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Biochemical Pharmacology

Çiğdem Yılmaz, Gülay Özcengiz
The discovery of penicillin followed by streptomycin, tetracycline, cephalosporins and other natural, semi-synthetic and synthetic antimicrobials completely revolutionized medicine by reducing human morbidity and mortality from most of the common infections. However, shortly after they were introduced to clinical practice, the development of resistance was emerged. The decreasing interest from antibiotic industry in spite of rapid global emergence of antibiotic resistance is a tough dilemma from the pointview of public health...
October 17, 2016: Biochemical Pharmacology
Yi-Te Lin, Yu-Chin Liu, Chuck C-K Chao
Cisplatin is a potent chemotherapeutic drug widely used for the treatment of human cancer. However, its efficacy against hepatocellular carcinoma (HCC) is poor for reasons that remain unclear. We show here that prothymosin-alpha (PTMA) is overexpressed in HCC cell lines. Silencing PTMA using short-hairpin RNA sensitizes HCC cells to cisplatin, while ectopic expression of PTMA induces cell resistance to the drug. Cisplatin inhibits both the JNK pathway and PTMA in a dose-dependent manner. Treatment with a JNK inhibitor also reduces PTMA protein stability and sensitizes HCC cells to cisplatin...
October 14, 2016: Biochemical Pharmacology
Yang Tan, Xingxin Wu, Jing Sun, Wenjie Guo, Fangyuan Gong, Fenli Shao, Tao Tan, Yi Cao, Bingfeng Zheng, Yanhong Gu, Yang Sun, Qiang Xu
Interferon gamma (IFN-γ) signaling in T cells plays an important role in developing T helper 1 (Th1)-mediated inflammation. Selective regulation of IFN-γ signaling is an attractive strategy for treating Th1-mediated immune diseases. In this study, we aimed to explore possible means of targeting IFN-γ signaling by using small molecule compound. A synthetic small molecule FC9 was identified as it selectively inhibited IFN-γ signaling in T cells without suppressing interleukin 4 (IL-4) signaling. Furthermore, FC9 inhibited IFN-γ-induced Janus kinase 2 (JAK2) activation via competing with IFN-γ for binding to IFN-γ receptor 1 (IFN-γ R1)...
October 14, 2016: Biochemical Pharmacology
Rituparna Mittra, Megan Pavy, Nanditha Subramanian, Anthony M George, Megan L O'Mara, Ian D Kerr, Richard Callaghan
The multidrug resistance P-glycoprotein (P-gp) is characterised by the ability to bind and/or transport an astonishing array of drugs. This poly-specificity is imparted by at least four pharmacologically distinct binding sites within the transmembrane domain. Whether or not these sites are spatially distinct has remained unclear. Biochemical and structural investigations have implicated a central cavity as the likely location for the binding sites. In the present investigation, a number of contact residues that are involved in drug binding were identified through biochemical assays using purified, reconstituted P-gp...
October 8, 2016: Biochemical Pharmacology
Rustam Aminov
The introduction of antibiotics into clinical practice revolutionized the treatment and management of infectious diseases. Before the introduction of antibiotics, these diseases were the leading cause of morbidity and mortality in human populations. This review presents a brief history of discovery of the main antimicrobial classes (arsphenamines, β-lactams, sulphonamides, polypeptides, aminoglycosides, tetracyclines, amphenicols, lipopeptides, macrolides, oxazolidinones, glycopeptides, streptogramins, ansamycins, quinolones, and lincosamides) that have changed the landscape of contemporary medicine...
October 5, 2016: Biochemical Pharmacology
Weicheng Wang, Wenjie Guo, Lele Li, Zan Fu, Wen Liu, Jian Gao, Yongqian Shu, Qiang Xu, Yang Sun, Yanhong Gu
5-FU is the first line therapy for colorectal cancer, however, treatment effect is often hampered by the development of drug resistance or toxicity at high doses. Andrographolide is a natural diterpenoid from Andrographis paniculata which has anti-bacterial, anti-antiviral and anti-inflammation activities. In the current study, we test the hypothesis that Andrographolide reverses 5-FU resistance in colorectal cancer and examine the underlying mechanism. In vitro and vivo studies indicated that Andrographolide treatment significantly re-sensitizes HCT116/5-FUR cells (HCT116 cells which are 5-FU resistant) to cytotoxicity of 5-FU...
October 1, 2016: Biochemical Pharmacology
T G Villa, L Feijoo-Siota, J L R Rama, J M Ageitos
Antivirals are compounds used since the 1960s that can interfere with viral development. Some of these antivirals can be isolated from a variety of sources, such as animals, plants, bacteria or fungi, while others must be obtained by chemical synthesis, either designed or random. Antivirals display a variety of mechanisms of action, and while some of them enhance the animal immune system, others block a specific enzyme or a particular step in the viral replication cycle. As viruses are mandatory intracellular parasites that use the host's cellular machinery to survive and multiply, it is essential that antivirals do not harm the host...
September 30, 2016: Biochemical Pharmacology
Supriya V Vartak, Mahesh Hegde, Divyaanka Iyer, Snehal Gaikwad, Vidya Gopalakrishnan, Mrinal Srivastava, Subhas S Karki, Bibha Choudhary, Pritha Ray, T R Santhoshkumar, Sathees C Raghavan
Antiapoptotic protein BCL2, serves as an excellent target for anticancer therapy owing to its increased level in cancers. Previously, we have described characterization of a novel BCL2 inhibitor, Disarib, which showed selective cytotoxicity in BCL2 'high' cancer cells and CLL patient cells. Here, we have investigated the mechanism of Disarib-induced cytotoxicity, and compared its efficacy with a well-established BCL2 inhibitor, ABT199. We show that Disarib administration caused tumor regression in mouse allograft and xenograft models, exhibited platelet sparing property and did not exhibit significant side effects...
September 29, 2016: Biochemical Pharmacology
Somnath Mazumder, Rudranil De, Souvik Sarkar, Asim Azhar Siddiqui, Shubhra Jyoti Saha, Chinmoy Banerjee, Mohd Shameel Iqbal, Shiladitya Nag, Subhashis Debsharma, Uday Bandyopadhyay
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to treat multiple inflammatory diseases and pain but severe gastric mucosal damage is the worst outcome of NSAID-therapy. Here we report that mitoTEMPO, a mitochondrially targeted superoxide (O2(-)) scavenger protected as well as healed gastric injury induced by diclofenac (DCF), the most commonly used NSAID. Common existing therapy against gastric injury involves suppression of gastric acid secretion by proton pump inhibitors and histamine H2 receptor antagonists; however, dyspepsia, vitamin B12 deficiency and gastric microfloral dysbalance are the major drawbacks of acid suppression...
September 28, 2016: Biochemical Pharmacology
In Sook Kim, Dae-Hyeong Yoo, Il-Hoon Jung, Sumin Lim, Jin-Ju Jeong, Kyeong-A Kim, Ok-Nam Bae, Hye Hyun Yoo, Dong-Hyun Kim
In this study, we investigated the effects of antibiotics on the pharmacological effects of aspirin. The antithrombotic activity of aspirin was evaluated after antibiotic treatment using tail bleeding assay. The pyrosequencing analysis and selective medium culture assay were performed to investigate the alterations in gut microbiota. In addition, the in vitro metabolism assay with fecal suspension and in vivo pharmacokinetic experiments with antibiotic treatment were conducted. Ampicillin treatment significantly prolonged the bleeding time in aspirin-dosed rats...
September 26, 2016: Biochemical Pharmacology
Takuji Nakashima, Yōko Takahashi, Satoshi Ōmura
The Ōmura research group of the Kitasato Institute has isolated multiple microorganisms over a period of five decades. The resulting collection comprises a broad spectrum of microbes, including strains producing novel and diverse compounds with biological activities. A bioassay-guided fractionation of microbial culture broths has been employed to screen the microbial collection for compounds with new biological activities. And numerous novel natural products have been discovered among the microbial metabolites produced by members of the collection...
September 26, 2016: Biochemical Pharmacology
Prabhavathi Fernandes, Evan Martens
Most pharmaceutical companies have stopped or have severely limited investments to discover and develop new antibiotics to treat the increasing prevalence of infections caused by multi-drug resistant bacteria, because the return on investment has been mostly negative for antibiotics that received marketing approved in the last few decades. In contrast, a few small companies have taken on this challenge and are developing new antibiotics. This review describes those antibiotics in late-stage clinical development...
September 26, 2016: Biochemical Pharmacology
Simon B M Kretschmer, Stefano Woltersdorf, Dominik Vogt, Felix F Lillich, Michael Rühl, Michael Karas, Isabelle V Maucher, Jessica Roos, Ann-Kathrin Häfner, Astrid Kaiser, Mario Wurglics, Manfred Schubert-Zsilavecz, Carlo Angioni, Gerd Geisslinger, Holger Stark, Dieter Steinhilber, Bettina Hofmann
5-Lipoxygenase (5-LO, EC1.13.11.34) has been implicated in the pathogenesis of inflammatory and immune diseases. Recently, aminothiazole comprising inhibitors have been discovered for this valuable target. Yet, the molecular mode of action of this class of substances is only poorly understood. Here, we present the detailed molecular mechanism of action of the compound class and the in vitro pharmacological profile of two lead compounds ST-1853 and ST-1906. Mechanistic studies with recombinant proteins as well as intact cell assays enabled us to define this class as a novel type of 5-LO inhibitors with unique characteristics...
September 23, 2016: Biochemical Pharmacology
XiaoMei Zhuang, TianHong Zhang, SiJia Yue, Juan Wang, Huan Luo, YunXia Zhang, Zheng Li, JinJing Che, HaiYing Yang, Hua Li, MingShe Zhu, Chuang Lu
Icotinib (ICO), a novel small molecule and a tyrosine kinase inhibitor, was developed and approved recently in China for non-small cell lung cancer. During screening for CYP inhibition potential in human liver microsomes (HLM), heterotropic activation toward CYP3A5 was revealed. Activation by icotinib was observed with CYP3A-mediated midazolam hydroxylase activity in HLM (∼40% over the baseline) or recombinant human CYP3A5 (rhCYP3A5) (∼70% over the baseline), but not in the other major CYPs including rhCYP3A4...
September 22, 2016: Biochemical Pharmacology
Jen-Chung Ko, Hao-Yu Zheng, Wen-Ching Chen, Yi-Shuan Peng, Chia-Hung Wu, Chia-Li Wei, Jyh-Cheng Chen, Yun-Wei Lin
Salinomycin, a polyether antibiotic, acts as a highly selective potassium ionophore and has anticancer activity on various cancer cell lines. Cisplatin has been proved as chemotherapy drug for advanced human non-small cell lung cancer (NSCLC). Thymidylate synthase (TS) is a key enzyme in the pyrimidine salvage pathway, and increased expression of TS is thought to be associated with resistance to cisplatin. In this study, we showed that salinomycin (0.5-2μg/mL) treatment down-regulating of TS expression in an AKT inactivation manner in two NSCLC cell lines, human lung adenocarcinoma A549 and squamous cell carcinoma H1703 cells...
September 22, 2016: Biochemical Pharmacology
Rana Abdelnabi, Daryl Staveness, Katherine E Near, Paul A Wender, Leen Delang, Johan Neyts, Pieter Leyssen
Previously, we reported that salicylate-based analogs of bryostatin protect cells from chikungunya virus (CHIKV)-induced cell death. Interestingly, 'capping' the hydroxyl group at C26 of a lead bryostatin analog, a position known to be crucial for binding to and modulation of protein kinase C (PKC), did not abrogate the anti-CHIKV activity of the scaffold, putatively indicating the involvement of a pathway independent of PKC. The work detailed in this study demonstrates that salicylate-derived analog 1 and two capped analogs (2 and 3) are not merely cytoprotective compounds, but act as selective and specific inhibitors of CHIKV replication...
September 21, 2016: Biochemical Pharmacology
B Hernández-Breijo, M Chaparro, D Cano-Martínez, I Guerra, M Iborra, J L Cabriada, L Bujanda, C Taxonera, V García-Sánchez, I Marín-Jiménez, M Barreiro-de Acosta, I Vera, M D Martín-Arranz, F Mesonero, L Sempere, F Gomollón, J Hinojosa, J P Gisbert, L G Guijarro
BACKGROUND: The availability of a quantitative method to measure anti-infliximab (IFX) antibodies (ATI) would facilitate the implementation of therapeutic drug monitoring in clinical decision-making. Our aim was to standardize the homogeneous mobility shift assay (HMSA) used in the measure of ATI levels. METHODS: In this prospective longitudinal multicenter study, 50 IFX-treated Crohn's disease (CD) patients were followed up for 54weeks. During this period 360 human serum samples were analysed...
September 21, 2016: Biochemical Pharmacology
Kidong Kang, Minho Won, Jae-Min Yuk, Chan-Yong Park, Hee Sun Byun, Kyeong Ah Park, So-Ra Lee, Young-Goo Kang, Han-Ming Shen, Ill Young Lee, Gang Min Hur
A specific small-molecule inhibitor of the TLR4 signaling complex upstream of the IKK would likely provide therapeutic benefit for NF-κB-mediated inflammatory disease. We previously identified brazilin as a selective upstream IKK inhibitor targeting the Myddosome complex. In this study, using a cell-based ubiquitination assay for IRAK1 and a chemical library comprising a series of structural analogues of brazilin, a novel small molecule, 2-hydroxy-5,6-dihydroisoindolo[1,2-a]isoquinoline-3,8-dione (IinQ), was identified as a selective and potent inhibitor of IRAK1-dependent NF-κB activation upon TLR4 ligation...
September 21, 2016: Biochemical Pharmacology
J M Ageitos, A Sánchez-Pérez, P Calo-Mata, T G Villa
Antimicrobial peptides (AMPs) are short peptidic molecules produced by most living creatures. They help unicellular organisms to successfully compete for nutrients with other organisms sharing their biological niche, while AMPs form part of the immune system of multicellular creatures. Thus, these molecules represent biological weapons that have evolved over millions of years as a result of an escalating arms race for survival among living organisms. All AMPs share common features, such as a small size, with cationic and hydrophobic sequences within a linear or cyclic structure...
September 20, 2016: Biochemical Pharmacology
Elisabeth Heylen, Johan Neyts, Dirk Jochmans
The development of antiviral strategies to prevent or treat respiratory syncytial virus (RSV) infections is of great importance, especially considering the fact that RSV is one of the most important causes of pediatric respiratory infections. However, despite intense efforts, there is no antiviral or vaccine approved for the prevention or treatment of RSV infections. Several inhibitors, targeting different RSV proteins have been discovered over the past decade. We here review the most important chemical series as well as recent developments in understanding which viral proteins and/or host cell factors are good targets for inhibition of viral replication...
September 19, 2016: Biochemical Pharmacology
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