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Biochemical Pharmacology

Virginia Correani, Sara Martire, Giuseppina Mignogna, Lisa Beatrice Caruso, Italo Tempera, Alessandra Giorgi, Maddalena Grieco, Luciana Mosca, M Eugenia Schininà, Bruno Maras, Maria d'Erme
Amyloid-treated microglia prime and sustain neuroinflammatory processes in the central nervous system activating different signalling pathways inside the cells. Since a key role for PARP-1 has been demonstrated in inflammation and in neurodegeneration, we investigated PARylated proteins in resting and in β-amyloid peptide treated BV2 microglial cells. A total of 1158 proteins were identified by mass spectrometry with 117 specifically modified in the amyloid-treated cells. Intervention of PARylation on the proteome of microglia showed to be widespread in different cellular districts and to affect various cellular pathways, highlighting the role of this dynamic post-translational modification in cellular regulation...
November 8, 2018: Biochemical Pharmacology
Cristian A Zambrano, Daniela Escobar, Tania Ramos-Santiago, Ian Bollinger, Jerry Stitzel
BACKGROUND AND PURPOSE: Chronic nicotine exposure upregulates α4β2* nicotinic acetylcholine receptors (nAChRs) in the brain. The goal of this study was to examine the role of three serine residues in the large cytoplasmic loop of the α4 subunit on α4β2* upregulation in neurons. EXPERIMENTAL APPROACH: Serine residues S336, S470 and S530 in mouse α4 were mutated to alanine and then re-expressed in primary neurons from cortex, hippocampus and subcortex of α4 KO mice...
November 8, 2018: Biochemical Pharmacology
Ulises Daniel Orlando, Ana Fernanda Castillo, Mayra Agustina Ríos Medrano, Angela Rosaria Solano, Paula Mariana Maloberti, Ernesto Jorge Podesta
Acyl-CoA synthetase-4 (ACSL4) is an enzyme implicated in estrogen receptor α (ERα) negative regulation and hormone therapy resistance in breast cancer. In addition, ACSL4 has been associated to certain types of hormone resistance in prostate cancer. Chemotherapeutic treatment of disseminated breast cancer is usually faced with therapy resistance associated to ATP-binding cassette (ABC) transporter expression, which detect and eject anti-cancer drugs from cells. In this context, the aim of the present work was to study the role of ACSL4 in anti-cancer drug resistance and the involvement of ABC transporters in the underlying mechanisms...
November 8, 2018: Biochemical Pharmacology
Mangreed M Atef, Norhan M El-Sayed, Amal A M Ahmed, Yasser M Mostafa
Diabetic neuropathy (DN) is a common complication of diabetes mellitus and is associated with structural changes in the nerves. However, the molecular basis for DN is poorly understood. Adenosine monophosphate activated protein kinase (AMPK) has been shown to regulate the activity of some kinases including protein kinase B (AKT), mitogen-activated protein kinases (MAPK) and mammalian target of rapamycin complex 1 (mTORC1) that represent important signalling pathways modulating the function of peripheral nociceptive neuron...
November 8, 2018: Biochemical Pharmacology
François M Vallette, Christophe Olivier, Frédéric Lézot, Lisa Oliver, Denis Cochonneau, Lisenn Lalier, Pierre-François Cartron, Dominique Heymann
Although many drugs/treatments are now available for most diseases, too often, resistance to these treatments impedes complete therapeutic success. Acquired resistance is a major problem in many pathologies but it is an acute one in cancers and infections. This is probably because these diseases often require long durations of treatment, which ascribe to the selection of resistant cells. However, the actual mechanisms implicated in the selection process are still under debate. It is becoming increasingly clear that resistance is associated with the heterogeneity of cancer cells or micro-organisms and that multiple mechanisms underlie the emergence of drug-resistant subpopulations...
November 8, 2018: Biochemical Pharmacology
Vassilios Myrianthopoulos, Emmanuel Mikros
The discipline of drug discovery has greatly benefited by computational tools and in silico algorithms aiming at rationalization of many related processes, from the stage of early hit identification to the preclinical phases of drug candidate validation. The various methodologies referred to as molecular modeling tools span a broad spectrum of applications, from straightforward approaches such as virtual screening of compound libraries to more advanced techniques involving the precise estimation of free energy upon binding of the candidate drug to its macromolecular target...
November 8, 2018: Biochemical Pharmacology
Qingqing Hu, Na Yao, Jie Wu, Mingyi Liu, Fanglan Liu, Hong Zhang, Yuqing Xiong, Chunhua Xia
Nuclear receptors pregnane X receptor (PXR; NR1I2) and constitutive androstane receptor (CAR; NR1I3) play a vital role in regulating CYP3A4. Our previous studies have demonstrated that panaxytriol (PXT) upregulates the expression of CYP3A4 via the PXR regulatory pathway. This study aimed to explore how CAR mediates the regulation of CYP3A4 in the presence of PXT using HepG2 cell, hCAR-overexpressing HepG2 cell and hCAR-silenced HepG2 cell models. In HepG2 cells, PXT induced the expression of CYP3A4 in a concentration-dependent manner (10-80 μM) and the high concentration of PXT (80 μM) upregulated the expression of CAR...
November 8, 2018: Biochemical Pharmacology
Cai Liang, Yunting Zhang, Duan Zhuo, Chun-Yin Lo, Libo Yu, Chi-Wai Lau, Yiu-Wa Kwan, Gary Tse, Yu Huang, Xiaoqiang Yao
Augmented endothelium-dependent contractions (EDC) contributes to endothelial dysfunction and vascular disease progression. An early signal in EDC is cytosolic [Ca2+ ]i rise in endothelial cells, which stimulates the production of contractile prostanoids, leading to vascular contraction. In this study, the molecular identity of Ca2+ -permeable channels in endothelial cells and its function were investigated. Vascular tension was measured by wire myograph. EDCs were elicited by acetylcholine (ACH) in the presence of NG -nitro-L-arginine methyl ester (L-NAME)...
November 7, 2018: Biochemical Pharmacology
Liang-Jun Wang, Yuan-Chin Lee, Chia-Hui Huang, Yi-Jun Shi, Ying-Jung Chen, Sung-Nan Pei, Yu-Wei Chou, Long-Sen Chang
Albendazole (ABZ) is a microtubule-targeting anthelmintic that acts against a variety of human cancer cells, but the dependence of its cytotoxicity on non-mitotic effect remains elusive. Thus, we aimed to explore the mechanistic pathway underlying the cytotoxicity of ABZ in human leukemia U937 cells. ABZ-induced apoptosis of U937 cells was characterized by mitochondrial ROS generation, p38 MPAK activation, TNF-α upregulation and activation of the death receptor-mediated pathway. Meanwhile, ABZ induced tubulin depolymerization and G2/M cell cycle arrest...
November 7, 2018: Biochemical Pharmacology
Tadatoshi Tanino, Toru Bando, Yukie Nojiri, Yuna Okada, Noriaki Nagai, Yukari Ueda, Eiichi Sakurai
Mast cells and Kupffer cells secrete interleukin (IL)-1β, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α, which stimulate excess nitric oxide (NO) producing-inducible NO synthase (iNOS). Unlike Kupffer cells, immunoglobulin E-sensitized mast cells elicit sustained NO production. We investigated the participation of mast cell-released NO and cytokine-derived iNOS activation in type 1 allergy-suppressed hepatic cytochrome P450 (CYP) metabolism. Aminoguanidine, a selective iNOS inhibitor, completely suppressed serum nitrate plus nitrite (NOx) concentrations after primary and secondary sensitization of ICR mice and markedly attenuated allergy-suppressed hepatic CYP1A2, CYP2C, CYP2E1, and CYP3A activities...
November 2, 2018: Biochemical Pharmacology
Chia-Hung Christine Hsiao, Andrew J Wiemer
Phosphoantigens stimulate Vγ9Vδ2 T cells after binding to BTN3A1 in target cells and cell-cell contact. We evaluated phosphoantigens including diphosphates, bisphosphonates, and prodrugs for ability to induce leukemia cells to stimulate Vγ9Vδ2 Tcell interferon-γ secretion. Most compounds displayed time-dependent activity at exposure times between 15-240 minutes. Potency (EC50 values) ranged between 8.4 nM and >100 µM. The diphosphate C-HMBPP displayed a shallow dose-response slope (Hill slope = 0.71), while the bisphosphonate slopes were steep (Hill slopes >2), and the prodrugs intermediate...
November 1, 2018: Biochemical Pharmacology
Zibin Lu, Pei Xie, Dongmei Zhang, Pinghua Sun, Huayi Yang, Jiaxi Ye, Huihui Cao, Chuying Huo, Hongling Zhou, Yuyao Chen, Wencai Ye, Linzhong Yu, Junshan Liu
Acute lung injury (ALI) is a deadly disease without effective chemotherapy, so far. Traditional Chinese medicine andrographis herba is frequently used in the treatment of respiratory diseases. In searching for natural anti-ALI components from andrographis herba, the activities of 3-dehydroandrographolide (3-DA), a new natural andrographolide product from andrographis herba were evaluated. In this study, murine macrophage RAW 264.7 cells and BALB/c mice were treated with LPS (lipopolysaccharide, 100 ng/ml in vitro; 3 mg/kg, intratracheal) to establish inflammation models...
November 1, 2018: Biochemical Pharmacology
Ankita Misra, Prem Prakash, Hobby Aggarwal, Priyanka Dhankani, Sachin Kumar, Chandra Prakash Pandey, Nicholas Pugh, Dominique Bihan, Manoj Kumar Barthwal, Richard W Farndale, Dinesh Kumar Dikshit, Madhu Dikshit
No abstract text is available yet for this article.
November 1, 2018: Biochemical Pharmacology
Camila Rubio-Patiño, Andrew Paul Trotta, Jerry Edward Chipuk
Decades of research reveal that MDM2 participates in cellular processes ranging from macro-molecular metabolism to cancer signaling mechanisms. Two recent studies uncovered a new role for MDM2 in mitochondrial bioenergetics. Through the negative regulation of NDUFS1 (NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1) and MT-ND6 (NADH dehydrogenase 6), MDM2 decreases the function and efficiency of Complex I (CI). These observations propose several important questions: (1) Where does MDM2 affect CI activity? (2) What are the cellular consequences of MDM2-mediated regulation of CI? (3) What are the physiological implications of these interactions? Here, we will address these questions and position these observations within the MDM2 literature...
October 31, 2018: Biochemical Pharmacology
E Albini, A Coletti, F Greco, M T Pallotta, G Mondanelli, M Gargaro, M L Belladonna, C Volpi, R Bianchi, U Grohmann, A Macchiarulo, C Orabona
Indoleamine 2,3 dioxygenase 1 (IDO1) is a metabolic enzyme that catalyzes the conversion of the essential amino acid tryptophan (Trp) into a series of immunoactive catabolites, collectively known as kynurenines. Through the depletion of Trp and the generation of kynurenines, IDO1 represents a key regulator of the immune responses involved in physiologic homeostasis as well as in neoplastic and autoimmune pathologies. The IDO1 enzyme has been described as an important immune checkpoint to be targeted by catalytic inhibitors in the treatment of cancer...
October 31, 2018: Biochemical Pharmacology
Chang Hoon Lee
Epithelial mesenchymal transition (EMT) is a biological process that plays a critical role in cancer progression. Blocking the process of EMT can be an essential strategy in the development of anticancer drugs. In this paper, we briefly introduce recent research trends and issues of EMT, focusing on the relationship of EMT with the entire cycle of inflammation (from initiation to resolution of inflammation). Recent findings on the relationship between EMT and immune evasion are discussed. We will also explore the importance of controlling inflammation by anti-inflammatory compounds and specialized pro-resolving lipids to inhibit EMT process in cancer...
October 31, 2018: Biochemical Pharmacology
Simona Daniele, Chiara Giacomelli, Claudia Martini
Ageing is defined as a time-dependent functional decline that occurs in most of live organisms. Brain modification during the ageing process has been considered to predispose to neurodegenerative disorders. Despite intensive research, the exact mechanisms accounting for the switch from physiological brain ageing to neurodegeneration remain to be fully elucidated. At a cellular level, brain ageing is characterized by growing inflammation, oxidative stress, increased genomic instability, altered metabolism and the destruction of protein homeostasis, which causes the accumulation of cellular waste...
October 28, 2018: Biochemical Pharmacology
Kiyomitsu Katsumata, Koji Chono, Hiroshi Suzuki
Existing treatments have limited efficacy against severe infection associated with herpes simplex virus (HSV) and herpes zoster virus (VZV), particularly in immunocompromized patients and those with multidermatomal infection. This issue, along with issues regarding drug resistance, support the need for improved therapeutic options. To investigate the antiviral effect of amenamevir, a VZV and HSV helicase-primase inhibitor, in severe infection conditions, mouse models of severe HSV-1 infection were developed by immunosuppression or multidermatomal infection...
October 24, 2018: Biochemical Pharmacology
Nicolas Baeyens
Blood circulation, facilitating gas exchange and nutrient transportation, is a quintessential feature of life in vertebrates. Any disruption to blood flow, may it be by blockade or traumatic rupture, irrevocably leads to tissue infarction or death. Therefore, it is not surprising that hemostasis and vascular adaptation measures have been evolutionarily selected to mitigate the adverse consequences of altered circulation. Blood vessels can be broadly categorized as arteries, veins, or capillaries, based on their structure, hemodynamics, and gas exchange...
October 24, 2018: Biochemical Pharmacology
Hee Sun Byun, Wei Zhou, InWha Park, Kidong Kang, So-Ra Lee, Xuezhe Piao, Jin Bong Park, Taeg Kyu Kwon, MinKyun Na, Gang Min Hur
Despite recent tremendous progress, targeting of TNF-related apoptosis-inducing ligand (TRAIL) as a cancer therapy has limited success in many clinical trials, in part due to inactivation of death inducing signaling complex (DISC)-mediated caspase-8 signaling cascade in highly malignant tumors such as glioblastoma. In this study, screening of constituents derived from Astilbe rivularis for TRAIL-sensitizing activity identified C-27-carboxylated oleanolic acid derivatives (C27OAs) including 3β-hydroxyolean-12-en-27-oic acid (C27OA-1), 3β,6β,7α-trihydroxyolean-12-en-27-oic acid (C27OA-2), and 3β-trans-p-coumaroyloxy-olean-12-en-27-oic acid (C27OA-3) as novel TRAIL sensitizers...
October 22, 2018: Biochemical Pharmacology
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