gain of affinity for vegf165 binding within the vegfr2/nrp1 cellular complex detected by an HTRF-based binding assay.
Abstract Neuroplin 1 (NRP1), a transmembrane protein interacting with Vascular Endothelial Growth Factor VEGF-A165 (called here VEGF165) and the tyrosine kinase Receptor 2 (VEGFR2) promote angiogenesis and vascular homeostasis. In a pathophysiological context, several studies suggested that VEGFR2 and NRP1 mediate tumor development and progression. Given the involvement of the VEGF165 network in promoting tumor angiogenesis, NRP1, VEGFR2 and VEGF165 have been identified as targets for anti-angiogenic therapy. No binding assay exists to monitor specifically the binding of VEGF165 to the VEGFR2/NRP1 complex in intac...
Source: Biochemical Pharmacology - September 17, 2018 Category: Drugs & Pharmacology Authors: Auriau J, Roujeau C, Choucair ZB, Oishi A, Derviaux C, Roux T, Trinquet E, Hermine O, Jockers R, Dam J Tags: Biochem Pharmacol Source Type: research

The potential role of adenosine signaling in the pathogenesis of melanoma.
Abstract Melanoma cancer cell proliferation, motility, invasion, and tumor growth is affected by the adenosine pathway that consists of adenosine-synthesizing enzymes, receptors, and their respective agonists/antagonists. Accumulating evidence suggests that ischemia and inflammation, two conditions associated with melanoma, display dysregulated adenosine metabolism, which implicates it as the mechanism responsible for the pathogenesis of melanoma, thereby resulting in advanced diagnosis and therapy. Suppression of adenosine signaling by inhibiting adenosine receptors or adenosine-generating enzymes (CD39 and CD73)...
Source: Biochemical Pharmacology - September 16, 2018 Category: Drugs & Pharmacology Authors: Bahreyni A, Rezaei M, Khazaei M, Fuiji H, Ferns GA, Ryzhikov M, Avan A, Hassanian SM Tags: Biochem Pharmacol Source Type: research

Computational systems biology approach to identify novel pharmacological targets for diabetic retinopathy.
Abstract Diabetic retinopathy was included by the World Health Organization in the eye disease priority list. Up to now, only proliferative diabetic retinopathy can be treated with approved drugs such as intravitreal anti-vascular endothelial growth factor (VEGF) agents or steroids. In this perspective, there is the urgent need to explore novel pharmacological targets for treatment of diabetic retinopathy. Drug discovery todays exploits the noticeable ability of computational systems biology methods to identify novel drug targets in complex pathologies bearing multifactorial etiology and wide and varying symptomat...
Source: Biochemical Pharmacology - September 14, 2018 Category: Drugs & Pharmacology Authors: Platania CBM, Leggio GM, Drago F, Salomone S, Bucolo C Tags: Biochem Pharmacol Source Type: research

Specific tissue factor delivery using a tumor-homing peptide for inducing tumor infarction.
In this study, we investigated the thrombogenic activity and anti-tumor potential of a novel fusion protein (tTF-CREKA) comprising the extracellular domain of human tissue factor (truncated TF, tTF) and a tumor targeting pentapeptide, Cys-Arg-Glu-Lys-Ala (CREKA). tTF is soluble and inactive in its free state, but when it is targeted to the plasma membrane of both tumor vessel endothelial cells and stromal cells by the CREKA peptide, its native coagulation-inducing activity is restored. Systemic administration of the tTF-CREKA fusion protein into tumor-bearing mice induced tumor-selective intravascular thrombosis and reduce...
Source: Biochemical Pharmacology - September 14, 2018 Category: Drugs & Pharmacology Authors: Shi Q, Zhang Y, Liu S, Liu G, Xu J, Zhao X, Anderson GJ, Nie G, Li S Tags: Biochem Pharmacol Source Type: research

LKB1 loss is associated with glutathione deficiency under oxidative stress and sensitivity of cancer cells to cytotoxic drugs and γ-irradiation.
LKB1 loss is associated with glutathione deficiency under oxidative stress and sensitivity of cancer cells to cytotoxic drugs and γ-irradiation. Biochem Pharmacol. 2018 Sep 14;: Authors: Zulato E, Ciccarese F, Agnusdei V, Pinazza M, Nardo G, Iorio E, Curtarello M, Silic-Benussi M, Rossi E, Venturoli C, Panieri E, Santoro MM, Di Paolo V, Quintieri L, Ciminale V, Indraccolo S Abstract The liver kinase B1 (LKB1) gene is a tumor suppressor associated with the hereditary Peutz-Jeghers syndrome and frequently mutated in non-small cell lung cancer and in cervical cancer. Previous studies showed that th...
Source: Biochemical Pharmacology - September 14, 2018 Category: Drugs & Pharmacology Authors: Zulato E, Ciccarese F, Agnusdei V, Pinazza M, Nardo G, Iorio E, Curtarello M, Silic-Benussi M, Rossi E, Venturoli C, Panieri E, Santoro MM, Di Paolo V, Quintieri L, Ciminale V, Indraccolo S Tags: Biochem Pharmacol Source Type: research

About canonical, non-canonical and immunogenic cell death: basic mechanisms and translational applications: a meeting report of the International Cell Death Society.
Abstract International Cell Death Society held its 25th meeting, entitled "About canonical, non-canonical, and immunogenic cell death: basic mechanisms and translational applications" in Seoul, South Korea, May 31-June 2, 2018, addressed the most current issues in the field. Now that many types and pathways of cell death are recognized, attention has turned to how the threshold to death is maintained or surpassed, and how and what intracellular signals control the process. Most of the speakers addressed these topics, focusing on mitochondria and on new high-resolution techniques that promise to answer cu...
Source: Biochemical Pharmacology - September 14, 2018 Category: Drugs & Pharmacology Authors: Zakeri Z, Lockshin RA, Diederich M Tags: Biochem Pharmacol Source Type: research

Pancreatic Ductal Adenocarcinoma Cell Secreted Extracellular Vesicles Containing Ceramide-1-Phosphate Promote Pancreatic Cancer Stem Cell Motility.
Abstract The high mortality rate associated with pancreatic ductal adenocarcinoma (PDAC) is in part due to lack of effective therapy for this highly chemoresistant tumor. Cancer stem cells, a subset of cancer cells responsible for tumor initiation and metastasis, are not targeted by conventional cytotoxic agents, which renders the identification of factors that facilitate cancer stem cell activation useful in defining targetable mechanisms. We determined that bioactive sphingolipid induced migration of pancreatic cancer stem cells (PCSC) and signaling was specific to ceramide-1-phosphate (C1P). Furthermore, PDAC c...
Source: Biochemical Pharmacology - September 14, 2018 Category: Drugs & Pharmacology Authors: Kuc N, Doermann A, Shirey C, Lee DD, Lowe CW, Awasthi N, Schwarz RE, Stahelin RV, Schwarz MA Tags: Biochem Pharmacol Source Type: research

Metformin downregulates the mitochondrial carrier SLC25A10 in a glucose dependent manner.
In this study we addressed the role of a mitochondrial transporter commonly upregulated in cancer cells, SLC25A10, for cell survival and metabolism in the presence of metformin. SLC25A10 is a carrier in the mitochondrial inner membrane that transports malate and succinate out of the mitochondria, in exchange of phosphate and sulfate. We show that metformin treatment results in decreased gene expression of the SLC25A10 carrier both in lung cancer A549 mock cells and A549 SLC25A10 knockdown (siSLC25A10) cells. The decrease was even more pronounced when cells were grown at low glucose concentrations. The expression levels of ...
Source: Biochemical Pharmacology - September 14, 2018 Category: Drugs & Pharmacology Authors: Zhao Q, Zhou X, Curbo S, Karlsson A Tags: Biochem Pharmacol Source Type: research

Corrigendum to "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. 154 (2018) 452-463].
Corrigendum to "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. 154 (2018) 452-463]. Biochem Pharmacol. 2018 Sep 12;156:396-397 Authors: Vosahlikova M, Ujcikova H, Hlouskova M, Musil S, Roubalova L, Alda M, Svoboda P PMID: 30218916 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - September 12, 2018 Category: Drugs & Pharmacology Authors: Vosahlikova M, Ujcikova H, Hlouskova M, Musil S, Roubalova L, Alda M, Svoboda P Tags: Biochem Pharmacol Source Type: research

Role of the endocannabinoid system in drug addiction.
es P, Maldonado R Abstract Drug addiction is a chronic relapsing disorder that produces a dramaticglobal health burden worldwide. Not effective treatment of drug addiction is currently available probably due to the difficulties to find an appropriate target to manage this complex disease raising the needs for further identification of novel therapeutic approaches.The endocannabinoid system has been found to play a crucial role in the neurobiological substrate underlying drug addiction. Endocannabinoids and cannabinoid receptors are widely expressed in the main areas of the mesocorticolimbic system that participate...
Source: Biochemical Pharmacology - September 11, 2018 Category: Drugs & Pharmacology Authors: Manzanares J, Cabañero D, Puente N, García-Gutiérrez MS, Grandes P, Maldonado R Tags: Biochem Pharmacol Source Type: research

Role of the Efflux Transporters BCRP and MRP1 in Human Placental Bio-disposition of Pravastatin.
Abstract The expression and activity of human placental transporters during pregnancy could be altered by several factors including pathological changes associated with preeclampsia. The aims of this study were to identify the placental efflux transporters involved in the bio-disposition of pravastatin, determine the protein expression of these transporters and their encoding genes as well as the activity of pravastatin uptake in placentas obtained from patients with preeclampsia. ATP-dependent uptake of [3H]-pravastatin by trophoblast tissue apical and basal membrane vesicles exhibited sigmoidal kinetics. The cur...
Source: Biochemical Pharmacology - September 11, 2018 Category: Drugs & Pharmacology Authors: Afrouzian M, Al-Lahham R, Patrikeeva S, Xu M, Fokina V, Fischer WG, Abdel-Rahman SZ, Costantine M, Ahmed MS, Nanovskaya T Tags: Biochem Pharmacol Source Type: research

Functional characterization of 40 CYP2B6 allelic variants by assessing efavirenz 8-hydroxylation.
In this study, we performed an in vitro analysis of 40 CYP2B6 allelic variant proteins including seven novel variants identified in 1070 Japanese individuals. Wild-type and 39 variant proteins were heterologously expressed in 293FT cells to estimate the kinetic parameters (Km, Vmax, and CLint) of EFZ 8-hydroxylation and 7-ethoxy-4-trifluoromethylcoumarin (7-ETC) O-deethylation activities. The concentrations of CYP2B6 variant holo-enzymes were measured by using carbon monoxide (CO)-reduced difference spectroscopy, and the wild-type and 28 variants showed a peak at 450 nm. The kinetic parameters were measured for the wild-ty...
Source: Biochemical Pharmacology - September 7, 2018 Category: Drugs & Pharmacology Authors: Watanabe T, Saito T, Rico EMG, Hishinuma E, Kumondai M, Maekawa M, Oda A, Saigusa D, Saito S, Yasuda J, Nagasaki M, Minegishi N, Yamamoto M, Yamaguchi H, Mano N, Hirasawa N, Hiratsuka M Tags: Biochem Pharmacol Source Type: research

Role Of Interleukin 1-Beta In The Inflammatory Response In A Fatty Acid Amide Hydrolase-Knockout Mouse Model Of Alzheimer's Disease.
avatt BF, Tolón RM, Romero J Abstract The search for novel therapies for the treatment of Alzheimer's disease is an urgent need, due to the current paucity of available pharmacological tools and the recent failures obtained in clinical trials. Among other strategies, the modulation of amyloid-triggered neuroinflammation by the endocannabinoid system seems of relevance. Previous data indicate that the enhancement of the endocannabinoid tone through the inhibition of the enzymes responsible for the degradation of their main endogenous ligands may render beneficial effects. Based on previously reported data, i...
Source: Biochemical Pharmacology - September 6, 2018 Category: Drugs & Pharmacology Authors: Aparicio N, Teresa Grande M, Ruiz de Martín Esteban S, López A, Ruiz-Pérez G, Amores M, Vázquez C, Martínez-Relimpio AM, Ruth Pazos M, Cravatt BF, Tolón RM, Romero J Tags: Biochem Pharmacol Source Type: research

Rifampicin ameliorates Lithium-Pilocarpine-induced seizures, consequent hippocampal damage and memory deficit in rats: impact on oxidative, inflammatory and apoptotic machineries.
Abstract Epilepsy is one of the serious neurological sequelae of bacterial meningitis. Rifampicin, the well-known broad spectrum antibiotic, is clinically used for chemoprophylaxis of meningitis. Besides its antibiotic effects, rifampicin has been proven to be an effective neuroprotective candidate in various experimental models of neurological diseases. In addition, rifampicin was found to have promising antioxidant, anti-inflammatory and anti-apoptotic effects. Herein, we investigated the anticonvulsant effect of rifampicin at experimental meningitis dose (20mg/kg, i.p.) using lithium-pilocarpine model of status...
Source: Biochemical Pharmacology - September 6, 2018 Category: Drugs & Pharmacology Authors: Ali AE, Mahdy HM, Elsherbiny DM, Azab SS Tags: Biochem Pharmacol Source Type: research

Smiglaside A ameliorates LPS-induced acute lung injury by modulating macrophage polarization via AMPK-PPAR γ pathway.
In this study, we evaluated the effects of the natural product smiglaside A, a phenylpropanoid glycoside isolated from the traditional Chinese medicinal herb Smilax riparia, on macrophage polarization and investigated the underlying mechanisms. We found that smiglaside A promoted M2 polarization and reduced M1 polarization in LPS-stimulated RAW264.7 cells and primary mouse peritoneal macrophages. Further mechanistic studies showed that the promoting effect of smiglaside A on M2 polarization was attenuated by pharmacological inhibition or gene silencing of AMP-activated protein kinase (AMPK) or peroxisome proliferator-activ...
Source: Biochemical Pharmacology - September 6, 2018 Category: Drugs & Pharmacology Authors: Wang Y, Xu Y, Zhang P, Ruan W, Zhang L, Yuan S, Pang T, Jia AQ Tags: Biochem Pharmacol Source Type: research

The activity of brain and liver cytochrome P450 2D (CYP2D) is differently affected by antidepressants in the chronic mild stress (CMS) model of depression in the rat.
Abstract The effect of two second-generation antidepressants escitalopram and venlafaxine on the activity of brain and liver cytochrome P450 2D (CYP2D) involved in the metabolism of psychotropics and neurotransmitters was determined in the chronic mild stress (CMS) model of depression. Escitalopram or venlafaxine (10 mg/kg ip/day each) were administered to control and CMS rats for 5 weeks. The activity of CYP2D was studied by measurement of the rate of bufuralol 1'-hydroxylation in microsomes derived from the liver or different brain structures. The obtained results indicate that CMS and the studied antidepressant...
Source: Biochemical Pharmacology - September 6, 2018 Category: Drugs & Pharmacology Authors: Haduch A, Rysz M, Papp M, Daniel WA Tags: Biochem Pharmacol Source Type: research

Glucagon-like peptide-1 receptor internalisation controls spatiotemporal signalling mediated by biased agonists.
Abstract The glucagon-like peptide-1 receptor (GLP-1R) is a major therapeutic target in the treatment of type 2 diabetes due to its roles in regulating blood glucose and in promoting weight loss. Like many GPCRs, it is pleiotropically coupled, can be activated by multiple ligands and is subject to biased agonism. The GLP-1R undergoes agonist mediated receptor internalisation that may be associated with spatiotemporal control of signalling and biased agonism, although to date, this has not been extensively explored. Here, we investigate GLP-1R trafficking and its importance with regard to signalling, including the ...
Source: Biochemical Pharmacology - September 6, 2018 Category: Drugs & Pharmacology Authors: Fletcher MM, Halls ML, Zhao P, Clydesdale L, Christopoulos A, Sexton PM, Wootten D Tags: Biochem Pharmacol Source Type: research

The endocannabinoid 2-arachidonoylglycerol regulates oligodendrocyte progenitor cell migration.
Abstract While the endocannabinoid 2-arachidonoylglycerol (2-AG) is thought to enhance the proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) in vitro, less is known about how endogenous 2-AG may influence the migration of these cells. When we assessed this in Agarose drop and Boyden chemotaxis chamber assays, inhibiting the sn-1-diacylglycerol lipases α and β (DAGLs) that are responsible for 2-AG synthesis significantly reduced the migration of OPCs stimulated by platelet-derived growth factor-AA (PDGF) and basic fibroblast growth factor (FGF). Likewise, antagonists of the CB1...
Source: Biochemical Pharmacology - September 6, 2018 Category: Drugs & Pharmacology Authors: Sanchez-Rodriguez MA, Gomez O, Esteban PF, Garcia-Ovejero D, Molina-Holgado E Tags: Biochem Pharmacol Source Type: research

PPAR α/CB1 receptor dual ligands as a novel therapy for alcohol use disorder: evaluation of a novel oleic acid conjugate in preclinical rat models.
PPARα/CB1 receptor dual ligands as a novel therapy for alcohol use disorder: evaluation of a novel oleic acid conjugate in preclinical rat models. Biochem Pharmacol. 2018 Sep 06;: Authors: Alen F, Decara J, Brunori G, You ZB, Bühler KM, López-Moreno JA, Cippitelli A, Pavon J, Suárez J, Gardner EL, de la Torre R, Ciccocioppo R, Serrano A, de Fonseca FR Abstract Recent studies have demonstrated the utility of drugs modulating the endogenous cannabinoid system to control excessive alcohol intake. Among them, drugs interacting with acylethanolamide receptors including cannabinoid ...
Source: Biochemical Pharmacology - September 6, 2018 Category: Drugs & Pharmacology Authors: Alen F, Decara J, Brunori G, You ZB, Bühler KM, López-Moreno JA, Cippitelli A, Pavon J, Suárez J, Gardner EL, de la Torre R, Ciccocioppo R, Serrano A, de Fonseca FR Tags: Biochem Pharmacol Source Type: research

Targeting Glioma Initiating Cells With A Combined Therapy Of Cannabinoids And Temozolomide.
Sepúlveda JM, Sánchez P, Lorente M, Velasco G Abstract Glioblastoma multiforme (GBM) is the most frequent and aggressive type of brain tumor due, at least in part, to its poor response to current anticancer treatments. These features could be explained, at least partially, by the presence within the tumor mass of a small population of cells termed Glioma Initiating Cells (GICs) that has been proposed to be responsible for the relapses occurring in this disease. Thus, the development of novel therapeutic approaches (and specifically those targeting the population of GICs) is urgently needed to improve...
Source: Biochemical Pharmacology - September 6, 2018 Category: Drugs & Pharmacology Authors: López-Valero I, Sáiz-Ladera C, Torres S, Hernández Tiedra S, García-Taboada E, Rodríguez-Fornés F, Barba M, de León DD, Salvador-Tormo N, Guzmán M, Sepúlveda JM, Sánchez P, Lorente M, Velasco G Tags: Biochem Pharmacol Source Type: research

Cannabidiol skews biased agonism at cannabinoid CB1 and CB2 receptors with smaller effect in CB1-CB2 heteroreceptor complexes.
nco R Abstract Currently, biased agonism is at the center stage of drug development approaches. We analyzed effects of a battery of cannabinoids plus/minus cannabidiol (CBD) in four functional parameters (cAMP levels, phosphorylation of extracellular signal-regulated kinases (ERK1/2), ß-arrestin recruitment and label-free/DMR) in HEK-293T cells expressing cannabinoid receptors, CB1 or CB2, or CB1-CB2 heteroreceptor complexes. In all cases two natural agonists plus two selective synthetic agonists were used. Furthermore, the effect of cannabidiol, at a dose (100 nM) that does not allow significant binding to ...
Source: Biochemical Pharmacology - September 5, 2018 Category: Drugs & Pharmacology Authors: Navarro G, Reyes-Resina I, Rivas-Santisteban R, Sánchez de Medina V, Morales P, Casano S, Ferreiro-Vera C, Lillo A, Aguinaga D, Jagerovic N, Nadal X, Franco R Tags: Biochem Pharmacol Source Type: research

Angiotensin-(1-9) reduces cardiovascular and renal inflammation in experimental renin-independent hypertension.
za MP Abstract Hypertension-induced cardiovascular and renal damage can be mediated by activation of the renin-angiotensin-aldosterone system. There are different factors beyond renin-angiotensin-aldosterone system involved in hypertension and renal damage. Inflammation has emerged as an important mediator of hypertension and cardiovascular and kidney damage. Angiotensin-(1-9), a peptide of the renin-angiotensin system, counter-regulates both the physiological and pathological actions of angiotensin II. Recent data has shown that angiotensin-(1-9) protects the heart and blood vessels from adverse cardiovascular re...
Source: Biochemical Pharmacology - September 1, 2018 Category: Drugs & Pharmacology Authors: Gonzalez L, Novoa U, Moya J, Gabrielli L, Jalil JE, García L, Chiong M, Lavandero S, Ocaranza MP Tags: Biochem Pharmacol Source Type: research

Identification of a Novel Metabolite of Vildagliptin in Humans: Cysteine Targets the Nitrile Moiety to Form a Thiazoline Ring.
In conclusion, we found that VG and ANG have the potential to covalently bind to a thiol residue of l-cysteine in proteins. Such binding may lead to unpredictable immune responses in humans. l-Cysteine, rather than GSH, would likely be useful to detect the potential for covalent binding that could initiate immune-mediated hepatotoxicity. PMID: 30172711 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - August 30, 2018 Category: Drugs & Pharmacology Authors: Mizuno K, Takeuchi K, Umehara K, Nakajima M Tags: Biochem Pharmacol Source Type: research

Operation of mitochondrial machinery in viral infection-induced immune responses.
Abstract Mitochondria have been recognized as ancient bacteria that contain evolutionary endosymbionts. Metabolic pathways and inflammatory signals interact within mitochondria in response to different stresses, such as viral infections. In this commentary, we address several interesting questions, including (1) how do mitochondrial machineries participate in immune responses; (2) how do mitochondria mediate antiviral immunity; (3) what mechanisms involved in mitochondrial machinery, including the downregulation of mitochondrial DNA (mtDNA), disturbances of mitochondrial dynamics, and the induction of mitophagy an...
Source: Biochemical Pharmacology - August 30, 2018 Category: Drugs & Pharmacology Authors: Lai JH, Luo SF, Ho LJ Tags: Biochem Pharmacol Source Type: research

When Orexins Meet Cannabinoids: Bidirectional Functional Interactions.
edo P Abstract A growing body of evidence suggests the existence of biochemical and functional interactions between the endocannabinoid and orexin systems. Cannabinoid and orexin receptors have been shown to form heterodimers in agreement with the overlapping distribution of both receptors in several brain areas, and the activation of common intracellular signaling pathways, such as the MAP kinase cascade. The activation of orexin receptors induces the synthesis of the endocannabinoid 2-arachidonoyl glycerol suggesting that the endocannabinoid system participates in some physiological functions of orexins. Indeed,...
Source: Biochemical Pharmacology - August 29, 2018 Category: Drugs & Pharmacology Authors: Berrendero F, Flores Á, Robledo P Tags: Biochem Pharmacol Source Type: research

Gut microbiota, cannabinoid system and neuroimmune interactions: New perspectives in multiple sclerosis.
aza C Abstract The gut microbiota plays a fundamental role on the education and function of the host immune system. Immunological dysregulation is the cause of numerous human disorders such as autoimmune diseases and metabolic disorders frequently associated with inflammatory processes therefore is critical to explore novel mechanisms involved in maintaining the immune system homeostasis. The cannabinoid system and related bioactive lipids participate in multiple central and peripheral physiological processes that affect metabolic, gastrointestinal and neuroimmune regulatory mechanisms displaying a modulatory role...
Source: Biochemical Pharmacology - August 29, 2018 Category: Drugs & Pharmacology Authors: Mestre L, Carrillo-Salinas FJ, Mecha M, Feliú A, Guaza C Tags: Biochem Pharmacol Source Type: research

Central galanin receptor 2 mediates galanin action to promote systemic glucose metabolism of type 2 diabetic rats.
In conclusion, activation of central GALR2 promotes glucose metabolism and ameliorates insulin resistance mainly through the PGC-1α/GLUT4 pathways. The central GALR2 is crucial to whole-body insulin sensitivity and energy homeostasis. PMID: 30170096 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - August 28, 2018 Category: Drugs & Pharmacology Authors: Fang P, He B, Yu M, Shi M, Zhu Y, Zhang Z, Bo P Tags: Biochem Pharmacol Source Type: research

Methylglyoxal at metronomic doses sensitizes breast cancer cells to doxorubicin and cisplatin causing synergistic induction of programmed cell death and inhibition of stemness.
This report documents for the first time the preferential targeting of breast cancer stem cells by methylglyoxal. Combination treatment with doxorubicin or cisplatin hindered mammosphere forming efficiency and inclusively eliminated both cancer stem as well as non-stem cancer cells. The synergistic effect was validated in Ehrlich mammary carcinoma cell induced murine ascites model and the combination advantage in vivo was achieved without any additional deleterious effect to liver and kidney. Our present study evidences the implications of methylglyoxal inclusion in adjuvant multimodal chemotherapeutics against breast canc...
Source: Biochemical Pharmacology - August 28, 2018 Category: Drugs & Pharmacology Authors: Roy A, Sarker S, Upadhyay P, Pal A, Adhikary A, Jana K, Ray M Tags: Biochem Pharmacol Source Type: research

PR-957, a selective immunoproteasome inhibitor, reactivates latent HIV-1 through p-TEFb activation mediated by HSF-1.
In conclusion, the immunoproteasome inhibitor PR-957 is a promising candidate LRA for future HIV-1 eradication strategies. PMID: 30170098 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - August 28, 2018 Category: Drugs & Pharmacology Authors: Lin J, Zhang X, Lu W, Xu X, Pan X, Liang T, Duan S, Chen Y, Li L, Liu S Tags: Biochem Pharmacol Source Type: research

The deubiquitinase inhibitor b-AP15 induces strong proteotoxic stress and mitochondrial damage.
Abstract Human cancers are characterized by intrinsic or acquired resistance to apoptosis and evasion of apoptosis has been proposed to contribute to treatment resistance. Bis-benzylidine piperidone compounds, containing ,-unsaturated carbonyl functionalities, have been extensively documented as being effective in killing apoptosis-resistant cells and to display promising antineoplastic activities in a number of tumor models. We here explored the phenotypic response of colon cancer cells to b-AP15, a bis-benzylidine piperidone previously shown to inhibit the proteasome deubiquitinases (DUBs) USP14 and UCHL5. Where...
Source: Biochemical Pharmacology - August 24, 2018 Category: Drugs & Pharmacology Authors: Zhang X, Pellegrini P, Saei AA, Hillert EK, Mazurkiewicz M, Olofsson MH, Zubarev RA, D'Arcy P, Linder S Tags: Biochem Pharmacol Source Type: research

Platelet mitochondrial dysfunction and mitochondria-targeted quinone-and hydroquinone-derivatives: Review on new strategy of antiplatelet activity.
Abstract Platelet mitochondrial dysfunction has been identified in different diseases. Platelet mitochondrial dysfunction favors platelet activation with a considerable increase in oxidative stress, which is implicated in platelet non-responsiveness to current antiplatelet therapy. The inhibition of platelet mitochondrial dysfunction could potentially be used as a new strategy for the development of antiplatelet activity drugs. In this context, we described quinone and hydroquinone derivatives and mitochondrially targeted compounds as initial precursors for the synthesis of new antiplatelet agents. PMID: 3014...
Source: Biochemical Pharmacology - August 24, 2018 Category: Drugs & Pharmacology Authors: Fuentes M, Araya-Maturana R, Palomo I, Fuentes E Tags: Biochem Pharmacol Source Type: research

Novel venom-derived inhibitors of the human EAG channel, a putative antiepileptic drug target.
Abstract Recently, we and other groups revealed that gain-of-function mutations in the human ether à go-go voltage-gated potassium channel hEAG1 (Kv10.1) lead to developmental disorders with associated infantile-onset epilepsy. However, the physiological role of hEAG1 in the central nervous system remains elusive. Potent and selective antagonists of hEAG1 are therefore much sought after, both as pharmacological tools for studying the (patho)physiological functions of this enigmatic channel and as potential leads for development of anti-epileptic drugs. Since animal venoms are a rich source of potent ion cha...
Source: Biochemical Pharmacology - August 24, 2018 Category: Drugs & Pharmacology Authors: Ma L, Chin YKY, Dekan Z, Herzig V, Yuen Chow C, Heighway J, Wing Lam S, Guillemin GJ, Alewood PF, King GF Tags: Biochem Pharmacol Source Type: research

Differential engagement of polar networks in the glucagon-like peptide 1 receptor by endogenous variants of the glucagon-like peptide 1.
This study builds on our existing work examining the effect of mutation of conserved transmembrane polar residues within the receptor to understand the nature of binding and pleiotropic signaling in response to these alternatively processed versions of this important incretin hormone. We show that extended and processed peptides differ not only in their binding to the receptor but also in the way the receptor is engaged for activation that leads to differential signalling bias exhibited by these peptides. PMID: 30149018 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - August 24, 2018 Category: Drugs & Pharmacology Authors: Furness SGB, Christopoulos A, Sexton PM, Wootten D Tags: Biochem Pharmacol Source Type: research

Expression and genotype-dependent catalytic activity of N-acetyltransferase 2 (NAT2) in human peripheral blood mononuclear cells and its modulation by Sirtuin 1.
ortales-Pérez DP Abstract N-acetyltransferase 2 (NAT2) catalyzes the biotransformation of numerous arylamine and hydrazine drugs and carcinogens. Genetic polymorphisms of NAT2 modify drug efficacy and toxicity and susceptibility to diseases such as cancer and type 2 diabetes. Expression of NAT2 has been documented in the liver and gastrointestinal tract but not in other tissues. Deacetylation of cytosolic proteins by sirtuins is a post translational modification important in regulatory networks of diverse cellular processes. The aim of the present study was to investigate NAT2 expression in peripheral blood...
Source: Biochemical Pharmacology - August 24, 2018 Category: Drugs & Pharmacology Authors: Salazar-González RA, Turiján-Espinoza E, Hein DW, Milán-Segovia RC, Uresti-Rivera EE, Portales-Pérez DP Tags: Biochem Pharmacol Source Type: research

Glutaminase-1 Stimulates the Proliferation, Migration, and Survival of Human Endothelial Cells.
In conclusion, the metabolism of glutamine by GLS1 promotes human EC proliferation, migration, and survival irrespective of the vascular source. While cyclin A contributes to the proliferative action of GLS1, HO-1 mediates its pro-survival effect. These results identify GLS1 as a promising therapeutic target in treating diseases associated with aberrant EC proliferation, migration, and viability. PMID: 30144404 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - August 22, 2018 Category: Drugs & Pharmacology Authors: Peyton KJ, Liu XM, Yu Y, Yates B, Behnammanesh G, Durante W Tags: Biochem Pharmacol Source Type: research

The critical role of porcine cytochrome P450 3A46 in the bioactivation of aflatoxin B1.
This study broadens our knowledge of AFB1 bioactivation in pigs and may contribute to reduce the deleterious effects of AFB1 in pigs and humans. PMID: 30142320 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - August 21, 2018 Category: Drugs & Pharmacology Authors: Jiang H, Wu J, Zhang F, Wen J, Jiang J, Deng Y Tags: Biochem Pharmacol Source Type: research

Let-7b ameliorates Crohn's disease-associated adherent-invasive E coli induced intestinal inflammation via modulating Toll-Like Receptor 4 expression in intestinal epithelial cells.
Abstract Crohn's disease (CD)-associated adherent invasive Escherichia coli (AIEC) has been implicated as a causative or contributory factor in CD pathology. MicroRNA let-7b/ Toll-like receptor 4 (TLR-4) signaling pathways may play an important role in microbiota-mucosa interactions. We aimed to investigate whether AIEC influences IECs' function of expressing TLR4, and the potential role of let-7b in regulating AIEC induced gut inflammation. Wild type (WT) and interleukin-10 knockout (IL-10 KO) mice in specific pathogen free (SPF) housing were infected by AIEC LF82, and IL-10 KO mice were treated with pre-let7b or...
Source: Biochemical Pharmacology - August 21, 2018 Category: Drugs & Pharmacology Authors: Zhen G, Xingchen C, Xian G, Yihan X, Jianfeng G, Yi L, Weiming Z Tags: Biochem Pharmacol Source Type: research

Evaluation of resistance to HIV-1 infection ex vivo of PBMCs isolated from patients with chronic myeloid leukemia treated with different tyrosine kinase inhibitors.
cute; JM, Alcamí J, Coiras M Abstract Current antiretroviral treatment (ART) may control HIV-1 replication but it cannot cure the infection due to the formation of a reservoir of latently infected cells. CD4+ T cell activation during HIV-1 infection eliminates the antiviral function of the restriction factor SAMHD1, allowing proviral integration and the reservoir establishment. The role of tyrosine kinases during T-cell activation is essential for these processes. Therefore, the inhibition of tyrosine kinases could control HIV-1 infection and restrict the formation of the reservoir. A family of tyrosine kin...
Source: Biochemical Pharmacology - August 21, 2018 Category: Drugs & Pharmacology Authors: Bermejo M, Ambrosioni J, Bautista G, Climent N, Mateos E, Rovira C, Rodríguez-Mora S, López-Huertas MR, García-Gutiérrez V, Steegmann JL, Duarte R, Cervantes F, Plana M, Miró JM, Alcamí J, Coiras M Tags: Biochem Pharmacol Source Type: research

Activity profile of the cisplatin analogue PN149 in different tumor cell lines.
e B Abstract The efficacy of the anticancer drug cisplatin is restricted by tumor cell resistance and occurrence of severe side effects. One strategy to overcome these limitations is the development of new, improved platinum drugs. Previous investigations showed that platinum(IV)-nitroxyl complexes are able to circumvent cisplatin resistance in bladder cancer cells. In the present study the mode of action of the platinum(IV)-nitroxyl complex PN149 was investigated in the bladder cancer cell line RT112 and the renal cell carcinoma cell line A498 on the molecular and cellular level. Gene expression analysis showed t...
Source: Biochemical Pharmacology - August 20, 2018 Category: Drugs & Pharmacology Authors: Schoch S, Sen V, Gajewski S, Golubev V, Strauch B, Hartwig A, Köberle B Tags: Biochem Pharmacol Source Type: research

The endocannabinoid system of the skin. A potential approach for the treatment of skin disorders.
eMesa J, Muñoz E Abstract The skin is the largest organ of the body and has a complex and very active structure that contributes to homeostasis and provides the first line defense against injury and infection. In the past few years it has become evident that the endocannabinoid system (ECS) plays a relevant role in healthy and diseased skin. Specifically, we review how the dysregulation of ECS has been associated to dermatological disorders such as atopic dermatitis, psoriasis, scleroderma and skin cancer. Therefore, the druggability of the ECS could open new research avenues for the treatment of the pathol...
Source: Biochemical Pharmacology - August 20, 2018 Category: Drugs & Pharmacology Authors: Río CD, Millán E, García V, Appendino G, DeMesa J, Muñoz E Tags: Biochem Pharmacol Source Type: research

Ligand-dependent modulation of hOCT1 transport reveals discrete ligand binding sites within the substrate translocation channel.
Abstract The human hepatic organic cation transporter 1 (hOCT1) is a well-known transporter of both xenobiotic and endogenous cations. The substrates and inhibitors of hOCT1 are structurally and physiochemically diverse and include some widely prescribed drugs (metformin and imatinib), vitamins (thiamine), and neurotransmitters (serotonin). It has been demonstrated that the closely related renal isoform, hOCT2, is subject to ligand-dependent modulation, wherein one ligand may enhance or inhibit transport of a second, chemically unrelated, ligand. This phenomenon has important implications for drug-drug interaction...
Source: Biochemical Pharmacology - August 20, 2018 Category: Drugs & Pharmacology Authors: Boxberger KH, Hagenbuch B, Lampe JN Tags: Biochem Pharmacol Source Type: research

Cellular pharmacology of evofosfamide (TH-302): A critical re-evaluation of its bystander effects.
Abstract Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug with proven efficacy against hypoxic cells in preclinical tumour models. TH-302 is designed to release the DNA crosslinking agent bromo-isophosphoramide mustard (Br-IPM) when reduced in hypoxic tissue. Br-IPM is considered to diffuse locally from hypoxic regions, eliciting additional tumour cell killing, but the latter 'bystander effect' has not been demonstrated directly. Previous studies with multicellular co-cultures that included cells expressing the E. coli nitroreductase NfsA as a model TH-302 reductase have provided clear evidence ...
Source: Biochemical Pharmacology - August 19, 2018 Category: Drugs & Pharmacology Authors: Hong CR, Dickson BD, Jaiswal JK, Pruijn FB, Hunter FW, Hay MP, Hicks KO, Wilson WR Tags: Biochem Pharmacol Source Type: research

Delta9-tetrahydrocannabinol modulates the proteasome system in the brain.
Oliva B, Ozaita A Abstract Cannabis is the most consumed illicit drug worldwide. Its principal psychoactive component, Δ9-tetrahydrocannabinol (THC), affects multiple brain functions, including cognitive performance, by modulating cannabinoid type-1 (CB1) receptors. These receptors are strongly enriched in presynaptic terminals, where they modulate neurotransmitter release. We analyzed, through a proteomic screening of hippocampal synaptosomal fractions, those proteins and pathways modulated 3 hours after a single administration of an amnesic dose of THC (10 mg/kg, i.p.). Using an isobaric labeling approach,...
Source: Biochemical Pharmacology - August 19, 2018 Category: Drugs & Pharmacology Authors: Salgado-Mendialdúa V, Aguirre-Plans J, Guney E, Reig-Viader R, Maldonado R, Bayés À, Oliva B, Ozaita A Tags: Biochem Pharmacol Source Type: research

Immunization with Na+/K+ ATPase DR peptide prevents bone loss in an ovariectomized rat osteoporosis model.
Abstract Osteoporosis is characterized by decreased bone strength and microarchitectural deterioration of bone tissue leading to an increase in bone fracture. Here we report a new agent named DR peptide, a conserved sequence of Na+/K+ ATPase (NKA), can be used to prevent osteoporosis. Our results showed that immunization with DR peptide conjunct with Keyhole limpet hemocyanin (DR-KLH) significantly strengthened trabecular bone and improved bone mineral density of femur and the 5th lumbar in the ovariectomized (OVX) rats when compared with those in OVX rats immunized with KLH alone. To study the underlying mechanis...
Source: Biochemical Pharmacology - August 19, 2018 Category: Drugs & Pharmacology Authors: Xiong S, Yang X, Yan X, Hua F, Zhu M, Guo L, Wu Z, Bian JS Tags: Biochem Pharmacol Source Type: research

Ethanol Targets Nucleoredoxin/Dishevelled Interactions and Stimulates Phosphatidylinositol 4-phosphate Production In vivo and In vitro.
In conclusion, two-hit model of ethanol exposure disrupts NXN/DVL homeostatic status to allow DVL/FZD/PI4K2A complex formation and stimulates PI(4)P production. These results provide a new mechanism showing that NXN also participates in the regulation of phosphoinositides production that is altered by ethanol during alcoholic liver disease progression. PMID: 30125555 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - August 17, 2018 Category: Drugs & Pharmacology Authors: Arellanes-Robledo J, Reyes-Gordillo K, Ibrahim J, Leckey L, Shah R, Raj Lakshman M Tags: Biochem Pharmacol Source Type: research

Optimization Of A Preclinical Therapy Of Cannabinoids In Combination With Temozolomide Against Glioma.
veda JM, Velasco G, Lorente M Abstract Glioblastoma multiforme (GBM) is the most frequent and aggressive form of brain cancer. These features are explained at least in part by the high resistance exhibited by these tumors to current anticancer therapies. Thus, the development of novel therapeutic approaches is urgently needed to improve the survival of the patients suffering this devastating disease. Δ9-Tetrahydrocannabinol (THC, the major active ingredient of marijuana), and other cannabinoids have been shown to exert antitumoral actions in animal models of cancer, including glioma. The mechanism of these a...
Source: Biochemical Pharmacology - August 17, 2018 Category: Drugs & Pharmacology Authors: López-Valero I, Torres S, Salazar-Roa M, García-Taboada E, Hernández Tiedra S, Guzmán M, Sepúlveda JM, Velasco G, Lorente M Tags: Biochem Pharmacol Source Type: research

Probing the molecular basis for affinity/potency- and efficacy-based subtype-selectivity exhibited by benzodiazepine-site modulators at GABAA receptors.
In conclusion, the molecular origins of subtype-selectivity exhibited by benzodiazepine-site modulators seem more complex than previously appreciated, and the importance of the α1-Gly201/α3-Glu225 residue for both potency- and efficacy-based subtype-selective modulation through this site is likely to be rooted in different molecular mechanisms. PMID: 30121248 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - August 16, 2018 Category: Drugs & Pharmacology Authors: Cecilia Söderhielm P, Balle T, Bak-Nyhus S, Zhang M, Hansen KM, Ahring PK, Jensen AA Tags: Biochem Pharmacol Source Type: research

Cannabinoid pharmacology/therapeutics in chronic degenerative disorders affecting the central nervous system.
uiz J Abstract The endocannabinoid system (ECS) exerts a modulatory effect of important functions such as neurotransmission, glial activation, oxidative stress, or protein homeostasis. Dysregulation of these cellular processes is a common neuropathological hallmark in aging and in neurodegenerative diseases of the central nervous system (CNS). The broad spectrum of actions of cannabinoids allows targeting different aspects of these multifactorial diseases. In this review, we examine the therapeutic potential of the ECS for the treatment of chronic neurodegenerative diseases of the CNS focusing on Alzheimer's disea...
Source: Biochemical Pharmacology - August 16, 2018 Category: Drugs & Pharmacology Authors: Aymerich MS, Aso E, Abellanas MA, Tolon RM, Ramos JA, Ferrer I, Romero J, Fernández-Ruiz J Tags: Biochem Pharmacol Source Type: research

JNK-AKT-NF- κB controls P-glycoprotein expression to attenuate the cytotoxicity of Deoxynivalenol in mammalian cells.
In this study, we found DON can induce the mRNA and protein levels of P-gp in a time- and dose-dependent manner. Mechanistically, the upregulation of P-gp expression is attributable to the induction of DON-induced proapoptotic pathways as reflected by the c-Jun N-terminal kinases (JNK) phosphorylation, AKT phosphorylation and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation to the nucleus. In DON-treated cells, the mitogen-activated protein kinases (MAPK) pathways were activated; however, only JNK, but not ERK or p38, activation determined P-gp induction. Activated JNK enhances the...
Source: Biochemical Pharmacology - August 16, 2018 Category: Drugs & Pharmacology Authors: Li X, Mu P, Qiao H, Wen J, Deng Y Tags: Biochem Pharmacol Source Type: research

The conformation and dynamics of P-glycoprotein in a lipid bilayer investigated by atomic force microscopy.
Abstract The membrane-bound P-glycoprotein (Pgp) transporter plays a major role in human disease and drug disposition because of its ability to efflux a chemically diverse range of drugs through ATP hydrolysis and ligand-induced conformational changes. Deciphering these structural changes is key to understanding the molecular basis of transport and to developing molecules that can modulate efflux. Here, atomic force microscopy (AFM) is used to directly image individual Pgp transporter molecules in a lipid bilayer under physiological pH and ambient temperature. Analysis of the Pgp AFM images revealed "small&qu...
Source: Biochemical Pharmacology - August 16, 2018 Category: Drugs & Pharmacology Authors: Sigdel KP, Wilt LA, Marsh BP, Roberts AG, King GM Tags: Biochem Pharmacol Source Type: research