ALBERT

Beschreibung: 〈p〉Publication date: Available online 28 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Marc Diederich〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉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 continue to yield novel drug candidates.〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 28 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Fang Liu, Shaohong Fang, Xinxin Liu, Ji Li, Xuedong Wang, Jinjin Cui, Tao Chen, Zhaoying Li, Fan Yang, Jiangtian Tian, Hulun Li, Li Yin, Bo Yu〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉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 endothelial dysfunction. In the present study, we analyzed the effect of omentin-1 on high glucose-induced endothelial dysfunction in isolated mouse aortas and mouse aortic endothelial cells (MAECs). Vascular reactivity in aortas was measured using wire myography. The expression levels of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor δ (PPARδ), Akt, endothelial nitric-oxide synthase (eNOS), and endoplasmic reticulum (ER)-stress markers in MAECs were determined by Western blotting. The production of reactive oxygen species (ROS) and nitric oxide (NO) was assessed by diluted fluoroprobe, 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM DA), respectively. We found that 〈em〉ex vivo〈/em〉 treatment with omentin-1 reversed impaired endothelial-dependent relaxations (EDR) in mouse aortas after high-glucose insult. Elevated ER-stress markers, oxidative stress, and reduction of NO production induced by high glucose in MAECs were reversed by omentin-1 treatment. Omentin-1 also effectively reversed tunicamycin-induced ER stress responses in MAECs, as well as ameliorated impairment of endothelial-dependent relaxation in mouse aortas. Moreover, omentin-1 increased AMPK phosphorylation with a subsequent increase in PPARδ expression, while also restoring the decreased phosphorylation of Akt and eNOS. The effects of omentin-1 were abolished by cotreatment of compound C (AMPK inhibitor) and GSK0660 (PPARδ antagonist). These data indicate that omentin-1 protects against high glucose-induced vascular-endothelial dysfunction through inhibiting ER stress and oxidative stress and increasing NO production via activation of AMPK/PPARδ pathway.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S000629522030040X-ga1.jpg" width="490" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 28 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Sumathy Mathialagan, Yi-an Bi, Chester Costales, Amit S. Kalgutkar, A. David Rodrigues, Manthena V.S. Varma〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nicotinic acid (NA) and nicotinamide (NAM) are biosynthetic precursors of nicotinamide adenine dinucleotide (NAD〈sup〉+〈/sup〉) – a physiologically important coenzyme that maintains the redox state of cells. Mechanisms driving their entry into cells are not well understood. Here we evaluated the hepatic uptake mechanism(s) of NA and NAM using transporter-transfected cell systems and primary human hepatocytes. NA showed robust organic anion transporter (OAT)2-mediated transport with an uptake ratio (i.e., ratio of accumulation in transfect cells to wild-type cells) of 9.7±0.3, and a Michaelis-Menten constant (K〈sub〉m〈/sub〉) of 13.5±3.3 µM. However, no transport was apparent via other major hepatic uptake and renal secretory transporters, including OAT1/3/4, organic anion transporting polypeptide (OATP)1B1/1B3/2B1, sodium-taurocholate co-transporting polypeptide, organ cation transporter 1/2/3. OAT2-specific transport of NA was inhibited by ketoprofen and indomethacin (known OAT2 inhibitors) in a concentration-dependent manner. Similarly, NA uptake into primary human hepatocytes showed pH- and concentration-dependence and was subject to inhibition by specific OAT2 inhibitors. Unlike NA, NAM was not transported by the hepatic and renal solute carriers upon assessment in transfected cells, although its uptake into human hepatocytes was significantly inhibited by excess unlabelled NAM and a pan-SLC inhibitor (rifamycin SV 1 mM). 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.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300393-ga1.jpg" width="489" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): 〈/p〉

Beschreibung: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Pei Yang, Mingfei Zhang, Xiang Wang, A-Lan Xu, Meiyu Shen, Baoping Jiang, Xueping Zhou, LingLing Zhou〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉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 differentiation of Th17 cells 〈em〉in vitro〈/em〉. And the disease severity in CIA mice was significantly alleviated after the treatment of let-7g-5p mimics, accompanied by the deficiency of Th17 cells. These findings indicated that the let-7g-5p could markedly block the differentiation of Th17 cells in RA, which provided a promising target for the clinical therapy of RA.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300320-ga1.jpg" width="375" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Ryota Yamagata, Wataru Nemoto, Osamu Nakagawasai, Kohei Takahashi, Koichi Tan-No〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉We have previously reported that the spinal angiotensin (Ang) system is involved in the modulation of streptozotocin (STZ)-induced diabetic neuropathic pain in mice. An important drawback of this model however is the fact that the neuropathic pain is independent of hyperglycemia and produced by the direct stimulation of peripheral nerves. Here, using the leptin deficient 〈em〉ob/ob〈/em〉 mouse as a type 2 diabetic model, we examined whether the spinal Ang system was involved in naturally occuring diabetic neuropathic pain. Blood glucose levels were increased in 〈em〉ob/ob〈/em〉 mice at 5-15 weeks of age. Following the hyperglycemia, persistent tactile and thermal hyperalgesia were observed at 11-14 and 9-15 weeks of age, respectively, which was ameliorated by insulin treatment. At 12 weeks of age, the expression of Ang-converting enzyme (ACE) 2 in the spinal plasma membrane fraction was decreased in 〈em〉ob/ob〈/em〉 mice. Spinal ACE2 was expressed in neurons and microglia but the number of NeuN-positive neurons was decreased in 〈em〉ob/ob〈/em〉 mice. In addition, the intrathecal administration of Ang (1-7) and SB203580, a p38 MAPK inhibitor, attenuated hyperalgesia in 〈em〉ob/ob〈/em〉 mice. The phosphorylation of spinal p38 MAPK was also attenuated by Ang (1-7) in 〈em〉ob/ob〈/em〉 mice. These inhibitory effects of Ang (1-7) were prevented by A779, a Mas receptor antagonist. In conclusion, we revealed that the Ang (1-7)-generating system is downregulated in 〈em〉ob/ob〈/em〉 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.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300356-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Joanna Wzorek, Radosław Bednarek, Cezary Watala, Magdalena Boncler〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉Adenosine analogues have high affinity and selectivity for adenosine receptors (AR), and exhibit anti-platelet activity. Plasma proteins play an important role in the regulation of platelet function and may influence the action of anti-platelet compounds. Little is known about the interactions of AR agonists with plasma proteins. This study investigates the interplay between AR agonists and plasma proteins and the consequences of those interactions.〈/p〉 〈p〉Surface plasmon resonance was employed together with molecular docking study to determine the binding kinetics of four selected AR agonists (PSB 0777, Cl-Ado, MRE 0094, UK 432097) to several carrier proteins and to clarify the nature of these interactions. The influence of a whole plasma and of some plasma components on the effectiveness of AR agonists in the inhibition of platelet function was assessed by flow cytometry (platelet activation) and ELISA (platelet adhesion).〈/p〉 〈p〉Plasma proteins remarkably diminished the effectiveness of AR agonists in inhibiting platelet activation and adhesion 〈em〉in vitro〈/em〉. AR agonists were found to strongly bind to human serum albumin (HSA) and the protein components of lipoproteins - apolipoproteins; HSA was essential for the binding of water-soluble PSB 0777, whereas apolipoproteins were needed for interactions with poorly-water soluble compounds such as UK 432097 and MRE 0094. In addition, HSA was shown to significantly reduce the effectiveness of PSB 0777 in inhibiting ADP-induced platelet activation.〈/p〉 〈p〉In conclusion, HSA and lipoproteins are important carriers for AR agonists, which can affect pharmacodynamics of AR agonists used as platelet inhibitors.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S000629522030037X-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Balázs Kelemen, Erika Lisztes, Anita Vladár, Martin Hanyicska, János Almássy, Attila Oláh, Attila Gábor Szöllősi, Zsófia Pénzes, János Posta, Thomas Voets, Tamás Bíró, Balázs István Tóth〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈h6〉Background〈/h6〉 〈p〉Volatile anaesthetics (VAs) are the most widely used compounds to induce reversible loss of consciousness and maintain general anaesthesia during surgical interventions. Although the mechanism of their action is not yet fully understood, it is generally believed, that VAs depress central nervous system functions mainly through modulation of ion channels in the neuronal membrane, including 2-pore-domain K+ channels, GABA and NMDA receptors. Recent research also reported their action on nociceptive and thermosensitive TRP channels expressed in the peripheral nervous system, including TRPV1, TRPA1, and TRPM8. Here, we investigated the effect of VAs on TRPM3, a less characterized member of the thermosensitive TRP channels playing a central role in noxious heat sensation.〈/p〉 〈/div〉 〈div〉 〈h6〉Methods〈/h6〉 〈p〉We investigated the effect of VAs on the activity of recombinant and native TRPM3, by monitoring changes in the intracellular Ca〈sup〉2+〈/sup〉 concentration and measuring TRPM3-mediated transmembrane currents.〈/p〉 〈/div〉 〈div〉 〈h6〉Results〈/h6〉 〈p〉All the investigated VAs (chloroform, halothane, isoflurane, sevoflurane) inhibited both the agonist-induced (pregnenolone sulfate, CIM0216) and heat-activated Ca〈sup〉2+〈/sup〉 signals and transmembrane currents in a concentration dependent way in HEK293T cells overexpressing recombinant TRPM3. Among the tested VAs, halothane was the most potent blocker (IC〈sub〉50〈/sub〉=0.52±0.05 mM). We also investigated the effect of VAs on native TRPM3 channels expressed in sensory neurons of the dorsal root ganglia. While VAs activated certain sensory neurons independently of TRPM3, they strongly and reversibly inhibited the agonist-induced TRPM3 activity.〈/p〉 〈/div〉 〈div〉 〈h6〉Conclusions〈/h6〉 〈p〉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.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300368-ga1.jpg" width="389" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 24 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Sumit Mukherjee, Juliet N.E. Baidoo, Angela Fried, Probal Banerjee〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉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 〈em〉in vivo〈/em〉 curcumin concentration achieved in humans is only about 6 µM. Additionally, a decade ago, no improvement over the placebo groups was observed in clinical studies using free curcumin as an anticancer agent. The lack of anticancer efficacy was attributed to its low bioavailability, which results from the low water-solubility and high metabolic rate 〈em〉in vivo〈/em〉. Newer lipid-complexed or antibody-targeted forms have been used and these studies have revealed an exciting property of curcumin, which involves repolarization of the tumor-promoting, tumor-associated microglia/macrophages (TAMs) into a tumoricidal form and recruitment of natural killer cells from the periphery. This review will cover some efforts to explore the effect of appropriately-delivered curcumin to dramatically alter the tumor microenvironment, thereby launching an indirect attack on the tumor cells and the tumor stem cells. Reviewing some aspects of immunotherapy, this article will argue for the use of the innate immune cells in cancer therapy.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300344-ga1.jpg" width="305" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Elisa Zuccarello, Erica Acquarone, Elisa Calcagno, Elentina K. Argyrousi, Shi-Xian Deng, Donald W. Landry, Ottavio Arancio, Jole Fiorito〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉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 to NO donors, several other pharmacological agents, such as phosphodiesterase 5 (PDE5) inhibitors have been used to activate the pathway and rescue memory disorders. PDE5 inhibitors, including sildenafil, tadalafil and vardenafil, are marketed for the treatment of erectile dysfunction and arterial pulmonary hypertension due to their vasodilatory properties. The ability of PDE5 inhibitors to interfere with the NO/cGMP/PKG/CREB signaling pathway by increasing the levels of cGMP has prompted the hypothesis that PDE5 inhibition might be used as an effective therapeutic strategy for the treatment of AD. To this end, newly designed PDE5 inhibitors belonging to different chemical classes with improved pharmacologic profile (e.g. higher potency, improved selectivity, and blood-brain barrier penetration) have been synthesized and evaluated in several animal models of AD. In addition, recent medicinal chemistry effort has led to the development of agents concurrently acting on the PDE5 enzyme and a second target involved in AD. Both marketed and investigational PDE5 inhibitors have shown to reverse cognitive defects in young and aged wild type mice as well as transgenic mouse models of AD and tauopathy using a variety of behavioral tasks. These studies confirmed the therapeutic potential of PDE5 inhibitors as cognitive enhancers. However, clinical studies assessing cognitive functions using marketed PDE5 inhibitors have not been conclusive. Drug discovery efforts by our group and others are currently directed towards the development of novel PDE5 inhibitors tailored to AD with improved pharmacodynamic and pharmacokinetic properties. In summary, the present perspective reports an overview of the correlation between the NO signaling and AD, as well as an outline of the PDE5 inhibitors used as an alternative approach in altering the NO pathway leading to an improvement of learning and memory. The last two sections describe the preclinical and clinical evaluation of PDE5 inhibitors for the treatment of AD, providing a comprehensive analysis of the current status of the AD drug discovery efforts involving PDE5 as a new therapeutic target.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300289-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 25 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Dewi Safitri, Matthew Harris, Harriet Potter, Ho Yan Yeung, Ian Winfield, Liliya Kopanitsa, Fredrik Svensson, Taufiq Rahman, Matthew T Harper, David Bailey, Graham Ladds〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉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 G〈sub〉2〈/sub〉/M phase cell cycle arrest. In contrast, trequinsin (a non-selective PDE2/3/7 inhibitor), not only inhibited cell growth via PKA, but also stimulated (independent of PKA) caspase-3/-7 and induced an aneuploidy phenotype. Interestingly, a cocktail of individual PDE 2,3,7 inhibitors suppressed cell growth in a manner analogous to forskolin but not trequinsin. Finally, we demonstrate that concomitant targeting of both AC and PDEs synergistically elevated intracellular cAMP levels thereby potentiating their antiproliferative actions.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300332-ga1.jpg" width="495" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 16 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Zhe Pei, Kuo-Chieh Lee, Amber Khan, Gabriell Erisnor, Hoau-Yan Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉 〈p〉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 combining previously published data from gene-mutation/mRNA sequencing databases together with protein–protein interaction (PPI) network analysis results. The summarized results indicate that glutamatergic and calcium signaling may provide positive feedback to promote glioma formation through 1) metabolic reprogramming and genetic switching to accelerate glioma duplication and progression; 2) upregulation of cytoskeleton proteins and elevation of intracellular Ca〈sup〉2+〈/sup〉 levels to increase glutamate release and facilitate formation of synaptic-like connections with surrounding cells in their microenvironment. The upregulated glutamatergic neuronal activities in turn stimulate glioma growth and signaling. Importantly, the enhanced electrical and molecular signals from both neurons and glia propagate out to enable glioma symptoms such as epilepsy and migraine. The elevated intracellular Ca〈sup〉2+〈/sup〉 also activates nitric oxide synthase to produce nitric oxide (NO) that can either promote or inhibit tumorigenesis.〈/p〉 〈p〉By analyzing the network effects for complex interaction among neurotransmitters such as glutamate, Ca〈sup〉2+〈/sup〉 and NO in brain tumor progression, especially GBM, we identified the glutamatergic signaling as the potential therapeutic targets and suggest manipulation of glutamatergic signaling may be an effective treatment strategy for this aggressive brain cancer.〈/p〉 〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300241-ga1.jpg" width="251" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Chang-Fang Chiu, Jing-Ru Weng, Shou-Lun Lee, Chia-Yung Wu, Po-Chen Chu, Yan-Shen Shan, Horng-Ren Yang, Li-Yuan Bai〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Pyruvate kinase M2 (PKM2) is a key enzyme responsible for the final step of glycolysis. It is still unclear whether PKM2 is involved in reactive oxygen species (ROS)-mediated cytotoxicity in gastrointestinal cancer, and what mechanisms are involved. One duodenal (AZ521) and two gastric (NUGC and SCM-1) cancer cell lines were treated with an indole-3-carbinol derivative OSU-A9, which caused cytotoxicity in acute myeloid leukemia through ROS generation. OSU-A9 caused a dose- and time-dependent cytotoxicity and induced apoptosis in duodenal and gastric cancer cells through ROS generation. Pretreatment with ROS scavengers rescued cancer cells from apoptosis and concomitant poly (ADP-ribose) polymerase cleavage, implying a key role of ROS in OSU-A9-induced cell death. Moreover, OSU-A9-induced ROS generation decreased protein levels of p〈sup〉Tyr105〈/sup〉-PKM2, and this effect was rescued by pretreatment with ROS scavengers. Interestingly, p〈sup〉Tyr105〈/sup〉-PKM2 protein levels decreased in the cell nucleus rather than in the cytoplasm. PKM2 overexpression partially rescued the survival of duodenal and gastric cancer cells treated with OSU-A9. Furthermore, the anticancer activity of OSU-A9 extended 〈em〉in vivo〈/em〉, as OSU-A9 administered by oral gavage suppressed the growth of AZ521 xenograft tumors in nude mice without obvious toxicity. In conclusion, OSU-A9 inhibited duodenal and gastric cancer cell proliferation through ROS generation and caused a subsequent decrease in nuclear p〈sup〉Tyr105〈/sup〉-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.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300216-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 172〈/p〉 〈p〉Author(s): 〈/p〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Vanessa P. Cedron, Andrea M.J. Weiner, Manuel Vera, Laura Sanchez〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉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-fertilization) were detected, suggesting the involvement of this compound in the development of black pigment cells as described recently for human epidermal melanocytes. Morphological abnormalities such as aberrant craniofacial structures, pericardial edemas, and blood accumulation were also found. All these effects could be due to higher levels of apoptotic cells detected in treated embryos. Therefore, teratogenic effects of acetaminophen cannot be ruled out, and its wide use should be taken with caution.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300265-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 20 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Ashwini Gore, Alex G. Gauthier, Mosi Lin, Vivek Patel, Douglas D. Thomas, Charles R. Ashb, Lin L. Mantell〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Mechanical ventilation (MV) with supraphysiological levels of oxygen (hyperoxia) is a life-saving therapy for the management of patients with respiratory distress. However, a significant number of patients on MV develop ventilator-associated pneumonia (VAP). Previously, we have reported that prolonged exposure to hyperoxia impairs the capacity of macrophages to phagocytize 〈em〉Pseudomonas aeruginosa〈/em〉 (PA), which can contribute to the compromised innate immunity in VAP. 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% O〈sub〉2〈/sub〉) in the presence or absence of the NO donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate/D-NO). Interestingly, D-NO (up to 37.5 µM) significantly attenuated hyperoxia-compromised macrophage migratory, phagocytic, and bactericidal function. To determine whether the administration of exogenous NO enhances the host defense in bacteria clearance, C57BL/6 mice were exposed to hyperoxia (99% O〈sub〉2〈/sub〉) and intranasally inoculated with PA in the presence or absence of D-NO. D-NO (300 µM - 800 µM) significantly increased the survival of mice inoculated with PA under hyperoxic conditions, and significantly decreased bacterial loads in the lung and attenuated lung injury. These results suggest the NO donor, D-NO, can improve the clinical outcomes in VAP by augmenting the innate immunity in bacterial clearance. Thus, provided these results can be extrapolated to humans, NO supplementation may represent a potential therapeutic strategy for preventing and treating patients with VAP.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300277-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Young Shin Ko, Hana Jin, Sang Won Park, Hye Jung Kim〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉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 (〈em〉Salvia miltiorrhiza〈/em〉), 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-dependently decreased oxLDL- and high Glu–mediated induction of lectin-like oxLDL receptor-1 and significantly decreased oxLDL- and high Glu–induced mitochondrial ROS (mtROS) production and mitochondrial DNA (mtDNA) expression. In addition, oxLDL stimulation under high-Glu conditions activated the intrinsic apoptosis pathway in ECs. These effects were abolished by Sal B through reductions in mtROS and mtDNA. Furthermore, Sal B inhibited oxLDL- and high Glu–induced increases in fission protein (p-DRP 1 and FIS 1) levels. OxLDL and high Glu activated the ROCK1 pathway, which is involved in apoptosis and mitophagy, while Sal B significantly reduced ROCK1 protein levels. The protective effects of Sal B against oxLDL- and high Glu–induced endothelial dysfunction may be mediated by reductions in apoptosis-related proteins and fission proteins through suppression of the ROCK1-mediated pathway.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300253-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 21 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Sevda Gheibi, Alan P. Samsonov, Shahsanam Gheibi, Alexandra B. Vazquez, Khosrow Kashfi〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nitric oxide (NO) and hydrogen sulfide (H〈sub〉2〈/sub〉S) 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 H〈sub〉2〈/sub〉S 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 H〈sub〉2〈/sub〉S in pathophysiology of diabetes is however controversial; H〈sub〉2〈/sub〉S production is decreased during development of obesity, diabetes, and its complications, suggesting the potential therapeutic effects of H〈sub〉2〈/sub〉S. On the other hand, increased H〈sub〉2〈/sub〉S levels disturb the pancreatic β-cell function and decrease insulin secretion. In addition, there appear to be important interactions between NO and H〈sub〉2〈/sub〉S at the levels of both biosynthesis and signaling pathways, yet clear an insight into this relationship is lacking. H〈sub〉2〈/sub〉S potentiates the effects of NO in the cardiovascular system as well as NO release from its storage pools. Likewise, NO increases the activity and the expression of H〈sub〉2〈/sub〉S-generating enzymes. Inhibition of NO production leads to elimination/attenuation of the cardioprotective effects of H〈sub〉2〈/sub〉S. Regarding the increasing interest in the therapeutic applications of NO or H〈sub〉2〈/sub〉S-releasing molecules in a variety of diseases, particularly in the cardiovascular disorders, much is to be learned about their function in glucose/insulin metabolism, especially in diabetes. The aim of this review is to provide a better understanding of the individual and the interactive roles of NO and H〈sub〉2〈/sub〉S in carbohydrate metabolism.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300290-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Christian Bailly, Gérard Vergoten〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉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 homodimers prevents binding of PD-L1 to PD-1, thus blocking the downstream signaling. We have analyzed this phenomenon of drug-induced protein dimerization to show that PD-L1 is not an isolated case. Several examples of drug-mediated protein homodimer stabilization are presented here. In particular, a similar phenomenon has been observed with small molecules, such as NSC13728 and KI-MS2-008, which stabilize Max-Max protein homodimers, to block the formation of Myc-Max heterodimers and the ensuing signalization. PD-L1, Max and ten other examples of drug-stabilized protein homodimers point to a general mechanism of protein regulation by small molecules. Nevertheless, the extent and functions of drug-induced PD-L1 homodimers await validation in vivo.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300319-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 20 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Jun-Wan Shin, Kyung-Soo Chun, Do-Hee Kim, Su-Jung Kim, Seong Hoon Kim, Nam-Chul Cho, Hye-Kyung Na, Young-Joon Surh〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉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 〈em〉in vivo〈/em〉 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 transcript. Treatment of cells with curcumin stabilized Nrf2 by inhibiting ubiquitination and subsequent 26S proteasomal degradation of this transcription factor. Tetrahydrocurcumin, a non-electrophilic analogue of curcumin that lacks the α,β-unsaturated carbonyl group, failed to induce HO-1 expression as well as Nrf2 nuclear translocation of Nrf2 and its binding to the antioxidant/electrophile response elements. Cells transfected with a mutant Keap1 protein in which cysteine 151 is replaced by serine exhibited marked reduction in curcumin-induced Nrf2 transactivation. Mass spectrometric analysis revealed that curcumin binds to Keap1 Cys151, supporting that this amino acid is a critical target for curcumin modification of Keap1, which facilitates the liberation of Nrf2. Thus, it is likely that the α,β-unsaturated carbonyl moiety of curcumin is critical essential for its binding to Keap1 and stabilization of Nrf2 by hampering ubiquitination and proteasomal degradation.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300307-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Amit S. Kalgutkar, James P. Driscoll〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Basic amine substituents provide several pharmacokinetic benefits relative to acidic and neutral functional groups, and have been extensively utilized as substituents of choice in drug design. On occasions, basic amines have been associated with off-target pharmacology via interactions with aminergic G-protein coupled receptors, ion-channels, kinases, etc. Structural features associated with the promiscuous nature of basic amines have been well-studied, and can be mitigated in a preclinical drug discovery environment. In addition to the undesirable secondary pharmacology, α-carbon oxidation of certain secondary or tertiary cycloalkyl amines can generate electrophilic iminium and aldehyde metabolites, potentially capable of covalent adduction to proteins or DNA. Consequently, cycloalkyl amines have been viewed as structural alerts (SAs), analogous to functional groups such as anilines, furans, thiophenes, etc., which are oxidized to reactive metabolites that generate immunogenic haptens by covalently binding to host proteins. Detailed survey of the literature, however, suggests that cases where preclinical or clinical toxicity has been explicitly linked to the metabolic activation of a cycloalkyl amine group are extremely rare. Moreover, there is a distinct possibility for the formation of electrophilic iminium/amino-aldehyde metabolites with numerous cycloalkyl amine-containing marketed drugs, since stable ring cleavage products have been characterized as metabolites in human mass balance studies. In the present work, a critical analysis of the evidence for and against the role of iminium ions/aldehydes as mediators of toxicity is discussed with a special emphasis on often time overlooked detoxication pathways of these reactive species to innocuous metabolites.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S000629522030006X-ga1.jpg" width="391" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Tao Yu, Zhibin Wang, Wang Jie, Xiuxiu Fu, Bing Li, Hong Xu, Yan Liu, Min Li, Eunji Kim, Yanyan Yang, Jae Youl Cho〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉BX795, a small molecule with an aminopyrimidine backbone, is a potent ATP-competitive inhibitor of phosphoinositide-dependent kinase 1 (PDK1) and TANK-binding kinase 1 (TBK1). BX795 has significant functions in various immune responses and cancer. Few reports on the anti-inflammatory effect of BX795 are available, and its molecular mechanisms have not been fully elucidated. 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) are targeted by BX795 rather than nuclear factor (NF)-κB. Moreover, TBK1 and AKT, transforming growth factor activated kinase (TAK)-1/c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase kinase 4 (MKK4) for AP-1 activation, and Janus kinase 2 (JAK2)/STAT1 were inhibited by BX795. Consistent with these findings, BX795 strongly ameliorated inflammatory symptoms in colitis models. These results suggest that BX795 can suppress inflammatory responses triggered by Gram-positive bacteria by suppressing multiple pathways.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300071-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 10 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Rana Gbyli, Yuanbin Song, Stephanie Halene〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Humanized mice have proven to be invaluable for human hematological translational research since they offer essential tools to dissect disease biology and to bridge the gap between pre-clinical testing of novel therapeutics and their clinical applications. Many efforts have been placed to advance and optimize humanized mice to support the engraftment, differentiation, and maintenance of hematopoietic stem cells (HSCs) and the human hematological system in order to broaden the scope of applications of such models. This review covers the background of humanized mice, how they are used as platforms to model myeloid malignancies, and the various current and potential approaches to further enhance their utilization in biomedical research.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300046-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 9 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Nadire Özenver, Thomas Efferth〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Nitric oxide synthases (NOS) are a family of isoforms, which generate nitric oxide (NO). NO is one of the smallest molecules in nature and acts mainly as a potent vasodilator. It participates in various biological processes ranging from physiological to pathological conditions. Inducible NOS (iNOS, NOS2) is a calcium-independent and inducible isoform. Despite high iNOS expression in many tumors, the role of iNOS is still unclear and complex with both enhancing and prohibiting actions in tumorigenesis. Nature presents a broad variety of natural stimulators and inhibitors, which may either promote or inhibit iNOS response. In the present review, we give an overview of iNOS-modulating agents with a special focus on both natural and synthetic molecules and their effects in related biological processes. The role of iNOS in physiological and pathological conditions is also discussed.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300022-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Samir Jana, B. Madhu Krishna, Jyotsana Singhal, David Horne, Sanjay Awasthi, Ravi Salgia, Sharad S. Singhal〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉SRY-related high-mobility group box 9 (SOX9) is an indispensable transcription factor that regulates multiple developmental pathways related to stemness, differentiation, and progenitor development. Previous studies have demonstrated that the SOX9 protein directs pathways involved in tumor initiation, proliferation, migration, chemoresistance, and stem cell maintenance, thereby regulating tumorigenesis as an oncogene. SOX9 overexpression is a frequent event in breast cancer (BC) subtypes. Of note, the molecular mechanisms and functional regulation underlying SOX9 upregulation during BC progression are still being uncovered. The focus of this review is to appraise recent advances regarding the involvement of SOX9 in BC pathogenesis. First, we provide a general overview of SOX9 structure and function, as well as its involvement in various kinds of cancer. Next, we discuss pathways of SOX9 regulation, particularly its miRNA-mediated regulation, in BC. Finally, we describe the involvement of SOX9 in BC pathogenesis via its regulation of pathways involved in regulating cancer hallmarks, as well as its clinical and therapeutic importance. In general, this review article aims to serve as an ample source of knowledge on the involvement of SOX9 in BC progression. Targeting SOX9 activity may improve therapeutic strategies to treat BC, but precisely inhibiting SOX9 using drugs and/or small peptides remains a huge challenge for forthcoming cancer research.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295219304885-ga1.jpg" width="305" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 27 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Zhenzhu Sun, Wenqiang Lu, Na Lin, Hui Lin, Jie Zhang, Tingjuan Ni, Liping Meng, Chuanjing Zhang, Hangyuan Guo〈/p〉

Beschreibung: 〈p〉Publication date: Available online 27 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Xunzhen Zheng, Veani Fernando, Vandana Sharma, Yashna Walia, Joshua Letson, Saori Furuta〈/p〉

Beschreibung: 〈p〉Publication date: Available online 24 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Dianne Ford〈/p〉

Beschreibung: 〈p〉Publication date: Available online 21 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Ping Cheng, Huan Liu, Yinchuan Li, Peiling Pi, Yu Jiang, Shaozhen Zang, Xiaorong Li, Ailing Fu, Xiaoyuan Ren, Jianqiang Xu, Arne Holmgren, Jun Lu〈/p〉

Beschreibung: 〈p〉Publication date: Available online 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Seo Woo Kim, Alain Goossens, Claude Libert, Filip Van Immerseel, Jens Staal, Rudi Beyaert〈/p〉

Beschreibung: 〈p〉Publication date: Available online 21 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Camilla Gadgaard, Anders A. Jensen〈/p〉

Beschreibung: 〈p〉Publication date: Available online 20 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Charlotte Lübow, Judith Bockstiegel, Günther Weindl〈/p〉

Beschreibung: 〈p〉Publication date: May 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 175〈/p〉 〈p〉Author(s): Michela Asperti, Andrea Denardo, Magdalena Gryzik, Annalisa Castagna, Domenico Girelli, Annamaria Naggi, Paolo Arosio, Maura Poli〈/p〉

Beschreibung: 〈p〉Publication date: Available online 21 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Fiorella Faienza, Matteo Lambrughi, Salvatore Rizza, Chiara Pecorari, Paola Giglio, Juan Salamanca Viloria, Maria Francesca Allega, Giovanni Chiappetta, Joëlle Vinh, Francesca Pacello, Andrea Battistoni, Andrea Rasola, Elena Papaleo, Giuseppe Filomeni〈/p〉

Beschreibung: 〈p〉Publication date: Available online 18 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Francisco Isaac F. Gomes, Fernando Q. Cunha, Thiago M. Cunha〈/p〉

Beschreibung: 〈p〉Publication date: Available online 5 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Linda E. Greenbaum, Chinweike Ukomadu, Jan S.Tchorz〈/p〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Ruirui Wu, Hechuan Zhang, Muxin Zhao, Jin Li, Yuxin Hu, Jingqi Fu, Jingbo Pi, Huihui Wang, Yuanyuan Xu〈/p〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Sean A. Piwarski, Chelsea Thompson, Ateeq R. Chaudhry, James Denvir, Donald A. Primerano, Jun Fan, Travis B. Salisbury〈/p〉

Beschreibung: 〈p〉Publication date: Available online 4 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Maria Peleli, Sofia-Iris Bibli, Zhen Li, Athanasia Chatzianastasiou, Aimilia Varela, Antonia Katsouda, Sven Zukunft, Mariarosaria Bucci, Valentina Vellecco, Constantinos H. Davos, Noriyuki Nagahara, Giuseppe Cirino, Ingrid Fleming, David J. Lefer, Andreas Papapetropoulos〈/p〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): P.H. Nguyen, K.P. Sigdel, K.G. Schaefer, G.A.K. Mensah, G.M. King, A.G. Roberts〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉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. While only differing by a single hydroxyl functional group, DNR has a 4 to 5-fold higher transport rate than DOX. They both non-competitively inhibited Pgp-mediated ATP hydrolysis below basal levels. The 〈em〉K〈sub〉m〈/sub〉〈/em〉 of Pgp-mediated ATP hydrolysis extracted from the kinetics curves was lower for DOX than DNR. However, the dissociation constants (〈em〉K〈sub〉D〈/sub〉s〈/em〉) for these drugs determined by fluorescence quenching were virtually identical. Acrylamide quenching of Pgp tryptophan fluorescence to probe the tertiary structure of Pgp suggested that DNR shifts Pgp to a “closed” conformation, while DOX shifts Pgp to an “intermediate” conformation. The effects of these drugs on the Pgp conformational distributions in a lipid bilayer were also examined by atomic force microscopy (AFM). Analysis of AFM images revealed that DNR and DOX cause distinct and significant shifts in the conformational distribution of Pgp. The results were combined to build a conformational distribution model for anthracycline transport by Pgp.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S000629522030023X-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 16 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Soraya Salas-Silva, Arturo Simoni-Nieves, María Valeria Razori, Jocelyn López-Ramirez, Jonatan Barrera-Chimal, Roberto Lazzarini, Oscar Bello, Verónica Souza, Roxana U. Miranda-Labra, María Concepción Gutiérrez-Ruiz, Luis Enrique Gomez-Quiroz, Marcelo G. Roma, Leticia Bucio-Ortiz〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Cholestasis is a clinical syndrome common to a large number of hepatopathies, in which either bile production or its transit through the biliary tract is impaired due to functional or obstructive causes; the consequent intracellular retention of toxic biliary constituents generates parenchyma damage, largely via oxidative stress-mediated mechanisms. Hepatocyte growth factor (HGF) and its receptor c-Met represent one of the main systems for liver repair damage and defense against hepatotoxic factors, leading to an antioxidant and repair response. 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 seems to have been also preserved, as suggested by normalization in serum GGT levels, CFTR expression and cholangyocyte primary cilium structure our results clearly show for the first time that HGF protects the liver from a cholestatic injury.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300228-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Nenggang Zhang, Asis K. Sarkar, Feng Li, Silviya A. Demerzhan, Scott R. Gilbertson, Debananda Pati〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Separase, a sister chromatid cohesion-resolving enzyme, is an oncogene and overexpressed in many human cancers. Sepin-1 (2,2-dimethyl-5-nitro-〈em〉2H〈/em〉-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 at three different (5, 10, and 20 mg/kg) doses. Blood samples were collected after administration of doses on days 1 and 28. Sepin-1 is unstable and isomerizes in basic solutions, but it is stable in acidic buffer such as citrate-buffered saline (pH 4.0). UHPLC-MS analysis indicated Sepin-1 was rapidly metabolized 〈em〉in vivo〈/em〉. One of the major metabolites was an amine adduct of 2,2-dimethyl-5-nitro-2〈em〉H〈/em〉-benzimidazole (named Sepin-1.55). The concentration of Sepin-1.55 in blood samples was Sepin-1 dose-dependent and used for pharmacokinetic analysis of Sepin-1. T〈sub〉max〈/sub〉 was approximately 5–15 min. The data suggest that no Sepin-1 accumulation occurred from daily repeat dosing and similar exposures on the first and final day of dosing. Data also suggest a gender difference, namely that female rats have more exposure and slower clearance than male rats. The data support that Sepin-1 is a potential drug candidate that can be further developed to treat Separase-overexpressing human tumors.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300186-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 8 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Jack R. Lancaster〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉The award of the 1998 Nobel Prize in Physiology or Medicine to Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad “for their discoveries concerning nitric oxide as a signaling molecule in the cardiovascular system” highlighted the discovery of 〈img src="https://sdfestaticassets-eu-west-1.sciencedirectassets.com/shared-assets/16/entities/rad"〉NO in mammals. This breakthrough also coincided with the discoveries of the role of 〈img src="https://sdfestaticassets-eu-west-1.sciencedirectassets.com/shared-assets/16/entities/rad"〉NO as a cytotoxic effector in the immune system and as an intercellular neurotransmitter in the nervous system. This brief overview describes the chronological development of this trilinear convergence in 1986–1988, including background chemistry and history of human/nitrogen oxide interactions in general.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉 〈p〉Symbol used for nitric oxide by John Dalton, the father of modern chemistry; blue dot added by present author to denote unpaired electron (Coward, H.F. 〈em〉J. Chem. Ed.〈/em〉 4:23 (1927)).〈/p〉 〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300034-ga1.jpg" width="371" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉 〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 3 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Sukriti Sharma, Amarjit S. Naura〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Atopic diseases (atopic dermatitis, asthma and allergic rhinitis) affects a huge number of people around the world and their incidence rate is on rise. Atopic dermatitis (AD) is more prevalent in paediatric population which sensitizes an individual to develop allergic rhinitis and asthma later in life. The complex pathogenesis of these allergic diseases though involves numerous cellular signalling pathways but redox imbalance has been reported to be critical for induction/perpetuation of inflammatory process under such conditions. The realm of complementary and alternative medicine has gained greater attention because of the reported anti-oxidant/anti-inflammatory properties. Several case studies of treating atopic diseases with homeopathic remedies have provided positive results. Likewise, pre-clinical studies suggest that various natural compounds suppress allergic response via exhibiting their anti-oxidant potential. Despite the reported beneficial effects of phytochemicals in experimental model system, the clinical success has not been documented so far. It appears that poor absorption and bioavailability of natural compounds may be one of the reasons for realizing their full potential. The current paper throws light on impact of phytochemicals in the redox linked cellular and signalling pathways that may be critical in manifestation of atopic diseases. Further, an effort has been made to identify the gaps in the area so that future strategies could be evolved to exploit the medicinal value of various phytochemicals for an improved efficiency.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295219304897-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: Available online 28 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Marta Smeda, Kamil Przyborowski, Marta Stojak, Stefan Chlopicki〈/p〉

Beschreibung: 〈p〉Publication date: Available online 27 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Salvatore Rizza, Luca Di Leo, Sara Mandatori, Daniela De Zio, Giuseppe Filomeni〈/p〉

Beschreibung: 〈p〉Publication date: May 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 175〈/p〉 〈p〉Author(s): S. Martin, A.M. Dudek-Perić, H. Maes, A.D. Garg, M. Gabrysiak, S. Demirsoy, J.V. Swinnen, P. Agostinis〈/p〉

Beschreibung: 〈p〉Publication date: May 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 175〈/p〉 〈p〉Author(s): Mincheol Kwon, Mina Jang, Gun-Hee Kim, Taehoon Oh, In-Ja Ryoo, Hyung Won Ryu, Sei-Ryang Oh, Bo Yeon Kim, Jae-Hyuk Jang, Sung-Kyun Ko, Jong Seog Ahn〈/p〉

Beschreibung: 〈p〉Publication date: May 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 175〈/p〉 〈p〉Author(s): Zhigang Rao, Paul M. Jordan, Yan Wang, Dirk Menche, Simona Pace, Jana Gerstmeier, Oliver Werz〈/p〉

Beschreibung: 〈p〉Publication date: May 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 175〈/p〉 〈p〉Author(s): Tariq Fellous, Fabrizia De Maio, Hilal Kalkan, Biagio Carannante, Serena Boccella, Stefania Petrosino, Sabatino Maione, Vincenzo Di Marzo, Fabio Arturo Iannotti〈/p〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Wei Du, David Machalz, Qi Yan, Erik J. Sorensen, Gerhard Wolber, Matthias Bureik〈/p〉

Beschreibung: 〈p〉Publication date: Available online 8 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Chao-Yun Cai, Wei Zhang, Jing-Quan Wang, Zi-Ning Lei, Yun-Kai Zhang, Yi-Jun Wang, Pranav Gupta, Cai-Ping Tan, Bo Wang, Zhe-Sheng Chen〈/p〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Jin Wang, Sam Toan, Ruibing Li, Hao Zhou〈/p〉

Beschreibung: 〈p〉Publication date: Available online 28 January 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Thomas Phelan, Mark A Little, Gareth Brady〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉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 Interferon Regulatory Factor (IRF)-family and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-family transcription factors which drive a program of pro-inflammatory and anti-viral gene expression. Here we review DNA viruses that have been shown to inhibit this pathway and the inhibitors they have evolved to do it.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300411-ga1.jpg" width="403" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Cheng Zeng, Dong Fan, Ying Xu, Xiaoju Li, Jiani Yuan, Qian Yang, Xuanxuan Zhou, Jianguo Lu, Cun Zhang, Jun Han, Jintao Gu, Yuan Gao, Lijuan Sun, Siwang Wang〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Chemoresistance is a major cause of recurrence and poor prognosis in triple-negative breast cancer (TNBC) patients. The essential oil of Rhizoma Curcumae has been recently reported to enhance the chemosensitivity of cancer cells. However, few reports have systematically illuminated the mechanism. Curcumol is the major component of the essential oil of Rhizoma Curcumae. Therefore, we wondered whether curcumol combined with chemotherapy could increase the anticancer effects. In the present study, we evaluated the anticancer effects of doxorubicin and curcumol alone or in combination by a series of growth proliferation and apoptosis assays in TNBC cells. Our results showed that curcumol enhanced the sensitivity of MDA-MB-231 cells to doxorubicin 〈em〉in vitro〈/em〉 and 〈em〉in vivo〈/em〉. Through miRNA-seq, we found that miR-181b-2-3p was involved in the curcumol-mediated promotion of doxorubicin-sensitivity in both parental and doxorubicin-resistant MDA-MB-231 (MDA-MB-231/ADR) cells. Further study showed that miR-181b-2-3p suppressed ABCC3 expression by targeting its 3′UTR. More importantly, we identified that overexpression of miR-181b-2-3p sensitized MDA-MB-231/ADR cells to doxorubicin by inhibiting the drug efflux transporter ABCC3. Furthermore, we found that NFAT1 could be activated by curcumol. In addition, ChIP assay results revealed that NFAT1 could directly bind to the promoter region of miR-181b-2-3p. Finally, using PDX models, we identified that curcumol could enhance sensitivity to doxorubicin to suppress tumor growth by the miR-181b-2-3p-ABCC3 axis 〈em〉in vivo〈/em〉. Taken together, our study provides novel mechanistic evidence for curcumol-mediated sensitization to doxorubicin in TNBC, and it highlights the potential therapeutic usefulness of curcumol as an adjunct drug in TNBC patients with doxorubicin-resistance.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300058-ga1.jpg" width="500" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Xiaohan Zhang, Xiao Min, Anlin Zhu, Kyeong-Man Kim〈/p〉 〈div xml:lang="en"〉 〈h5〉Abstract〈/h5〉 〈div〉〈p〉Protein kinase C (PKC) is one of the major effectors involved in the heterologous regulatory pathways of G protein-coupled receptors (GPCRs). On the other hand, GRK2 and β-arrestins are the players of homologous regulatory pathway of GPCRs that affect the receptor functions in agonist-selective manner. Even though two pathways can occur independently, crosstalks between two pathways add more diverse modes of regulations on GPCR functions. Even if extensive studies have been conducted, a commonly applicable molecular mechanism involved in the crosstalks between two regulatory pathways has yet to be elucidated. Here we show that PKCβII was phosphorylated at its activation loop of kinase domain (T500) through constitutive interaction with phosphoinositide-dependent kinase 1 (PDK1) that is phosphorylated at S214. With agonist stimulation, dopamine D〈sub〉2〈/sub〉 receptor interacted with 14-3-3η in GRK2/β-arrestin2-dependent manner, resulting in the recruitment of PDK1. The PDK1 recruited to 14-3-3η was dephosphorylated at S241 and dissociated from PKCβII, abrogating the phosphorylation of PKCβII at T500. This signaling cascade resulted in the inhibition of PKCβII functions, including its phosphorylation in the C-terminal tail, intracellular translocation, and kinase activity. Thus, this study revealed a novel and commonly applicable molecular mechanism involved in the inhibition of PKCβII functions through GRK2/β-arrestin2-mediated homologous pathway of GPCRs. The results obtained in this study could be expanded to other GPCRs and provide new strategies for the treatment of PKCβII-related disorders.〈/p〉〈/div〉 〈/div〉 〈div xml:lang="en"〉 〈h5〉Graphical abstract〈/h5〉 〈div〉〈p〉〈figure〉〈img src="https://ars.els-cdn.com/content/image/1-s2.0-S0006295220300010-ga1.jpg" width="364" alt="Graphical abstract for this article" title=""〉〈/figure〉〈/p〉〈/div〉 〈/div〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): 〈/p〉

Beschreibung: 〈p〉Publication date: May 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 175〈/p〉 〈p〉Author(s): Ruqin Lin, Yu Sun, Peiqiang Mu, Ting Zheng, Haibin Mu, Fengru Deng, Yiqun Deng, Jikai Wen〈/p〉

Beschreibung: 〈p〉Publication date: Available online 21 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Monica Patel, Jamie J. Manning, David B. Finlay, Jonathan A. Javitch, Samuel D. Banister, Natasha L. Grimsey, Michelle Glass〈/p〉

Beschreibung: 〈p〉Publication date: May 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 175〈/p〉 〈p〉Author(s): Dongling Liu, Xiang Zeng, Xiao Li, Chaochu Cui, Ruanling Hou, Zhikun Guo, Jawahar L. Mehta, Xianwei Wang〈/p〉

Beschreibung: 〈p〉Publication date: Available online 14 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Mitali Chattopadhyay, Ravinder Kodela, Gabriela Santiago, Thuy Tien C. Le, Niharika Nath, Khosrow Kashfi〈/p〉

Beschreibung: 〈p〉Publication date: May 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 175〈/p〉 〈p〉Author(s): Jin Zhong, Pengbo Sun, Naihan Xu, Meijian Liao, Chenke Xu, Yipei Ding, Jin Cai, Yaou Zhang, Weidong Xie〈/p〉

Beschreibung: 〈p〉Publication date: May 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 175〈/p〉 〈p〉Author(s): Yue Liu, Zhuang-Zhuang Tang, Yu-Meng Zhang, Li Kong, Wei-Fen Xiao, Teng-Fei Ma, Yao-Wu Liu〈/p〉

Beschreibung: 〈p〉Publication date: Available online 13 February 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology〈/p〉 〈p〉Author(s): Silvia Ghione, Nesrine Mabrouk, Catherine Paul, Ali Bettaieb, Stéphanie Plenchette〈/p〉

Beschreibung: 〈p〉Publication date: April 2020〈/p〉 〈p〉〈b〉Source:〈/b〉 Biochemical Pharmacology, Volume 174〈/p〉 〈p〉Author(s): Yasuhiro Uno, Shotaro Uehara, Saki Tanaka, Norie Murayama, Hiroshi Yamazaki〈/p〉