardy, Celeste C Finnerty, Jonathan D Hommel, Stanley J Watowich
There is a critical need for new mechanism-of-action drugs that reduce the burden of obesity and associated chronic metabolic comorbidities. A potentially novel target to treat obesity and type 2 diabetes is nicotinamide-N-methyltransferase (NNMT), a cytosolic enzyme with newly identified roles in cellular metabolism and energy homeostasis. To validate NNMT as an anti-obesity drug target, we investigated the permeability, selectivity, mechanistic, and physiological properties of a series of small molecule NNMT inhibitors...
November 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29155146/hdac-inhibitor-suppresses-proliferation-and-invasion-of-breast-cancer-cells-through-regulation-of-mir-200c-targeting-crkl
#5
Xuehai Bian, Zhongxing Liang, Amber Feng, Eric Salgado, Hyunsuk Shim
Although histone deacetylase (HDAC) inhibitors have been shown to effectively induce the inhibition of proliferation and migration in breast cancer, the anticancer mechanism remains poorly understood. Our studies show that miR-200c was significantly downregulated in breast cancer cell lines compared to normal cell lines and inversely correlated with the levels of class IIa HDACs and CRKL. HDAC inhibitors and the ectopic expression of miR-200c as tumor suppressors inhibited the proliferation, invasion, and migration of breast cancer cells by downregulating CRKL...
November 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29155145/differential-effects-of-the-nrf2-activators-tbhq-and-cddo-im-on-the-early-events-of-t-cell-activation
#6
Joseph W Zagorski, Alexandra E Turley, Robert A Freeborn, Kelly R VanDenBerg, Heather E Dover, Brian R Kardell, Karen T Liby, Cheryl E Rockwell
We previously demonstrated that activation of the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) promotes CD4+ Th2 differentiation. In the current study, we assessed the role of Nrf2 in early events following T cell activation. The Nrf2 activators, tBHQ (tert-butylhydroquinone) and CDDO-Im (the imidazolide derivative of the triterpenoid CDDO), were used in conjunction with splenocytes derived from wild-type and Nrf2-null mice to distinguish between Nrf2-specific and off-target effects...
November 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29155144/bay-60-2770-activates-two-isoforms-of-nitric-oxide-sensitive-guanylyl-cyclase-evidence-for-stable-insertion-of-activator-drugs
#7
Anne Sömmer, Peter Sandner, Sönke Behrends
Nitric oxide sensitive guanylyl cyclase (NOsGC), a hemoprotein and the major physiological receptor for nitric oxide (NO), is a heterodimer with the α1/β1 and α2/β1 isoforms known to be important for NO-signaling and conversion of GTP to cGMP in humans. Two innovative classes of compounds modulating the NO/cGMP signaling pathway have been discovered: the heme-dependent sGC stimulators, that stimulate NOsGC directly and also increase the affinity towards NO, and the heme-independent sGC activators, that are thought to bind to oxidized and heme-free NOsGC in tissues exposed to oxidative stress...
November 15, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29132976/investigations-into-the-carbonic-anhydrase-inhibition-of-cos-releasing-donor-core-motifs
#8
Andrea K Steiger, Yu Zhao, Won Jin Choi, Alder Crammond, McKinna R Tillotson, Michael D Pluth
Carbonyl sulfide (COS) releasing scaffolds are gaining popularity as hydrogen sulfide (H2S) donors through exploitation of the carbonic anhydrase (CA)-mediated hydrolysis of COS to H2S. The majority of compounds in this emerging class of donors undergo triggerable decomposition (often referred to as self-immolation) to release COS, and a handful of different COS-releasing structures have been reported. One benefit of this donation strategy is that numerous caged COS-containing core motifs are possible and are poised for development into self-immolative COS/H2S donors...
November 10, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29129483/pharmacological-evaluation-of-new-bioavailable-small-molecules-targeting-eph-ephrin-interaction
#9
Carmine Giorgio, Matteo Incerti, Miriam Corrado, Marco Rusnati, Paola Chiodelli, Simonetta Russo, Donatella Callegari, Francesca Ferlenghi, Vigilio Ballabeni, Elisabetta Barocelli, Alessio Lodola, Massimiliano Tognolini
Eph/ephrin system is an emerging target for cancer therapy but the lack of potent, stable and orally bioavailable compounds is impairing the development of the field. Since 2009 our research group has been devoted to the discovery and development of small molecules targeting Eph/ephrin system and our research culminated with the synthesis of UniPR129, a potent but problematic Eph/ephrin antagonist. Herein, we describe the in vitro pharmacological properties of two derivatives (UniPR139 and UniPR502) stemmed from structure of UniPR129...
November 9, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29128368/a-look-into-centrosome-abnormalities-in-colon-cancer-cells-how-they-arise-and-how-they-might-be-targeted-therapeutically
#10
REVIEW
Lauren E Harrison, Marina Bleiler, Charles Giardina
Cancer cells have long been noted for alterations in centrosome structure, number, and function. Colorectal cancers are interesting in this regard since two frequently mutated genes, APC and CTNNB1 (ß-catenin), encode proteins that directly interact with the centrosome and affect its ability to direct microtubule growth and establish cell polarity. Colorectal cancers also frequently display centrosome over-duplication and clustering. Efforts have been directed towards understanding how supernumerary centrosomes cluster and whether disrupting this clustering may be a way to induce aberrant/lethal mitoses of cancer cells...
November 8, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29102678/a-monoclonal-antibody-raised-against-a-thermo-stabilised-%C3%AE-1-adrenoceptor-interacts-with-extracellular-loop-2-and-acts-as-a-negative-allosteric-modulator-of-a-sub-set-of-%C3%AE-1-adrenoceptors-expressed-in-stable-cell-lines
#11
Mark Soave, Gabriella Cseke, Catherine J Hutchings, Alastair J H Brown, Jeanette Woolard, Stephen J Hill
Recent interest has focused on antibodies that can discriminate between different receptor conformations. Here we have characterised the effect of a monoclonal antibody (mAb3), raised against a purified thermo-stabilised turkey β1-adrenoceptor (β1AR-m23 StaR), on β1-ARs expressed in CHO-K1 or HEK 293 cells. Immunohistochemical and radioligand-binding studies demonstrated that mAb3 was able to bind to ECL2 of the tβ1-AR, but not its human homologue. Specific binding of mAb3 to tβ1-AR was inhibited by a peptide based on the turkey, but not the human, ECL2 sequence...
November 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29102677/kinetics-of-human-cannabinoid-1-cb1-receptor-antagonists-structure-kinetics-relationships-skrs-and-implications-for-insurmountable-antagonism
#12
Lizi Xia, Henk de Vries, Xue Yang, Eelke B Lenselink, Athina Kyrizaki, Francis Barth, Julien Louvel, Matthias Dreyer, Daan van der Es, Adriaan P IJzerman, Laura H Heitman
While equilibrium binding affinities and in vitro functional antagonism of CB1 receptor antagonists have been studied in detail, little is known on the kinetics of their receptor interaction. In this study, we therefore conducted kinetic assays for nine 1-(4,5-diarylthiophene-2-carbonyl)-4-phenylpiperidine-4-carboxamide derivatives and included the CB1 antagonist rimonabant as a comparison. For this we newly developed a dual-point competition association assay with [(3)H]CP55940 as the radioligand. This assay yielded Kinetic Rate Index (KRI) values from which structure-kinetics relationships (SKRs) of hCB1 receptor antagonists could be established...
November 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29102676/a-partnership-with-the-proteasome-the-destructive-nature-of-gsk3
#13
REVIEW
Holly Robertson, John D Hayes, Calum Sutherland
Glycogen Synthase Kinase-3 (GSK3) was originally reported as a key enzyme of glucose homeostasis through regulation of the rate of glycogen synthesis. It has subsequently been found to influence most cellular processes, including growth, differentiation and death, as part of its role in modulating response to hormonal, nutritional and cellular stress stimuli. More than 100 protein targets for GSK3 have been proposed although only a small fraction of these have been convincingly validated in physiological cell systems...
November 1, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29106905/characterisation-of-endogenous-a2a-and-a2b-receptor-mediated-cyclic-amp-responses-in-hek-293-cells-using-the-glosensor%C3%A2-biosensor-evidence-for-an-allosteric-mechanism-of-action-for-the-a2b-selective-antagonist-psb-603
#14
Joelle Goulding, Lauren T May, Stephen J Hill
Endogenous adenosine A2B receptors (A2BAR) mediate cAMP accumulation in HEK 293 cells. Here we have used a biosensor to investigate the mechanism of action of the A2BAR antagonist PSB 603 in HEK 293 cells. The A2A agonist CGS 21680 elicited a small response in these cells (circa 20% of that obtained with NECA), suggesting that they also contain a small population of A2A receptors. The responses to NECA and adenosine were antagonised by PSB 603, but not by the selective A2AAR antagonist SCH 58261. In contrast, CGS 21680 responses were not antagonised by high concentrations of PSB 603, but were sensitive to inhibition by SCH 58261...
October 26, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29074106/role-of-endogenous-and-exogenous-nitric-oxide-carbon-monoxide-and-hydrogen-sulfide-in-hct116-colon-cancer-cell-proliferation
#15
Gabor Oláh, Katalin Módis, Gabor Törö, Mark R Hellmich, Bartosz Szczesny, Csaba Szabo
The role of the three gasotransmitter systems - nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) - in cancer cells has not yet been studied simultaneously in the same experimental system. We measured the expression of NO and CO and H2S generating enzymes in primary colon cancer tissues and HCT116 colon cancer cells, and evaluated the effect of their pharmacological inhibition or pharmacological donation on cell proliferation. Increased expression of iNOS, nNOS, HO-1, CBS and 3-MST was detected in colon cancer...
October 23, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29074105/endogenous-hydrogen-sulfide-regulates-histone-demethylase-jmjd3-mediated-inflammatory-response-in-lps-stimulated-macrophages-and-in-a-mouse-model-of-lps-induced-septic-shock
#16
Siyu Liu, Xiling Wang, Lilong Pan, Weijun Wu, Di Yang, Ming Qin, Wanwan Jia, Chenxi Xiao, Fen Long, Junbo Ge, Xinhua Liu, YiZhun Zhu
Overproduction of inflammatory mediators contributes to uncontrolled inflammation during endotoxin shock.Cystathionine-γ-lyase (CSE), an enzyme involved in hydrogen sulfide (H2S) biosynthesis, has potential anti-inflammatory activity in a variety of inflammatory diseases. Jumonji domain-containing protein 3 (JMJD3), a histone 3 Lys27 (H3K27) demethylase, has been implicated in macrophage activation, but its function in CSE-mediated anti-inflammatory activities remains unknown. In the present study CSE was found to be upregulated in macrophages and mouse lipopolysaccharide (LPS) challenge models...
October 23, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29074104/the-cycloartane-triterpenoid-adcx-impairs-autophagic-degradation-through-akt-overactivation-and-promotes-apoptotic-cell-death-in-multidrug-resistant-hepg2-adm-cells
#17
Haiyan Sun, Maohua Huang, Nan Yao, Jianyang Hu, Yingjie Li, Liping Chen, Nan Hu, Wencai Ye, William Chi-Shing Tai, Dongmei Zhang, Sibao Chen
Multidrug resistance is the main obstacle in cancer chemotherapy. Emerging evidence demonstrates the important role of autophagy in cancer cell resistance to chemotherapy. Therefore, autophagy inhibition by natural compounds may be a promising strategy for overcoming drug resistance in liver cancer cells. Here, we found that ADCX, a natural cycloartane triterpenoid extracted from the traditional Chinese medicine (TCM) source Cimicifugae rhizoma (Shengma), impaired autophagic degradation by suppressing lysosomal cathepsin B (CTSB) expression in multidrug-resistant liver cancer HepG2/ADM cells, thereby leading to autophagic flux inhibition...
October 23, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29066190/identification-of-new-shikonin-derivatives-as-stat3-inhibitors
#18
Han-Yue Qiu, Jiang-Yan Fu, Min-Kai Yang, Hong-Wei Han, Peng-Fei Wang, Ya-Han Zhang, Hong-Yan Lin, Cheng-Yi Tang, Jin-Liang Qi, Rong-Wu Yang, Xiao-Ming Wang, Hai-Liang Zhu, Yong-Hua Yang
The signal transducer and activator of transcription 3 is a constitutively activated oncogenic protein in various human tumors and represents a valid target for anticancer drug design. In this study, we have achieved a new type of STAT3 inhibitors based on structural modifications on shikonin scaffold, guided by computational modelling. By tests, PMMB-187 exhibited a more outstanding profile than shikonin on a small panel of human breast cancer cells, especially for the MDA-MB-231 cells. For the cellular mechanisms research, PMMB-187 was found to induce cell apoptosis in MDA-MB-231 cells, associated with the reduction of mitochondrial membrane potential, production of ROS and alteration of the levels of apoptosis-related proteins...
October 21, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29061342/pharmacological-targeting-of-exercise-adaptations-in-skeletal-muscle-benefits-and-pitfalls
#19
REVIEW
Martin Weihrauch, Christoph Handschin
Exercise exerts significant effects on the prevention and treatment of many diseases. However, even though some of the key regulators of training adaptation in skeletal muscle have been identified, this biological program is still poorly understood. Accordingly, exercise-based pharmacological interventions for many muscle wasting diseases and also for pathologies that are triggered by a sedentary lifestyle remain scarce. The most efficacious compounds that induce muscle hypertrophy or endurance are hampered by severe side effects and are classified as doping...
October 20, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29061341/drug-resistance-induces-the-upregulation-of-h2s-producing-enzymes-in-hct116-colon-cancer-cells
#20
Ashley A Untereiner, Athanasia Pavlidou, Nadiya Druzhyna, Andreas Papapetropoulos, Mark R Hellmich, Csaba Szabo
Hydrogen sulfide (H2S) production in colon cancer cells supports cellular bioenergetics and proliferation. The aim of the present study was to investigate the alterations in H2S homeostasis during the development of resistance to 5-fluorouracil (5-FU), a commonly used chemotherapeutic agent. A 5-FU-resistant HCT116 human colon cancer cell line was established by serial passage in the presence of increasing 5-FU concentrations. The 5-FU-resistant cells also demonstrated a partial resistance to an unrelated chemotherapeutic agent, oxaliplatin...
October 20, 2017: Biochemical Pharmacology
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