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Biochemical Pharmacology

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https://www.readbyqxmd.com/read/27908660/targeting-of-multiple-senescence-promoting-genes-and-signaling-pathways-by-triptonide-induces-complete-senescence-of-acute-myeloid-leukemia-cells
#1
Yanyan Pan, Mei Meng, Nana Zheng, Zhifei Cao, Ping Yang, Xiaodong Xi, Quansheng Zhou
Leukemia cells aberrantly overexpress senescence-suppression telomerase reverse transcriptase (TERT) and down-regulate key senescence-promoting genes to escape complete senescence, resulting in immortalization and malignant progression. Accordingly, induction of complete senescence is a sensible strategy for anti-leukemia therapy. However, effective senescence-based anti-leukemia drugs with low toxicity are currently lacking. In this study, we found that triptonide (chemical name diterpene triepoxide), a small molecule derived from the herb Tripterygium wilfordii Hook, strongly induced complete senescence in cultured acute myeloid leukemia (AML) cell lines, and potently inhibited growth and colony formation of U937 and HL-60 AML cell line with IC50 values of 7...
November 28, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27899300/role-of-the-endocannabinoid-system-in-the-control-of-mouse-myometrium-contractility-during-the-menstrual-cycle
#2
Ester Pagano, Pierangelo Orlando, Stefania Finizio, Antonietta Rossi, Lorena Buono, Fabio Arturo Iannotti, Fabiana Piscitelli, Angelo A Izzo, Vincenzo Di Marzo, Francesca Borrelli
Cannabis and cannabinoids are known to affect female reproduction. However, the role of the endocannabinoid system in mouse uterine contractility in the dioestrus and oestrus phases has not been previously investigated. The present study aimed at filling this gap. Endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were measured in mouse uterus at dioestrus and oestrus phases by liquid chromatography-mass spectrometry; quantitative reverse transcription-PCR measured mRNA expression of cannabinoid receptors and enzymes involved in the metabolism of endocannabinoids...
November 26, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27894856/glycopeptide-resistance-links-with-inorganic-phosphate-metabolism-and-cell-envelope-stress
#3
REVIEW
Fernando Santos-Beneit, María Ordóñez-Robles, Juan F Martín
Antimicrobial resistance is a critical health issue today. Many pathogens have become resistant to many or all available antibiotics and limited new antibiotics are in the pipeline. Glycopeptides are used as a 'last resort' antibiotic treatment for many bacterial infections, but worryingly, glycopeptide resistance has spread to very important pathogens such as Enterococcus faecium and Staphylococcus aureus. Bacteria confront multiple stresses in their natural environments, including nutritional starvation and the action of cell-wall stressing agents...
November 25, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27890727/synthetic-tambjamine-analogues-induce-mitochondrial-swelling-and-lysosomal-dysfunction-leading-to-autophagy-blockade-and-necrotic-cell-death-in-lung-cancer
#4
Ananda M Rodilla, Luís Korrodi-Gregório, Elsa Hernando, Pilar Manuel-Manresa, Roberto Quesada, Ricardo Pérez-Tomás, Vanessa Soto-Cerrato
Current pharmacological treatments for lung cancer show very poor clinical outcomes, therefore, the development of novel anticancer agents with innovative mechanisms of action is urgently needed. Cancer cells have a reversed pH gradient compared to normal cells, which favours cancer progression by promoting proliferation, metabolic adaptation and evasion of apoptosis. In this regard, the use of ionophores to modulate intracellular pH appears as a promising new therapeutic strategy. Indeed, there is a growing body of evidence supporting ionophores as novel antitumour drugs...
November 24, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27890726/sources-of-antibiotics-hot-springs
#5
REVIEW
Girish B Mahajan, Lakshmi Balachandran
The discovery of antibiotics heralded an era of improved health care. However, the over-prescription and misuse of antibiotics resulted in the development of resistant strains of various pathogens. Since then, there has been an incessant search for discovering novel compounds from bacteria at various locations with extreme conditions. The soil is one of the most explored locations for bioprospecting. In recent times, hypersaline environments and symbiotic associations have been investigated for novel antimicrobial compounds...
November 24, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27890725/functional-selectivity-at-g-protein-coupled-receptors-advancing-cannabinoid-receptors-as-drug-targets
#6
REVIEW
Srikrishnan Mallipeddi, David R Janero, Nikolai Zvonok, Alexandros Makriyannis
The phenomenon of functional selectivity, whereby a ligand preferentially directs the information output of a G-protein coupled receptor (GPCR) along (a) particular effector pathway(s) and away from others, has redefined traditional GPCR signaling paradigms to provide a new approach to structure-based drug design. The two principal cannabinoid receptors (CBRs) 1 and 2 belong to the class-A GPCR subfamily and are considered tenable therapeutic targets for several indications. Yet conventional orthosteric ligands (agonists, antagonists/inverse agonists) for these receptors have had very limited clinical utility due to their propensity to incite on-target adverse events...
November 24, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27889539/pharmacodynamics-of-s-dimethylarsino-glutathione-a-putative-metabolic-intermediate-of-inorganic-arsenic-in-mice
#7
Ayaka Kato, Yayoi Kobayashi, Osamu Udagawa, Seishiro Hirano
Inorganic arsenicals are well-known carcinogens, whereas arsenite (iAs(III)) compounds are now recognized as potent therapeutic agents for several leukemias, and arsenic trioxide has been used for the treatment of recurrent acute promyelocytic leukemia (APL). However, recent clinical trials revealed that arsenite is not always effective for non-APL malignancies. Another arsenical, S-dimethylarsino-glutathione ([DMA(III)(GS)]), which is a putative metabolic intermediate in the hepatic metabolism of iAs(III), shows promise for treating several types of lymphoma...
November 23, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27884742/antifungals
#8
REVIEW
Sonia Campoy, José L Adrio
The need for new antifungal agents is undeniable. Current therapeutics choices for the treatment of invasive fungal infections are limited to three classes of drugs. Most used antifungals agents are not completely effective due to the development of resistance, host toxicity and undesirable side effects that limit their use in medical practice. Invasive fungal infections have significantly increased over the last decades and the mortality rates remain unacceptably high. More threatening, new resistance patterns have been observed including simultaneous resistance to different antifungal classes...
November 21, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27867014/the-cave-microbiome-as-a-source-for-drug-discovery-reality-or-pipe-dream
#9
REVIEW
Soumya Ghosh, Nomeda Kuisiene, Naowarat Cheeptham
This review highlights cave habitats, cave microbiomes and their potential for drug discovery. Such studies face many challenges, including access to remote and pristine caves, and sample collection and transport. Inappropriate physical and chemical growth conditions in the laboratory for the isolation and cultivation of cave microorganisms pose many complications including length of cultivation; some cave microorganisms can take weeks and even months to grow. Additionally, DNA extraction from cave environmental samples may be difficult due to the high concentration of various minerals that are natural DNA blocking agents...
November 17, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27867013/characterization-of-p2x4-receptor-agonists-and-antagonists-by-calcium-influx-and-radioligand-binding-studies
#10
Aliaa Abdelrahman, Vigneshwaran Namasivayam, Sonja Hinz, Anke C Schiedel, Meryem Köse, Maggi Burton, Ali El-Tayeb, Michel Gillard, Jürgen Bajorath, Marc de Ryck, Christa E Müller
Antagonists for ATP-activated P2X4 ion channel receptors are currently in the focus as novel drug targets, in particular for the treatment of neuropathic and inflammatory pain. We stably expressed the human, rat and mouse P2X4 receptors in 1321N1 astrocytoma cells, which is devoid of functional nucleotide receptors, by retroviral transfection, and established monoclonal cell lines. Calcium flux assay conditions were optimized for high-throughput screening resulting in a Z'-factor of > 0.8. The application of ready-to-use frozen cells did not negatively affect the results of the calcium assays, which is of great advantage for the screening of compound libraries...
November 17, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27865713/platensimycin-and-platencin-inspirations-for-chemistry-biology-enzymology-and-medicine
#11
REVIEW
Jeffrey D Rudolf, Liao-Bin Dong, Ben Shen
Natural products have served as the main source of drugs and drug leads, and natural products produced by microorganisms are one of the most prevalent sources of clinical antibiotics. Their unparalleled structural and chemical diversities provide a basis to investigate fundamental biological processes while providing access to a tremendous amount of chemical space. There is a pressing need for novel antibiotics with new mode of actions to combat the growing challenge of multidrug resistant pathogens. This review begins with the pioneering discovery and biological activities of platensimycin (PTM) and platencin (PTN), two antibacterial natural products isolated from Streptomyces platensis...
November 16, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27865712/role-for-human-arylamine-n-acetyltransferase-1-in-the-methionine-salvage-pathway
#12
Katey L Witham, Rodney F Minchin, Neville J Butcher
The Phase II drug metabolizing enzyme arylamine N-acetyltransferase 1 (NAT1) has been implicated in the growth and survival of cancer cells, although the mechanisms that underlies these effects are unknown. Here, a focused metabolomics approach was used to identify changes in folate catabolism as well as the S-adenosylmethionine (SAM) cycle following NAT1 knockdown with shRNA. Although acetylation of the folate catabolite p-aminobenzoylglutamate (pABG) was significantly decreased, there were no changes in intracellular pABG or the various components of the SAM cycle...
November 16, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27845050/impaired-thromboxane-receptor-dimerization-reduces-signaling-efficiency-a-potential-mechanism-for-reduced-platelet-function-in-vivo
#13
Valérie Capra, Mario Mauri, Francesca Guzzi, Marta Busnelli, Maria Rosa Accomazzo, Pascale Gaussem, Shaista P Nisar, Stuart J Mundell, Marco Parenti, G Enrico Rovati
Thromboxane A2 is a potent mediator of inflammation and platelet aggregation exerting its effects through the activation of a G protein-coupled receptor (GPCR), termed TP. Although the existence of dimers/oligomers in Class A GPCRs is widely accepted, their functional significance still remains controversial. Recently, we have shown that TPα and TPβ homo-/hetero-dimers interact through an interface of residues in transmembrane domain 1 (TM1) whose disruption impairs dimer formation. Here, biochemical and pharmacological characterization of this dimer deficient mutant (DDM) in living cells indicates a significant impairment in its response to agonists...
November 11, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27845049/a-novel-role-for-pht1-in-the-disposition-of-l-histidine-in-brain-in-vitro-slice-and-in-vivo-pharmacokinetic-studies-in-wildtype-and-pht1-null-mice
#14
Xiao-Xing Wang, Yongjun Hu, Richard F Keep, Noriko Toyama-Sorimachi, David E Smith
PHT1 (SLC15A4) is responsible for translocating L-histidine (L-His), di/tripeptides and peptide-like drugs across biological membranes. Previous studies have indicated that PHT1 is located in brain parenchyma, however, its role and significance in brain along with effect on the biodistribution of substrates is unknown. In this study, adult gender-matched Pht1-competent (wildtype) and Pht1-deficient (null) mice were used to investigate the effect of PHT1 on L-His brain disposition via in vitro slice and in vivo pharmacokinetic approaches...
November 11, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27845048/augmented-reversible-photoswitching-of-drug-target-interaction-through-surface-borrowing
#15
Frank Erdmann, Weilin Lin, Charlott Platzer, Matthias Schmidt, Wolfgang Sippl, Gunter Fischer, Yixin Zhang
Reversibly switching bioactive molecules by light could allow spatiotemporal control of their biological functions, but designing such drug molecules with large functional differences between two light-switchable states remains difficult. We extend the concept of "borrowing protein" to "borrowing surface" for the design of photo-switchable molecules. By using an azobenzene conjugated cyclosporin derivative as a model system we have demonstrated that the enhanced steric hindrance resulting from this "borrowing surface" design can cause augmentation of the functional difference between the cis and trans conformers of this light-switchable compound...
November 11, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27838496/a-tumoural-angiogenic-gateway-blocker-benzophenone-1b-represses-the-hif-1%C3%AE-nuclear-translocation-and-its-target-gene-activation-against-neoplastic-progression
#16
Prabhu Thirusangu, V Vigneshwaran, V Lakshmi Ranganatha, B R Vijay Avin, Shaukath Ara Khanum, Riaz Mahmood, K Jayashree, B T Prabhakar
Hypoxia is an important module in all solid tumours to promote angiogenesis, invasion and metastasis. Stabilization and subsequent nuclear localization of HIF-1α subunits result in the activation of tumour promoting target genes such as VEGF, MMPs, Flt-1, Ang-1 etc. which plays a pivotal role in adaptation of tumour cells to hypoxia. Increased HIF-α and its nuclear translocation have been correlated with pronounced angiogenesis, aggressive tumour growth and poor patient prognosis leading to current interest in HIF-1α as an anticancer drug target...
November 9, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27836671/glycine-prevents-pressure-overload-induced-cardiac-hypertrophy-mediated-by-glycine-receptor
#17
Yan Lu, Xudong Zhu, Jinjie Li, Ru Fang, Zhuoyun Wang, Jing Zhang, Kexue Li, Xiaoyu Li, Hui Bai, Qing Yang, Jingjing Ben, Hanwen Zhang, Qi Chen
As a major amino acid, glycine has multiple functions in metabolism, growth, immunity, cytoprotection, and survival. The aim of this study was to determine the effects of glycine on pathologic cardiac hypertrophy and the mechanism underlying it. Pre-treatment with glycine significantly attenuated murine cardiac hypertrophy induced by transverse aortic constriction or by administration of angiotensin II (Ang II). This action was associated with a suppressive extracellular signal-regulated kinase 1/2 phosphorylation in myocardium...
November 9, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27836670/in-vitro-to-in-vivo-extrapolation-of-the-complex-drug-drug-interaction-of-bupropion-and-its-metabolites-with-cyp2d6-simultaneous-reversible-inhibition-and-cyp2d6-downregulation
#18
Jennifer E Sager, Sasmita Tripathy, Lauren S L Price, Abhinav Nath, Justine Chang, Alyssa Stephenson-Famy, Nina Isoherranen
Bupropion is a widely used antidepressant and smoking cessation aid and a strong inhibitor of CYP2D6 in vivo. Bupropion is administered as a racemic mixture of R- and S-bupropion and has stereoselective pharmacokinetics. Four primary metabolites of bupropion, threo- and erythro-hydrobupropion and R,R- and S,S-OH-bupropion, circulate at higher concentrations than the parent drug and are believed to contribute to the efficacy and side effects of bupropion as well as to the CYP2D6 inhibition. However, bupropion and its metabolites are only weak inhibitors of CYP2D6 in vitro, and the magnitude of the in vivo drug-drug interactions (DDI) caused by bupropion cannot be explained by the in vitro data even when CYP2D6 inhibition by the metabolites is accounted for...
November 9, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27832934/abcb1-2677-g-t-a-variant-enhances-chemosensitivity-to-anti-cancer-agents-acting-on-microtubule-dynamics-through-lamp1-inhibition
#19
Woo Sun Kwon, Sun Young Rha, Hei-Cheul Jeung, Joong Bae Ahn, Jae -Joon Jung, Dong Hyuk Ki, Tae Soo Kim, Hyun Cheol Chung
Overexpression of ABCB1 associated with single nucleotide variants in cancers was reported to encode a protein responsible for drug resistance. We studied chemosensitivity-related genes associated with ABCB1 2677G>T/A variant. The associated genes were identified based on the results of the significance analysis of microarray, and then prediction accuracy was evaluated using the prediction analysis of microarray. Functional assay of the selected gene was performed by using siRNA and drug accumulation study...
November 7, 2016: Biochemical Pharmacology
https://www.readbyqxmd.com/read/27823964/michael-acceptor-containing-drugs-are-a-novel-class-of-5-lipoxygenase-inhibitor-targeting-the-surface-cysteines-c416-and-c418
#20
Isabelle V Maucher, Michael Rühl, Simon Bm Kretschmer, Bettina Hofmann, Benjamin Kühn, Jasmin Fettel, Anja Vogel, Karsten T Flügel, Georg Manolikakes, Nadine Hellmuth, Ann-Kathrin Häfner, Vahid Golghalyani, Ann-Katrin Ball, Matthias Piesche, Carmela Matrone, Gerd Geisslinger, Michael J Parnham, Michael Karas, Dieter Steinhilber, Jessica Roos, Thorsten J Maier
Recently, we published that nitro-fatty acids (NFA) are potent electrophilic molecules which inhibit 5-lipoxygenase (5-LO) by interacting with catalytically cysteine residues next to a substrate entry channel. The electrophilicity is derived from an intramolecular Michael acceptor moiety consisting of an electron-withdrawing group in close proximity to a double bond. The potential of the Michael acceptor moiety to interact with functionally relevant cysteines of proteins potentially renders them effective and sustained enzyme activity modulators...
November 4, 2016: Biochemical Pharmacology
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