Inorganic polyphosphate protects against lipopolysaccharide-induced lethality and tissue injury through regulation of macrophage recruitment.


:Sepsis is an etiologically complex and often fatal inflammatory process involving a multitude of cytokine signaling pathways. Tumor necrosis factor α (TNFα) acts as a central regulator of the acute-phase inflammatory response by recruiting immune cells, including circulating monocyte/macrophages, to sites of infection or tissue damage. Inorganic polyphosphate (polyP), a linear polymer of orthophosphate residues, has been found in almost all cells and tissues, but its functions in immunity remain largely unknown. In this study, we show that pre- or post-treatment of mice with polyP150 (average chain length of 150 phosphate residues) markedly increases survival from lipopolysaccharide (LPS)-induced shock and inhibits macrophage recruitment to the liver and lungs, resulting in protection against tissue injury. In accord with these in vivo results, pretreatment of cultured peritoneal macrophages with polyP150 inhibited chemotaxis and actin polarization in response to TNFα. PolyP150 also inhibited phosphorylation of stress-activated protein kinases c-Jun N-terminal kinase (JNK) and p38, two downstream signaling molecules of the TNFα cascade, thereby preventing cyclooxygenase-2 gene expression by macrophages. These findings suggest that polyP150 inhibits recruitment of macrophages into organs by regulating the TNFα-JNK/p38 pathway, which may, in turn, protect against multi-organ dysfunction and lethality induced by LPS. Our findings identify polyP regulation as a novel therapeutic target for sepsis.


Biochem Pharmacol


Biochemical pharmacology


Terashima-Hasegawa M,Ashino T,Kawazoe Y,Shiba T,Manabe A,Numazawa S




Has Abstract


2019-01-01 00:00:00












  • Modulation of 6-hydroxydopamine oxidation by various proteins.

    abstract::The spontaneous autoxidation of the neurotoxin 6-hydroxydopamine proceeds by a free radical chain reaction involving the superoxide anion radical and produces the corresponding chromogen 6-hydroxydopamine quinone and hydrogen peroxide. The rate of this reaction is increased in the presence of ceruloplasmin and peroxid...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章,评审


    authors: Padiglia A,Medda R,Lorrai A,Biggio G,Sanna E,Floris G

    更新日期:1997-04-25 00:00:00

  • Characterization of AN6001, a positive allosteric modulator of α6β2-containing nicotinic acetylcholine receptors.

    abstract::α6β2-Containing nicotinic acetylcholine receptors (α6β2* nAChRs) are predominantly expressed in midbrain dopaminergic neurons, including substantia nigra pars compacta (SNc) neurons and their projections to striatal regions, where they regulate dopamine release and nigrostriatal activity. It is well established that n...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: van Hout M,Klein J,Ahring PK,Brown DT,Thaneshwaran S,Dos Santos AB,Jensen AA,Kohlmeier KA,Christophersen P,Dyhring T

    更新日期:2020-04-01 00:00:00

  • Bioactivation of N-arylhydroxamic acids by rat hepatic N-acetyltransferase. Detection of multiple enzyme forms by mechanism-based inactivation.

    abstract::Enzymatic N,O-acyltransfer of carcinogenic N-arylhydroxamic acids such as N-hydroxy-2-acetylaminofluorene (N-OH-AAF) results in the production of reactive electrophiles that can bond covalently with nucleophiles and also can cause inactivation of acyltransferase activity in a mechanism-based manner. Incubation of part...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Wick MJ,Hanna PE

    更新日期:1990-03-15 00:00:00

  • Intracellular glutathione as a determinant of responsiveness to antitumor drugs.

    abstract::The effect of glutathione depletion on cytotoxicity of the anthracycline daunorubicin, and of a copper:bis-thiosemicarbazone chelate, was examined in the P388 murine leukemia and its anthracycline-resistant subline, P388/ADR. Depletion of intracellular glutathione was accomplished through exposure to buthionine sulfox...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Romine MT,Kessel D

    更新日期:1986-10-01 00:00:00

  • Contribution of different phospholipases and arachidonic acid metabolites in the response of gallbladder smooth muscle to cholecystokinin.

    abstract::Guinea pig gallbladder muscle strips were used to investigate the contribution of different sources of diacylglicerol (DAG) in the cholecystokinin (CCK)-induced contraction. The involvement of arachidonic acid (AA) in this response was also investigated. Three distinct pathways for DAG production were investigated wit...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Alcón S,Morales S,Camello PJ,Pozo MJ

    更新日期:2002-10-01 00:00:00

  • Modulation of 5-fluorouracil cytotoxicity through thymidylate synthase and NF-kappaB down-regulation and its application on the radiolabelled iododeoxyuridine therapy on human hepatoma cell.

    abstract::The inhibition of thymidylate synthase (TS) by 5-fluorouracil (5-FU) was known to increase the incorporation of radiolabelled iododeoxyuridine (IdUrd) into DNA. The relatively non-toxic compounds such as thiol-containing antioxidant pyrrolidinodithiocarbamte (PDTC) or aromatic fatty acid phenylbutyrate (PB) had been r...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Wang HE,Wu HC,Kao SJ,Tseng FW,Wang YS,Yu HM,Chou SL,Yen SH,Chi KH

    更新日期:2005-02-15 00:00:00

  • Inhibition of phosphate transport in rat heart mitochondria by 3'-azido-3'-deoxythymidine due to stimulation of superoxide anion mitochondrial production.

    abstract::In order to gain some insight into the mechanism by which 3'-azido-3'-deoxythymidine (AZT) damages mitochondria, we investigated whether externally added AZT can stimulate reactive oxygen species (ROS) production by rat heart mitochondria (RHM). An increase in superoxide anion ((O(2)(.-)) production was measured in RH...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Valenti D,Atlante A,Barile M,Passarella S

    更新日期:2002-07-15 00:00:00

  • Studies on the action of nystatin on cultured rat myocardial cells and cell membranes, isolated rat hearts, and intact rats.

    abstract::The action of nystatin, a polyene antibiotic, was studied in rat myocardial cells, isolated rat hearts, and intact rats. Myocardial cells responded to 10 and 25 micrograms nystatin/ml with arrhythmias that could be minimized by elevated concentrations of K+ and Mg2+ or reversed by washing the cells. Similarly, the iso...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Aszalos A,Bradlaw JA,Reynaldo EF,Yang GC,El-Hage AN

    更新日期:1984-12-01 00:00:00

  • A novel fluorinated triazole derivative suppresses macrophage activation and alleviates experimental colitis via a Twist1-dependent pathway.

    abstract::Hyperactivated macrophages play a key role in the initiation and perpetuation of mucosal inflammation in Crohn's disease (CD). Increasing evidence suggests that the basic helix-loop-helix (bHLH) repressor Twist1 can suppress activation of nuclear factor-κB (NF-κB) and the subsequent production of TNF-α, which are both...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Tu T,Yu M,Zhang Y,Shi X,Xu J,Hu J,Gan J,He W,Dong L,Han J,Huang Z,Pan Y,Zhang J

    更新日期:2018-09-01 00:00:00

  • Coordinate regulation between the nuclear receptor peroxisome proliferator-activated receptor-γ and cyclooxygenase-2 in renal epithelial cells.

    abstract::The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors involved in lipid metabolism and glucose utilization, in cell growth, differentiation and apoptosis, and in the regulation of pro-inflammatory genes expression such as cyclooxygenase-2 (COX-2). PPARγ is the main isoform ...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Casali CI,Weber K,Faggionato D,Gómez EM,Tome MC

    更新日期:2014-08-15 00:00:00

  • Serotonin glucuronidation by Ah receptor- and oxidative stress-inducible human UDP-glucuronosyltransferase (UGT) 1A6 in Caco-2 cells.

    abstract::Caco-2 cells are a widely used model in drug development to study intestinal drug transport and metabolism. Recently, serotonin (5-hydroxytryptamine, 5-HT) has been characterized as a highly selective substrate of human UDP-glucuronosyltransferase UGT1A6 [Krishnaswamy S, Duan SX, von Moltke LL, Greenblatt DJ, Court MH...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Köhle C,Badary OA,Nill K,Bock-Hennig BS,Bock KW

    更新日期:2005-05-01 00:00:00

  • Inhibition of hyaluronan export from human fibroblasts by inhibitors of multidrug resistance transporters.

    abstract::In a previous report we described the export of hyaluronan from Streptococcus pyogenes by an ABC transporter. Extending these findings a sequence homology search against human proteins revealed a strong homology to the multidrug resistance transporter ABC-B (MDR-1) and ABC-C (MRP 5). Using several inhibitors directed ...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Prehm P,Schumacher U

    更新日期:2004-10-01 00:00:00

  • An indirubin derivative, E804, exhibits potent angiosuppressive activity.

    abstract::Angiogenesis, the development of neovessels from pre-existing vessels, is obligatory for solid tumors survival, growth, invasion, and metastasis. Many anti-angiogenic agents are small molecules originated from natural sources. Recently, angiosuppressive effects of indirubin and its derivatives, the active components i...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Chan YK,Kwok HH,Chan LS,Leung KS,Shi J,Mak NK,Wong RN,Yue PY

    更新日期:2012-03-01 00:00:00

  • Superoxide anion mediates the L-selectin down-regulation induced by non-steroidal anti-inflammatory drugs in human neutrophils.

    abstract:UNLABELLED:Non-steroidal anti-inflammatory drugs (NSAIDs) induce the shedding of L-selectin in human neutrophils through a mechanism still not well understood. In this work we studied both the functional effect of NSAIDs on the neutrophils/endothelial cells dynamic interaction, and the potential involvement of reactive...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Domínguez-Luis M,Herrera-García A,Arce-Franco M,Armas-González E,Rodríguez-Pardo M,Lorenzo-Díaz F,Feria M,Cadenas S,Sánchez-Madrid F,Díaz-González F

    更新日期:2013-01-15 00:00:00

  • In vivo chronic exposure to heroin or naltrexone selectively inhibits liver microsome formation of estradiol-3-glucuronide in the rat.

    abstract::We have previously found that repeated exposure to heroin reduces liver synthesis of morphine-3-glucuronide (M3G) and increases the production of morphine-6-glucuronide (M6G), which normally is not formed in the rat. By contrast repeated exposure to naltrexone does not activate M6G synthesis but increases the V(max) o...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Antonilli L,Brusadin V,Milella MS,Sobrero F,Badiani A,Nencini P

    更新日期:2008-09-01 00:00:00

  • Effects of chronic administration of the peroxisome proliferator, clofibrate, on cytosolic acetyl-CoA hydrolase in rat liver.

    abstract::The hypolipidemic drug ethyl chlorophenoxyisobutyrate (clofibrate) is known to induce peroxisome proliferation and to be carcinogenic after long term administration to rats and mice. We examined the effects of treatment with this drug for periods of up to 18 months on cytosolic ATP-stimulated and ADP-inhibited acetyl-...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Nakanishi Y,Okamoto K,Isohashi F

    更新日期:1993-04-06 00:00:00

  • Deoxyelephantopin inhibits cancer cell proliferation and functions as a selective partial agonist against PPARgamma.

    abstract::Deoxyelephantopin (ESD) was reported to potentiate apoptosis, inhibit invasion and abolish osteoclastogenesis but no target protein was disclosed. Here, we discovered that ESD could significantly inhibit the proliferation of different cancer cells and induce apoptosis and cell cycle arrest at G(2)/M phase in HeLa cell...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Zou G,Gao Z,Wang J,Zhang Y,Ding H,Huang J,Chen L,Guo Y,Jiang H,Shen X

    更新日期:2008-03-15 00:00:00

  • Protein phosphatase 2A: who shall regulate the regulator?

    abstract::Protein phosphatases are responsible for keeping the signaling output of stimulus-activated protein kinases in check; but protein phosphatases are also themselves targets and conveyors of biological signals. Among the major serine/threonine phosphatases, protein phosphatase 2A (PP2A) appears to play a privileged role ...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章,评审


    authors: Goldberg Y

    更新日期:1999-02-15 00:00:00

  • Niacin induces PPARgamma expression and transcriptional activation in macrophages via HM74 and HM74a-mediated induction of prostaglandin synthesis pathways.

    abstract::HM74 and HM74a have been identified as receptors for niacin. HM74a mediates the pharmacological anti-lipolytic effects of niacin in adipocytes by reducing intracellular cyclic AMP (cAMP) and inhibiting release of free fatty acids into the circulation. In macrophages, niacin induces peroxisome proliferator-activated re...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Knowles HJ,te Poele RH,Workman P,Harris AL

    更新日期:2006-02-28 00:00:00

  • Ethanol binding to a model carbohydrate, glycogen.

    abstract::The binding affinity of ethanol for carbohydrates is unknown. Glycoconjugates are postulated to be sensitive targets of ethanol action. The glycogen content of muscle, liver, and brain is sensitive to ethanol. To explore whether carbohydrates as a class have a specific affinity to bind ethanol, we measured the binding...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Channareddy S,Jose SS,Janes N

    更新日期:1996-12-24 00:00:00

  • Cudratricusxanthone G inhibits human colorectal carcinoma cell invasion by MMP-2 down-regulation through suppressing activator protein-1 activity.

    abstract::Cudratricusxanthone G (CTXG), a natural bioactive cudratricusxanthone extracted from C. tricuspidata, has shown anti-cancer properties. However, the function and mechanism of CTXG in tumor invasion have not been elucidated to date. In this study, we investigated the inhibitory effect of CTXG on the proliferation, migr...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Kuang L,Wang L,Wang Q,Zhao Q,Du B,Li D,Luo J,Liu M,Hou A,Qian M

    更新日期:2011-05-15 00:00:00

  • Regulation of serotonin transporter activity by adenosine in intestinal epithelial cells.

    abstract::Serotonin plays a critical role in the regulation of intestinal physiology. The serotonin transporter (SERT) expressed in the intestinal epithelium determines 5-HT availability and activity. The serotoninergic system and SERT activity have been described as being altered in chronic intestinal pathologies such as infla...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Matheus N,Mendoza C,Iceta R,Mesonero JE,Alcalde AI

    更新日期:2009-11-01 00:00:00

  • H1 and H2 histamine receptors in N-nitroso-N-methylurea (NMU)-induced carcinomas with atypical coupling to signal transducers.

    abstract::Two specific binding sites for histamine were characterized in the cell membrane of N-nitroso-N-methylurea (NMU)-induced tumors. The first one, with higher affinity (Kd = 4 +/- 2 nM), was further identified as an H2 type, while the lower affinity one (35 +/- 10 nM) corresponded to an H1 receptor. Histamine concentrati...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Davio CA,Cricco GP,Bergoc RM,Rivera ES

    更新日期:1995-06-29 00:00:00

  • Strain differences in susceptibility of normal and diabetic rats to acetaminophen hepatotoxicity.

    abstract::The effects of streptozotocin (STZ)-induced diabetes on acetaminophen metabolism and hepatotoxicity in male Sprague-Dawley (SD) and Long Evans Hooded (LEH) rats were compared. In agreement with earlier studies, normal SD rats were more resistant to acetaminophen-induced hepatic necrosis than normal LEH rats. In contra...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Price VF,Jollow DJ

    更新日期:1986-02-15 00:00:00

  • Reduction and transport of lipoic acid by human erythrocytes.

    abstract::Reduction of exogenous lipoic acid to dihydrolipoate is known to occur in several mammalian cells and tissues. Dihydrolipoate is a potent radical scavenger, and may provide significant antioxidant protection. Because lipoic acid appears in the bloodstream after oral administration, we have examined the reduction of ex...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Constantinescu A,Pick U,Handelman GJ,Haramaki N,Han D,Podda M,Tritschler HJ,Packer L

    更新日期:1995-07-17 00:00:00

  • Brain cholinergic vulnerability: relevance to behavior and disease.

    abstract::The major populations of cholinergic neurons in the brain include two "projection" systems, located in the pontine reticular formation and in the basal forebrain. These two complexes comprise, in part, the anatomical substrates for the "ascending reticular activating system" (ARAS). The pontine cholinergic system rela...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章,评审


    authors: McKinney M,Jacksonville MC

    更新日期:2005-10-15 00:00:00

  • The role of cytochrome P450 and cytochrome P450 reductase in the reductive bioactivation of the novel benzotriazine di-N-oxide hypoxic cytotoxin 3-amino-1,2,4-benzotriazine-1,4-dioxide (SR 4233, WIN 59075) by mouse liver.

    abstract::SR 4233 or WIN 59075 (3-amino-1,2,4-benzotriazine-1,4-dioxide) is a novel and highly selective hypoxic cell cytotoxin requiring reductive bioactivation for its impressive antitumour effects. Expression of appropriate reductases will contribute to therapeutic selectivity. Here we provide more detailed information on th...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Walton MI,Wolf CR,Workman P

    更新日期:1992-07-22 00:00:00

  • Concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, JAK2 and BCMA in human multiple myeloma cells by multi-kinase targeting.

    abstract::The identification of proliferation/survival pathways constitutively activated by genetic alterations in multiple myeloma (MM), or sustained by the bone marrow (BM) microenvironment, provides novel opportunities for the development of targeted therapies. The deregulated function of protein tyrosine kinases plays a cri...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Cassinelli G,Ronchetti D,Laccabue D,Mattioli M,Cuccuru G,Favini E,Nicolini V,Greco A,Neri A,Zunino F,Lanzi C

    更新日期:2009-11-01 00:00:00

  • Effect of oxygen tension on the generation of alkanes and malondialdehyde by peroxidizing rat liver microsomes.

    abstract::The alkanes, ethane and pentane, are often used as indices of lipid peroxidation. Because it has been indicated that O2 tension can affect the yield of these compounds, a systematic study of this was carried out. Rat liver microsomes were peroxidized using an iron-ascorbate system. The incubations were carried out in ...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Reiter R,Burk RF

    更新日期:1987-03-15 00:00:00

  • Stereoselective metabolism of 3-isopropyl-5-(1-naphthoxymethyl)oxazolidine, a prodrug of propranolol.

    abstract::This investigation suggests that the oxazolidine derivative of propranolol is a prodrug which is hydrolysed stereoselectively to propranolol by hepatic post-mitochondrial supernatant. The (S)-form of the prodrug is more stable in the biological system than its (R)-form. ...

    journal_title:Biochemical pharmacology

    pub_type: 杂志文章


    authors: Kamal A,Rao AB,Rao MV

    更新日期:1991-05-01 00:00:00