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    Anti-inflammatory nitro-fatty acids suppress tumor growth by triggering mitochondrial dysfunction and activation of the intrinsic apoptotic pathway in colorectal cancer cells.
    Biochem Pharmacol 2018 Jun 14. Epub 2018 Jun 14.
    Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt/Main, Germany; Department of Biomedicine, Aarhus University, Bartholins Allé 6, 8000 Aarhus C, Denmark.
    Nitro-fatty acids (NFAs) are endogenously occurring lipid mediators exerting strong anti-inflammatory effects and acting as anti-oxidants in a number of animal models of inflammation. These NFA effects are mediated by targeting important regulatory proteins involved in inflammatory processes, such as 5-lipoxygenase, soluble epoxide hydrolase, or NF-κB. In the present study, we investigated the anti-tumorigenic effects of NFAs on colorectal cancer (CRC) cells in cell culture-based experiments and in a murine xenograft model of human CRC. Read More

    Connective tissue growth factor stimulates osteosarcoma cell migration and induces osteosarcoma metastasis by upregulating VCAM-1 expression.
    Biochem Pharmacol 2018 Jun 14. Epub 2018 Jun 14.
    Department of Orthopedic Surgery, National Taiwan University Hospital, NO 1, Jen-Ai Road, Taipei 100, Taiwan.
    Osteosarcoma is the most common bone malignancy that occurs in the young population. After osteosarcoma cells metastasize to the lung, prognosis is very poor owing to difficulties in early diagnosis and effective treatment. Recently, connective tissue growth factor (CTGF) was reported to be a critical contributor to osteosarcoma metastasis. Read More

    Liver Metabolomics in a Mouse Model of Erythropoietic Protoporphyria.
    Biochem Pharmacol 2018 Jun 12. Epub 2018 Jun 12.
    Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA. Electronic address:
    Erythropoietic protoporphyria (EPP) is a genetic disease that results from the defective mutation in the gene encoding ferrochelatase (FECH), the enzyme that converts protoporphyrin IX (PPIX) to heme. Liver injury and even liver failure can occur in EPP patients because of PPIX accumulation in the liver. The current study profiled the liver metabolome in an EPP mouse model caused by a Fech mutation (Fech-mut). Read More

    Inhibition of p21-activated kinase 1 attenuates the cardinal features of asthma through suppressing the lymph node homing of dendritic cells.
    Biochem Pharmacol 2018 Jun 12;154:464-473. Epub 2018 Jun 12.
    Department of Pharmacology and Key Laboratory of CFDA for Respiratory Drug Research, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address:
    Dendritic cell (DC) trafficking from lung to the draining mediastinal lymph nodes (MLNs) is a key step for initiation of T cell responses in allergic asthma. In the present study, we investigate the role of DC-mediated airway inflammation after inhibition of p21-activated kinase-1 (PAK1), an effector of Rac and Cdc42 small GTPases, in the allergen-induced mouse models of asthma. Systemic administration of PAK1 specific inhibitor IPA-3 significantly attenuates not only the airway inflammation but also the airway hyperresponsiveness in a mouse model of ovalbumin-induced asthma. Read More

    Tarps differentially affect the pharmacology of ampakines.
    Biochem Pharmacol 2018 Jun 12;154:446-451. Epub 2018 Jun 12.
    RespireRx Pharmaceuticals Inc., 126 Valley Road, Glen Rock, NJ 07452,United States.
    Transmembrane AMPA receptor regulatory proteins (TARPs) govern AMPA receptor cell surface expression and distinct physiological properties including agonist affinity, desensitization and deactivation kinetics. The prototypical TARP, STG or γ2 and TARPs γ3, γ4, γ7 and γ8 are all expressed to varying degrees in the mammalian brain and differentially regulate AMPAR gating parameters. Positive allosteric AMPA receptor modulators or ampakines alter receptor rates of agonist binding/unbinding, channel opening and can offset receptor desensitization and deactivation. Read More

    Ischemia/Reperfusion Model Impairs Endocannabinoid Signaling and Na/K ATPase Expression and Activity in Kidney Proximal Tubule Cells.
    Biochem Pharmacol 2018 Jun 8. Epub 2018 Jun 8.
    Instituto de Biofísica Carlos Chagas Filho, UFRJ, Rio de Janeiro, Brazil. Electronic address:
    LLC-PK1 cells, an immortalized epithelial cell line derived from pig renal proximal tubules, express all the major players of the endocannabinoid system (ECS) such as CB1, CB2 and TRPV1 receptor, as well as the main enzymes involved in the biosynthesis and degradation of the major endocannabinoids named 2-arachidonoylglycerol, 2-AG and anandamide, AEA. Here we investigated whether the damages caused by ischemic insult either in vitro using LLC-PK1 cells exposed to antimycin A (an inductor of ATP-depletion) or in vivo using Wistar rats in a classic renal ischemia and reperfusion (IR) protocol, lead to changes in AEA and 2-AG levels, as well as altered expression of genes from the main enzymes involved in the regulation of the ECS. Our data show that the mRNA levels of CB1 receptor gene were downregulated, while the transcript levels of monoacylglycerol lipase (MAGL), the main 2-AG degradative enzyme, are upregulated in LLC-PK1 cells after IR model. Read More

    Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases.
    Biochem Pharmacol 2018 Jun 8;154:424-434. Epub 2018 Jun 8.
    Infection and Immunity Research Laboratory, Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea; KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34141, Republic of Korea. Electronic address:
    Despite remarkable advances in medical science, infection-associated diseases remain among the leading causes of death worldwide. There is a great deal of interest and concern at the rate at which new pathogens are emerging and causing significant human health problems. Expanding our understanding of how cells regulate signaling networks to defend against invaders and retain cell homeostasis will reveal promising strategies against infection. Read More

    Effects of digitoxin on cell migration in ovarian cancer inflammatory microenvironment.
    Biochem Pharmacol 2018 Jun 8;154:414-423. Epub 2018 Jun 8.
    Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy. Electronic address:
    Clinical and experimental evidence supports a role for cardiac glycosides (CGs) as potential novel anticancer drugs. However, there are no studies reporting the effect of CGs on the inflammatory tumor microenvironment (TME), which plays a central role in tumor progression and invasiveness. We investigated whether digitoxin affects a) specific pathways involved in motility and/or activation of different cell types shaping TME, and b) cancer cell growth and invasiveness in response to TME-associated factors. Read More

    Syringic acid prevents skin carcinogenesis via regulation of NoX and EGFR signaling.
    Biochem Pharmacol 2018 Jun 7;154:435-445. Epub 2018 Jun 7.
    Division of Functional Food Research, Korea Food Research Institute, Jeolabuk-do 55365, Republic of Korea; School of Food Science and Biotechnology, Kyungpook National University, Daegu 41566, Republic of Korea. Electronic address:
    Validation of nutraceutical and pharmaceutical targets is essential for the prediction of physiological and side effects. Epidemiologic evidence and molecular studies suggest that non-melanoma skin cancer is directly associated with excessive exposure to ultraviolet (UV) radiation. The aim of the present study was to evaluate the inhibitory effects of syringic acid on UVB-induced signaling and skin carcinogenesis, and determine the molecular targets. Read More

    Luteolin attenuates neutrophilic oxidative stress and inflammatory arthritis by inhibiting Raf1 activity.
    Biochem Pharmacol 2018 Jun 6;154:384-396. Epub 2018 Jun 6.
    Graduate Institute of Natural Products and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan; Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan; Department of Anesthesiology, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City 243, Taiwan. Electronic address:
    Neutrophils play a significant role in inflammatory tissue injury. Activated neutrophils produce reactive oxygen species (ROS), release proteases, and form neutrophil extracellular traps (NETs), significantly affecting the pathogenesis of inflammatory arthritis. We examined the therapeutic effects of luteolin, a flavone found in many plants, in neutrophilic inflammation and on acute inflammatory arthritis. Read More

    Induction of oxidative stress by long-term treatment of live HEK293 cells with therapeutic concentration of lithium is associated with down-regulation of δ-opioid receptor amount and function.
    Biochem Pharmacol 2018 Jun 5;154:452-463. Epub 2018 Jun 5.
    Department of Biomathematics, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
    The functional state of δ-opioid receptor signaling cascade in live cells exposed to a therapeutic concentration of lithium for a prolonged period of time (weeks) is not known because the previous studies of Li interference with OR were oriented to µ-OR only. The same applies to the analysis of the prolonged effect of Li on oxidative stress in context with δ-OR function. HEK293 cells stably expressing δ-OR were cultivated in the presence or absence of 1 mM LiCl for 7 or 21 days, homogenized and the post-nuclear (PNS) and plasma membrane (PM) fractions prepared from all four types of cells. Read More

    Carbonyl scavengers as pharmacotherapies in degenerative disease: Hydralazine repurposing and challenges in clinical translation.
    Biochem Pharmacol 2018 Jun 6;154:397-406. Epub 2018 Jun 6.
    Discipline of Pharmacology, School of Biomedical Science, The University of Western Australia, Crawley, WA 6007, Australia. Electronic address:
    During cellular metabolism, spontaneous oxidative damage to unsaturated lipids generates many electrophilic carbonyl compounds that readily attack cell macromolecules, forming adducts that are potential drivers of tissue dysfunction. Since such damage is heightened in many degenerative conditions, researchers have assessed the efficacy of nucleophilic carbonyl-trapping drugs in animal models of such disorders, anticipating that they will protect tissues by intercepting toxic lipid-derived electrophiles (LDEs) within cells. This Commentary explores recent animal evidence for carbonyl scavenger efficacy in two disparate yet significant conditions known to involve LDE production, namely spinal cord injury (SCI) and alcoholic liver disease (ALD). Read More

    A hispanolone-derived diterpenoid inhibits M2-Macrophage polarization in vitro via JAK/STAT and attenuates chitin induced inflammation in vivo.
    Biochem Pharmacol 2018 Jun 2;154:373-383. Epub 2018 Jun 2.
    Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid, Spain. Electronic address:
    Macrophages are highly plastic cells that adopt different functional phenotypes in response to environmental signals. Classically activated macrophages (M1) exhibit a pro-inflammatory role, mediating host defense against microorganisms or tumor cells; whereas alternatively activated macrophages (M2) perform a range of physiological processes, including inflammation, wound repair and tissue remodeling. Interestingly, M2 macrophages have been involved in pathological settings such as tumor progression, parasitic infection and respiratory disorders. Read More

    Molecular and functional interaction between GPR18 and cannabinoid CB G-protein-coupled receptors. Relevance in neurodegenerative diseases.
    Biochem Pharmacol 2018 Jun 2. Epub 2018 Jun 2.
    Molecular Neurobiology laboratory, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain; Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, C/ Sinesio Delgado, 4, 28029 Madrid, Spain. Electronic address:
    GPR18, still considered an orphan receptor, may respond to endocannabinoids, whose canonical receptors are CB and CB. GPR18 and CB receptors share a role in peripheral immune response regulation and are co-expressed in microglia, which are immunocompetent cells in the central nervous system (CNS). We aimed at identifying heteroreceptor complexes formed by GPR18 and CBR or CBR in resting and activated microglia. Read More

    SR-A1 suppresses colon inflammation and tumorigenesis through negative regulation of NF-κB signaling.
    Biochem Pharmacol 2018 May 31;154:335-343. Epub 2018 May 31.
    Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China. Electronic address:
    Inflammatory bowel disease is characterized by chronic intestinal inflammatory disorders associated with increased risk of developing colorectal cancer. However, the detailed mechanisms are not fully understood. The aim of this study was to determine the effect of macrophage scavenger receptor class A1 (SR-A1), a pattern recognition receptor primarily expressed in macrophages, on colitis and clarify the underlying mechanisms. Read More

    Taxodione induces apoptosis in BCR-ABL-positive cells through ROS generation.
    Biochem Pharmacol 2018 Jun 1;154:357-372. Epub 2018 Jun 1.
    Division of Hygienic Chemistry, Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. Electronic address:
    Chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) are hematopoietic malignancies caused by the constitutive activation of BCR-ABL tyrosine kinase. Although direct BCR-ABL inhibitors, such as imatinib, were initially successful in the treatment of leukemia, many patients developed drug resistance over time due to the gatekeeper mutation of BCR-ABL T315I. In the present study, we found that taxodione, a quinone methide diterpene isolated from Taxodium distichum, significantly induced apoptosis in human myelogenous leukemia-derived K562 cells, which were transformed by BCR-ABL. Read More

    Targeting forkhead box M1 transcription factor in breast cancer.
    Biochem Pharmacol 2018 May 31;154:407-413. Epub 2018 May 31.
    Departments of Pharmacology and Hematology & Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, United States. Electronic address:
    Breast cancer continues to be the most commonly diagnosed malignancy and second most common cause of cancer-related deaths among women in the United States. Improved understanding of the molecular heterogeneity of breast tumors and the approval of multiple targeted therapies have revolutionized the treatment landscape and long-term survival rates for patients with breast cancer. Despite the development of highly effective targeted agents, drug resistance and disease progression remain major clinical concerns. Read More

    Nano-delivery systems for encapsulation of dietary polyphenols: An experimental approach for neurodegenerative diseases and brain tumors.
    Biochem Pharmacol 2018 May 24;154:303-317. Epub 2018 May 24.
    Department of Medical, Surgical, Neurological, Metabolic Sciences, and Aging, 2nd Division of Neurology, Center for Rare Diseases and InterUniversity Center for Research in Neurosciences, University of Campania "Luigi Vanvitelli", Naples, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA. Electronic address:
    Neurodegenerative diseases (NDs) and brain tumors are severe, disabling, and incurable disorders that represent a critical problem regarding human suffering and the economic burden on the healthcare system. Because of the lack of effective therapies to treat NDs and brain tumors, the challenge for physicians is to discover new drugs to improve their patients' quality of life. In addition to risk factors such as genetics and environmental influences, increased cellular oxidative stress has been reported as one of the potential common etiologies in both disorders. Read More

    Selective killing of proinflammatory synovial fibroblasts via activation of transient receptor potential ankyrin (TRPA1).
    Biochem Pharmacol 2018 May 24;154:293-302. Epub 2018 May 24.
    Poliklinik, Funktionsbereich & Hiller Forschungszentrum für Rheumatologie, University Hospital Duesseldorf, D-40225 Duesseldorf, Germany. Electronic address:
    Background: Studies in rheumatoid arthritis synovial fibroblasts (RASF) demonstrated the expression of several transient receptor potential channels (TRP) such as TRPV1, TRPV2, TRPV4, TRPA1 and TRPM8. Upon ligation, these receptors increase intracellular calcium but they have also been linked to modulation of inflammation in several cell types. TNF was shown to increase the expression of TRPA1, the receptor for mustard oil and environmental poisons in SF, but the functional consequences have not been investigated yet. Read More

    Jacareubin inhibits FcεRI-induced extracellular calcium entry and production of reactive oxygen species required for anaphylactic degranulation of mast cells.
    Biochem Pharmacol 2018 May 24;154:344-356. Epub 2018 May 24.
    Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPN, Mexico. Electronic address:
    Mast cells (MCs) are important effectors in allergic reactions since they produce a number of pre-formed and de novo synthesized pro-inflammatory compounds in response to the high affinity IgE receptor (FcεRI) crosslinking. IgE/Antigen-dependent degranulation and cytokine synthesis in MCs have been recognized as relevant pharmacological targets for the control of deleterious inflammatory reactions. Despite the relevance of allergic diseases worldwide, efficient pharmacological control of mast cell degranulation has been elusive. Read More

    Globular adiponectin protects rat hepatocytes against acetaminophen-induced cell death via modulation of the inflammasome activation and ER stress: Critical role of autophagy induction.
    Biochem Pharmacol 2018 May 24;154:278-292. Epub 2018 May 24.
    College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea. Electronic address:
    Acetaminophen (APAP) overdose treatment causes severe liver injury. Adiponectin, a hormone predominantly produced by adipose tissue, exhibits protective effects against APAP-induced hepatotoxicity. However, the underlying mechanisms are not clearly understood. Read More

    Celecoxib inhibits mitochondrial O consumption, promoting ROS dependent death of murine and human metastatic cancer cells via the apoptotic signalling pathway.
    Biochem Pharmacol 2018 May 23;154:318-334. Epub 2018 May 23.
    Menzies Health Institute Queensland, School of Medical Science, Griffith University, Gold Coast, QLD, Australia. Electronic address:
    Capecitabine induced toxicities such as hand-foot syndrome (HFS) and progression of metastatic cancer are both treatable with concurrent celecoxib as shown in the ADAPT (Activating Cancer Stem Cells from Dormancy And Potentiate for Targeting) trial. In the present study, five commonly used NSAIDs, including celecoxib were compared for their pro-oxidative capacities as cytotoxic drugs against human and mouse metastatic melanoma or breast cancer cells in vitroand the source of cellular ROS production induced by celecoxib was examined in greater detail.

    Results: Celecoxib was unique among the NSAIDs in that it showed particular potency as a cytotoxic drug against the metastatic cancer cells with IC values in the low micromolar range. Read More

    Tanovea® for the treatment of lymphoma in dogs.
    Biochem Pharmacol 2018 May 17;154:265-269. Epub 2018 May 17.
    KU Leuven, Department of Microbiology and Immunology, Rega Institute for Medical Research, Herestraat 49, 3000 Leuven, Belgium. Electronic address:
    Tanovea® (first named GS-9219, then VDC-1101, generic name: rabacfosadine) is a pro-prodrug or "double" prodrug of PMEG [9-(2-phosphonylmethoxyethyl)guanine], which has been conditionally approved by the US FDA (Food and Drug Administration) for the treatment of lymphoma in dogs. Tanovea has been demonstrated to be effective against non-Hodgkin's lymphoma (NHL) in dogs, as well as canine cutaneous T-cell lymphoma, spontaneous canine multiple myeloma, naïve canine multicentric lymphoma and relapsed canine B-cell lymphoma. As a double prodrug of PMEG, GS-9219 is first converted intracellularly by hydrolysis to cPr-PMEDAP, then deaminated to PMEG, which is then phosphorylated twice to its active metabolite PMEGpp, acting at the level of the cellular DNA polymerases. Read More

    Repositioning of anti-cancer drug candidate, AZD7762, to an anti-allergic drug suppressing IgE-mediated mast cells and allergic responses via the inhibition of Lyn and Fyn.
    Biochem Pharmacol 2018 May 17;154:270-277. Epub 2018 May 17.
    Department of Immunology, College of Medicine, Konkuk University, Chungju 27478, Republic of Korea. Electronic address:
    Mast cells are critical effector cells in IgE-mediated allergic responses. The aim of this study was to investigate the anti-allergic effects of 3-[(aminocarbonyl)amino]-5-(3-fluorophenyl)-N-(3S)-3-piperidinyl-2-thiophenecarboxamide (AZD7762) in vitro and in vivo. AZD7762 inhibited the antigen-stimulated degranulation from RBL-2H3 (IC, ∼27. Read More

    Probing the binding site of novel selective positive allosteric modulators at the M muscarinic acetylcholine receptor.
    Biochem Pharmacol 2018 May 17;154:243-254. Epub 2018 May 17.
    Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia. Electronic address:
    Subtype-selective allosteric modulation of the M muscarinic acetylcholine (ACh) receptor (M mAChR) is an attractive approach for the treatment of numerous disorders, including cognitive deficits. The discovery of benzyl quinolone carboxylic acid, BQCA, a selective M mAChR positive allosteric modulator (PAM), spurred the subsequent development of newer generation M PAMs representing diverse chemical scaffolds, different pharmacodynamic properties and, in some instances, improved pharmacokinetics. Key exemplar molecules from such efforts include PF-06767832 (N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl)-5-methyl-4-(4-(thiazol-4-yl)benzyl)pyridine-2-carboxamide), VU6004256 (4,6-difluoro-N-(1S,2S)-2-hydroxycyclohexyl-1-((6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl)methyl)-1H-indole-3-carboxamide) and MIPS1780 (3-(2-hydroxycyclohexyl)-6-(2-((4-(1-methyl-1H-pyrazol-4-yl)-benzyl)oxy)phenyl)pyrimidin-4(3H)-one). Read More

    Inhibition of BET bromodomains restores corticosteroid responsiveness in a mixed granulocytic mouse model of asthma.
    Biochem Pharmacol 2018 May 17;154:222-233. Epub 2018 May 17.
    Department of Pharmacology & Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
    Asthma is a heterogeneous disease characterized by different endotypes/phenotypes. Th2/Th17 driven mixed granulocytic asthma is one of them and shows resistance to corticosteroid therapy. Bromodomain and extra-terminal (BET) proteins are required for differentiation of Th17 cells which play a pivotal role in neutrophilic inflammation. Read More


    The aryl hydrocarbon receptor is indispensable for dioxin-induced defects in sexually-dimorphic behaviors due to the reduction in fetal steroidogenesis of the pituitary-gonadal axis in rats.
    Biochem Pharmacol 2018 May 16;154:213-221. Epub 2018 May 16.
    Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. Electronic address:
    Many forms of the toxic effects produced by dioxins and related chemicals take place following activation of the aryl hydrocarbon receptor (AHR). Our previous studies have demonstrated that treating pregnant rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic dioxin, attenuates the pituitary expression of gonadotropins to reduce testicular steroidogenesis during the fetal stage, resulting in the impairment of sexually-dimorphic behaviors after the offspring reach maturity. To investigate the contribution of AHR to these disorders, we examined the effects of TCDD on AHR-knockout (AHR-KO) Wistar rats. Read More

    New tanshinone I derivatives S222 and S439 similarly inhibit topoisomerase I/II but reveal different p53-dependency in inducing G2/M arrest and apoptosis.
    Biochem Pharmacol 2018 May 16;154:255-264. Epub 2018 May 16.
    Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address:
    Tanshinone I (Tanshinone-1), a major active principle of the traditional Chinese medicine Salvia miltiorrhiza, possesses excellent anticancer properties, including inhibiting proliferation, angiogenesis and metastasis and overcoming multidrug resistance (MDR). However, its direct anticancer molecular target(s) remain unknown. Here we report that tanshinone-1 and its two new derivatives, S222 and S439, directly inhibit DNA topoisomerase I/II (Top1/2). Read More

    Quercetin ameliorates kidney injury and fibrosis by modulating M1/M2 macrophage polarization.
    Biochem Pharmacol 2018 May 15;154:203-212. Epub 2018 May 15.
    Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address:
    Interstitial inflammation is the main pathological feature in kidneys following injury, and the polarization of macrophages is involved in the process of inflammatory injury. Previous studies have shown that quercetin has a renal anti-inflammatory activity, but the potential molecular mechanism remains unknown. In obstructive kidneys, administration of quercetin inhibited tubulointerstitial injury and reduced the synthesis and release of inflammatory factors. Read More

    Tabersonine attenuates lipopolysaccharide-induced acute lung injury via suppressing TRAF6 ubiquitination.
    Biochem Pharmacol 2018 May 7;154:183-192. Epub 2018 May 7.
    Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou 221004, PR China; Research Center for Cancer Precision Medicine, Department of Laboratory Medicine, Bengbu Medical College, Bengbu 233030, PR China. Electronic address:
    Sepsis caused by Gram-negative bacteria is one of major causes for the progression of acute lung injury (ALI) with limited treatment and effective medicines. Tabersonine is an indole alkaloid mainly isolated from Catharanthus roseus, and a potential drug candidate for treatment of cancer and Alzheimer's disease (AD), however, its anti-inflammatory effect has not been revealed. In this study, we reported that tabersonine ameliorated lipopolysaccharides (LPS)-induced ALI in vivo and inhibited LPS-mediated macrophage activation in vitro. Read More

    Lansoprazole reduces renal cyst in polycystic kidney disease via inhibition of cell proliferation and fluid secretion.
    Biochem Pharmacol 2018 May 7;154:175-182. Epub 2018 May 7.
    Research Center of Transport Protein for Medical Innovation, Department of Physiology, Faculty of Science, Mahidol University, Rama VI Road, Ratchathewi, Bangkok 10400, Thailand; Excellent Center for Drug Discovery, Mahidol University, Rama VI Road, Ratchathewi, Bangkok 10400, Thailand. Electronic address:
    Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) is mediated by abnormal cyst-ling cell proliferation and fluid accumulation. Liver X receptor (LXR)-activating ligands suppresses renal cyst enlargement by modulation of cysticfibrosis transmembrane conductance regulator (CFTR)-mediated fluid accumulation. Lansoprazole has been reported as agonist of LXR, and shows an anti-proliferative effect in cancer cells. Read More

    Exploiting methionine restriction for cancer treatment.
    Biochem Pharmacol 2018 May 4;154:170-173. Epub 2018 May 4.
    Rutgers Cancer Institute of New Jersey, USA. Electronic address:
    Normal cells can synthesize sufficient methionine for growth requirements from homocysteine and 5-methyltetrahydrofolate and vitamin B12. However, many cancer-cell types require exogenous methionine for survival and therefore methionine restriction is a promising avenue for treatment. While the lack of the methionine salvage enzyme methylthioadenosine phosphorylase (MTAP) deficiency is associated with methionine dependence in cancer cells, there are other causes for tumors to require exogenous methionine. Read More

    Resistin facilitates VEGF-C-associated lymphangiogenesis by inhibiting miR-186 in human chondrosarcoma cells.
    Biochem Pharmacol 2018 May 3;154:234-242. Epub 2018 May 3.
    Department of Medicine, Mackay Medical College, New Taipei City, Taiwan; Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:
    Chondrosarcoma is a common primary malignant tumor of the bone that can metastasize through the vascular system to other organs. A key step in the metastatic process, lymphangiogenesis, involves vascular endothelial growth factor-C (VEGF-C). However, the effects of lymphangiogenesis in chondrosarcoma metastasis remain to be clarified. Read More

    RACking up ceramide-induced islet β-cell dysfunction.
    Biochem Pharmacol 2018 Apr 30;154:161-169. Epub 2018 Apr 30.
    Department of Ophthalmology and Anatomy and Cell Biology, Wayne State University, Detroit, MI 48201, USA.
    The International Diabetes Federation predicts that by 2045 the number of individuals afflicted with diabetes will increase to 629 million. Furthermore, ∼352 million individuals with impaired glucose tolerance are at increased risk for developing diabetes. Several mechanisms have been proposed for the onset of metabolic dysfunction and demise of the islet β-cell leading to the pathogenesis of diabetes. Read More

    New insights about the peculiar role of the 28-38 C-terminal segment and some selected residues in PACAP for signaling and neuroprotection.
    Biochem Pharmacol 2018 Apr 25;154:193-202. Epub 2018 Apr 25.
    INRS - Institut Armand-Frappier, Groupe de Recherche en Ingénierie des Peptides et en Pharmacothérapie (GRIPP), Université du Québec, Ville de Laval, QC, Canada. Electronic address:
    The pituitary adenylate cyclase-activating polypeptide (PACAP), which exists in two isoforms of 27 and 38 amino acids, can induce neuronal protection in vitro and in vivo following the activation of PAC1, a class B G protein-coupled receptor (GPCR). With its potent neuroprotective and anti-inflammatory effects, this peptide represents a promising avenue for the development of therapeutic strategies to potentially cure or at least slow the progression of neurodegenerative disorders. Beyond the canonical G protein signal effectors, GPCRs are also coupled to a multitude of intracellular signaling pathways that can be independently activated by biased ligands, thereby expanding vastly the potential for discovering new drugs. Read More

    Effect of a long-term treatment with metformin in dystrophic mdx mice: A reconsideration of its potential clinical interest in Duchenne muscular dystrophy.
    Biochem Pharmacol 2018 Apr 21;154:89-103. Epub 2018 Apr 21.
    Section of Pharmacology, Department of Pharmacy - Drug Sciences, University of Bari "Aldo Moro", Bari, Italy. Electronic address:
    The pharmacological stimulation of AMP-activated protein kinase (AMPK) via metabolic enhancers has been proposed as potential therapeutic strategy for Duchenne muscular dystrophy (DMD). Metformin, a widely-prescribed anti-hyperglycemic drug which activates AMPK via mitochondrial respiratory chain, has been recently tested in DMD patients in synergy with nitric oxide (NO)-precursors, with encouraging results. However, preclinical data supporting the use of metformin in DMD are still poor, and its actions on skeletal muscle appear controversial. Read More

    Identification of a pyrogallol derivative as a potent and selective human TLR2 antagonist by structure-based virtual screening.
    Biochem Pharmacol 2018 Apr 22;154:148-160. Epub 2018 Apr 22.
    Freie Universität Berlin, Institute of Pharmacy (Pharmacology and Toxicology), Germany. Electronic address:
    Toll-like receptor 2 (TLR2) induces early inflammatory responses to pathogen and damage-associated molecular patterns trough heterodimerization with either TLR1 or TLR6. Since overstimulation of TLR2 signaling is linked to several inflammatory and metabolic diseases, TLR2 antagonists may provide therapeutic benefits for the control of inflammatory conditions. We present virtual screening for the identification of novel TLR2 modulators, which combines analyses of known ligand sets with structure-based approaches. Read More

    Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells.
    Biochem Pharmacol 2018 Apr 21;154:118-126. Epub 2018 Apr 21.
    Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany; Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Electronic address:
    ABC transporters are key players in drug excretion with alterations in their expression and activity by therapeutic agents potentially leading to drug-drug interactions. The interaction potential of nomegestrol acetate (NMGA), a synthetic progestogen increasingly used as oral contraceptive, had never been explored. In this work we evaluated (1) the effect of NMGA on ABC transporters in the human hepatic cell line HepG2 and (2) the underlying molecular mechanism. Read More

    Angiotensin II cyclic analogs as tools to investigate ATR biased signaling mechanisms.
    Biochem Pharmacol 2018 Apr 20;154:104-117. Epub 2018 Apr 20.
    Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada. Electronic address:
    G protein coupled receptors (GPCRs) produce pleiotropic effects by their capacity to engage numerous signaling pathways once activated. Functional selectivity (also called biased signaling), where specific compounds can bring GPCRs to adopt conformations that enable selective receptor coupling to distinct signaling pathways, continues to be significantly investigated. However, an important but often overlooked aspect of functional selectivity is the capability of ligands such as angiotensin II (AngII) to adopt specific conformations that may preferentially bind to selective GPCRs structures. Read More

    Acetaminophen-induced liver injury is attenuated in transgenic fat-1 mice endogenously synthesizing long-chain n-3 fatty acids.
    Biochem Pharmacol 2018 Apr 18;154:75-88. Epub 2018 Apr 18.
    State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China. Electronic address:
    Acetaminophen (APAP) overdose-induced hepatotoxicity is the most commonly cause of drug-induced liver failure characterized by oxidative stress, mitochondrial dysfunction, and cell damage. Therapeutic efficacy of omega-3 polyunsaturated fatty acids (n-3 PUFA) in several models of liver disease is well documented. However, the impacts of n-3 PUFA on APAP hepatotoxicity are not adequately addressed. Read More

    A novel SMAC mimetic APG-1387 exhibits dual antitumor effect on HBV-positive hepatocellular carcinoma with high expression of cIAP2 by inducing apoptosis and enhancing innate anti-tumor immunity.
    Biochem Pharmacol 2018 Apr 18;154:127-135. Epub 2018 Apr 18.
    State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 51000, PR China; Suzhou Ascentage Pharma Inc., Jiangsu 215123, PR China. Electronic address:
    Check point inhibitor anti-PD1 antibody produced some efficacy in Hepatocellular Carcinoma (HCC) patients previously treated with sorafenib. Unfortunately, HCC patients with hepatitis B virus (HBV) infection did not respond as well as uninfected patients. Previously, Second mitochondria-derived activator of caspases (SMAC) mimetics-the antagonist for inhibitor of apoptosis proteins (IAPs) can rapidly reduce serum hepatitis B virus DNA in animal model. Read More

    Inhibitory effects of drugs on the metabolic activity of mouse and human aldehyde oxidases and influence on drug-drug interactions.
    Biochem Pharmacol 2018 Apr 17;154:28-38. Epub 2018 Apr 17.
    Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan.
    As aldehyde oxidase (AOX) plays an emerging role in drug metabolism, understanding its significance for drug-drug interactions (DDI) is important. Therefore, we tested 10 compounds for species-specific and substrate-dependent differences in the inhibitory effect of AOX activity using genetically engineered HEK293 cells over-expressing human AOX1, mouse AOX1 or mouse AOX3. The IC values of 10 potential inhibitors of the three AOX enzymes were determined using phthalazine and O-benzylguanine as substrates. Read More

    Sorafenib suppresses TGF-β responses by inducing caveolae/lipid raft-mediated internalization/degradation of cell-surface type II TGF-β receptors: Implications in development of effective adjunctive therapy for hepatocellular carcinoma.
    Biochem Pharmacol 2018 Apr 18;154:39-53. Epub 2018 Apr 18.
    Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung 80424, Taiwan, ROC; Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung 80424, Taiwan, ROC. Electronic address:
    Sorafenib is the only FDA approved drug for the treatment of advanced hepatocellular carcinoma (HCC) and other malignancies. Studies indicate that TGF-β signalling is associated with tumour progression in HCC. Autocrine and paracrine TGF-β promotes tumour growth and malignancy by inducing epithelial-mesenchymal transition (EMT). Read More

    Tanshinone IIA suppresses FcεRI-mediated mast cell signaling and anaphylaxis by activation of the Sirt1/LKB1/AMPK pathway.
    Biochem Pharmacol 2018 Jun 17;152:362-372. Epub 2018 Apr 17.
    College of Pharmacy, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk 38541, Republic of Korea. Electronic address:
    AMP-activated protein kinase (AMPK) and its upstream mediators liver kinase B1 (LKB1) and sirtuin 1 (Sirt1) are generally known as key regulators of metabolism. We have recently reported that the AMPK pathway negatively regulates mast cell activation and anaphylaxis. Tanshinone IIA (Tan IIA), an active component of Salvia miltiorrhiza extract that is currently used for the treatment of cardiovascular and cerebrovascular diseases, shows anti-diabetic activity and improves insulin resistance in db/db mice through activation of AMPK. Read More

    Dengue virus NS2 and NS4: Minor proteins, mammoth roles.
    Biochem Pharmacol 2018 Apr 17;154:54-63. Epub 2018 Apr 17.
    Department of Biotechnology, Sri Jayachamarajendra College of Engineering, JSS Science and Technology University, JSS TEI Campus, Mysuru 57006, Karnataka, India. Electronic address:
    Despite the ever-increasing global incidence of dengue fever, there are no specific chemotherapy regimens for its treatment. Structural studies on dengue virus (DENV) proteins have revealed potential drug targets. Major DENV proteins such as the envelope protein and non-structural (NS) proteins 3 and 5 have been extensively investigated in antiviral studies, but with limited success in vitro. Read More

    In vitro assessment of competitive and time-dependent inhibition of the nevirapine metabolism by nortriptyline in rats.
    Biochem Pharmacol 2018 Apr 17;154:1-9. Epub 2018 Apr 17.
    Department of Pharmacy and Pharmaceutical Technology and Parasitology, Faculty of Pharmacy, University of Valencia, Avda. V. Andrés Estellés, s/n, 46100 Burjassot, Valencia, Spain. Electronic address:
    Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1) widely used as a component of High Active Antiretroviral Therapy (HAART) since it is inexpensive, readily absorbed after oral administration and non-teratogenic. In the present work, the mechanism of a previously described pharmacokinetic interaction between NVP and the antidepressant drug nortriptyline (NT) was studied using rat hepatic microsomes. The obtained results showed a competitive inhibition of the NVP metabolism by NT. Read More

    Angiotensin II promotes pulmonary metastasis of melanoma through the activation of adhesion molecules in vascular endothelial cells.
    Biochem Pharmacol 2018 Apr 17;154:136-147. Epub 2018 Apr 17.
    National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan.
    Hypertension is considered as one of the cancer progressive factors, and often found comorbidity in cancer patients. Renin-angiotensin system (RAS) plays an important role in the regulation of blood pressure, and angiotensin II (Ang II) is well known pressor peptide associated with RAS. Ang II has been reported to accelerate progression and metastasis of cancer cells. Read More

    Ribociclib shows potential for pharmacokinetic drug-drug interactions being a substrate of ABCB1 and potent inhibitor of ABCB1, ABCG2 and CYP450 isoforms in vitro.
    Biochem Pharmacol 2018 Apr 16;154:10-17. Epub 2018 Apr 16.
    Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Czech Republic. Electronic address:
    Ribociclib is a novel cyclin-dependent kinase (CDK) 4 and 6 selective inhibitor that recently gained breakthrough therapy status and global approval for advanced breast cancer treatment. ATP-binding cassette (ABC) transporters may become a site of severe drug interactions and a mechanism of multidrug resistance (MDR) development. With respect to rapid progress of ribociclib in the clinical field, we aimed to identify its interactions with ABC transporters and cytochrome P450 (CYP) isoenzymes and evaluate its potential to overcome transporter-mediated MDR using established in vitro methods. Read More

    Metronomic vinorelbine is directly active on Non Small Cell Lung Cancer cells and sensitizes the EGFR cells to reversible EGFR tyrosine kinase inhibitors.
    Biochem Pharmacol 2018 Jun 13;152:327-337. Epub 2018 Apr 13.
    Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Pisa, Italy. Electronic address:
    Metronomic vinorelbine (mVNR) has been described primarily as an antiangiogenic therapy, and no direct effects of mVNR on Non Small Cell Lung Cancer (NSCLC) cells has yet been demonstrated. The aims of this study were i) to establish the direct activity of mVNR on NSCLC cells either EGFR wt or EGFR, and ii) to quantify the synergism of the combination with reversible EGFR tyrosine kinase inhibitors (TKIs), investigating the underlying mechanism of action. Proliferation assays were performed on A-549 (wt EGFR), H-292 (EGFR-wt), H-358 (EGFR-wt), H-1975 (EGFR) NSCLC cell lines exposed to mVNR, its active metabolite deacetyl-VNR (D-VNR), gefitinib and erlotinib for 144 h treatments. Read More

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