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The extracts from Psoralea corylifolia Linn. (P. corylifolia) seeds have been shown to display antitumor activity. To date, the prospects of this plant and its active compounds in the treatment of non-small-cell lung cancer (NSCLC) have not been thoroughly studied. In this study, we identified a novel psorachromene compound that displays selective cytotoxic effects on all NSCLC cells tested, including NSCLC cells harboring epidermal growth factor receptor (EGFR) activation mutants (H1975L858R/T790M and H1975-MS35L858R/T790M/C797S ). Psorachromene induces G1 arrest in NSCLC cells harboring wild-type EGFR but induces apoptosis in NSCLC cells harboring activating EGFR mutations. Psorachromene inhibits activated EGFR signaling and kinase activity and suppresses tumor growth of implanted H1975-MS35L858R/T790M/C797S cells in nude mice. Molecular docking analysis revealed that psorachromene could form stronger bonds with mutant EGFR than wild-type EGFR, which might account for the greater cytotoxic effects observed in NSCLC cells harboring activating EGFR mutations (H1975 and H1975-MS35) than wild-type EGFR (A549). In conclusion, it is suggested that psorachromene is an attractive agent to be further explored for its use in the treatment of NSCLC patients harboring EGFR L858R/T790M/C797S. [ABSTRACT FROM AUTHOR]

Licorice, an edible and medicinal plant, has long been used to treat various diseases, including liver diseases. Glycycoumarin (GCM) is a representative coumarin compound in licorice with favorable bioavailability feature. Recent studies by us demonstrated that GCM is highly effective against alcoholic liver disease, nonalcoholic fatty liver disease, acetaminophen-induced hepatotoxicity, and liver cancer through mechanisms involved in activation of Nrf2 antioxidant system, stimulation of AMPK-mediated energy homeostasis, induction of autophagy degradation process, and inhibiting oncogenic kinase T-lymphokine-activated killer cell-originated protein kinase activity. In this review, we summarize the findings on the hepatoprotective effect of GCM, discuss the signaling pathways underlying GCM-induced protective effect on liver diseases, and propose the issues that need to be addressed to promote further development of GCM as a clinically useful hepatoprotective agent. [ABSTRACT FROM AUTHOR]

Phosphatidylinositide 3-kinases (PI3Ks) are intracellular signal transducer enzymes that recruit protein kinase B (aka Akt) to the cell membrane, the subsequent activation of which regulates many cellular functions. PI3K/Akt activity is up-regulated within mesocorticolimbic structures in animal models of alcoholism, but less is known regarding PI3K/Akt activity in animal models of cocaine addiction. Given that prefrontal cortex (PFC) is grossly dysregulated in addiction, we studied how cocaine affects protein indices of PFC PI3K/Akt activity in rat and mouse models and examined the relevance of PI3K activity for cocaine-related learning. Immunoblotting of mouse medial PFC at 3 weeks withdrawal from a cocaine-sensitization regimen (seven injections of 30 mg/kg, intraperitoneal [IP]) revealed increased kinase activity, as did immunoblotting of tissue from the ventral PFC of rats with a history of long-access intravenous cocaine self-administration (0.25 mg/0.1 mL infusion; 10 days of 6 h/d cocaine access). Interestingly, increased Akt phosphorylation was observed in rat ventromedial PFC at both 3- and 30-day withdrawal only in animals re-exposed to cocaine-associated cues. A conditioned place-preference paradigm in mice and a cue-elicited drug-seeking test in rats were conducted to determine the functional relevance for elevated PI3K activity for addiction-related behavior. In both cases, an intra-PFC infusion of the PI3K inhibitor wortmannin (50μM) reduced drug-seeking behavior. Taken together, this cross-species, interdisciplinary, study provides convincing evidence that cocaine history produces an enduring increase in PI3K/Akt-dependent signaling within the more ventral aspect of the PFC that is relevant to behavioral reactivity to drug-associated cues/contexts. As such, PI3K inhibitors may well serve as an effective strategy for reducing drug cue reactivity and craving in cocaine addiction. [ABSTRACT FROM AUTHOR]

Background: Transient receptor potential vanilloid-1 (TRPV1), activated by heat, acidic pH, endogenous vanilloids and capsaicin, is essential for thermal hyperalgesia. Under inflammatory conditions, phosphorylation of TRPV1 by protein kinase C (PKC) can sensitize the channel and decrease the activation threshold. Src kinase also phosphorylates TRPV1, promoting channel trafficking to the plasma membrane. These post-translational modifications are important for several chronic pain conditions. This study presents a previously undescribed relationship between Src and PKC phosphorylation of TRPV1, influencing the thermal hypersensitivity associated with TRPV1 activation.Methods: We assessed TRPV1 channel activity using intracellular calcium imaging and patch-clamp electrophysiology in mouse dorsal root ganglion cultures. Additionally, we used behavioural experiments to evaluate plantar thermal sensitivity following intraplantar injections of activators of known modulators of TRPV1 with and without an Src antagonist.Results: Using calcium imaging and patch-clamp techniques, we demonstrated that pharmacological inhibition of Src kinase or mutation of the Src phosphorylation site on TRPV1 prevented PKC but not PKA-mediated sensitization of TRPV1 in vitro. We found that intraplantar injection of the PKC activator phorbol 12-myristate 13-acetate (PMA) or bradykinin produces thermal hypersensitivity that can be attenuated by pharmacological inhibition of Src. Additionally, complete Freund's Adjuvant (CFA)-induced inflammatory hypersensitivity could also be attenuated by local Src kinase inhibition.Conclusions: Our data demonstrate that Src phosphorylation is critical for PKC-mediated sensitization of TRPV1. Further, in a model of inflammatory pain, CFA, Src kinase inhibition could reduce thermal hypersensitivity. Targeting of Src kinase may have analgesic benefits in inflammatory pain conditions.Significance: Src kinase-mediated phosphorylation of TRPV1 is a critical regulator of the PKC-induced sensitization induced by multiple inflammatory mediators. This suggest a new regulatory mechanism governing TRPV1 function and a potential therapeutic target for inflammatory type pain, including cancer pain where Src antagonists are currently utilized. [ABSTRACT FROM AUTHOR]

Objective: Maternal high-fat diet (HFD) may alter the offspring intestinal immune system, thereby enhancing susceptibility toward inflammatory bowel disease. The objective of the current study was to investigate the impact of maternal HFD on offspring intestinal health using a mouse model of dextran sulfate sodium (DSS)-induced colitis.Methods: Dams were provided with either HFD (60%) or control diet. After weaning, female offspring from both groups were kept on 45% HFD. At 14 weeks of age, offspring were subjected to 2.5% DSS in drinking water for 5 days, followed by 5 days of recovery.Results: Offspring from maternal HFD had higher body weight gain before DSS induction and had higher liver and fat weights with increased adipocyte size at necropsy. When subjected to DSS treatment, HFD offspring had accelerated body weight loss and exaggerated disease activity index. HFD offspring had an elevated histopathological score and interleukin (IL)-1β, IL-6, and IL-17 expression with upregulated NF-κB signaling. Maternal HFD resulted in enhanced neutrophil infiltration associated with elevated expression of monocyte chemoattractant protein-1. Furthermore, maternal HFD suppressed AMP-activated protein kinase activity and decreased sirtuin 1 and p53 protein contents in offspring gut.Conclusions: Maternal HFD consumption predisposes offspring to a higher susceptibility to develop inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Background and Purpose: The pathogenesis of osteoarthritis implicates a low-grade inflammation associated to the innate immune system activation. Toll like receptor (TLR) stimulation triggers the release of inflammatory mediators, which aggravate osteoarthritis. We studied the preventive effect of 6-shogaol, a potential TLR4 inhibitor, on the treatment of experimental knee osteoarthritis.Experimental Approach: Osteoarthritis was induced in C57BL6 mice by surgical section of the medial meniscotibial ligament, which received 6-shogaol for eight weeks. Cartilage damage, inflammatory mediator presence and disease markers were assessed in joint tissues by immunohistochemistry. Computational modelling was used to predict binding modes of 6-shogaol into the TLR4/MD2 receptor and its permeability across cellular membranes. Employing LPS-stimulated chondrocytes and MAPK assay, we elucidated 6-shogaol action mechanisms.Key Results: 6-Shogaol treatment prevented articular cartilage lesions, synovitis and the presence of pro-inflammatory mediators, and disease markers in osteoarthritis animals. Molecular modelling studies predicted 6-shogaol interaction with the TLR4/MD-2 heterodimer in an antagonist conformation through its binding into the MD-2 pocket. In cell culture, we confirmed that 6-shogaol reduced LPS-induced TLR4 inflammatory signalling pathways. Besides, MAPK assay demonstrated that 6-shogaol directly inhibits the ERK1/2 phosphorylation activity.Conclusion and Implications: 6-Shogaol evoked a preventive action on cartilage and synovial inflammation in osteoarthritis mice. 6-shogaol effect may take place not only by hindering the interaction between TLR4 ligands and the TLR4/MD-2 complex in chondrocytes, but also through inhibition of ERK phosphorylation, implying a pleiotropic effect on different mediators activated during osteoarthritis, which proposes it as an attractive drug for osteoarthritis treatments. [ABSTRACT FROM AUTHOR]

Background and Purpose: Recent evidence links brain insulin resistance with neurodegenerative diseases, where hyperphosphorylated tau protein contributes to neuronal cell death. In the present study, we aimed to evaluate if d-pinitol inositol, which acts as an insulin sensitizer, affects the phosphorylation status of tau protein.Experimental Approach: We studied the pharmacological effect of d-pinitol on insulin signalling and tau phosphorylation in the hippocampus of Wistar and Zucker rats. To this end, we evaluated by western blotting the Akt pathway and its downstream proteins as being one of the main insulin-mediator pathways. Also, we explored the functional status of additional kinases phosphorylating tau, including PKA, ERK1/2, AMPK and CDK5. We utilized the 3xTg mouse model as a control for tauopathy, since it carries tau mutations that promote phosphorylation and aggregation.Key Results: Surprisingly, we discovered that oral d-pinitol treatment lowered tau phosphorylation significantly, but not through the expected kinase GSK-3 regulation. An extensive search for additional kinases phosphorylating tau revealed that this effect was mediated through a mechanism dependent on the reduction of the activity of the CDK5, affecting both its p35 and p25 subunits. This effect disappeared in leptin-deficient Zucker rats, uncovering that the association of leptin deficiency, obesity, dyslipidaemia and hyperinsulinaemia abrogates d-pinitol actions on tau phosphorylation. The 3xTg mice confirmed d-pinitol effectiveness in a genetic AD-tauopathy.Conclusion and Implications: The present findings suggest that d-pinitol, by regulating CDK5 activity through a decrease of CDK5R1, is a potential drug for developing treatments for neurological disorders such as tauopathies. [ABSTRACT FROM AUTHOR]

The membrane occupation and recognition nexus (MORN) motif was first defined in 2000, when it was identified in the junctophilin protein family. Dozens of studies have been published ever since, mainly focusing on the function of a given MORN motif-containing protein in parasites, plants or animal cells. Proteins with MORN motifs are not only expressed in most animal and plant cell types, but also significantly differ in their intracellular localization, suggesting that the MORN motifs may fulfill multiple physiological functions. Recent studies have found that MORN motif-containing proteins junctophilin-1/2 and MORN3 play a role in cardiac hypertrophy, skeletal muscle fiber stability and cancer. Hence, MORN motif-containing proteins may be exploited to develop improved treatments for various pathological conditions, such as cardiovascular diseases. Here, we review current research on MORN motif-containing proteins in different organisms and provide both ideas and approaches for follow-up exploration of their functions and applications. [ABSTRACT FROM AUTHOR]

This study investigated the potential therapeutic effects of the FDA-approved drug metformin on cue-induced reinstatement of cocaine seeking. Metformin (dimethyl-biguanide) is a first-line treatment for type II diabetes that, among other mechanisms, is involved in the activation of adenosine monophosphate activated protein kinase (AMPK). Cocaine self-administration and extinction is associated with decreased levels of phosphorylated AMPK within the nucleus accumbens core (NAcore). Previously, it was shown that increasing AMPK activity in the NAcore decreased cue-induced reinstatement of cocaine seeking. Decreasing AMPK activity produced the opposite effect. The goal of the present study was to determine if metformin in the NAcore reduces cue-induced cocaine seeking in adult male and female Sprague Dawley rats. Rats were trained to self-administer cocaine followed by extinction prior to cue-induced reinstatement trials. Metformin microinjected in the NAcore attenuated cue-induced reinstatement in male and female rats. Importantly, metformin's effects on cocaine seeking were not due to a general depression of spontaneous locomotor activity. In female rats, metformin's effects did generalize to a reduction in cue-induced reinstatement of sucrose seeking. These data support a potential role for metformin as a pharmacotherapy for cocaine use disorder but warrant caution given the potential for metformin's effects to generalize to a natural reward in female rats. [ABSTRACT FROM AUTHOR]

Insulin resistance, a smaller than expected response to a given dose of insulin, is associated with many common diseases including, ageing, polycystic ovarian disease, syndrome X, cancer, infections, trauma and, most significantly, obesity and type 2 diabetes mellitus. The biochemical basis of insulin resistance in type 2 diabetes has been the subject of many studies. Earlier studies have indicated that quantitative regulation of the insulin sensitive glucose transporters (Glut-4) and insulin receptors themselves may contribute to this disorder, however, these two factors are probably inadequate to explain the extent of insulin resistance. This point also became apparent by the development of only mild hyperinsulinaemia in mice with a targeted mutation in the Glut-4 gene. Studies on postreceptor defects in type 2 diabetes has recently focused on the intrinsic catalytic activity of the insulin receptor and downstream signalling events. A reduction in tyrosine phosphorylation of both the insulin receptor (IR) and the insulin receptor substrate-1 (IRS-1) has been noted in both animal and human type 2 diabetes. Importantly, this appears to occur in all of the major insulin-sensitive tissues, namely the muscle, fat and liver. It is now clear that decreased signalling capacity of the insulin receptor is an important component of this disease. I will review some of the potential mechanisms underlying this deficiency. [ABSTRACT FROM AUTHOR]

Background and Purpose: Kaempferol is a natural flavonoid widely investigated in various fields due to its antioxidant, anti-cancer, and anti-inflammatory activities, but few studies have shown its inhibitory effect on T cell activation. This study examined the therapeutic potential of kaempferol in atopic dermatitis by modulating T cell activation.Experimental Approach: Effects of kaempferol on T cell activation and the underlying mechanisms were investigated in Jurkat cells and mouse CD4+ T cells. A model of atopic dermatitis in mice was used to determine its therapeutic potential on T cell-mediated conditions in vivo. Western blots, RT-PCR, pulldown assays and ELISA were used, along with histological analysis of skin.Key Results: Pretreatment with kaempferol reduced CD69 expression and production of inflammatory cytokines including IL-2 from activated Jurkat cells and murine CD4+ T cells without cytotoxicity. Pulldown assays revealed that kaempferol physically binds to MRP-1 in T cells, inhibiting the action of MRP-1. In activated T cells, kaempferol suppressed JNK phosphorylation and the TAK1-IKKα mediated NF-κB pathway. Oral administration of kaempferol to mice showed improved manifestation of atopic dermatitis, a T cell-mediated condition. Western blot results showed that, as in the in vitro studies, decreased phosphorylation of JNK was associated with down-regulated MRP-1 activity in vivo, in the kaempferol-treated mice in the atopic dermatitis model.Conclusion and Implications: Kaempferol regulates T cell activation by inhibiting MRP-1 activity in activated T cells, thus showing protective effects against T cell mediated disease in vivo. [ABSTRACT FROM AUTHOR]

Axon regeneration is a conserved process across the animal kingdom. Recent studies using the soil worm Caenorhabditis elegans as a model system revealed that machineries regulating engulfment of dying cells also control axon regeneration and axon debris removal. In this review, the relationships between the engulfment machinery and the biological processes triggered by axon injury and subsequent axon regeneration drawn from divergent views are examined. In one study, it is found that engulfing cells directly promote axon regeneration. In this context, CED‐1 (Drosophila Draper/mouse MEGF10), an engulfment protein expressed on the surface of engulfing cells, functions as a receptor for axon debris removal and as an adhesion molecule for axon regeneration. In other studies, it is shown that those engulfment genes, previously known to function within the engulfing cells for cell corpse removal, can have a cell‐autonomous "non‐engulfing cell" role in axon regeneration. Together, these findings suggest that engulfment genes are repurposed for neuronal regeneration by acting in both engulfing cells and regenerating neurons. [ABSTRACT FROM AUTHOR]

Cholestasis is a common manifestation of decreased bile flow in various liver diseases. It results in fibrosis and even cirrhosis without proper treatment. It is believed that a wide range of factors, including transporter dysfunction, oxidative stress, inflammatory damage, and immune disruption, can cause cholestasis. In recent years, natural products have drawn much attention for specific multiple-target activities in diseases. Many attempts have been made to investigate the anticholestatic effects of natural products with advanced technology. This review summarizes recent studies on the biological activities and mechanisms of recognized compounds for cholestasis treatment. Natural products, including various flavonoids, phenols, acids, quinones, saponins, alkaloids, glycosides, and so on, function as comprehensive regulators via ameliorating oxidative stress, inflammation, and apoptosis, restoring bile acid balance with hepatic transporters, and adjusting immune disruption. Moreover, in this progress, nuclear factor erythroid 2-related factor 2, reactive oxygen species production, heme oxygenase-1, NF-κB, cholesterol 7 alpha-hydroxylase, and farnesoid X receptors are thought as main targets for the activity of natural products. Therefore, this review presents the detailed mechanisms that include multiple targets and diverse signalling pathways. Natural products are the valuable when seeking novel therapeutic agents to treat cholestatic liver diseases. [ABSTRACT FROM AUTHOR]

While current effective therapies are available for the symptomatic control of PD, treatments to halt the progressive neurodegeneration still do not exist. Loss of dopamine neurons in the SNc and dopamine terminals in the striatum drive the motor features of PD. Multiple lines of research point to several pathways which may contribute to dopaminergic neurodegeneration. These pathways include extensive axonal arborization, mitochondrial dysfunction, dopamine's biochemical properties, abnormal protein accumulation of α-synuclein, defective autophagy and lysosomal degradation, and synaptic impairment. Thus, understanding the essential features and mechanisms of dopaminergic neuronal vulnerability is a major scientific challenge and highlights an outstanding need for fostering effective therapies against neurodegeneration in PD. This article, which arose from the Movement Disorders 2018 Conference, discusses and reviews the possible mechanisms underlying neuronal vulnerability and potential therapeutic approaches in PD. © 2019 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Kava is a beverage made from the ground roots of the plant Piper Methysticum and has long-held a significant place within Pacific island communities. Active compounds were extracted from kava, and secondary metabolites include kavalactones, chalcones, cinnamic acid derivatives and flavanones. It is thought that components of kava may exert an antiproliferative effect through cell cycle arrest and promotion of apoptosis.Methods: We conducted a systematic review to summarize available evidence of the anticancer effects of kava components and investigate their potential use for oral squamous cell carcinoma (OSCC) treatment. Eligible studies were identified through a comprehensive search of OVID EMBASE, OVID MEDLINE and Web of Science, as at April 2018.Results: Of 39 papers that met the inclusion criteria, 32 included in vitro models and 13 included animal studies. A total of 26 different cancers were assessed with 32 studies solely assessing epithelial cancers, 6 mesenchymal cancers and 1 study including both. There was only one report assessing an OSCC cell line. Antiproliferative properties were demonstrated in 32 out of 39 papers. The most researched constituent of kava was flavokavain B followed by flavokavain A. Both were associated with increased expression of pro-apoptotic proteins and decreased expression of anti-apoptotic proteins. Further, they were associated with a dose-dependent reduction of angiogenesis.Conclusion: There was heterogeneity of study models and methods of investigation across the studies identified. Components of kava appear to present an area of interest with chemotherapeutic potential in cancer prevention and treatment, particularly for epithelial neoplasms. To date, there is a paucity of literature of the utility of kava components in the prevention and treatment of oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

The immune system plays a prominent role in the initiation and maintenance of hypertension. The innate immune system, via toll-like receptors (TLRs), identifies distinct signatures of invading microbes and damage-associated molecular patterns and triggers a chain of downstream signalling cascades, leading to secretion of pro-inflammatory cytokines and shaping the adaptive immune response. Over the past decade, a dysfunctional TLR-mediated response, particularly via TLR4, has been suggested to support a chronic inflammatory state in hypertension, inducing deleterious local and systemic effects in host cells and tissues and contributing to disease progression. While the underlying mechanisms triggering TLR4 need further research, evidence suggests that sustained elevations in BP disrupt homeostasis, releasing endogenous TLR4 ligands in hypertension. In this review, we discuss the emerging role of TLR4 in the pathogenesis of hypertension and whether targeting this receptor and its signalling pathways could offer a therapeutic strategy for management of this multifaceted disease. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc. [ABSTRACT FROM AUTHOR]

Berberine, a natural isoquinoline alkaloid isolated from the berberis species, has a wide array of biological properties such as anti-inflammatory, antibacterial, antifungal, and antihelminthic effects. We evaluated the antiviral effect of berberine against influenza A/FM1/1/47 (H1N1) in vivo and in vitro. The results showed that berberine strongly suppressed viral replication in A549 cells and in mouse lungs. Meanwhile, berberine relieved pulmonary inflammation and reduced necrosis, inflammatory cell infiltration, and pulmonary edema induced by viral infection in mice when compared with vehicle-treated mice. Berberine suppressed the viral infection-induced up-regulation of TLR7 signaling pathway, such as TLR7, MyD88, and NF-κB (p65), at both the mRNA and protein levels. Furthermore, berberine significantly inhibited the viral infection-induced increase in Th1/Th2 and Th17/Treg ratios as well as the production of inflammatory cytokines. Our data provide new insight into the potential of berberine as a therapeutic agent for viral infection via its antiviral activity. [ABSTRACT FROM AUTHOR]

In the last years, consumers are paying much more attention to natural medicines and principles, mainly due to the general sense that natural compounds are safe. On the other hand, there is a growing demand by industry for plants used in traditional medicine that could be incorporated in foods, nutraceuticals, cosmetics, or even pharmaceuticals. Glycyrrhiza glabra Linn. belongs to the Fabaceae family and has been recognized since ancient times for its ethnopharmacological values. This plant contains different phytocompounds, such as glycyrrhizin, 18β-glycyrrhetinic acid, glabrin A and B, and isoflavones, that have demonstrated various pharmacological activities. Pharmacological experiments have demonstrated that different extracts and pure compounds from this species exhibit a broad range of biological properties, including antibacterial, anti-inflammatory, antiviral, antioxidant, and antidiabetic activities. A few toxicological studies have reported some concerns. This review addresses all those issues and focuses on the pharmacological activities reported for G. glabra. Therefore, an updated, critical, and extensive overview on the current knowledge of G. glabra composition and biological activities is provided here in order to explore its therapeutic potential and future challenges to be utilized for the formulation of new products that will contribute to human well-being. [ABSTRACT FROM AUTHOR]

While cytokines such as TNF have long been recognized as essential to normal cerebral physiology, the implications of their chronic excessive production within the brain are now also increasingly appreciated. Syndromes as diverse as malaria and lead poisoning, as well as non-infectious neurodegenerative diseases, illustrate this. These cytokines also orchestrate changes in tau, α-synuclein, amyloid-β levels and degree of insulin resistance in most neurodegenerative states. New data on the effects of salbutamol, an indirect anti-TNF agent, on α-synuclein and Parkinson's disease, APOE4 and tau add considerably to the rationale of the anti-TNF approach to understanding, and treating, these diseases. Therapeutic advances being tested, and arguably useful for a number of the neurodegenerative diseases, include a reduction of excess cerebral TNF, whether directly, with a specific anti-TNF biological agent such as etanercept via Batson's plexus, or indirectly via surgically implanting stem cells. Inhaled salbutamol also warrants investigating further across the neurodegenerative disease spectrum. It is now timely to integrate this range of new information across the neurodegenerative disease spectrum, rather than keep seeing it through the lens of individual disease states. [ABSTRACT FROM AUTHOR]

Introduction: Volumetric muscle loss (VML) occurs following significant traumatic injury or surgical removal of skeletal muscle, resulting in nonrecoverable loss of tissue and long-term dysfunction. Perhaps less recognized is that VML injuries inherently disrupt the neuromuscular unit, resulting in fiber denervation and presumptive motor unit rearrangement, expansion, and/or loss. To characterize neural dysfunction we quantified motoneuron axotomy, in efforts to understand how this relates to the temporal coordination of neuromuscular and morphological alterations due to injury.Methods: In an established rat tibialis anterior (TA) VML injury model, we examined the motoneuron, skeletal muscle, and maximal isometric torque at 3, 7, 14, and 21 days postinjury.Results: Significant axotomy of 57-79% of all TA muscle motoneurons was observed through 21 days postinjury, which was coupled with a 45-90% TA maximal torque deficit.Discussion: A ∼20% partial ablation of the TA muscle causes disproportionate damage across the motor unit acutely postinjury. Muscle Nerve 57: 799-807, 2018. [ABSTRACT FROM AUTHOR]

p21-activated kinase 1 (Pak1) is a member of the highly conserved family of serine/threonine protein kinases regulated by Ras-related small G-proteins, Cdc42/Rac1. It has been previously demonstrated to be involved in cardiac protection. Based on recent studies, this review provides an overview of the role of Pak1 in cardiac diseases including disrupted Ca2+ homoeostasis-related cardiac arrhythmias, adrenergic stress- and pressure overload-induced hypertrophy, and ischaemia/reperfusion injury. These findings demonstrate the important role of Pak1 mediated through the phosphorylation and transcriptional modification of hypertrophy and/or arrhythmia-related genes. This review also discusses the anti-arrhythmic and anti-hypertrophic, protective function of Pak1 and the beneficial effects of fingolimod (an FDA-approved sphingolipid drug), a Pak1 activator, and its ability to prevent arrhythmias and cardiac hypertrophy. These findings also highlight the therapeutic potential of Pak1 signalling in the treatment and prevention of cardiac diseases.Linked Articles: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. [ABSTRACT FROM AUTHOR]

Hydrogen sulfide (H2 S), independently of any specific transporters, has a number of biological effects on the cardiovascular system. However, until now, the detailed mechanism of H2 S was not clear. Recently, a novel post-translational modification induced by H2 S, named S-sulfhydration, has been proposed. S-sulfhydration is the chemical modification of specific cysteine residues of target proteins by H2 S. There are several methods for detecting S-sulfhydration, such as the modified biotin switch assay, maleimide assay with fluorescent thiol modifying regents, tag-switch method and mass spectrometry. H2 S induces S-sulfhydration on enzymes or receptors (such as p66Shc, phospholamban, protein tyrosine phosphatase 1B, mitogen-activated extracellular signal-regulated kinase 1 and ATP synthase subunit α), transcription factors (such as specific protein-1, kelch-like ECH-associating protein 1, NF-κB and interferon regulatory factor-1), and ion channels (such as voltage-activated Ca2+ channels, transient receptor potential channels and ATP-sensitive K+ channels) in the cardiovascular system. Although significant progress has been achieved in delineating the role of protein S-sulfhydration by H2 S in the cardiovascular system, more proteins with detailed cysteine sites of S-sulfhydration as well as physiological function need to be investigated in further studies. This review mainly summarizes the role and possible mechanism of S-sulfhydration in the cardiovascular system. The S-sulfhydrated proteins may be potential novel targets for therapeutic intervention and drug design in the cardiovascular system, which may accelerate the development and application of H2 S-related drugs in the future.Linked Articles: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc. [ABSTRACT FROM AUTHOR]

The identification of pathogenic mutations in Ras analog in brain 39B (RAB39B) and Ras analog in brain 32 (RAB32) that cause Parkinson's disease (PD) has highlighted the emerging role of protein trafficking in disease pathogenesis. Ras analog in brain (Rab) Guanosine triphosphatase (GTPase) function as master regulators of membrane trafficking, including vesicle formation, movement along cytoskeletal networks, and membrane fusion. Recent studies have linked Rab GTPases with α-synuclein, Leucine-rich repeat kinase 2, and Vacuolar protein sorting 35, 3 key proteins in PD pathogenesis. In this review, we discuss the various RAB GTPases associated with PD, current progress in the research, and potential future directions. Investigations into the function of RAB GTPases will likely provide significant insight into the etiology of PD and identify novel therapeutic targets for a currently incurable disease. © 2018 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Platelet-derived growth factor (PDGF) isoforms and their receptors have important roles during embryogenesis, particularly in the development of various mesenchymal cell types in different organs. In the adult, PDGF stimulates wound healing and regulates tissue homeostasis. However, overactivity of PDGF signalling is associated with malignancies and other diseases characterized by excessive cell proliferation, such as fibrotic conditions and atherosclerosis. In certain tumours, genetic or epigenetic alterations of the genes for PDGF ligands and receptors drive tumour cell proliferation and survival. Examples include the rare skin tumour dermatofibrosarcoma protuberance, which is driven by autocrine PDGF stimulation due to translocation of a PDGF gene, and certain gastrointestinal stromal tumours and leukaemias, which are driven by constitute activation of PDGF receptors due to point mutations and formation of fusion proteins of the receptors, respectively. Moreover, PDGF stimulates cells in tumour stroma and promotes angiogenesis as well as the development of cancer-associated fibroblasts, both of which promote tumour progression. Inhibitors of PDGF signalling may thus be of clinical usefulness in the treatment of certain tumours. [ABSTRACT FROM AUTHOR]

Introduction: N-methyl-d-aspartate (NMDA) is expressed in sensory neurons and plays important roles in peripheral pain mechanisms. The aim of this study was to examine the effects and molecular mechanisms of NMDA on C2C12 myoblast proliferation and differentiation.Methods: Cytotoxicity and differentiation were examined by the MTT assay, reverse transcription-polymerase chain reaction, and immunofluorescence.Results: NMDA had no cytotoxicity (10-500 μM) and inhibited myoblastic differentiation of C2C12 cells, as assessed by F-actin immunofluorescence and levels of mRNAs encoding myogenic markers such as myogenin and myosin heavy-chain 2. It inhibited phosphorylation of mammalian target of rapamycin (mTOR) by inactivating mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38. It induced reactive oxygen species production. Furthermore, NMDA-suppressed expression of F-actin was reversed by adding the antioxidant N-acetylcysteine.Conclusions: Collectively, these results indicate that NMDA impairs myogenesis or myogenic differentiation in C2C12 cells through the mTOR/MAPK signaling pathways and may lead to skeletal muscle degeneration. Muscle Nerve 56: 510-518, 2017. [ABSTRACT FROM AUTHOR]

Insulin sensitivity and metabolic homeostasis depend on the capacity of adipose tissue to take up and utilize excess glucose and fatty acids. The key aspects that determine the fuel-buffering capacity of adipose tissue depend on the physiological levels of the small redox molecule, nitric oxide (NO). In addition to impairment of NO synthesis, excessive formation of the superoxide anion (О2•- ) in adipose tissue may be an important interfering factor diverting the signalling of NO and other reactive oxygen and nitrogen species in obesity, resulting in metabolic dysfunction of adipose tissue over time. Besides its role in relief from superoxide burst, enhanced NO signalling may be responsible for the therapeutic benefits of different superoxide dismutase mimetics, in obesity and experimental diabetes models. This review summarizes the role of NO in adipose tissue and highlights the effects of NO/О2•- ratio 'teetering' as a promising pharmacological target in the metabolic syndrome.Linked Articles: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc. [ABSTRACT FROM AUTHOR]

The intestine is composed of many distinct cell types that respond to commensal microbiota or pathogens with immune tolerance and proinflammatory signals respectively. ROS produced by mucosa-resident cells or by newly recruited innate immune cells are essential for antimicrobial responses and regulation of signalling pathways including processes involved in wound healing. Impaired ROS production due to inactivating patient variants in genes encoding NADPH oxidases as ROS source has been associated with Crohn's disease and pancolitis, whereas overproduction of ROS due to up-regulation of oxidases or altered mitochondrial function was linked to ileitis and ulcerative colitis. Here, we discuss recent advances in our understanding of how maintaining a redox balance is crucial to preserve gut homeostasis.Linked Articles: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc. [ABSTRACT FROM AUTHOR]

Phytoestrogens are plant-derived dietary compounds with structural similarity to 17-β-oestradiol (E2), the primary female sex hormone. This structural similarity to E2 enables phytoestrogens to cause (anti)oestrogenic effects by binding to the oestrogen receptors. The aim of the present review is to present a state-of-the-art overview of the potential health effects of dietary phytoestrogens. Various beneficial health effects have been ascribed to phytoestrogens, such as a lowered risk of menopausal symptoms like hot flushes and osteoporosis, lowered risks of cardiovascular disease, obesity, metabolic syndrome and type 2 diabetes, brain function disorders, breast cancer, prostate cancer, bowel cancer and other cancers. In contrast to these beneficial health claims, the (anti)oestrogenic properties of phytoestrogens have also raised concerns since they might act as endocrine disruptors, indicating a potential to cause adverse health effects. The literature overview presented in this paper illustrates that several potential health benefits of phytoestrogens have been reported but that, given the data on potential adverse health effects, the current evidence on these beneficial health effects is not so obvious that they clearly outweigh the possible health risks. Furthermore, the data currently available are not sufficient to support a more refined (semi) quantitative risk-benefit analysis. This implies that a definite conclusion on possible beneficial health effects of phytoestrogens cannot be made.Linked Articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. [ABSTRACT FROM AUTHOR]

Anthocyanins are a class of water-soluble flavonoids, which show a range of pharmacological effects, such as prevention of cardiovascular disease, obesity control and antitumour activity. Their potential antitumour effects are reported to be based on a wide variety of biological activities including antioxidant; anti-inflammation; anti-mutagenesis; induction of differentiation; inhibiting proliferation by modulating signal transduction pathways, inducing cell cycle arrest and stimulating apoptosis or autophagy of cancer cells; anti-invasion; anti-metastasis; reversing drug resistance of cancer cells and increasing their sensitivity to chemotherapy. In this review, the latest progress on the anticancer activities of anthocyanins and the underlying molecular mechanisms is summarized using data from basic research in vitro and in vivo, from clinical trials and taking into account theory and practice.Linked Articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. [ABSTRACT FROM AUTHOR]

The peptide hormone relaxin regulates the essential maternal haemodynamic adaptations in early pregnancy through direct actions on the renal and systemic vasculature. These vascular actions of relaxin occur mainly through endothelium-derived NO-mediated vasodilator pathways and improvements in arterial compliance in small resistance-size arteries. This work catalysed a plethora of studies which revealed quite heterogeneous responses across the different regions of the vasculature, and also uncovered NO-independent mechanisms of relaxin action. In this review, we first describe the role of endogenous relaxin in maintaining normal vascular function, largely referring to work in pregnant and male relaxin-deficient animals. We then discuss the diversity of mechanisms mediating relaxin action in different vascular beds, including the involvement of prostanoids, VEGF, endothelium-derived hyperpolarisation and antioxidant activity in addition to the classic NO-mediated vasodilatory pathway. We conclude the review with current perspectives on the vascular remodelling capabilities of relaxin.Linked Articles: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc. [ABSTRACT FROM AUTHOR]

In individuals with a history of drug taking, the capacity of drug-associated cues to elicit indices of drug craving intensifies or incubates with the passage of time during drug abstinence. This incubation of cocaine craving, as well as difficulties with learning to suppress drug-seeking behavior during protracted withdrawal, are associated with a time-dependent deregulation of ventromedial prefrontal cortex (vmPFC) function. As the molecular bases for cocaine-related vmPFC deregulation remain elusive, the present study assayed the consequences of extended access to intravenous cocaine (6 hours/day; 0.25 mg/infusion for 10 day) on the activational state of protein kinase C epsilon (PKCε), an enzyme highly implicated in drug-induced neuroplasticity. The opportunity to engage in cocaine seeking during cocaine abstinence time-dependently altered PKCε phosphorylation within vmPFC, with reduced and increased p-PKCε expression observed in early (3 days) and protracted (30 days) withdrawal, respectively. This effect was more robust within the ventromedial versus dorsomedial PFC, was not observed in comparable cocaine-experienced rats not tested for drug-seeking behavior and was distinct from the rise in phosphorylated extracellular signal-regulated kinase observed in cocaine-seeking rats. Further, the impact of inhibiting PKCε translocation within the vmPFC using TAT infusion proteins upon cue-elicited responding was determined and inhibition coinciding with the period of testing attenuated cocaine-seeking behavior, with an effect also apparent the next day. In contrast, inhibitor pretreatment prior to testing during early withdrawal was without effect. Thus, a history of excessive cocaine taking influences the cue reactivity of important intracellular signaling molecules within the vmPFC, with PKCε playing a critical role in the manifestation of cue-elicited cocaine seeking during protracted drug withdrawal. [ABSTRACT FROM AUTHOR]

Background and Purpose: Myocardial cAMP elevation confers cardioprotection against ischaemia/reperfusion (I/R) injury. cAMP activates two independent signalling pathways, PKA and Epac. This study investigated the cardiac effects of activating PKA and/or Epac and their involvement in cardioprotection against I/R.Experimental Approach: Hearts from male rats were used either for determination of PKA and PKC activation or perfused in the Langendorff mode for either cardiomyocyte isolation or used to monitor functional activity at basal levels and after 30 min global ischaemia and 2 h reperfusion. Functional recovery and myocardial injury during reperfusion (LDH release and infarct size) were evaluated. Activation of PKA and/or Epac in perfused hearts was induced using cell permeable cAMP analogues in the presence or absence of inhibitors of PKA, Epac and PKC. H9C2 cells and cardiomyocytes were used to assess activation of Epac and effect on Ca2+ transients.Key Results: Selective activation of either PKA or Epac was found to trigger a positive inotropic effect, which was considerably enhanced when both pathways were simultaneously activated. Only combined activation of PKA and Epac induced marked cardioprotection against I/R injury. This was accompanied by PKCε activation and repressed by inhibitors of PKA, Epac or PKC.Conclusion and Implications: Simultaneous activation of both PKA and Epac induces an additive inotropic effect and confers optimal and marked cardioprotection against I/R injury. The latter effect is mediated by PKCε activation. This work has introduced a new therapeutic approach and targets to protect the heart against cardiac insults. [ABSTRACT FROM AUTHOR]

The human intracellular enzyme AKR1B1 belongs to the aldo-keto reductase superfamily. The AKR1B1-catalyzed reduction of aldehydes is part of the intracellular inflammatory pathway leading to the activation of NF-κB and the expression of pro-inflammatory genes. The present study is aimed at determining the inhibition of AKR1B1 brought about by an extract of artichoke leaves (bracts), and the effects of this extract and three participating compounds on the expression of AKR1B1, COX-2, and MMP-2 proteins in THP-1 cells. It seeks to identify the ability of the test substances to modulate the lipopolysaccharide (LPS)-induced activation of NF-κB in cells and the intracellular oxidant effect of test substances after incubation with LPS. Low concentrations of the extract inhibit the enzyme AKR1B1. After stimulation by LPS, the extract attenuated the activity of NF-κB in THP-1 cells, but no changes in the expression of AKR1B1 were recorded. The extract diminished the expression of the inflammation-related enzymes COX-2 and MMP-2, probably by inhibiting the activity of NF-κB. The extract significantly diminished the intracellular reactive oxygen species after a brief LPS incubation, which may also have reduced intracellular inflammation. The diminished activity of NF-κB in the cells could be linked to the inhibition of the activity of AKR1B1. Copyright © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

As populations across the world both age and become more obese, the numbers of individuals with Alzheimer's disease and diabetes are increasing; posing enormous challenges for society and consequently becoming priorities for governments and global organizations. These issues, an ageing population at risk of neurodegenerative diseases such as Alzheimer's disease and an increasingly obese population at risk of metabolic alterations such as type 2 diabetes, are usually considered as independent conditions, but increasing evidence from both epidemiological and molecular studies link these disorders. The aim of this review was to highlight these multifactorial links. We will discuss the impact of direct links between insulin and IGF-1 signalling and the Alzheimer's disease-associated pathological events as well as the impact of other processes such as inflammation, oxidative stress and mitochondrial dysfunction either common to both conditions or perhaps responsible for a mechanistic link between metabolic and neurodegenerative disease. An understanding of such associations might be of importance not only in the understanding of disease mechanisms but also in the search for novel therapeutic options. [ABSTRACT FROM AUTHOR]

Classically, receptor-mediated signalling was conceived as a linear process involving one agonist, a variety of potential targets within a receptor family (e.g. α- and β-adrenoceptors) and a second messenger (e.g. cAMP)-triggered response. If distinct responses were stimulated by the same receptor in different tissues (e.g. lipolysis in adipocytes vs. increased beating rate in the heart caused by adrenaline), the differences were attributed to different second messenger targets in the different tissues. It is now realized that an individual receptor can couple to multiple effectors (different G proteins and different β-arrestins), even in the same cell, to drive very distinct responses. Furthermore, tailored agonists can mould the receptor conformation to activate one signal pathway versus another by a process termed 'biased signalling'. Complicating issues further, we now know that activating one receptor can rapidly trigger the local release of agonists for a second receptor via a process termed 'transactivation'. Thus, the end response can represent a cooperative signalling process involving two or more receptors linked by transactivation. This overview, with a focus on the GPCR, protease-activated receptor-1, integrates both of these processes to predict the complex array of responses that can arise when biased receptor signalling also involves the receptor transactivation process. The therapeutic implications of this signalling matrix are also briefly discussed. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein-Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc. [ABSTRACT FROM AUTHOR]

Mitochondria are dynamic organelles, which couple the various cellular processes that regulate metabolism, cell proliferation and survival. Environmental stress can cause mitochondrial dysfunction and dynamic changes including reduced mitochondrial biogenesis, oxidative phosphorylation and ATP production, as well as mitophagy impairment, which leads to increased ROS, inflammatory responses and cellular senescence. Oxidative stress, inflammation and cellular senescence all have important roles in the pathogenesis of chronic lung diseases, such as chronic obstructive pulmonary disease, pulmonary fibrosis and bronchopulmonary dysplasia. In this review, we discuss the current state on how mitochondrial dysfunction affects inflammatory responses and cellular senescence, the mechanisms of mitochondrial dysfunction underlying the pathogenesis of chronic lung diseases and the potential of mitochondrial transfer and replacement as treatments for these diseases. [ABSTRACT FROM AUTHOR]

Metabolic syndrome is associated with several disorders, including hypertension, diabetes, hyperlipidemia as well as cardiovascular diseases and stroke. Plant-derived polyphenols, compounds found in numerous plant species, play an important role as potential treatments for components of metabolic syndrome. Studies have provided evidence for protective effects of various polyphenol-rich foods against metabolic syndrome. Fruits, vegetables, cereals, nuts, and berries are rich in polyphenolic compounds. Grapes (Vitis vinifera), especially grape seeds, stand out as rich sources of polyphenol potent antioxidants and have been reported helpful for inhibiting the risk factors involved in the metabolic syndrome such as hyperlipidemia, hyperglycemia, and hypertension. There are also many studies about gastroprotective, hepatoprotective, and anti-obesity effects of grape polyphenolic compounds especially proanthocyanidins in the literature. The present study investigates the protective effects of grape seeds in metabolic syndrome. The results of this study show that grape polyphenols have significant effects on the level of blood glucose, lipid profile, blood pressure, as well as beneficial activities in liver and heart with various mechanisms. In addition, the pharmacokinetics of grape polyphenols is discussed. More detailed mechanistic investigations and phytochemical studies for finding the exact bioactive component(s) and molecular signaling pathways are suggested. [ABSTRACT FROM AUTHOR]

Unlabelled: Increasing evidence suggests that an overactive endocannabinoid system (ECS) may contribute to the development of diabetes by promoting energy intake and storage, impairing both glucose and lipid metabolism, by exerting pro-apoptotic effects in pancreatic beta cells and by facilitating inflammation in pancreatic islets. Furthermore, hyperglycaemia associated with diabetes has also been implicated in triggering perturbations of the ECS amplifying the pathological processes mentioned above, eventually culminating in a vicious circle. Compelling evidence from preclinical studies indicates that the ECS also influences diabetes-induced oxidative stress, inflammation, fibrosis and subsequent tissue injury in target organs for diabetic complications. In this review, we provide an update on the contribution of the ECS to the pathogenesis of diabetes and diabetic microvascular (retinopathy, nephropathy and neuropathy) and cardiovascular complications. The therapeutic potential of targeting the ECS is also discussed.Linked Articles: This article is part of a themed section on Endocannabinoids. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.7/issuetoc. [ABSTRACT FROM AUTHOR]

Neuroblastoma is an embryonal malignancy that commonly affects young children and is remarkably heterogenous in its malignant potential. Recently, the genetic basis of neuroblastoma has come into focus and not only has catalyzed a more comprehensive understanding of neuroblastoma tumorigenesis but also has revealed novel oncogenic vulnerabilities that are being therapeutically leveraged. Neuroblastoma is a model pediatric solid tumor in its use of recurrent genomic alterations, such as high-level MYCN (v-myc avian myelocytomatosis viral oncogene neuroblastoma-derived homolog) amplification, for risk stratification. Given the relative paucity of recurrent, activating, somatic point mutations or gene fusions in primary neuroblastoma tumors studied at initial diagnosis, innovative treatment approaches beyond small molecules targeting mutated or dysregulated kinases will be required moving forward to achieve noticeable improvements in overall patient survival. However, the clonally acquired, oncogenic aberrations in relapsed neuroblastomas are currently being defined and may offer an opportunity to improve patient outcomes with molecularly targeted therapy directed toward aberrantly regulated pathways in relapsed disease. This review summarizes the current state of knowledge about neuroblastoma genetics and genomics, highlighting the improved prognostication and potential therapeutic opportunities that have arisen from recent advances in understanding germline predisposition, recurrent segmental chromosomal alterations, somatic point mutations and translocations, and clonal evolution in relapsed neuroblastoma. [ABSTRACT FROM AUTHOR]

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13354/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates. [ABSTRACT FROM AUTHOR]

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13353/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates. [ABSTRACT FROM AUTHOR]

Background The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase ( EML4- ALK) rearrangement is almost in mutual exclusion to epidermal growth factor receptor ( EGFR) and v- Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS) mutations, with rare exceptions. This study aimed to search for the coexisting gene alterations in Chinese patients with lung adenocarcinoma (LAC). Methods We detected mutations in the EGFR, KRAS, and ALK gene rearrangements in samples from 131 Chinese patients with LAC. ALK rearrangements were identified by fluorescent in situ hybridization. Mutations in EGFR (exons 19 to 21) and KRAS (codons 12 and 13) were determined by real time polymerase chain reaction. Results All patients were classified into four distinct genotype groups: EGFR mutations ( n = 63; 48.1%), ALK rearrangements ( n = 9; 6.9%), KRAS mutations ( n = 8; 6.1%), and the wild-type (unmutated) genotype of all three genes ( WT/ WT/ WT) ( n = 53; 40.5%). Interestingly, two never-smoking women (2/131, 1.5%) harbored coexisting ALK rearrangement and EGFR mutation. ALK rearrangement occurred more frequently in young patients (8/9) ( P = 0.687), non-smokers (8/9) ( P = 0.077), and those who had no family history of LAC (8/9) ( P = 1.000); all KRAS mutations occurred in the EGFR wild type ( P = 0.007). KRAS mutations were generally detected in young patients (6/8) ( P = 0.658) and in those who had no family history (7/8) ( P = 1.000); EGFR mutations correlated with gender ( P = 0.001), and smoking status ( P < 0.001). Conclusions Two patients harboring both EGFR mutation and EML4- ALK rearrangement were detected in this study. Our data was apparently inconsistent with the traditional view that the EML4- ALK fusion gene in patients is resistant to EGFR- TKIs. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy is a lethal muscle-wasting disease that affects boys. Mutations in the dystrophin gene result in the absence of the dystrophin glycoprotein complex (DGC) from muscle plasma membranes. In healthy muscle fibers, the DGC forms a link between the extracellular matrix and the cytoskeleton to protect against contraction-induced membrane lesions and to regulate cell signaling. The absence of the DGC results in aberrant regulation of inflammatory signaling cascades. Inflammation is a key pathological characteristic of dystrophic muscle lesion formation. However, the role and regulation of this process in the disease time-course has not been sufficiently examined. The transcription factor nuclear factor-κB has been shown to contribute to the disease process and is likely involved with increased inflammatory gene expression, including cytokines and chemokines, found in dystrophic muscle. These aberrant signaling processes may regulate the early time-course of inflammatory events that contribute to the onset of disease. This review critically evaluates the possibility that dystrophic muscle lesions in both patients with Duchenne muscular dystrophy and mdx mice are the result of immune-mediated mechanisms that are regulated by inflammatory signaling and also highlights new therapeutic directions. [Copyright &y& Elsevier]

Toxoplasma gondii is an obligate intracellular protozoan parasite that can infect most warm-blooded animals and cause severe and life-threatening disease in developing fetuses and in immune-compromised patients. Although Toxoplasma was discovered over 100 years ago, we are only now beginning to appreciate the importance of the role that parasite modulation of its host has on parasite growth, bradyzoite development, immune evasion, and virulence. The goal of this review is to highlight these findings, to develop an integrated model for communication between Toxoplasma and its host, and to discuss new questions that arise out of these studies. [ABSTRACT FROM AUTHOR]

Background and Purpose: We showed previously that cisplatin inititates a signalling pathway mediated by PKC-delta/extracellular signal-regulated kinase (ERK), important for maintaining viability in PC Cl3 thyroid cells. The studies described herein examined whether c-fos was associated with cisplatin resistance and the signalling link between c-fos and PKC-delta/ERK.Experimental Approach: Cells were treated with various pharmacological inhibitors of PKCs and ERK, or were depleted of c-fos, PKC-delta, PKC-epsilon and caspase-3 by small interfering RNA (siRNA), then incubated with cisplatin and cytotoxicity assessed.Key Results: Cisplatin provokes the induction of c-fos and the activation of conventional PKC-beta, and novel PKC-delta and -epsilon. The cisplatin-provoked c-fos induction was decreased by Gö6976, a PKC-beta inhibitor; by siRNA for PKC-delta- but not that for PKC-epsilon or by PD98059, a mitogen-activated protein kinase/ERK kinase inhibitor. Expression of c-fos was abolished by GF109203X, an inhibitor of all PKC isoforms, or by PD98059 plus Gö6976 or by PKC-delta-siRNA plus Gö6976. When c-fos expression was blocked by siRNA, cisplatin cytotoxicity was strongly enhanced with increased caspase-3 activation. In PKC-delta-depleted cells treated with cisplatin, caspase-3 activation was increased and cell viability decreased. In these PKC-delta-depleted cells, PD98059 did not affect caspase-3 activation.Conclusions and Implications: In PC Cl3 cells, in the cell signalling pathways that lead to cisplatin resistance, PKC-delta controls ERK activity and, together with PKC-beta, also the induction of c-fos. Hence, the protective role of c-fos in thyroid cells has the potential to provide new opportunities for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Background and Purpose: While the 5-HT and Rho-kinase (ROCK) pathways have been implicated in the development of pulmonary arterial hypertension (PAH), the nature of any interactions between them remain unclear. This study investigated a role for ROCK in 5-HT-regulated proliferative responses in lung fibroblasts in vivo and in vitro.Experimental Approach: PAH was examined in mice over-expressing human 5-HT transporters (SERT+), from which pulmonary artery fibroblasts (PFs) were isolated to assess ROCK expression. In vitro analysis of 5-HT signalling employed CCL39 hamster lung fibroblasts.Key Results: ROCK inhibition ablated increased pulmonary remodelling and hypertension observed in SERT+ mice, and ROCK1/2 protein levels were elevated in SERT+ PFs. ROCK inhibition also reduced 5-HT-stimulated proliferation by suppressing MEK-stimulated ERK phosphorylation. While optimal 5-HT-stimulated proliferation required 5-HT(1B) and 5-HT(2A) receptors and SERT, receptor sensitivity to Y27632 was restricted to the 5-HT(1B) receptor. Also, while hypoxia-induced pulmonary vascular remodelling and hypertension were sensitive to Y27632 in WT and SERT+ animals, the proportions sensitive to ROCK inhibition were increased by SERT over-expression.Conclusions and Implications: SERT over-expression increased ROCK-dependent pulmonary remodelling in normoxia and hypoxia and SERT over-expression was associated with elevated ROCK1/2 levels. ROCK also potentiated 5-HT(1B) receptor-stimulated ERK activation and proliferation in vitro by facilitating MEK-ERK interaction. [ABSTRACT FROM AUTHOR]

The article presents abstracts of related to animal caring and reproduction, including research on cultured bovine zygotes and its developmental competence, an analysis concerning the reproduction variables in the Swiss Eringer, and bull epidermal sperm volume regulation ability.

Glycogen synthase kinase 3 (GSK3, of which there are two isoforms, GSK3alpha and GSK3beta) was originally characterized in the context of regulation of glycogen metabolism, though it is now known to regulate many other cellular processes. Phosphorylation of GSK3alpha(Ser21) and GSK3beta(Ser9) inhibits their activity. In the heart, emphasis has been placed particularly on GSK3beta, rather than GSK3alpha. Importantly, catalytically-active GSK3 generally restrains gene expression and, in the heart, catalytically-active GSK3 has been implicated in anti-hypertrophic signalling. Inhibition of GSK3 results in changes in the activities of transcription and translation factors in the heart and promotes hypertrophic responses, and it is generally assumed that signal transduction from hypertrophic stimuli to GSK3 passes primarily through protein kinase B/Akt (PKB/Akt). However, recent data suggest that the situation is far more complex. We review evidence pertaining to the role of GSK3 in the myocardium and discuss effects of genetic manipulation of GSK3 activity in vivo. We also discuss the signalling pathways potentially regulating GSK3 activity and propose that, depending on the stimulus, phosphorylation of GSK3 is independent of PKB/Akt. Potential GSK3 substrates studied in relation to myocardial hypertrophy include nuclear factors of activated T cells, beta-catenin, GATA4, myocardin, CREB, and eukaryotic initiation factor 2Bvarepsilon. These and other transcription factor substrates putatively important in the heart are considered. We discuss whether cardiac pathologies could be treated by therapeutic intervention at the GSK3 level but conclude that any intervention would be premature without greater understanding of the precise role of GSK3 in cardiac processes. [ABSTRACT FROM AUTHOR]

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase with a multitude of functions. Although Cdk5 is widely expressed, it has been studied most extensively in neurons. Since its initial characterization, the fundamental contribution of Cdk5 to an impressive range of neuronal processes has become clear. These phenomena include neural development, dopaminergic function and neurodegeneration. Data from different fields have recently converged to provide evidence for the participation of Cdk5 in synaptic plasticity, learning and memory. In this review, we consider recent data implicating Cdk5 in molecular and cellular mechanisms underlying synaptic plasticity. We relate these findings to its emerging role in learning and memory. Particular attention is paid to the activation of Cdk5 by p25, which enhances hippocampal synaptic plasticity and memory, and suggests formation of p25 as a physiological process regulating synaptic plasticity and memory. [ABSTRACT FROM AUTHOR]

Despite abundance of fat, exclusive dependency on fat oxidation can only sustain a metabolic rate corresponding to 50–60% of VO2max in humans. This puzzling finding has been subject to intense research for many years. Lately, it has gained renewed interest as a consequence of increased obesity and physical inactivity imposed by Western lifestyle. Why are humans so poor at metabolizing fat? Can fat metabolism be manipulated by exercise, training, diet and hormones? And why is fat stored in specialized adipose tissue and not just as lipid droplets inside muscle cells? In the present review, human fat metabolism is discussed in relation to how human fat metabolism is designed. Limitations in this design are explored and examples of different designs for fat metabolism from animal physiology are included to illustrate these limitations. Various means of manipulating fat metabolism are discussed with special emphasis on exercise, training, growth hormone (GH) physiology and GH administration. It is concluded that fat stores, non-esterified fatty acids (NEFAs) availability and enzymes for fat oxidation can be increased substantially. However, it is almost impossible to increase fat oxidation during endurance exercise at higher intensities. It seems that, for some reason, the human being is far from optimally designed for fat oxidation during exercise. Acute GH administration has several unexpected effects on fat and carbohydrate metabolism during aerobic exercise, and future research in this area is likely to provide valuable information with respect to GH physiology and the regulation of fat and carbohydrate metabolism during aerobic exercise. [ABSTRACT FROM AUTHOR]