Inhibition of thioredoxin reductase 1 correlates with platinum-based chemotherapeutic induced tissue injury.
Abstract Platinum-containing drugs (PtDs; e.g. cisplatin, carboplatin, and oxaliplatin) have been widely used as anticancer reagents against various cancers. However, treatment with these drugs results in undesirable adverse effects with unknown mechanisms. Herein, we found a strong correlation between the inhibitory effects of PtDs on cytosolic thioredoxin reductase (TXNRD1) and tissue injury. Of the PtDs tested, cisplatin was found to be the most effective inhibitory PtD against TXRND1, causing the severest kidney injury. The initial inhibition of TXNRD1 in the kidney resulted from cisplatin-induced transcriptio...
Source: Biochemical Pharmacology - February 21, 2020 Category: Drugs & Pharmacology Authors: Cheng P, Liu H, Li Y, Pi P, Jiang Y, Zang S, Li X, Fu A, Ren X, Xu J, Holmgren A, Lu J Tags: Biochem Pharmacol Source Type: research

Lactobacillus rhamnosus GG supplementation modulates the gut microbiota to promote butyrate production, protecting against deoxynivalenol exposure in nude mice.
In conclusion, LGG supplementation modulated the gut microbiota to promote butyrate production, protecting against DON exposure in nude mice. Both LGG and butyrate show promise for use in protecting against DON exposure. PMID: 32088259 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - February 20, 2020 Category: Drugs & Pharmacology Authors: Lin R, Sun Y, Mu P, Zheng T, Mu H, Deng F, Deng Y, Wen J Tags: Biochem Pharmacol Source Type: research

Pentosan Polysulfate to control hepcidin expression in vitro and in vivo.
Abstract Hepcidin peptide is crucial in the regulation of systemic iron availability controlling its uptake from the diet and its release from the body storage tissues. Hepcidin dysregulation causes different human disorders ranging from iron overload (e.g. hemochromatosis) to iron deficiency (e.g. anemia). Hepcidin excess is common in the Anemia of Chronic Diseases or Anemia of Inflammation and in the genetic form of anemia named IRIDA; the pharmacological downregulation of hepcidin in these disorders could improve the anemia. Commercial heparins were shown to be strong inhibitors of hepcidin expression, by inter...
Source: Biochemical Pharmacology - February 20, 2020 Category: Drugs & Pharmacology Authors: Asperti M, Denardo A, Gryzik M, Castagna A, Girelli D, Naggi A, Arosio P, Poli M Tags: Biochem Pharmacol Source Type: research

Phytohormones: Multifunctional nutraceuticals against metabolic syndrome and comorbid diseases.
Abstract Metabolic syndrome is characterized by the co-occurrence of diverse symptoms initiating the development of type 2 diabetes, cardiovascular diseases, and a variety of comorbid diseases. The complex constellation of numerous comorbidities makes it difficult to develop common therapeutic approaches that ameliorate these pathological features simultaneously. The plant hormones abscisic acid, salicylic acid, auxin, and cytokinins, have shown promising anti-inflammatory and pro-metabolic effects that could mitigate several disorders relevant to metabolic syndrome. Intriguingly, besides plants, human cells and g...
Source: Biochemical Pharmacology - February 20, 2020 Category: Drugs & Pharmacology Authors: Woo Kim S, Goossens A, Libert C, Van Immerseel F, Staal J, Beyaert R Tags: Biochem Pharmacol Source Type: research

S-nitrosylation affects TRAP1 structure and ATPase activity and modulates cell response to apoptotic stimuli.
Abstract The mitochondrial chaperone TRAP1 has been involved in several mitochondrial functions, and modulation of its expression/activity has been suggested to play a role in the metabolic reprogramming distinctive of cancer cells. TRAP1 posttranslational modifications, i.e. phosphorylation, can modify its capability to bind to different client proteins and modulate its oncogenic activity. Recently, it has been also demonstrated that TRAP1 is S-nitrosylated at Cys501, a redox modification associated with its degradation via the proteasome. Here we report molecular dynamics simulations of TRAP1, together with anal...
Source: Biochemical Pharmacology - February 20, 2020 Category: Drugs & Pharmacology Authors: Faienza F, Lambrughi M, Rizza S, Pecorari C, Giglio P, Salamanca Viloria J, Francesca Allega M, Chiappetta G, Vinh J, Pacello F, Battistoni A, Rasola A, Papaleo E, Filomeni G Tags: Biochem Pharmacol Source Type: research

Signalling profiles of a structurally diverse panel of synthetic cannabinoid receptor agonists.
In this study, we aimed to characterise the signalling profiles of a structurally diverse panel of novel SCRAs at CB1. We compare SCRAs to traditional reference cannabinoids CP55,940, WIN55,212-2, and THC. The activity of the SCRAs was assessed in key receptor signalling and regulatory pathways, including cAMP production, translocation of β-arrestin 1 and 2, and receptor internalisation. The activity profiles of the ligands were also evaluated using operational analysis to identify ligand bias. Results revealed that SCRAs activities were relatively balanced in the pathways evaluated (compared to WIN55,212-2), although...
Source: Biochemical Pharmacology - February 20, 2020 Category: Drugs & Pharmacology Authors: Patel M, Manning JJ, Finlay DB, Javitch JA, Banister SD, Grimsey NL, Glass M Tags: Biochem Pharmacol Source Type: research

Functional characterization of 5-HT1A and 5-HT1B serotonin receptor signaling through G-protein-activated inwardly rectifying K+ channels in a fluorescence-based membrane potential assay.
Abstract The 5-HT1A and 5-HT1B serotonin receptors are abundantly expressed in the CNS and constitute validated as well as putative drug targets in a variety of psychiatric and cognitive disorders, alcoholism/addiction, pain and migraine. In the present study we have characterized the functional properties of human 5-HT1A and 5-HT1B stably co-expressed with the human G-protein-activated inwardly rectifying K+ channel 2 (GIRK2) in HEK293 cells in the fluorescence-based FLIPR® Membrane Potential Blue (FMP) assay. Serotonin and other agonists induced robust decreases in fluorescence levels in the 5-HT1A/GIRK2- an...
Source: Biochemical Pharmacology - February 20, 2020 Category: Drugs & Pharmacology Authors: Gadgaard C, Jensen AA Tags: Biochem Pharmacol Source Type: research

Lysosomotropic drugs enhance pro-inflammatory responses to IL-1 β in macrophages by inhibiting internalization of the IL-1 receptor.
Lysosomotropic drugs enhance pro-inflammatory responses to IL-1β in macrophages by inhibiting internalization of the IL-1 receptor. Biochem Pharmacol. 2020 Feb 20;:113864 Authors: Lübow C, Bockstiegel J, Weindl G Abstract Interleukin (IL)-1 signaling leads to production of pro-inflammatory mediators and is regulated by receptor endocytosis. Lysosomotropic drugs have been linked to increased pro-inflammatory responses under sterile inflammatory conditions but the underlying mechanisms have not been fully elucidated. Here, we report that lysosomotropic drugs potentiate pro-inflammatory effects...
Source: Biochemical Pharmacology - February 20, 2020 Category: Drugs & Pharmacology Authors: Lübow C, Bockstiegel J, Weindl G Tags: Biochem Pharmacol Source Type: research

Corrigendum to "Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells" [Biochem. Pharmacol. 93 (3) (2015) 290-304].
Corrigendum to "Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells" [Biochem. Pharmacol. 93 (3) (2015) 290-304]. Biochem Pharmacol. 2020 Feb 18;175:113810 Authors: Martin S, Dudek-Perić AM, Maes H, Garg AD, Gabrysiak M, Demirsoy S, Swinnen JV, Agostinis P PMID: 32085947 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - February 18, 2020 Category: Drugs & Pharmacology Authors: Martin S, Dudek-Perić AM, Maes H, Garg AD, Gabrysiak M, Demirsoy S, Swinnen JV, Agostinis P Tags: Biochem Pharmacol Source Type: research

Kushenol E inhibits autophagy and impairs lysosomal positioning via VCP/p97 inhibition.
In this study, we evaluated the autophagy-regulatory effects of kushenol E (KE), a bi-prenylated flavonoid isolated from Sophora flavescens and found that KE increased LC3B-II levels while inducing the formation of autophagic vacuoles and immature autophagosomes in HeLa and HCT116 cells. Transmission electron microscopy images revealed that KE treatment generates immature autophagosomes. Furthermore, KE inhibited autophagosome maturation as demonstrated by blocking the degradation of EGFP puncta in HeLa cells stably expressing EGFP-mRFP-LC3B. It also reduced lysosomal activity and cathepsin maturation by disrupting lysosom...
Source: Biochemical Pharmacology - February 17, 2020 Category: Drugs & Pharmacology Authors: Kwon M, Jang M, Kim GH, Oh T, Ryoo IJ, Ryu HW, Oh SR, Kim BY, Jang JH, Ko SK, Ahn JS Tags: Biochem Pharmacol Source Type: research

Peripheral nitric oxide signaling directly blocks inflammatory pain.
Abstract Pain is a classical sign of inflammation, and sensitization of primary sensory neurons (PSN) is the most important mediating mechanism. This mechanism involves direct action of inflammatory mediators such as prostaglandins and sympathetic amines. Pharmacologic control of inflammatory pain is based on two principal strategies: (i) non-steroidal anti-inflammatory drugs targeting inhibition of prostaglandin production by cyclooxygenases and preventing nociceptor sensitization in humans and animals; (ii) opioids and dipyrone that directly block nociceptor sensitization via activation of the NO signaling pathw...
Source: Biochemical Pharmacology - February 17, 2020 Category: Drugs & Pharmacology Authors: F Gomes FI, Cunha FQ, Cunha TM Tags: Biochem Pharmacol Source Type: research

Advances in the molecular mechanisms of NLRP3 inflammasome activators and inacativators.
Abstract NLRP3 inflammasome is an intracellular protein complex that initiates cellular injury via assembly of NLRP3, ASC and caspase-1 in response to microbial infection and sterile stressors. The importance of NLRP3 inflammasome in immunity and human diseases has been well documented. Up to now, targeted inhibition of the assembly of NLRP3 inflammasome complex and of its activation was thought to be therapeutic strategy for associated diseases. Recent studies show that a host of molecules such as NIMA-related kinase 7 (Nek7) and DEAD-box helicase 3 X-linked (DDX3X) and a large number of biological mediators incl...
Source: Biochemical Pharmacology - February 17, 2020 Category: Drugs & Pharmacology Authors: Liu D, Zeng X, Li X, Cui C, Hou R, Guo Z, Mehta JL, Wang X Tags: Biochem Pharmacol Source Type: research

NOSH-aspirin (NBS-1120) inhibits pancreatic cancer cell growth in a xenograft mouse model: Modulation of FoxM1, p53, NF- κB, iNOS, caspase-3 and ROS.
In this study we evaluated the effects of NOSH-aspirin against pancreatic cancer using cell lines and a xenograft mouse model. NOSH-aspirin inhibited growth of MIA PaCa-2 and BxPC-3 pancreatic cancer cells with IC50s of 47 ± 5, and 57 ± 4 nM, respectively, while it did not inhibit growth of a normal pancreatic epithelial cell line at these concentrations. NOSH-aspirin inhibited cell proliferation, caused G0/G1 phase cycle arrest, leading to increased apoptosis. Treated cells displayed increases in reactive oxygen species (ROS) and caspase-3 activity. In MIA PaCa-2 cell xenografts, NOSH-aspirin significantly r...
Source: Biochemical Pharmacology - February 13, 2020 Category: Drugs & Pharmacology Authors: Chattopadhyay M, Kodela R, Santiago G, Tien LeCao T, Nath N, Kashfi K Tags: Biochem Pharmacol Source Type: research

Canagliflozin inhibits p-gp function and early autophagy and improves the sensitivity to the antitumor effect of doxorubicin.
This study is the first to report that a classical antidiabetic drug, CAN improved the sensitivity to the antitumor effect of DOX, and the potential molecular mechanisms of CAN may involve the inhibition of P-gp function and the autophagy pathway. PMID: 32061772 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - February 13, 2020 Category: Drugs & Pharmacology Authors: Zhong J, Sun P, Xu N, Liao M, Xu C, Ding Y, Cai J, Zhang Y, Xie W Tags: Biochem Pharmacol Source Type: research

Phytocannabinoids promote viability and functional adipogenesis of bone marrow-derived mesenchymal stem cells through different molecular targets.
In this study, we explored the potential therapeutic effect of some of the most abundant non-euphoric compounds derived from the Cannabis sativa plant (or phytocannabinoids) including tetrahydrocannabivarin (THCV), cannabidiol (CBD), cannabigerol (CBG), cannabidiolic acid (CBDA) and cannabigerolic acid (CBGA), by analysing their pharmacological activity on the viability of endogenous BM-MSCs as well as their ability to alter BM-MSC proliferation and differentiation into mature adipocytes. We provide evidence that CBD, CBDA, CBGA and THCV (5 µM) increase the number of viable BM-MSCs; whereas only CBG (5 µM) and ...
Source: Biochemical Pharmacology - February 13, 2020 Category: Drugs & Pharmacology Authors: Fellous T, Di Maio F, Kalkann H, Carannante B, Boccella S, Petrosino S, Maione S, Di Marzo V, Arturo Iannotti F Tags: Biochem Pharmacol Source Type: research

Differential role of vacuolar (H+)-ATPase in the expression and activity of cyclooxygenase-2 in human monocytes.
Abstract Monocytes are professional immune cells that produce abundant levels of pro-inflammatory eicosanoids including prostaglandins and leukotrienes during inflammation. Vacuolar (H+)-ATPase (V-ATPase) is critically involved in a variety of inflammatory processes including cytokine trafficking and lipid mediator biosynthesis. However, its role in eicosanoid biosynthetic pathways in monocytes remains elusive. Here, we present a differential role of V-ATPase in the expression and in the activity of cyclooxygenase (COX)-2 in human monocytes. Pharmacological targeting of V-ATPase increased the expression of COX-2 p...
Source: Biochemical Pharmacology - February 13, 2020 Category: Drugs & Pharmacology Authors: Rao Z, Jordan PM, Wang Y, Menche D, Pace S, Gerstmeier J, Werz O Tags: Biochem Pharmacol Source Type: research

Protein kinase inhibitor-based cancer therapies: considering the potential of nitric oxide (NO) to improve cancer treatment.
Abstract The deregulation of a wide variety of protein kinases is associated with cancer cell initiation and tumor progression. Owing to their indispensable function in signaling pathways driving malignant cell features, protein kinases constitute major therapeutic targets in cancer. Over the past two decades, intense efforts in drug development have been dedicated to this field. The development of protein kinase inhibitors (PKIs) have been a real breakthrough in targeted cancer therapy. Despite obvious successes across patients with different types of cancer, the development of PKI resistance still prevails. Comb...
Source: Biochemical Pharmacology - February 12, 2020 Category: Drugs & Pharmacology Authors: Ghione S, Mabrouk N, Paul C, Bettaieb A, Plenchette S Tags: Biochem Pharmacol Source Type: research

Thrombin/PAR-1 activation induces endothelial damages via NLRP1 inflammasome in gestational diabetes.
This study was to investigate roles of thrombin and its receptor protease-activated receptor 1 (PAR-1) and NLRP1 inflammasome in endothelial injury in GDM condition. Umbilical cord and plasma of GDM patients and high glucose (HG) cultured human umbilical vein endothelial cells (HUVECs) were used to examine the pathological changes of these pathways. Meanwhile, ameliorative effects and potential mechanisms of a natural product sarsasapogenin (Sar) were investigated in HUVECs. Thrombin/PAR-1 pathway, advanced glycation endproducts (AGEs) and their receptor (RAGE) axis, and the nucleotide-binding domain and leucine-rich repea...
Source: Biochemical Pharmacology - February 11, 2020 Category: Drugs & Pharmacology Authors: Liu Y, Tang ZZ, Zhang YM, Kong L, Xiao WF, Ma TF, Liu YW Tags: Biochem Pharmacol Source Type: research

Biological evaluation of non-basic chalcone CYB-2 as a dual ABCG2/ABCB1 inhibitor.
Abstract The enhancement of drug efflux caused by ATP-binding cassette (ABC) transporters (including ABCG2 and ABCB1) overexpression is an important factor for multidrug resistance (MDR) in cancers. After testing the reversal activities of 19 chalcone and bis-chalcone derivatives on MDR cancer cell lines, we found that non-basic chalcone CYB-2 exhibited the most potent reversal activities against both ABCG2- and ABCB1-mediated MDR. The mechanistic studies show that this compound can increase the accumulation of anticancer drugs in both ABCG2- and ABCB1-overexpressing cancer cell lines, resulting from the blocked e...
Source: Biochemical Pharmacology - February 7, 2020 Category: Drugs & Pharmacology Authors: Cai CY, Zhang W, Wang JQ, Lei ZN, Zhang YK, Wang YJ, Gupta P, Tan CP, Wang B, Chen ZS Tags: Biochem Pharmacol Source Type: research

Importance of asparagine-381 and arginine-487 for substrate recognition in CYP4Z1.
Abstract The human cytochrome P450 enzyme CYP4Z1 remains an understudied enzyme despite its association with poor prognosis and overexpression in breast cancer. Hence, CYP4Z1 has previously been suggested as an anti-breast cancer target. In the present study we employed extended mutation analysis to increase our understanding of the substrate binding mode of this enzyme. In a combined in vitro and in silico approach we show for the first time that residue Arg487 plays an important role in substrate recognition and binding of CYP4Z1. Using a large array of recombinant CYP4Z1 mutants we show that, apart from Asn381,...
Source: Biochemical Pharmacology - February 7, 2020 Category: Drugs & Pharmacology Authors: Du W, Machalz D, Yan Q, Sorensen EJ, Wolber G, Bureik M Tags: Biochem Pharmacol Source Type: research

Clinical translation of liver regeneration therapies: a conceptual road map.
Abstract The increasing incidence of severe liver diseases worldwide has resulted in a high demand for curative liver transplantation. Unfortunately, the need for transplants by far eclipses the availability of suitable grafts leaving many waitlisted patients to face liver failure and often death. Routine use of smaller grafts (for example left lobes, split livers) from living or deceased donors could increase the number of life-saving transplants but is often limited by the graft versus recipient weight ratio defining the safety margins that minimize the risk of small for size syndrome (SFSS). SFSS is a severe co...
Source: Biochemical Pharmacology - February 5, 2020 Category: Drugs & Pharmacology Authors: Greenbaum LE, Ukomadu C, S Tchorz J Tags: Biochem Pharmacol Source Type: research

Nrf2 in keratinocytes protects against skin fibrosis via regulating epidermal lesion and inflammatory response.
Abstract Nuclear factor-E2-related factor 2 (Nrf2) is a master transcription factor in antioxidant response, protecting against oxidative damage and various diseases. Previous studies suggest that Nrf2 is suppressed in fibrotic skin and Nrf2 agonists represent a therapeutic strategy, which is mainly attributed to Nrf2 function in fibroblasts. However, constitutive activation of Nrf2 may endow cells with proliferation and survival advantage, facilitating skin tumorigenesis. Non-invasive and mild modulation of Nrf2 via topical application may be helpful. Keratinocytes, which are essential for epidermal formation and...
Source: Biochemical Pharmacology - February 4, 2020 Category: Drugs & Pharmacology Authors: Wu R, Zhang H, Zhao M, Li J, Hu Y, Fu J, Pi J, Wang H, Xu Y Tags: Biochem Pharmacol Source Type: research

The putative endogenous AHR ligand ITE reduces JAG1 and associated NOTCH1 signaling in triple negative breast cancer cells.
Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor. Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype. TNBC expresses AHR and AHR ligands have anti-cancer activity in TNBC. The aggressiveness of TNBC is due in part to JAG1-NOTCH1 signaling. ITE is a putative endogenous AHR ligand. We show that ITE reduces the expression of JAG1 the amount of Notch 1 intracellular domain (NICD1) and the phosphorylation of STAT3 (at tyrosine 705) in TNBC MDA-MB-231 cells. The STAT3 inhibitor STATTIC also reduced JAG1. STAT3, thus, mediates regulation of JAG1 in MDA...
Source: Biochemical Pharmacology - February 4, 2020 Category: Drugs & Pharmacology Authors: Piwarski SA, Thompson C, Chaudhry AR, Denvir J, Primerano DA, Fan J, Salisbury TB Tags: Biochem Pharmacol Source Type: research

Systematic characterization of glutathione S-transferases in common marmosets.
In this study, 20 GSTs [including 3 microsomal GSTs (MGSTs)] were identified and characterized in marmosets. Marmoset GSTs had amino acid sequences highly identical (86-99%) to human GSTs, except for GSTA4L, which had lower identities (59-62%) with human GSTAs. Phylogenetic analysis revealed that marmoset GSTs were closely clustered with their human counterparts. Marmoset GSTs had gene and genomic structures generally similar to their human counterparts, with some differences in GSTA, GSTM, and GSTT clusters. Marmoset GST mRNAs exhibited distinct tissue expression patterns: GSTA1, GSTA3, GSTA4L, GSTK1, GSTT1, GSTZ1, and MG...
Source: Biochemical Pharmacology - February 3, 2020 Category: Drugs & Pharmacology Authors: Uno Y, Uehara S, Tanaka S, Murayama N, Yamazaki H Tags: Biochem Pharmacol Source Type: research

In silico screening of GMQ-like compounds reveals guanabenz and sephin1 as new allosteric modulators of acid-sensing ion channel 3.
Abstract Acid-sensing ion channels (ASICs) are voltage-independent cation channels that detect decreases in extracellular pH. Dysregulation of ASICs underpins a number of pathologies. Of particular interest is ASIC3, which is recognised as a key sensor of acid-induced pain and is important in the establishment of pain arising from inflammatory conditions, such as rheumatoid arthritis. Thus, the identification of new ASIC3 modulators and the mechanistic understanding of how these compounds modulate ASIC3 could be important for the development of new strategies to counteract the detrimental effects of dysregulated A...
Source: Biochemical Pharmacology - February 3, 2020 Category: Drugs & Pharmacology Authors: Callejo G, Pattison LA, Greenhalgh JC, Chakrabarti S, Andreopoulou E, Hockley JRF, Smith ESJ, Rahman T Tags: Biochem Pharmacol Source Type: research

Cardiovascular phenotype of mice lacking 3-mercaptopyruvate sulfurtransferase.
CONCLUSIONS: Overall, genetic ablation of 3-MST impacts on the mouse cardiovascular system in an age-dependent manner. Loss of 3-MST exerts a cardioprotective role in young adult mice, while with ageing it predisposes them to hypertension and cardiac hypertrophy. PMID: 32027885 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - February 3, 2020 Category: Drugs & Pharmacology Authors: Peleli M, Bibli SI, Li Z, Chatzianastasiou A, Varela A, Katsouda A, Zukunft S, Bucci M, Vellecco V, Davos CH, Nagahara N, Cirino G, Fleming I, Lefer DJ, Papapetropoulos A Tags: Biochem Pharmacol Source Type: research

Melatonin fine-tunes intracellular calcium signals and eliminates myocardial damage through the IP3R/MCU pathways in cardiorenal syndrome type 3.
Abstract Cardiorenal syndrome type-3 (CRS-3) is characterized by acute cardiac injury induced by acute kidney injury. Here, we investigated the causes of CRS-3 by analyzing cardiac function after renal ischemia-reperfusion injury (IRI) using echocardiography and evaluation of pro-inflammatory markers, calcium balance, mitochondrial function, and cardiomyocyte death. Our results show that renal IRI reduces cardiac diastolic function associated with cardiomyocyte death and inflammatory responses. Renal IRI also disrupts cardiomyocyte energy metabolism, induces calcium overload, and impairs mitochondrial function, as...
Source: Biochemical Pharmacology - January 29, 2020 Category: Drugs & Pharmacology Authors: Wang J, Toan S, Li R, Zhou H Tags: Biochem Pharmacol Source Type: research

Targeting of the cGAS-STING system by DNA viruses.
Abstract Innate sensing of viruses by cytosolic nucleic acid sensors is a key feature of anti-viral immunity against these pathogens. The DNA sensing pathway through the sensor cyclic GMP-AMP synthase (cGAS) and its downstream effector stimulator of interferon genes (STING) has emerged in recent years as a key, front-line means of driving interferons and pro-inflammatory cytokines in response to DNA virus infection in vertebrates. Unsurprisingly, many DNA viruses have evolved effective inhibitors of this signalling system which target at a wide variety of points from sensing all the way down to the activation of I...
Source: Biochemical Pharmacology - January 28, 2020 Category: Drugs & Pharmacology Authors: Phelan T, Little MA, Brady G Tags: Biochem Pharmacol Source Type: research

Omentin-1 protects against high glucose-induced endothelial dysfunction via the AMPK/PPAR δ signaling pathway.
Omentin-1 protects against high glucose-induced endothelial dysfunction via the AMPK/PPARδ signaling pathway. Biochem Pharmacol. 2020 Jan 27;:113830 Authors: Liu F, Fang S, Liu X, Li J, Wang X, Cui J, Chen T, Li Z, Yang F, Tian J, Li H, Yin L, Yu B Abstract High glucose-induced endothelial dysfunction is a critical initiating factor in the development of diabetic vascular complications. Omentin-1 has been regarded as a novel biomarker of endothelial function in subjects with type-2 diabetes (T2D); however, it is unclear whether omentin-1 has any direct effect in ameliorating high glucose-induced...
Source: Biochemical Pharmacology - January 27, 2020 Category: Drugs & Pharmacology Authors: Liu F, Fang S, Liu X, Li J, Wang X, Cui J, Chen T, Li Z, Yang F, Tian J, Li H, Yin L, Yu B Tags: Biochem Pharmacol Source Type: research

Nicotinic acid transport into human liver involves organic anion transporter 2 (SLC22A7).
In conclusion, these studies demonstrate, for the first time, a specific transport mechanism for NA uptake in the human liver and suggest that OAT2 (SLC22A7) has a critical role in its physiological and pharmacological functions. PMID: 32001236 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - January 27, 2020 Category: Drugs & Pharmacology Authors: Mathialagan S, Bi YA, Costales C, Kalgutkar AS, David Rodrigues A, Varma MVS Tags: Biochem Pharmacol Source Type: research

Natural products target the hallmarks of chronic diseases.
Abstract Natural compounds are known to display therapeutic potential against a variety of chronic conditions, including cancer and inflammation. The efficacy of these natural substances can be associated with numerous molecular scaffolds present in extracts of living organisms, both terrestrial and marine. Recently, investigators have identified the ability of natural compounds to trigger immunogenic cell death and subsequent activation of the adaptive immune system. Such findings indicate that the full therapeutic potential of natural products has yet to be defined, and further investigations on such agents will...
Source: Biochemical Pharmacology - January 27, 2020 Category: Drugs & Pharmacology Authors: Diederich M Tags: Biochem Pharmacol Source Type: research

Using Curcumin to Turn the Innate Immune System Against Cancer.
Abstract Curcumin has been at the center of vigorous research and major debate during the past decade. Inspired by its anti-inflammatory properties, many curcumin-based products are being sold now to manage various forms of arthritis. Parallel preclinical studies have established its role in dissolving beta-amyloid plaques, tau-based neurofibrillary tangles, and also alpha-synuclein-linked protein aggregates typically observed in Parkinson's disease. In cancer research, most cancer cells in culture are eliminated by curcumin at an IC50 of 15-30 µM, whereas the maximum in vivo curcumin concentration achieved ...
Source: Biochemical Pharmacology - January 24, 2020 Category: Drugs & Pharmacology Authors: Mukherjee S, Baidoo JNE, Fried A, Banerjee P Tags: Biochem Pharmacol Source Type: research

Binding of adenosine derivatives to carrier proteins may reduce their antiplatelet activity.
In conclusion, HSA and lipoproteins are important carriers for ARagonists, which can affect pharmacodynamics of ARagonists used as platelet inhibitors. PMID: 31987853 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - January 24, 2020 Category: Drugs & Pharmacology Authors: Wzorek J, Bednarek R, Watala C, Boncler M Tags: Biochem Pharmacol Source Type: research

Downregulation of spinal angiotensin converting enzyme 2 is involved in neuropathic pain associated with type 2 diabetes mellitus in mice.
In conclusion, we revealed that the Ang (1-7)-generating system is downregulated in ob/ob mice and is accompanied by a loss of ACE2-positive neurons. Furthermore, Ang (1-7) decreased the diabetic neuropathic pain through inhibition of p38 MAPK phosphorylation via spinal Mas receptors. PMID: 31987854 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - January 24, 2020 Category: Drugs & Pharmacology Authors: Yamagata R, Nemoto W, Nakagawasai O, Takahashi K, Tan-No K Tags: Biochem Pharmacol Source Type: research

MicroRNA let-7g-5p improves murine collagen-induced arthritis by inhibiting Th17 cell differentiation.
Abstract Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease with complicated pathogenesis. IL-17-producing T helper cells (Th17) are important players in the RA process. Despite numerous researches have proven that microRNAs (miRNAs) were crucial regulators of autoimmune diseases including RA, the effect of miRNAs on the development and function of Th17 cells in the RA progress is not clear. Here, our results showed that the expression of miRNA let-7g-5p was substantially lower in RA patients and CIA mice compared with healthy controls. Furthermore, let-7g-5p could notably suppress the differen...
Source: Biochemical Pharmacology - January 24, 2020 Category: Drugs & Pharmacology Authors: Yang P, Zhang M, Wang X, Xu AL, Shen M, Jiang B, Zhou X, Zhou L Tags: Biochem Pharmacol Source Type: research

Elevated intracellular cAMP concentration mediates growth suppression in glioma cells.
Abstract Supressed levels of intracellular cAMP have been associated with malignancy. Thus, elevating cAMP through activation of adenylyl cyclase (AC) or by inhibition of phosphodiesterase (PDE) may be therapeutically beneficial. Here, we demonstrate that elevated cAMP levels suppress growth in C6 cells (a model of glioma) through treatment with forskolin, an AC activator, or a range of small molecule PDE inhibitors with differing selectivity profiles. Forskolin suppressed cell growth in a PKA-dependent manner by inducing a G2/M phase cell cycle arrest. In contrast, trequinsin (a non-selective PDE2/3/7 inhibitor),...
Source: Biochemical Pharmacology - January 24, 2020 Category: Drugs & Pharmacology Authors: Safitri D, Harris M, Potter H, Yan Yeung H, Winfield I, Kopanitsa L, Svensson F, Rahman T, Harper MT, Bailey D, Ladds G Tags: Biochem Pharmacol Source Type: research

Volatile anaesthetics inhibit the thermosensitive nociceptor ion channel transient receptor potential melastatin 3 (TRPM3).
CONCLUSIONS: These data provide a better insight into the molecular mechanism beyond the analgesic effect of VAs and propose novel strategies to attenuate TRPM3 dependent nociception. PMID: 31987857 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - January 24, 2020 Category: Drugs & Pharmacology Authors: Kelemen B, Lisztes E, Vladár A, Hanyicska M, Almássy J, Oláh A, Gábor Szöllősi A, Pénzes Z, Posta J, Voets T, Bíró T, István Tóth B Tags: Biochem Pharmacol Source Type: research

Development of novel phosphodiesterase 5 inhibitors for the therapy of alzheimer's disease.
Abstract Nitric oxide (NO) is a gaseous molecule that plays a multifactorial role in several cellular processes. In the central nervous system, the NO dual nature in neuroprotection and neurotoxicity has been explored to unveil its involvement in Alzheimer's disease (AD). A growing body of research shows that the activation of the NO signaling pathway leading to the phosphorylation of the transcription factor cyclic adenine monophosphate responsive element binding protein (CREB) (so-called NO/cGMP/PKG/CREB signaling pathway) ameliorates altered neuroplasticity and memory deficits in AD animal models. In addition t...
Source: Biochemical Pharmacology - January 21, 2020 Category: Drugs & Pharmacology Authors: Zuccarello E, Acquarone E, Calcagno E, Argyrousi EK, Deng SX, Landry DW, Arancio O, Fiorito J Tags: Biochem Pharmacol Source Type: research

Protein homodimer sequestration with small molecules: focus on PD-L1.
Abstract Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have emerged as efficient cancer biotherapeutics. In parallel, small molecules targeting PD-L1 are actively searched to offer novel therapeutic opportunities and to reduce treatment costs. Thus far, all PD-L1 small molecule inhibitors identified present the unique property to induce and to stabilize the formation of PD-L1 protein homodimers. PD-L1 itself can form heterodimers with B7-1 (CD80) but it is essentially monomeric in solution, although the homolog viral protein vOX2 is known to dimerize. Drug-induced sequestration of PD-L1 homodime...
Source: Biochemical Pharmacology - January 20, 2020 Category: Drugs & Pharmacology Authors: Bailly C, Vergoten G Tags: Biochem Pharmacol Source Type: research

Salvianolic acid B protects against oxLDL-induced endothelial dysfunction under high-glucose conditions by downregulating ROCK1-mediated mitophagy and apoptosis.
Abstract Diabetes is related to alterations in glucose and lipid metabolism, which are linked to endothelial cell (EC) dysfunction. Salvianolic acid B (Sal B), one of the major ingredient of Danshen (Salvia miltiorrhiza), possesses many of the biological activities. However, protective effect of Sal B against oxLDL induced ECs dysfunction under high glucose condition (high Glu) is not well known. Thus, in this study, we investigated the protective effects of Sal B against EC dysfunction induced by oxLDL and high Glu and examined the associated mechanisms. Our results showed that Sal B significantly and dose-depend...
Source: Biochemical Pharmacology - January 20, 2020 Category: Drugs & Pharmacology Authors: Shin Ko Y, Jin H, Won Park S, Jung Kim H Tags: Biochem Pharmacol Source Type: research

Acetaminophen affects the survivor, pigmentation and development of craniofacial structures in zebrafish (Danio rerio) embryos.
Abstract In spite of its toxic effects, N-acetyl-p-aminophenol (APAP), also commonly known as acetaminophen or paracetamol, is one of the most widely used analgesic and antipyretic agents. It can be obtained without a medical prescription. To test the effect over the zebrafish embryonic development, a Fish Embryo acute Toxicity (FET) test was carried out with acetaminophen to establish the range of concentrations that cause a harmful effect on the zebrafish development. Diminished pigmentation (in embryos treated from 0 h post-fertilization) and blockage of melanin synthesis (in larvae treated from 72 h post-ferti...
Source: Biochemical Pharmacology - January 20, 2020 Category: Drugs & Pharmacology Authors: Cedron VP, Mj Weiner A, Vera M, Sanchez L Tags: Biochem Pharmacol Source Type: research

The nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO), increases survival by attenuating hyperoxia-compromised innate immunity in bacterial clearance in a mouse model of ventilator-associated pneumonia.
In this study, we show that the high mortality rate in mice subjected to hyperoxia and PA infection was accompanied by a significant decrease in the airway levels of nitric oxide (NO). Decreased NO levels were found to be, in part, due to a significant reduction in NO release by macrophages upon exposure to PA lipopolysaccharide (LPS). Based on these findings, we postulated that NO supplementation should restore hyperoxia-compromised innate immunity and decrease mortality by increasing the clearance of PA under hyperoxic conditions. To test this hypothesis, cultured macrophages were exposed to hyperoxia (95% O2) in the pre...
Source: Biochemical Pharmacology - January 20, 2020 Category: Drugs & Pharmacology Authors: Gore A, Gauthier AG, Lin M, Patel V, Thomas DD, Ashb CR, Mantell LL Tags: Biochem Pharmacol Source Type: research

Regulation of carbohydrate metabolism by nitric oxide and hydrogen sulfide: Implications in diabetes.
Abstract Nitric oxide (NO) and hydrogen sulfide (H2S) are two gasotransmitters that are produced in the human body and have a key role in many of the physiological activities of the various organ systems. Decreased NO bioavailability and deficiency of H2S are involved in the pathophysiology of type 2 diabetes and its complications. Restoration of NO levels have favorable metabolic effects in diabetes. The role of H2S in pathophysiology of diabetes is however controversial; H2S production is decreased during development of obesity, diabetes, and its complications, suggesting the potential therapeutic effects of H2S...
Source: Biochemical Pharmacology - January 20, 2020 Category: Drugs & Pharmacology Authors: Gheibi S, Samsonov AP, Gheibi S, Vazquez AB, Kashfi K Tags: Biochem Pharmacol Source Type: research

Curcumin induces stabilization of Nrf2 protein through Keap1 cysteine modification.
Abstract The present study was aimed to investigate the effects of curcumin, a representative chemopreventive phytochemical with pronounced antioxidant and anti-inflammatory properties, on activation of Nrf2 and its target protein heme oxygenase-1 (HO-1) in mouse skin in vivo and in cultured murine epidermal cells. Treatment of mouse epidermal JB-6 cells with curcumin resulted in the induction of HO-1 expression, and this was abrogated in cells transiently transfected with Nrf2 siRNA. While curcumin treatment increased protein expression of Nrf2, it failed to did not alter the steady-state level of the Nrf2 mRNA t...
Source: Biochemical Pharmacology - January 20, 2020 Category: Drugs & Pharmacology Authors: Shin JW, Chun KS, Kim DH, Kim SJ, Hoon Kim S, Cho NC, Na HK, Surh YJ Tags: Biochem Pharmacol Source Type: research

Pathway analysis of glutamate-mediated, calcium-related signaling in glioma progression.
Abstract Brain tumors, particularly high-grade glioblastomas, are a crucial public health issue due to poor prognosis and an extremely low survival rate. The glioblastoma multiforme (GBM) grows rapidly within its unique microenvironment that is characterized by active neural communications. Therefore, diverse neurotransmitters not only maintain normal brain functions but also influence glioma progression. To fully appreciate the relationship between neurotransmitters and glioma progression, we reviewed potential neurotransmitter contributors in human GBM and the much less aggressive Low-grade glioma (LGG) by combi...
Source: Biochemical Pharmacology - January 16, 2020 Category: Drugs & Pharmacology Authors: Pei Z, Lee KC, Khan A, Erisnor G, Wang HY Tags: Biochem Pharmacol Source Type: research

The effects of anthracycline drugs on the conformational distribution of mouse P-glycoprotein explains their transport rate differences.
Abstract P-glycoprotein (Pgp) is an ATP-dependent efflux transporter and plays a major role in anti-cancer drug resistance by pumping a chemically diverse range of cytotoxic drugs from cancerous tumors. Despite numerous studies with the transporter, the molecular features that drive anti-cancer drug efflux are not well understood. Even subtle differences in the anti-cancer drug molecular structure can lead to dramatic differences in their transport rates. To unmask these structural differences, this study focused on two closely-related anthracycline drugs, daunorubicin (DNR), and doxorubicin (DOX), with mouse Pgp....
Source: Biochemical Pharmacology - January 16, 2020 Category: Drugs & Pharmacology Authors: Nguyen PH, Sigdel KP, Schaefer GAK, Mensah KG, King GM, Roberts AG Tags: Biochem Pharmacol Source Type: research

HGF induces protective effects in α-naphthylisothiocyanate-induced intrahepatic cholestasis by counteracting oxidative stress.
In this study, we evaluated the capability of HGF to counteract the damage caused by the model cholestatic agent, α-naphthyl isothiocyanate (ANIT). HGF had clear anti-cholestatic effects, as apparent from the improvement in both bile flow and liver function test. Histology examination revealed a significant reduction of injured areas. HGF also preserved the tight-junctional structure. These anticholestatic effects were associated with the induction of basolateral efflux ABC transporters, which facilitates extrusion of toxic biliary compounds and its further alternative depuration via urine. The biliary epithelium see...
Source: Biochemical Pharmacology - January 16, 2020 Category: Drugs & Pharmacology Authors: Salas-Silva S, Simoni-Nieves A, Razori MV, López-Ramirez J, Barrera-Chimal J, Lazzarini R, Bello O, Souza V, Miranda-Labra RU, Gutiérrez-Ruiz MC, Gomez-Quiroz LE, Roma MG, Bucio-Ortiz L Tags: Biochem Pharmacol Source Type: research

OSU-A9 induced-reactive oxygen species cause cytotoxicity in duodenal and gastric cancer cells by decreasing phosphorylated nuclear pyruvate kinase M2 protein levels.
In conclusion, OSU-A9 inhibited duodenal and gastric cancer cell proliferation through ROS generation and caused a subsequent decrease in nuclear pTyr105-PKM2 protein. These findings provide evidence for the non-canonical activity of PKM2 in cancer cell survival. Furthermore, they highlight the potential role of PKM2 as a future therapeutic target for duodenal and gastric cancer. Chemical compounds studies in this article: N-acetylcysteine (PubChem CID: 12035); Glutathione (PubChem CID: 124886); Dimethyl sulfoxide (PubChem CID: 679); Methylcellulose (PubChem CID: 44263857). PMID: 31954719 [PubMed - as supplied by publ...
Source: Biochemical Pharmacology - January 16, 2020 Category: Drugs & Pharmacology Authors: Chiu CF, Weng JR, Lee SL, Wu CY, Chu PC, Shan YS, Yang HR, Bai LY Tags: Biochem Pharmacol Source Type: research

Stability and pharmacokinetics of separase inhibitor-sepin-1 in sprague-dawley rats.
Abstract Separase, a sister chromatid cohesion-resolving enzyme, is an oncogene and overexpressed in many human cancers. Sepin-1 (2,2-dimethyl-5-nitro-2H-benzimidazole-1,3-dioxide) is a potent Separase inhibitor that impedes cancer cell growth, cell migration, and wound healing, suggesting that Sepin-1 possesses a great potential to target separase-overexpressing tumors. As a part of the IND-enabling studies to bring Sepin-1 to clinic, herein we report the results from a 28-day repeat-dose pharmacokinetic study of Sepin-1 in rats. Sepin-1 was intravenously administered to Sprague-Dawley rats once daily for 28 days...
Source: Biochemical Pharmacology - January 10, 2020 Category: Drugs & Pharmacology Authors: Zhang N, Sarkar AK, Li F, Demerzhan SA, Gilbertson SR, Pati D Tags: Biochem Pharmacol Source Type: research

The kinase inhibitor BX795 suppresses the inflammatory response via multiple kinases.
In this study, lipopolysaccharide (LPS)-treated macrophages (RAW264.7 cells), luciferase reporter gene assay, knock-down and overexpression strategies, kinase assay, protein chip, immunoprecipitation, and immunoblotting analyses were employed to clarify the anti-inflammatory mechanism of BX795. BX795 was found to dose-dependently inhibit the production of pro-inflammatory mediators without exhibiting cytotoxicity. Luciferase assay and immunoblotting analysis with nuclear fractions showed that activator protein-1 (AP-1), signal transducer and activator of transcription 1 (STAT1), and interferon regulatory factor 3 (IRF3) ar...
Source: Biochemical Pharmacology - January 9, 2020 Category: Drugs & Pharmacology Authors: Yu T, Wang Z, Jie W, Fu X, Li B, Xu H, Liu Y, Li M, Kim E, Yang Y, Youl Cho J Tags: Biochem Pharmacol Source Type: research