Connective tissue growth factor stimulates osteosarcoma cell migration and induces osteosarcoma metastasis by upregulating VCAM-1 expression.
Abstract Osteosarcoma is the most common bone malignancy that occurs in the young population. After osteosarcoma cells metastasize to the lung, prognosis is very poor owing to difficulties in early diagnosis and effective treatment. Recently, connective tissue growth factor (CTGF) was reported to be a critical contributor to osteosarcoma metastasis. However, the detailed mechanism associated with CTGF-directed migration in bone neoplasms is still mostly unknown. Through the in vivo and in vitro examination of osteosarcoma cells, this study suggests that VCAM-1 up-regulation and increased osteosarcoma cell migratio...
Source: Biochemical Pharmacology - June 14, 2018 Category: Drugs & Pharmacology Authors: Hou CH, Yang RS, Tsao YT Tags: Biochem Pharmacol Source Type: research

Anti-inflammatory nitro-fatty acids suppress tumor growth by triggering mitochondrial dysfunction and activation of the intrinsic apoptotic pathway in colorectal cancer cells.
This study delivers a novel mechanistic approach for nitro-fatty acid-induced inhibition of CRC cell growth by targeting mitochondrial functions such as the mitochondrial membrane potential and mitochondrial respiration. We suggest these naturally occurring lipid mediators as a new class of well tolerated chemotherapeutic drug candidates for treatment of CRC or potentially other inflammation-driven cancer types. PMID: 29909078 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - June 14, 2018 Category: Drugs & Pharmacology Authors: Kühn B, Brat C, Fettel J, Hellmuth N, Maucher IV, Bulut U, Hock KJ, Grimmer J, Manolikakes G, Rühl M, Kühn A, Zacharowski K, Matrone C, Urbschat A, Roos J, Steinhilber D, Maier TJ Tags: Biochem Pharmacol Source Type: research

TARPs differentially affect the pharmacology of Ampakines.
Abstract Transmembrane AMPA receptor regulatory proteins (TARPs) govern AMPA receptor cell surface expression and distinct physiological properties including agonist affinity, desensitization and deactivation kinetics. The prototypical TARP, STG or γ2 and TARPs γ3, γ4, γ7 and γ8 are all expressed to varying degrees in the mammalian brain and differentially regulate AMPAR gating parameters. Positive allosteric AMPA receptor modulators or ampakines alter receptor rates of agonist binding/unbinding, channel opening and can offset receptor desensitization and deactivation. The effects of ...
Source: Biochemical Pharmacology - June 12, 2018 Category: Drugs & Pharmacology Authors: Radin DP, Li YX, Rogers G, Purcell R, Lippa A Tags: Biochem Pharmacol Source Type: research

Inhibition of p21-activated kinase 1 attenuates the cardinal features of asthma through suppressing the lymph node homing of dendritic cells.
Abstract Dendritic cell (DC) trafficking from lung to the draining mediastinal lymph nodes (MLNs) is a key step for initiation of T cell responses in allergic asthma. In the present study, we investigate the role of DC-mediated airway inflammation after inhibition of p21-activated kinase-1 (PAK1), an effector of Rac and Cdc42 small GTPases, in the allergen-induced mouse models of asthma. Systemic administration of PAK1 specific inhibitor IPA-3 significantly attenuates not only the airway inflammation but also the airway hyperresponsiveness in a mouse model of ovalbumin-induced asthma. Specifically, intratracheal a...
Source: Biochemical Pharmacology - June 12, 2018 Category: Drugs & Pharmacology Authors: Lu M, Xu C, Zhang Q, Wu X, Tang L, Wang X, Wu J, Wu X Tags: Biochem Pharmacol Source Type: research

Liver Metabolomics in a Mouse Model of Erythropoietic Protoporphyria.
Abstract Erythropoietic protoporphyria (EPP) is a genetic disease that results from the defective mutation in the gene encoding ferrochelatase (FECH), the enzyme that converts protoporphyrin IX (PPIX) to heme. Liver injury and even liver failure can occur in EPP patients because of PPIX accumulation in the liver. The current study profiled the liver metabolome in an EPP mouse model caused by a Fech mutation (Fech-mut). As expected, we observed the accumulation of PPIX in the liver of Fech-mut mice. In addition, our metabolomic analysis revealed the accumulation of bile acids and ceramide (Cer) in the liver of Fech...
Source: Biochemical Pharmacology - June 12, 2018 Category: Drugs & Pharmacology Authors: Wang P, Sachar M, Guo GL, Shehu AI, Lu J, Zhong XB, Ma X Tags: Biochem Pharmacol Source Type: research

Effects of digitoxin on cell migration in ovarian cancer inflammatory microenvironment.
PMID: 29890142 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - June 8, 2018 Category: Drugs & Pharmacology Authors: Trenti A, Boscaro C, Tedesco S, Cignarella A, Trevisi L, Bolego C Tags: Biochem Pharmacol Source Type: research

Aminoacyl-tRNA synthetases, therapeutic targets for infectious diseases.
Abstract Despite remarkable advances in medical science, infection-associated diseases remain among the leading causes of death worldwide. There is a great deal of interest and concern at the rate at which new pathogens are emerging and causing significant human health problems. Expanding our understanding of how cells regulate signaling networks to defend against invaders and retain cell homeostasis will reveal promising strategies against infection. It has taken scientists decades to appreciate that eukaryotic aminoacyl-tRNA synthetases (ARSs) play a role as global cell signaling mediators to regulate cell homeo...
Source: Biochemical Pharmacology - June 8, 2018 Category: Drugs & Pharmacology Authors: Lee EY, Kim S, Kim MH Tags: Biochem Pharmacol Source Type: research

Ischemia/Reperfusion Model Impairs Endocannabinoid Signaling and Na+/K+ ATPase Expression and Activity in Kidney Proximal Tubule Cells.
In conclusion, the ECS and Na+/K+ ATPase are down-regulated following IR model in LLC-PK1 cells and rat kidney. We suggest that CB1 agonists might represent a potential strategy to reverse the consequences of IR injury in kidney tissues. PMID: 29890144 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - June 8, 2018 Category: Drugs & Pharmacology Authors: Sampaio LS, Iannotti FA, Veneziani L, Borelli-Tôrres RT, De Maio F, Piscitelli F, Reis RAM, Di Marzo V, Einicker-Lamas M Tags: Biochem Pharmacol Source Type: research

Syringic acid prevents skin carcinogenesis via regulation of NoX and EGFR signaling.
Abstract Validation of nutraceutical and pharmaceutical targets is essential for the prediction of physiological and side effects. Epidemiologic evidence and molecular studies suggest that non-melanoma skin cancer is directly associated with excessive exposure to ultraviolet (UV) radiation. The aim of the present study was to evaluate the inhibitory effects of syringic acid on UVB-induced signaling and skin carcinogenesis, and determine the molecular targets. Treatment of human epidermal keratinocytes (HaCaT) cells with syringic acid resulted in the suppression of UVB-induced cyclooxygenase-2, matrix metalloprotei...
Source: Biochemical Pharmacology - June 7, 2018 Category: Drugs & Pharmacology Authors: Ha SJ, Lee J, Park J, Kim YH, Lee NH, Kim YE, Song KM, Chang PS, Jeong CH, Keun Jung S Tags: Biochem Pharmacol Source Type: research

Carbonyl Scavengers as Pharmacotherapies in Degenerative Disease: Hydralazine Repurposing and Challenges in Clinical Translation.
Abstract During cellular metabolism, spontaneous oxidative damage to unsaturated lipids generates many electrophilic carbonyl compounds that readily attack cell macromolecules, forming adducts that are potential drivers of tissue dysfunction. Since such damage is heightened in many degenerative conditions, researchers have assessed the efficacy of nucleophilic carbonyl-trapping drugs in animal models of such disorders, anticipating that they will protect tissues by intercepting toxic lipid-derived electrophiles (LDEs) within cells. This Commentary explores recent animal evidence for carbonyl scavenger efficacy in ...
Source: Biochemical Pharmacology - June 5, 2018 Category: Drugs & Pharmacology Authors: Burcham PC Tags: Biochem Pharmacol Source Type: research

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.
Induction of oxidative stress by long-term treatment of live HEK293 cells with therapeutic concentration of lithium is associated with down-regulation of δ-opioid receptor amount and function. Biochem Pharmacol. 2018 Jun 05;: Authors: Vosahlikova M, Ujcikova H, Musil S, Roubalova L, Alda M, Svoboda P Abstract The functional state of δ-opioid receptor signalling cascade in live cells exposed to a therapeutic concentration of lithium for a prolonged period of time (weeks) is not known because the previous studies of Li interference with OR were oriented to µ-OR only. The same applies t...
Source: Biochemical Pharmacology - June 5, 2018 Category: Drugs & Pharmacology Authors: Vosahlikova M, Ujcikova H, Musil S, Roubalova L, Alda M, Svoboda P Tags: Biochem Pharmacol Source Type: research

Luteolin Attenuates Neutrophilic Oxidative Stress and Inflammatory Arthritis by Inhibiting Raf1 Activity.
In conclusion, in addition to its known ROS scavenging effect, this study is the first to provide evidence that luteolin diminishes human neutrophil inflammatory responses by inhibiting Raf1-MEK-1-Erk. Our results focused on the importance of neutrophil activation in inflammatory tissue injury and offer opportunities for the development of luteolin's therapeutic potential to attenuate neutrophilic inflammatory diseases. PMID: 29883707 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - June 5, 2018 Category: Drugs & Pharmacology Authors: Yang SC, Chen PJ, Chang SH, Weng YT, Chang FR, Chang KY, Chen CY, Kao TI, Hwang TL Tags: Biochem Pharmacol Source Type: research

Molecular and functional interaction between GPR18 and cannabinoid CB2 G-protein-coupled receptors. Relevance in neurodegenerative diseases.
o R Abstract GPR18, still considered an orphan receptor, may respond to endocannabinoids, whose canonical receptors are CB1 and CB2. GPR18 and CB2 receptors share a role in peripheral immune response regulation and are co-expressed in microglia, which are immunocompetent cells in the central nervous system (CNS). We aimed at identifying heteroreceptor complexes formed by GPR18 and CB1R or CB2R in resting and activated microglia. Receptor-receptor interaction was assessed using energy-transfer approaches, and receptor function by determining cAMP levels and ERK1/2 phosphorylation in heterologous cells and primary c...
Source: Biochemical Pharmacology - June 2, 2018 Category: Drugs & Pharmacology Authors: Reyes-Resina I, Navarro G, Aguinaga D, Canela EI, Schoeder CT, Zaluski M, Kiec-Kononowicz K, Saura CA, Müller CE, Franco R Tags: Biochem Pharmacol Source Type: research

A hispanolone-derived diterpenoid inhibits M2-Macrophage polarization in vitro via JAK/STAT and attenuates chitin induced inflammation in vivo.
, de Las Heras B, Hortelano S Abstract Macrophages are highly plastic cells that adopt different functional phenotypes in response to environmental signals.Classically activated macrophages (M1) exhibit a pro-inflammatory role, mediating host defense against microorganisms or tumor cells; whereas alternatively activated macrophages (M2) perform a range of physiological processes, including inflammation, wound repair and tissue remodeling. Interestingly, M2 macrophages have been involved in pathological settings such as tumor progression, parasitic infection and respiratory disorders. Consequently, the search of ne...
Source: Biochemical Pharmacology - June 2, 2018 Category: Drugs & Pharmacology Authors: Jiménez-García L, Higueras MÁ, Herranz S, Hernández-López M, Luque A, de Las Heras B, Hortelano S Tags: Biochem Pharmacol Source Type: research

Targeting Forkhead Box M1 Transcription Factor in Breast Cancer.
Abstract Breast cancer continues to be the most commonly diagnosed malignancy and second most common cause of cancer-related deaths among women in the United States. Improved understanding of the molecular heterogeneity of breast tumors and the approval of multiple targeted therapies have revolutionized the treatment landscape and long-term survival rates for patients with breast cancer. Despite the development of highly effective targeted agents, drug resistance and disease progression remain major clinical concerns. Improved understanding of the molecular mechanisms mediating drug resistance will allow new treat...
Source: Biochemical Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: O'Regan RM, Nahta R Tags: Biochem Pharmacol Source Type: research

Taxodione induces apoptosis in BCR-ABL-positive cells through ROS generation.
Abstract Chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) are hematopoietic malignancies caused by the constitutive activation of BCR-ABL tyrosine kinase. Although direct BCR-ABL inhibitors, such as imatinib, were initially successful in the treatment of leukemia, many patients developed drug resistance over time due to the gatekeeper mutation of BCR-ABL T315I. In the present study, we found that taxodione, a quinone methide diterpene isolated from Taxodium distichum, significantly induced apoptosis in human myelogenous leukemia-derived K562 cells, which were transformed by BCR-ABL. Taxodione ...
Source: Biochemical Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Uchihara Y, Tago K, Taguchi H, Narukawa Y, Kiuchi F, Tamura H, Funakoshi-Tago M Tags: Biochem Pharmacol Source Type: research

SR-A1 suppresses colon inflammation and tumorigenesis through negative regulation of NF- κB signaling.
SR-A1 suppresses colon inflammation and tumorigenesis through negative regulation of NF-κB signaling. Biochem Pharmacol. 2018 May 31;: Authors: Zong G, Zhu Y, Zhang Y, Wang Y, Bai H, Yang Q, Ben J, Zhang H, Li X, Zhu X, Chen Q Abstract Inflammatory bowel disease is characterized by chronic intestinal inflammatory disorders associated with increased risk of developing colorectal cancer. However, the detailed mechanisms are not fully understood. The aim of this study was to determine the effect of macrophage scavenger receptor class A1 (SR-A1), a pattern recognition receptor primarily expressed in...
Source: Biochemical Pharmacology - May 31, 2018 Category: Drugs & Pharmacology Authors: Zong G, Zhu Y, Zhang Y, Wang Y, Bai H, Yang Q, Ben J, Zhang H, Li X, Zhu X, Chen Q Tags: Biochem Pharmacol Source Type: research

Globular adiponectin protects rat hepatocytes against acetaminophen-induced cell death via modulation of the inflammasome activation and ER stress: Critical role of autophagy induction.
Abstract Acetaminophen (APAP) overdose treatment causes severe liver injury. Adiponectin, a hormone predominantly produced by adipose tissue, exhibits protective effects against APAP-induced hepatotoxicity. However, the underlying mechanisms are not clearly understood. In the present study, we examined the protective effect of globular adiponectin (gAcrp) on APAP-induced hepatocyte death and its underlying mechanisms. We found that APAP (2 mM)-induced hepatocyte death was prevented by inhibition of the inflammasome. In addition, treatment with gAcrp (0.5 and 1 μg/ml) inhibited APAP-induced activation of the...
Source: Biochemical Pharmacology - May 24, 2018 Category: Drugs & Pharmacology Authors: Kim EH, Park PH Tags: Biochem Pharmacol Source Type: research

Selective killing of proinflammatory synovial fibroblasts via activation of transient receptor potential ankyrin (TRPA1).
Abstract BACKGROUND: Studies in rheumatoid arthritis synovial fibroblasts (RASF) demonstrated the expression of several transient receptor potential channels (TRP) such as TRPV1, TRPV2, TRPV4, TRPA1 and TRPM8. Upon ligation, these receptors increase intracellular calcium but they have also been linked to modulation of inflammation in several cell types. TNF was shown to increase the expression of TRPA1, the receptor for mustard oil and environmental poisons in SF, but the functional consequences have not been investigated yet. METHODS: TRPA1 was detected by immunocytochemistry, western blot and cell-based ELI...
Source: Biochemical Pharmacology - May 24, 2018 Category: Drugs & Pharmacology Authors: Lowin T, Bleck J, Schneider M, Pongratz G Tags: Biochem Pharmacol Source Type: research

Nano-delivery systems for encapsulation of dietary polyphenols: an experimental approach for neurodegenerative diseases and brain tumors.
Abstract Neurodegenerative diseases (NDs) and brain tumors are severe, disabling, and incurable disorders that represent a critical problem regarding human suffering and the economic burden on the healthcare system. Because of the lack of effective therapies to treat NDs and brain tumors, the challenge for physicians is to discover new drugs to improve their patients' quality of life. In addition to risk factors such as genetics and environmental influences, increased cellular oxidative stress has been reported as one of the potential common etiologies in both disorders. Given their antioxidant and anti-inflammato...
Source: Biochemical Pharmacology - May 24, 2018 Category: Drugs & Pharmacology Authors: Squillaro T, Cimini A, Peluso G, Giordano A, Melone M Tags: Biochem Pharmacol Source Type: research

Jacareubin inhibits Fc εRI-induced extracellular calcium entry and production of reactive oxygen species required for anaphylactic degranulation of mast cells.
Jacareubin inhibits FcεRI-induced extracellular calcium entry and production of reactive oxygen species required for anaphylactic degranulation of mast cells. Biochem Pharmacol. 2018 May 23;: Authors: Castillo-Arellano JI, Guzmán-Gutiérrez SL, Ibarra-Sánchez A, Hernández-Ortega S, Nieto-Camacho A, Medina-Campos ON, Pedraza-Chaverri J, Reyes-Chilpa R, González-Espinosa C Abstract Mast cells (MCs) are important effectors in allergic reactions since they produce a number of pre-formed and de novo synthesized pro-inflammatory compounds in response to the high aff...
Source: Biochemical Pharmacology - May 23, 2018 Category: Drugs & Pharmacology Authors: Castillo-Arellano JI, Guzmán-Gutiérrez SL, Ibarra-Sánchez A, Hernández-Ortega S, Nieto-Camacho A, Medina-Campos ON, Pedraza-Chaverri J, Reyes-Chilpa R, González-Espinosa C Tags: Biochem Pharmacol Source Type: research

Celecoxib inhibits mitochondrial O2 consumption, promoting ROS dependent death of murine and human metastatic cancer cells via the apoptotic signalling pathway.
Conclusion: These novel findings for direct effects of celecoxib on mitochondria to induce metastatic cancer cell death via a ROS-dependent pro-oxidative mechanism provide supportive evidence for its combinatorial use as a chemosensitizing agent complementing chemotherapies to improve response rates in patients with advanced metastatic cancers. PMID: 29800556 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - May 22, 2018 Category: Drugs & Pharmacology Authors: Pritchard R, Rodríguez-Enríquez S, Pacheco-Velázquez SC, Bortnik V, Moreno-Sánchez R, Ralph S Tags: Biochem Pharmacol Source Type: research

Tanovea ® for the treatment of lymphoma in dogs.
Tanovea® for the treatment of lymphoma in dogs. Biochem Pharmacol. 2018 May 17;: Authors: De Clercq E Abstract Tanovea® (first named GS-9219, then VDC-1101, generic name: rabacfosadine) is a pro-prodrug or "double" prodrug of PMEG [9-(2-phosphonylmethoxyethyl)guanine], which has been conditionally approved by the US FDA (Food and Drug Administration) for the treatment of lymphoma in dogs. Tanovea has been demonstrated to be effective against non-Hodgkin's lymphoma (NHL) in dogs, as well as canine cutaneous T-cell lymphoma, spontaneous canine multiple myeloma, naïve canine multic...
Source: Biochemical Pharmacology - May 17, 2018 Category: Drugs & Pharmacology Authors: De Clercq E Tags: Biochem Pharmacol Source Type: research

Inhibition of BET bromodomains restores corticosteroid responsiveness in a mixed granulocytic mouse model of asthma.
Abstract Asthma is a heterogeneous disease characterized by different endotypes/phenotypes. Th2/Th17 driven mixed granulocytic asthma is one of them and shows resistance to corticosteroid therapy. Bromodomain and extra-terminal (BET) proteins are required for differentiation of Th17 cells which play a pivotal role in neutrophilic inflammation. Therefore, we sought to characterize the differential effects of BET inhibitor versus corticosteroids, and their potential synergism in cockroach allergen extract (CE)-induced mixed granulocytic (eosinophilic and neutrophilic) mouse model of asthma having Th2/Th17 endotype. ...
Source: Biochemical Pharmacology - May 16, 2018 Category: Drugs & Pharmacology Authors: Nadeem A, Ahmad SF, Al-Harbi NO, Siddiqui N, Ibrahim KE, Attia SM Tags: Biochem Pharmacol Source Type: research

Probing the binding site of novel selective positive allosteric modulators at the M1 mAChR.
s A Abstract Subtype-selective allosteric modulation of the M1 muscarinic acetylcholine (ACh) receptor (M1 mAChR) is an attractive approach for the treatment of numerous disorders, including cognitive deficits. The discovery of benzyl quinolone carboxylic acid, BQCA, a selective M1 mAChR positive allosteric modulator (PAM), spurred the subsequent development of newer generation M1 PAMs representing diverse chemical scaffolds, different pharmacodynamic properties and, in some instances, improved pharmacokinetics. Key exemplar molecules from such efforts include PF-06767832 (N-((3R,4S)-3-hydroxytetrahydro-2H-pyran-4...
Source: Biochemical Pharmacology - May 16, 2018 Category: Drugs & Pharmacology Authors: Khajehali E, Valant C, Jörg M, Tobin AB, Jeffrey Conn P, Lindsley CW, Sexton PM, Scammells PJ, Christopoulos A Tags: Biochem Pharmacol Source Type: research

Repositioning of anti-cancer drug candidate, AZD7762, to an anti-allergic drug suppressing IgE-mediated mast cells and allergic responses via the inhibition of Lyn and Fyn.
Abstract Mast cells are critical effector cells in IgE-mediated allergic responses. The aim of this study was to investigate the anti-allergic effects of 3-[(aminocarbonyl)amino]-5-(3-fluorophenyl)-N-(3S)-3-piperidinyl-2-thiophenecarboxamide (AZD7762) in vitro and in vivo. AZD7762 inhibited the antigen-stimulated degranulation from RBL-2H3 (IC50, ∼ 27.9 nM) and BMMCs (IC50, ∼ 99.3 nM) in a dose-dependent manner. AZD7762 also inhibited the production of TNF-α and IL-4. As the mechanism of its action, AZD7762 inhibited the activation of Syk and its downstream signaling proteins, such as Linker of activ...
Source: Biochemical Pharmacology - May 16, 2018 Category: Drugs & Pharmacology Authors: Park YH, Kim DK, Kim HW, Kim HS, Lee D, Lee MB, Young Min K, Koo J, Kim SJ, Kang C, Mi Kim Y, Kim HS, Choi WS Tags: Biochem Pharmacol Source Type: research

Quercetin ameliorate kidney injury and fibrosis by modulating M1/M2 macrophage polarization.
Abstract Interstitial inflammation is the main pathological feature in kidneys following injury, and the polarization of macrophages is involved in the process of inflammatory injury. Previous studies have shown that quercetin has a renal anti-inflammatory activity, but the potential molecular mechanism remains unknown. In obstructive kidneys, administration of quercetin inhibited tubulointerstitial injury and reduced the synthesis and release of inflammatory factors. Further study revealed that quercetin inhibited the infiltration of CD68+ macrophages in renal interstitium. Moreover, the decrease in levels of iNO...
Source: Biochemical Pharmacology - May 10, 2018 Category: Drugs & Pharmacology Authors: Lu H, Wu L, Liu L, Ruan Q, Zhang X, Hong W, Wu S, Jin G, Bai Y Tags: Biochem Pharmacol Source Type: research

New tanshinone I derivatives S222 and S439 similarly inhibit topoisomerase I/II but reveal different p53-dependency in inducing G2/M arrest and apoptosis.
Abstract Tanshinone I (Tanshinone-1), a major active principle of the traditional Chinese medicine Salvia miltiorrhiza, possesses excellent anticancer properties, including inhibiting proliferation, angiogenesis and metastasis and overcoming multidrug resistance (MDR). However, its direct anticancer molecular target(s) remain unknown. Here we report that tanshinone-1 and its two new derivatives, S222 and S439, directly inhibit DNA topoisomerase I/II (Top1/2). With significantly improved water solubility, S222 and S439 displayed 12- and 14-times more potent proliferative inhibition than their parent tanshinone-1 in...
Source: Biochemical Pharmacology - May 10, 2018 Category: Drugs & Pharmacology Authors: Tian QT, Ding CY, Song SS, Wang YQ, Zhang A, Miao ZH Tags: Biochem Pharmacol Source Type: research

The aryl hydrocarbon receptor is indispensable for dioxin-induced defects in sexually-dimorphic behaviors due to the reduction in fetal steroidogenesis of the pituitary-gonadal axis in rats.
Abstract Many forms of the toxic effects produced by dioxins and related chemicals take place following activation of the aryl hydrocarbon receptor (AHR). Our previous studies have demonstrated that treating pregnant rats with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly toxic dioxin, attenuates the pituitary expression of gonadotropins to reduce testicular steroidogenesis during the fetal stage, resulting in the impairment of sexually-dimorphic behaviors after the offspring reach maturity. To investigate the contribution of AHR to these disorders, we examined the effects of TCDD on AHR-knockout (AHR-KO) W...
Source: Biochemical Pharmacology - May 10, 2018 Category: Drugs & Pharmacology Authors: Hattori Y, Takeda T, Nakamura A, Nishida K, Shioji Y, Fukumitsu H, Yamada H, Ishii Y Tags: Biochem Pharmacol Source Type: research

Corrigendum to "In vivo α-hydroxylation of a 2-alkylindole antagonist of the OXE receptor for the eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid in monkeys" [Biochem. Pharmacol. 138 (2017) 107-118].
Corrigendum to "In vivo α-hydroxylation of a 2-alkylindole antagonist of the OXE receptor for the eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid in monkeys" [Biochem. Pharmacol. 138 (2017) 107-118]. Biochem Pharmacol. 2018 May 10;154:174 Authors: Chourey S, Ye Q, Reddy CN, Cossette C, Gravel S, Zeller M, Slobodchikova I, Vuckovic D, Rokach J, Powell WS PMID: 29754018 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - May 10, 2018 Category: Drugs & Pharmacology Authors: Chourey S, Ye Q, Reddy CN, Cossette C, Gravel S, Zeller M, Slobodchikova I, Vuckovic D, Rokach J, Powell WS Tags: Biochem Pharmacol Source Type: research

Lansoprazole reduces renal cyst in polycystic kidney disease via inhibition of cell proliferation and fluid secretion.
Abstract Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) is mediated by abnormal cyst-ling cell proliferation and fluid accumulation. Liver X receptor (LXR)-activating ligands suppresses renal cyst enlargement by modulation of cysticfibrosis transmembrane conductance regulator (CFTR)-mediated fluid accumulation. Lansoprazole has been reported as agonist of LXR, and shows an anti-proliferative effect in cancer cells. Here, lansoprazole's pharmacological effect and underlying mechanism on renal cyst development and expansion in in vitro; human ADPKD cyst-lining epithelial...
Source: Biochemical Pharmacology - May 7, 2018 Category: Drugs & Pharmacology Authors: Nantavishit J, Chatsudthipong V, Soodvilai S Tags: Biochem Pharmacol Source Type: research

Tabersonine attenuates lipopolysaccharide-induced acute lung injury via suppressing TRAF6 ubiquitination.
In this study, we reported that tabersonine ameliorated lipopolysaccharides (LPS)-induced ALI in vivo and inhibited LPS-mediated macrophage activation in vitro. By using murine ALI model, we found that tabersonine significantly attenuated LPS-induced pathological injury in the lung. Tabersonine also inhibited LPS-mediated neutrophil infiltration, elevation of MPO activity and the production of TNF-α, IL-6 and IL-1β. Furthermore, tabersonine inhibited LPS-induced the production of pro-inflammatory mediators such as iNOS, NO and cytokines by suppressing NF-κB and p38 MAPK/MK2 signaling cascades. Tabersonine ...
Source: Biochemical Pharmacology - May 7, 2018 Category: Drugs & Pharmacology Authors: Zhang D, Li X, Hu Y, Jiang H, Wu Y, Ding Y, Yu K, He H, Xu J, Sun L, Qian F Tags: Biochem Pharmacol Source Type: research

Exploiting Methionine Restriction for Cancer Treatment.
Abstract Normal cells can synthesize sufficient methionine for growth requirements from homocysteine and 5-methyltetrahydrofolate and vitamin B12. However, many cancer-cell types require exogenous methionine for survival and therefore methionine restriction is a promising avenue for treatment. While the lack of the methionine salvage enzyme methylthioadenosine phosphorylase (MTAP) deficiency is associated with methionine dependence in cancer cells, there are other causes for tumors to require exogenous methionine. In this review we describe studies that show restricting methionine to certain cancers by diet or by ...
Source: Biochemical Pharmacology - May 4, 2018 Category: Drugs & Pharmacology Authors: Chaturvedi S, Hoffman RM, Bertino JR Tags: Biochem Pharmacol Source Type: research

Resistin facilitates VEGF-C-associated lymphangiogenesis by inhibiting miR-186 in human chondrosarcoma cells.
This study is the first to evaluate the mechanism underlying resistin-induced promotion of LEC-associated lymphangiogenesis via the upregulation of VEGF-C expression in human chondrosarcomas. We suggest that resistin may represent a molecular target in VEGF-C-associated tumor lymphangiogenesis in chondrosarcoma metastasis. PMID: 29730230 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - May 3, 2018 Category: Drugs & Pharmacology Authors: Su CM, Tang CH, Chi MJ, Lin CY, Fong YC, Liu YC, Chen WC, Wang SW Tags: Biochem Pharmacol Source Type: research

RACking up ceramide-induced islet β-cell dysfunction.
RACking up ceramide-induced islet β-cell dysfunction. Biochem Pharmacol. 2018 Apr 28;: Authors: Kowluru A, Kowluru RA Abstract The International Diabetes Federation predicts that by 2045 the number of individuals afflicted with diabetes will increase to 629 million. Furthermore, ∼352 million individuals with impaired glucose tolerance are at increased risk for developing diabetes. Several mechanisms have been proposed for the onset of metabolic dysfunction and demise of the islet β-cell leading to the pathogenesis of diabetes. It is widely accepted that the onset of type 2 diabetes is du...
Source: Biochemical Pharmacology - April 28, 2018 Category: Drugs & Pharmacology Authors: Kowluru A, Kowluru RA Tags: Biochem Pharmacol Source Type: research

New insights about the peculiar role of the 28-38 C-terminal segment and some selected residues in PACAP for signaling and neuroprotection.
This study will definitely improve our understanding of the molecular and cellular mechanisms associated with PACAP neuroprotection. PMID: 29704474 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - April 25, 2018 Category: Drugs & Pharmacology Authors: de Molliens MP, Létourneau M, Devost D, Hébert TE, Fournier A, Chatenet D Tags: Biochem Pharmacol Source Type: research

Angiotensin II cyclic analogs as tools to investigate AT1R biased signaling mechanisms.
In this study, we examined the properties of AngII cyclic analogs to impart biased agonism on the angiotensin type 1 receptor (AT1R). Positions 3 and 5 of AngII were substituted for cysteine and homocysteine residues ([Sar1Hcy3,5]AngII, [Sar1Cys3Hcy5]AngII and [Sar1Cys3,5]AngII) and the resulting analogs were evaluated for their capacity to activate the Gq/11, G12, Gi2, Gi3, Gz, ERK and β-arrestin (βarr) signaling pathways via AT1R. Interestingly, [Sar1Hcy3,5]AngII exhibited potency and full efficacy on all pathways tested with the exception of the Gq pathway. Molecular dynamic simulations showed that the energy ...
Source: Biochemical Pharmacology - April 20, 2018 Category: Drugs & Pharmacology Authors: St-Pierre D, Cabana J, Holleran BJ, Besserer-Offroy É, Escher E, Guillemette G, Lavigne P, Leduc R Tags: Biochem Pharmacol Source Type: research

Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells.
li JP Abstract ABC transporters are key players in drug excretion with alterations in their expression and activity by therapeutic agents potentially leading to drug-drug interactions. The interaction potential of nomegestrol acetate (NMGA), a synthetic progestogen increasingly used as oral contraceptive, had never been explored. In this work we evaluated (1) the effect of NMGA on ABC transporters in the human hepatic cell line HepG2 and (2) the underlying molecular mechanism. NMGA (5, 50 and 500 nM) increased P-glycoprotein (P-gp) expression at both protein and mRNA levels and reduced intracellular calcein accumu...
Source: Biochemical Pharmacology - April 20, 2018 Category: Drugs & Pharmacology Authors: Tocchetti GN, Domínguez CJ, Zecchinati F, Arana MR, Ruiz ML, Villanueva SSM, Weiss J, Mottino AD, Rigalli JP Tags: Biochem Pharmacol Source Type: research

Identification of a pyrrogallol derivative as a potent and selective human TLR2 antagonist by structure-based virtual screening.
We present virtual screening for the identification of novel TLR2 modulators, which combines analyses of known ligand sets with structure-based approaches. The 13 identified compounds were pharmacologically characterized in HEK293T-TLR2 cells, THP-1 macrophages and peripheral blood mononuclear cells for their ability to inhibit TLR2-mediated responses. Four out of 13 selected compounds show concentration-dependent activity, representing a hit rate of 31%. The most active compound is the pyrogallol derivative MMG-11 that inhibits both TLR2/1 and TLR2/6 signaling and shows a higher potency than the previously discovered CU-C...
Source: Biochemical Pharmacology - April 20, 2018 Category: Drugs & Pharmacology Authors: Grabowski M, Murgueitio MS, Bermudez M, Rademann J, Wolber G, Weindl G Tags: Biochem Pharmacol Source Type: research

Effect of a long-term treatment with metformin in dystrophic mdx mice: a reconsideration of its potential clinical interest in Duchenne muscular dystrophy.
Abstract The pharmacological stimulation of AMP-activated protein kinase (AMPK) via metabolic enhancers has been proposed as potential therapeutic strategy for Duchenne muscular dystrophy (DMD). Metformin, a widely-prescribed anti-hyperglycemic drug which activates AMPK via mitochondrial respiratory chain, has been recently tested in DMD patients in synergy with nitric oxide (NO)-precursors, with encouraging results. However, preclinical data supporting the use of metformin in DMD are still poor, and its actions on skeletal muscle appear controversial. Therefore, we investigated the effects of a long-term treatmen...
Source: Biochemical Pharmacology - April 20, 2018 Category: Drugs & Pharmacology Authors: Mantuano P, Sanarica F, Conte E, Morgese MG, Capogrosso RF, Cozzoli A, Fonzino A, Quaranta A, Rolland JF, De Bellis M, Camerino GM, Trabace L, De Luca A Tags: Biochem Pharmacol Source Type: research

A Novel Smac Mimetic APG-1387 Exhibited Dual Antitumor Effect on HBV-positive Hepatocellular Carcinoma with High Expression of cIAP2 by Inducing Apoptosis and Enhancing Innate Anti-Tumor Immunity.
Abstract Check point inhibitor anti-PD1 antibody produced some efficacy in Hepatocellular Carcinoma (HCC) patients previously treated with sorafenib. Unfortunately, HCC patients with hepatitis B virus (HBV) infection did not respond as well as uninfected patients. Previously, SMAC mimetics-the antagonist for inhibitor of apoptosis proteins (IAPs) can rapidly reduce serum hepatitis B virus DNA in animal model. APG-1387 is a novel SMAC-mimetic, small molecule inhibitor targeting inhibitor of apoptosis proteins (IAPs). In our study, firstly, we found that HCC patients with copy number alteration of cIAP1, cIAP2, and ...
Source: Biochemical Pharmacology - April 18, 2018 Category: Drugs & Pharmacology Authors: Pan W, Luo Q, Yan X, Yuan L, Yi H, Zhang L, Li B, Zhang Y, Sun J, Qiu MZ, Yang DJ Tags: Biochem Pharmacol Source Type: research

Acetaminophen-induced Liver Injury is Attenuated in Transgenic fat-1 Mice Endogenously Synthesizing Long-chain n-3 Fatty Acids.
In this study, the fat-1 transgenic mice that synthesize endogenous n-3 PUFA and wild type (WT) littermates were injected intraperitoneally with APAP at the dose of 400 mg/kg to induce liver injury, and euthanized at 0 h, 2 h, 4 h and 6 h post APAP injection for sampling. APAP overdose caused severe liver injury in WT mice as indicated by serum parameters, histopathological changes and hepatocyte apoptosis, which were remarkably ameliorated in fat-1 mice. These protective effects of n-3 PUFA were associated with regulation of the prolonged JNK activation via inhibition of apoptosis signal-regulating kinase 1 (ASK1) / mitog...
Source: Biochemical Pharmacology - April 18, 2018 Category: Drugs & Pharmacology Authors: Feng R, Wang Y, Liu C, Yan C, Zhang H, Su H, Kang JX, Shang CZ, Wan JB Tags: Biochem Pharmacol Source Type: research

Sorafenib suppresses TGF- β responses by inducing caveolae/lipid raft-mediated internalization/degradation of cell-surface type II TGF-β receptors: implications in development of effective adjunctive therapy for hepatocellular carcinoma.
In this study, we demonstrate that sorafenib suppresses TGF-β responsiveness in hepatoma cells, hepatocytes, and animal liver, mainly by downregulating cell-surface type II TGF-β receptors (TβRII) localized in caveolae/lipid rafts and non-lipid raft microdomains via caveolae/lipid rafts-mediated internalization and degradation. Furthermore, sorafenib-induced downregulation and degradation of cell-surface TβRII is prevented by simultaneous treatment with a caveolae disruptor or lysosomal inhibitors. On the other hand, sorafenib only downregulates cell-surface TβRII localized in caveolae/lipid rafts ...
Source: Biochemical Pharmacology - April 17, 2018 Category: Drugs & Pharmacology Authors: Chung CL, Wang SW, Sun WC, Shu CW, Kao YC, Shiao MS, Chen CL Tags: Biochem Pharmacol Source Type: research

Inhibitory effects of drugs on the metabolic activity of mouse and human aldehyde oxidases and influence on drug-drug interactions.
Abstract As aldehyde oxidase (AOX) plays an emerging role in drug metabolism, understanding its significance for drug-drug interactions (DDI) is important. Therefore, we tested 10 compounds for species-specific and substrate-dependent differences in the inhibitory effect of AOX activity using genetically engineered HEK293 cells over-expressing human AOX1, mouse AOX1 or mouse AOX3. The IC50 values of 10 potential inhibitors of the three AOX enzymes were determined using phthalazine and O6-benzylguanine as substrates. 17β-Estradiol, menadione, norharmane and raloxifene exhibited marked differences in inhibitory...
Source: Biochemical Pharmacology - April 17, 2018 Category: Drugs & Pharmacology Authors: Takaoka N, Sanoh S, Okuda K, Kotake Y, Sugahara G, Yanagi A, Ishida Y, Tateno C, Tayama Y, Sugihara K, Kitamura S, Kurosaki M, Terao M, Garattini E, Ohta S Tags: Biochem Pharmacol Source Type: research

Ribociclib shows potential for pharmacokinetic drug-drug interactions being a substrate of ABCB1 and potent inhibitor of ABCB1, ABCG2 and CYP450 isoforms in vitro.
Abstract Ribociclib is a novel cyclin-dependent kinase (CDK) 4 and 6 selective inhibitor that recently gained breakthrough therapy status and global approval for advanced breast cancer treatment. ATP-binding cassette (ABC) transporters may become a site of severe drug interactions and a mechanism of multidrug resistance (MDR) development. With respect to rapid progress of ribociclib in the clinical field, we aimed to identify its interactions with ABC transporters and cytochrome P450 (CYP) isoenzymes and evaluate its potential to overcome transporter-mediated MDR using established in vitro methods. Our data showed...
Source: Biochemical Pharmacology - April 16, 2018 Category: Drugs & Pharmacology Authors: Sorf A, Hofman J, Kučera R, Staud F, Ceckova M Tags: Biochem Pharmacol Source Type: research

Angiotensin II promotes pulmonary metastasis of melanoma through the activation of adhesion molecules in vascular endothelial cells.
In this study, we sought to elucidate the mechanisms by which Ang II exacerbates hematogenous metastasis in mouse melanoma cells, focusing the adhesion pathway in vascular endothelial cells. For this purpose, B16/F10 mouse melanoma cells, which do not express the Ang II type 1 receptor (AT1R), were intravenously injected into C57BL/6 mice. Two weeks after cell injection, the number of lung metastatic colonies was significantly higher in the Ang II-treated group (1 μg/kg/min) than in the vehicle-treated group. The AT1R blocker valsartan (40 mg/kg/day), but not the calcium channel blocker amlodipine (5 or 10 mg/kg/day), s...
Source: Biochemical Pharmacology - April 16, 2018 Category: Drugs & Pharmacology Authors: Ishikane S, Hosoda H, Nojiri T, Tokudome T, Mizutani T, Miura K, Akitake Y, Kimura T, Imamichi Y, Kawabe S, Toyohira Y, Yanagihara N, Takahashi-Yanaga F, Miyazato M, Miyamoto K, Kangawa K Tags: Biochem Pharmacol Source Type: research

In vitro assessment of competitive and time-dependent inhibition of the nevirapine metabolism by nortriptyline in rats.
Abstract Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1) widely used as a component of High Active Antiretroviral Therapy (HAART) since it is inexpensive, readily absorbed after oral administration and non-teratogenic. In the present work, the mechanism of a previously described pharmacokinetic interaction between NVP and the antidepressant drug nortriptyline (NT) was studied using rat hepatic microsomes. The obtained results showed a competitive inhibition of the NVP metabolism by NT. The three main NVP metabolites (2-OH-NVP, 3-OH-NVP and 12-OH-N...
Source: Biochemical Pharmacology - April 16, 2018 Category: Drugs & Pharmacology Authors: Usach I, Ferrer JM, Peris JE Tags: Biochem Pharmacol Source Type: research

Dengue virus NS2 and NS4: minor proteins, mammoth roles.
Abstract Despite the ever increasing global incidence of dengue fever, there are no specific chemotherapy regimens for its treatment. Structural studies on dengue virus (DENV) proteins have revealed potential drug targets. Major DENV proteins such as the envelope protein and non-structural (NS) proteins 3 and 5 have been extensively investigated in antiviral studies, but with limited success in vitro. However, the minor NS proteins NS2 and NS4 have remained relatively underreported. Emerging evidence indicating their indispensable roles in virus propagation and host immunomodulation should encourage us to target t...
Source: Biochemical Pharmacology - April 16, 2018 Category: Drugs & Pharmacology Authors: Bhargavi Gopala Reddy S, Chin WX, Swamy Shivananju N Tags: Biochem Pharmacol Source Type: research

Tanshinone IIA suppresses Fc εRI-mediated mast cell signaling and anaphylaxis by activation of the Sirt1/LKB1/AMPK Pathway.
In conclusion, Tan IIA suppresses FcεRI-mediated mast cell activation and anaphylaxis through activation of the inhibitory Sirt1-LKB1-AMPK pathway. Thus, Tan IIA may be useful as a new therapeutic agent for mast cell-mediated allergic diseases. PMID: 29674003 [PubMed - as supplied by publisher] (Source: Biochemical Pharmacology)
Source: Biochemical Pharmacology - April 16, 2018 Category: Drugs & Pharmacology Authors: Li X, Park SJ, Jin F, Deng Y, Yang JH, Chang JH, Kim DY, Kim JA, Lee YJ, Murakami M, Son KH, Chang HW Tags: Biochem Pharmacol Source Type: research

Nrf2 as a therapeutic target for rheumatic diseases.
az MJ Abstract Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master regulator of cellular protective processes. Rheumatic diseases are chronic conditions characterized by inflammation, pain, tissue damage and limitations in function. Main examples are rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis and osteoporosis. Their high prevalence constitutes a major health problem with an important social and economic impact. A wide range of evidence indicates that Nrf2 may control different mechanisms involved in the physiopathology of rheumatic conditions. Therefore, the appropriate expressio...
Source: Biochemical Pharmacology - April 13, 2018 Category: Drugs & Pharmacology Authors: Ferrándiz ML, Nacher-Juan J, Alcaraz MJ Tags: Biochem Pharmacol Source Type: research