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Sample records for receptor potential therapeutic

  1. Therapeutic Potential of Metabotropic Glutamate Receptor Modulators

    PubMed Central

    Hovelsø, N; Sotty, F; Montezinho, L.P; Pinheiro, P.S; Herrik, K.F; Mørk, A

    2012-01-01

    Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and is a major player in complex brain functions. Glutamatergic transmission is primarily mediated by ionotropic glutamate receptors, which include NMDA, AMPA and kainate receptors. However, glutamate exerts modulatory actions through a family of metabotropic G-protein-coupled glutamate receptors (mGluRs). Dysfunctions of glutamatergic neurotransmission have been implicated in the etiology of several diseases. Therefore, pharmacological modulation of ionotropic glutamate receptors has been widely investigated as a potential therapeutic strategy for the treatment of several disorders associated with glutamatergic dysfunction. However, blockade of ionotropic glutamate receptors might be accompanied by severe side effects due to their vital role in many important physiological functions. A different strategy aimed at pharmacologically interfering with mGluR function has recently gained interest. Many subtype selective agonists and antagonists have been identified and widely used in preclinical studies as an attempt to elucidate the role of specific mGluRs subtypes in glutamatergic transmission. These studies have allowed linkage between specific subtypes and various physiological functions and more importantly to pathological states. This article reviews the currently available knowledge regarding the therapeutic potential of targeting mGluRs in the treatment of several CNS disorders, including schizophrenia, addiction, major depressive disorder and anxiety, Fragile X Syndrome, Parkinson’s disease, Alzheimer’s disease and pain. PMID:22942876

  2. gp130 receptor ligands as potential therapeutic targets for obesity

    PubMed Central

    Febbraio, Mark A.

    2007-01-01

    Obesity and its related cluster of pathophysiologic conditions including insulin resistance, glucose intolerance, dyslipidemia, and hypertension are recognized as growing threats to world health. It is now estimated that 10% of the world’s population is overweight or obese. As a result, new therapeutic options for the treatment of obesity are clearly warranted. Recent research has focused on the role that gp130 receptor ligands may play as potential therapeutic targets in obesity. One cytokine in particular, ciliary neurotrophic factor (CNTF), acts both centrally and peripherally and mimics the biologic actions of the appetite control hormone leptin, but unlike leptin, CNTF appears to be effective in obesity and as such may have therapeutic potential. In addition, CNTF suppresses inflammatory signaling cascades associated with lipid accumulation in liver and skeletal muscle. This review examines the potential role of gp130 receptor ligands as part of a therapeutic strategy to treat obesity. PMID:17404609

  3. Pharmacology and therapeutic potential of sigma(1) receptor ligands.

    PubMed

    Cobos, E J; Entrena, J M; Nieto, F R; Cendán, C M; Del Pozo, E

    2008-12-01

    Sigma (sigma) receptors, initially described as a subtype of opioid receptors, are now considered unique receptors. Pharmacological studies have distinguished two types of sigma receptors, termed sigma(1) and sigma(2). Of these two subtypes, the sigma(1) receptor has been cloned in humans and rodents, and its amino acid sequence shows no homology with other mammalian proteins. Several psychoactive drugs show high to moderate affinity for sigma(1) receptors, including the antipsychotic haloperidol, the antidepressant drugs fluvoxamine and sertraline, and the psychostimulants cocaine and methamphetamine; in addition, the anticonvulsant drug phenytoin allosterically modulates sigma(1) receptors. Certain neurosteroids are known to interact with sigma(1) receptors, and have been proposed to be their endogenous ligands. These receptors are located in the plasma membrane and in subcellular membranes, particularly in the endoplasmic reticulum, where they play a modulatory role in intracellular Ca(2+) signaling. Sigma(1) receptors also play a modulatory role in the activity of some ion channels and in several neurotransmitter systems, mainly in glutamatergic neurotransmission. In accordance with their widespread modulatory role, sigma(1) receptor ligands have been proposed to be useful in several therapeutic fields such as amnesic and cognitive deficits, depression and anxiety, schizophrenia, analgesia, and against some effects of drugs of abuse (such as cocaine and methamphetamine). In this review we provide an overview of the present knowledge of sigma(1) receptors, focussing on sigma(1) ligand neuropharmacology and the role of sigma(1) receptors in behavioral animal studies, which have contributed greatly to the potential therapeutic applications of sigma(1) ligands. PMID:19587856

  4. Metabotropic glutamate receptors: their therapeutic potential in anxiety.

    PubMed

    Spooren, Will; Lesage, Anne; Lavreysen, Hilde; Gasparini, Fabrizio; Steckler, Thomas

    2010-01-01

    Psychiatric and neurological disorders are linked to changes in synaptic excitatory processes with a key role for glutamate, that is, the most abundant excitatory amino-acid. Molecular cloning of the metabotropic glutamate (mGlu) receptors has led to the identification of eight mGlu receptors, which, in contrast to ligand-gated ion channels (responsible for fast excitatory transmission), modulate and fine-tune the efficacy of synaptic transmission. mGlu receptors are G protein-coupled and constitute a new group of "drugable" targets for the treatment of various CNS disorders. The recent discovery of small molecules that selectively bind to receptors of Groups I (mGlu1 and mGlu5) and II (mGlu2 and mGlu3) allowed significant advances in our understanding of the roles of these receptors in brain function and dysfunction including anxiety. Although investigation of the role of the Group III (mGlu4, 6, 7, and 8) receptors is less advanced, the generation of genetically manipulated animals and recent advances in the identification of subtype-selective compounds have revealed some first insights into the therapeutic potential of this group of receptors. PMID:21309118

  5. 5-Hydroxytryptamine Receptor Subtypes and their Modulators with Therapeutic Potentials

    PubMed Central

    Pithadia, Anand B.; Jain, Sunita M.

    2009-01-01

    5-hydroxytryptamine (5-HT) has become one of the most investigated and complex biogenic amines. The main receptors and their subtypes, e.g., 5-HTI (5-HT1A, 5-HT1B, 5-HTID, 5-HTIE and 5-HT1F), 5-HT2 (5-HT2A, 5-HT2B and 5-HT2C), 5-HT3, 5-HT4, 5-HT5 (5-HT5A, 5-HT5B), 5-HT6 and 5-HT7 have been identified. Specific drugs which are capable of either selectively stimulating or inhibiting these receptor subtypes are being designed. This has generated therapeutic potentials of 5-HT receptor modulators in a variety of disease conditions. Conditions where 5-HT receptor modulators have established their use with distinct efficacy and advantages include migraine, anxiety, psychosis, obesity and cancer therapy-induced vomiting by cytotoxic drugs and radiation. Discovery of 5-HT, its biosynthesis, metabolism, physiological role and the potential of 5-HT receptor modulators in various nervous, cardiovascular and gastrointestinal tract disorders, bone growth and micturition have been discussed in this article. Keywords 5-hydroxytryptamine (5-HT) receptors; Modulators; Biogenic amines PMID:22505971

  6. Therapeutic Potential of 5-HT6 Receptor Agonists.

    PubMed

    Karila, Delphine; Freret, Thomas; Bouet, Valentine; Boulouard, Michel; Dallemagne, Patrick; Rochais, Christophe

    2015-10-22

    Given its predominant expression in the central nervous system (CNS), 5-hydroxytryptamine (5-HT: serotonin) subtype 6 receptor (5-HT6R) has been considered as a valuable target for the development of CNS drugs with limited side effects. After 2 decades of intense research, numerous selective ligands have been developed to target this receptor; this holds potential interest for the treatment of neuropathological disorders. In fact, some agents (mainly antagonists) are currently undergoing clinical trial. More recently, a series of potent and selective agonists have been developed, and preclinical studies have been conducted that suggest the therapeutic interest of 5-HT6R agonists. This review details the medicinal chemistry of these agonists, highlights their activities, and discusses their potential for treating cognitive issues associated with Alzheimer's disease (AD), depression, or obesity. Surprisingly, some studies have shown that both 5-HT6R agonists and antagonists exert similar procognitive activities. This article summarizes the hypotheses that could explain this paradox. PMID:26099069

  7. Identification of potential glucocorticoid receptor therapeutic targets in multiple myeloma

    PubMed Central

    Thomas, Alexandra L.; Coarfa, Cristian; Qian, Jun; Wilkerson, Joseph J.; Rajapakshe, Kimal; Krett, Nancy L.; Gunaratne, Preethi H.; Rosen, Steven T.

    2015-01-01

    Glucocorticoids (GC) are a cornerstone of combination therapies for multiple myeloma. However, patients ultimately develop resistance to GCs frequently based on decreased glucocorticoid receptor (GR) expression. An understanding of the direct targets of GC actions, which induce cell death, is expected to culminate in potential therapeutic strategies for inducing cell death by regulating downstream targets in the absence of a functional GR. The specific goal of our research is to identify primary GR targets that contribute to GC-induced cell death, with the ultimate goal of developing novel therapeutics around these targets that can be used to overcome resistance to GCs in the absence of GR. Using the MM.1S glucocorticoid-sensitive human myeloma cell line, we began with the broad platform of gene expression profiling to identify glucocorticoid-regulated genes further refined by combination treatment with phosphatidylinositol-3’-kinase inhibition (PI3Ki). To further refine the search to distinguish direct and indirect targets of GR that respond to the combination GC and PI3Ki treatment of MM.1S cells, we integrated 1) gene expression profiles of combination GC treatment with PI3Ki, which induces synergistic cell death; 2) negative correlation between genes inhibited by combination treatment in MM.1S cells and genes over-expressed in myeloma patients to establish clinical relevance and 3) GR chromatin immunoprecipitation with massively parallel sequencing (ChIP-Seq) in myeloma cells to identify global chromatin binding for the glucocorticoid receptor (GR). Using established bioinformatics platforms, we have integrated these data sets to identify a subset of candidate genes that may form the basis for a comprehensive picture of glucocorticoid actions in multiple myeloma. As a proof of principle, we have verified two targets, namely RRM2 and BCL2L1, as primary functional targets of GR involved in GC-induced cell death. PMID:26715915

  8. Purinergic receptors as potential therapeutic targets in Alzheimer's disease.

    PubMed

    Woods, Lucas T; Ajit, Deepa; Camden, Jean M; Erb, Laurie; Weisman, Gary A

    2016-05-01

    Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory and cognitive ability and is a serious cause of mortality. Many of the pathological characteristics associated with AD are revealed post-mortem, including amyloid-β plaque deposition, neurofibrillary tangles containing hyperphosphorylated tau proteins and neuronal loss in the hippocampus and cortex. Although several genetic mutations and risk factors have been associated with the disease, the causes remain poorly understood. Study of disease-initiating mechanisms and AD progression in humans is inherently difficult as most available tissue specimens are from late-stages of disease. Therefore, AD researchers rely on in vitro studies and the use of AD animal models where neuroinflammation has been shown to be a major characteristic of AD. Purinergic receptors are a diverse family of proteins consisting of P1 adenosine receptors and P2 nucleotide receptors for ATP, UTP and their metabolites. This family of receptors has been shown to regulate a wide range of physiological and pathophysiological processes, including neuroinflammation, and may contribute to the pathogenesis of neurodegenerative diseases like Parkinson's disease, multiple sclerosis and AD. Experimental evidence from human AD tissue has suggested that purinergic receptors may play a role in AD progression and studies using selective purinergic receptor agonists and antagonists in vitro and in AD animal models have demonstrated that purinergic receptors represent novel therapeutic targets for the treatment of AD. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID:26519903

  9. Human rhabdomyosarcoma cells express functional erythropoietin receptor: Potential therapeutic implications

    PubMed Central

    PONIEWIERSKA-BARAN, AGATA; SUSZYNSKA, MALWINA; SUN, WENYUE; ABDELBASET-ISMAIL, AHMED; SCHNEIDER, GABRIELA; BARR, FREDERIC G.; RATAJCZAK, MARIUSZ Z.

    2015-01-01

    The erythropoietin receptor (EpoR) is expressed by cells from the erythroid lineage; however, evidence has accumulated that it is also expressed by some solid tumors. This is an important observation, because recombinant erythropoietin (EPO) is employed in cancer patients to treat anemia related to chemo/radiotherapy. In our studies we employed eight rhabdomyosarcoma (RMS) cell lines (three alveolar-type RMS cell lines and five embrional-type RMS cell lines), and mRNA samples obtained from positive, PAX7-FOXO1-positive, and fusion-negative RMS patient samples. Expression of EpoR was evaluated by RT-PCR, gene array and FACS. The functionality of EpoR in RMS cell lines was evaluated by chemotaxis, adhesion, and direct cell proliferation assays. In some of the experiments, RMS cells were exposed to vincristine (VCR) in the presence or absence of EPO to test whether EPO may impair the therapeutic effect of VCR. We report for a first time that functional EpoR is expressed in human RMS cell lines as well as by primary tumors from RMS patients. Furthermore, EpoR is detectably expressed in both embryonal and alveolar RMS subtypes. At the functional level, several human RMS cell lines responded to EPO stimulation by enhanced proliferation, chemotaxis, cell adhesion, and phosphorylation of MAPKp42/44 and AKT. Moreover, RMS cells became more resistant to VCR treatment in the presence of EPO. Our findings have important potential clinical implications, indicating that EPO supplementation in RMS patients may have the unwanted side effect of tumor progression. PMID:26412593

  10. Human rhabdomyosarcoma cells express functional erythropoietin receptor: Potential therapeutic implications.

    PubMed

    Poniewierska-Baran, Agata; Suszynska, Malwina; Sun, Wenyue; Abdelbaset-Ismail, Ahmed; Schneider, Gabriela; Barr, Frederic G; Ratajczak, Mariusz Z

    2015-11-01

    The erythropoietin receptor (EpoR) is expressed by cells from the erythroid lineage; however, evidence has accumulated that it is also expressed by some solid tumors. This is an important observation, because recombinant erythropoietin (EPO) is employed in cancer patients to treat anemia related to chemo/radiotherapy. In our studies we employed eight rhabdomyosarcoma (RMS) cell lines (three alveolar-type RMS cell lines and five embrional-type RMS cell lines), and mRNA samples obtained from positive, PAX7-FOXO1-positive, and fusion-negative RMS patient samples. Expression of EpoR was evaluated by RT-PCR, gene array and FACS. The functionality of EpoR in RMS cell lines was evaluated by chemotaxis, adhesion, and direct cell proliferation assays. In some of the experiments, RMS cells were exposed to vincristine (VCR) in the presence or absence of EPO to test whether EPO may impair the therapeutic effect of VCR. We report for a first time that functional EpoR is expressed in human RMS cell lines as well as by primary tumors from RMS patients. Furthermore, EpoR is detectably expressed in both embryonal and alveolar RMS subtypes. At the functional level, several human RMS cell lines responded to EPO stimulation by enhanced proliferation, chemotaxis, cell adhesion, and phosphorylation of MAPKp42/44 and AKT. Moreover, RMS cells became more resistant to VCR treatment in the presence of EPO. Our findings have important potential clinical implications, indicating that EPO supplementation in RMS patients may have the unwanted side effect of tumor progression. PMID:26412593

  11. Sphingosine-1-Phosphate Receptor-2 Antagonists: Therapeutic Potential and Potential Risks

    PubMed Central

    Blankenbach, Kira V.; Schwalm, Stephanie; Pfeilschifter, Josef; Meyer zu Heringdorf, Dagmar

    2016-01-01

    The sphingosine-1-phosphate (S1P) signaling system with its specific G-protein-coupled S1P receptors, the enzymes of S1P metabolism and the S1P transporters, offers a multitude of promising targets for drug development. Until today, drug development in this area has nearly exclusively focused on (functional) antagonists at the S1P1 receptor, which cause a unique phenotype of immunomodulation. Accordingly, the first-in class S1P1 receptor modulator, fingolimod, has been approved for the treatment of relapsing-remitting multiple sclerosis, and novel S1P1 receptor (functional) antagonists are being developed for autoimmune and inflammatory diseases such as psoriasis, inflammatory bowel disease, lupus erythematodes, or polymyositis. Besides the S1P1 receptor, also S1P2 and S1P3 are widely expressed and regulate many diverse functions throughout the body. The S1P2 receptor, in particular, often exerts cellular functions which are opposed to the functions of the S1P1 receptor. As a consequence, antagonists at the S1P2 receptor have the potential to be useful in a contrasting context and different areas of indication compared to S1P1 antagonists. The present review will focus on the therapeutic potential of S1P2 receptor antagonists and discuss their opportunities as well as their potential risks. Open questions and areas which require further investigations will be emphasized in particular. PMID:27445808

  12. Therapeutic Potential of α7 Nicotinic Acetylcholine Receptors.

    PubMed

    Bertrand, Daniel; Lee, Chih-Hung L; Flood, Dorothy; Marger, Fabrice; Donnelly-Roberts, Diana

    2015-10-01

    Progress in the fields of neuroscience and molecular biology has identified the forebrain cholinergic system as being important in many higher order brain functions. Further analysis of the genes encoding the nicotinic acetylcholine receptors (nAChRs) has highlighted, in particular, the role of α7 nAChRs in these higher order brain functions as evidenced by their peculiar physiologic and pharmacological properties. As this receptor has gained the attention of scientists from academia and industry, our knowledge of its roles in various brain and bodily functions has increased immensely. We have also seen the development of small molecules that have further refined our understanding of the roles of α7 nAChRs, and these molecules have begun to be tested in clinical trials for several indications. Although a large body of data has confirmed a role of α7 nAChRs in cognition, the translation of small molecules affecting α7 nAChRs into therapeutics has to date only progressed to the stage of testing in clinical trials. Notably, however, most recent human genetic and biochemical studies are further underscoring the crucial role of α7 nAChRs and associated genes in multiple organ systems and disease states. The aim of this review is to discuss our current knowledge of α7 nAChRs and their relevance as a target in specific functional systems and disease states. PMID:26419447

  13. Metabotropic glutamate receptor ligands as potential therapeutics for addiction

    PubMed Central

    Olive, M. F.

    2009-01-01

    There is now compelling evidence that the excitatory amino acid neurotransmitter glutamate plays a pivotal role in drug addiction and alcoholism. As a result, there has been increasing interest in developing glutamate-based therapies for the treatment of addictive disorders. Receptors for glutamate are primarily divided into two classes: ionotropic glutamate receptors (iGluRs) that mediate fast excitatory glutamate transmission, and metabotropic glutamate receptors (mGluRs), which are G-protein coupled receptors that mediate slower, modulatory glutamate transmission. Most iGluR antagonists, while showing some efficacy in animal models of addiction, exhibit serious side effects when tested in humans. mGluR ligands, on the other hand, which have been advanced to testing in clinical trials for various medical conditions, have demonstrated the ability to reduce drug reward, reinforcement, and relapse-like behaviors in animal studies. mGluR ligands that have been shown to be primarily effective are Group I (mGluR1 and mGluR5) negative allosteric modulators and Group II (mGluR2 and mGluR3) orthosteric presynaptic autoreceptor agonists. In this review, we will summarize findings from animal studies suggesting that these mGluR ligands may be of potential benefit in reducing on-going drug self-administration and may aid in the prevention of relapse. The neuroanatomical distribution of mGluR1, mGluR2/3, and mGluR5 receptors and the pharmacological properties of Group I negative allosteric modulators and Group II agonists will also be overviewed. Finally, we will discuss the current status of mGluR ligands in human clinical trials. PMID:19630739

  14. Combined therapeutic potential of nuclear receptors with receptor tyrosine kinase inhibitors in lung cancer

    SciTech Connect

    Wairagu, Peninah M.; Park, Kwang Hwa; Kim, Jihye; Choi, Jong-Whan; Kim, Hyun-Won; Yeh, Byung-Il; Jung, Soon-Hee; Yong, Suk-Joong; Jeong, Yangsik

    2014-05-09

    Highlights: • The 48 NR genes and 48 biological anti-cancer targets are profiled in paired-cells. • Growth inhibition by NR ligands or TKIs is target receptor level-dependent. • T0901317 with gefitinib/PHA665752 shows additive growth inhibition in lung cells. - Abstract: Cancer heterogeneity is a big hurdle in achieving complete cancer treatment, which has led to the emergence of combinational therapy. In this study, we investigated the potential use of nuclear receptor (NR) ligands for combinational therapy with other anti-cancer drugs. We first profiled all 48 NRs and 48 biological anti-cancer targets in four pairs of lung cell lines, where each pair was obtained from the same patient. Two sets of cell lines were normal and the corresponding tumor cell lines while the other two sets consisted of primary versus metastatic tumor cell lines. Analysis of the expression profile revealed 11 NRs and 15 cancer targets from the two pairs of normal versus tumor cell lines, and 9 NRs and 9 cancer targets from the primary versus metastatic tumor cell lines had distinct expression patterns in each category. Finally, the evaluation of nuclear receptor ligand T0901317 for liver X receptor (LXR) demonstrated its combined therapeutic potential with tyrosine kinase inhibitors. The combined treatment of cMET inhibitor PHA665752 or EGFR inhibitor gefitinib with T0901317 showed additive growth inhibition in both H2073 and H1993 cells. Mechanistically, the combined treatment suppressed cell cycle progression by inhibiting cyclinD1 and cyclinB expression. Taken together, this study provides insight into the potential use of NR ligands in combined therapeutics with other biological anti-cancer drugs.

  15. Therapeutic potential of Toll-like receptor 9 activation.

    PubMed

    Krieg, Arthur M

    2006-06-01

    In the decade since the discovery that mouse B cells respond to certain unmethylated CpG dinucleotides in bacterial DNA, a specific receptor for these 'CpG motifs' has been identified, Toll-like receptor 9 (TLR9), and a new approach to immunotherapy has moved into the clinic based on the use of synthetic oligodeoxynucleotides (ODN) as TLR9 agonists. This review highlights the current understanding of the mechanism of action of these CpG ODN, and provides an overview of the preclinical data and early human clinical trial results using these drugs to improve vaccines and treat cancer, infectious disease and allergy/asthma. PMID:16763660

  16. The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome

    PubMed Central

    Braat, Sien; D'Hulst, Charlotte; Heulens, Inge; De Rubeis, Silvia; Mientjes, Edwin; Nelson, David L; Willemsen, Rob; Bagni, Claudia; Van Dam, Debby; De Deyn, Peter P; Kooy, R Frank

    2015-01-01

    Previous research indicates that the GABAAergic system is involved in the pathophysiology of the fragile X syndrome, a frequent form of inherited intellectual disability and associated with autism spectrum disorder. However, the molecular mechanism underlying GABAAergic deficits has remained largely unknown. Here, we demonstrate reduced mRNA expression of GABAA receptor subunits in the cortex and cerebellum of young Fmr1 knockout mice. In addition, we show that the previously reported underexpression of specific subunits of the GABAA receptor can be corrected in YAC transgenic rescue mice, containing the full-length human FMR1 gene in an Fmr1 knockout background. Moreover, we demonstrate that FMRP directly binds several GABAA receptor mRNAs. Finally, positive allosteric modulation of GABAA receptors with the neurosteroid ganaxolone can modulate specific behaviors in Fmr1 knockout mice, emphasizing the therapeutic potential of the receptor. PMID:25790165

  17. P2Y Receptors in Synaptic Transmission and Plasticity: Therapeutic Potential in Cognitive Dysfunction

    PubMed Central

    Guzman, Segundo J.; Gerevich, Zoltan

    2016-01-01

    ATP released from neurons and astrocytes during neuronal activity or under pathophysiological circumstances is able to influence information flow in neuronal circuits by activation of ionotropic P2X and metabotropic P2Y receptors and subsequent modulation of cellular excitability, synaptic strength, and plasticity. In the present paper we review cellular and network effects of P2Y receptors in the brain. We show that P2Y receptors inhibit the release of neurotransmitters, modulate voltage- and ligand-gated ion channels, and differentially influence the induction of synaptic plasticity in the prefrontal cortex, hippocampus, and cerebellum. The findings discussed here may explain how P2Y1 receptor activation during brain injury, hypoxia, inflammation, schizophrenia, or Alzheimer's disease leads to an impairment of cognitive processes. Hence, it is suggested that the blockade of P2Y1 receptors may have therapeutic potential against cognitive disturbances in these states. PMID:27069691

  18. The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome.

    PubMed

    Braat, Sien; D'Hulst, Charlotte; Heulens, Inge; De Rubeis, Silvia; Mientjes, Edwin; Nelson, David L; Willemsen, Rob; Bagni, Claudia; Van Dam, Debby; De Deyn, Peter P; Kooy, R Frank

    2015-01-01

    Previous research indicates that the GABAAergic system is involved in the pathophysiology of the fragile X syndrome, a frequent form of inherited intellectual disability and associated with autism spectrum disorder. However, the molecular mechanism underlying GABAAergic deficits has remained largely unknown. Here, we demonstrate reduced mRNA expression of GABAA receptor subunits in the cortex and cerebellum of young Fmr1 knockout mice. In addition, we show that the previously reported underexpression of specific subunits of the GABAA receptor can be corrected in YAC transgenic rescue mice, containing the full-length human FMR1 gene in an Fmr1 knockout background. Moreover, we demonstrate that FMRP directly binds several GABAA receptor mRNAs. Finally, positive allosteric modulation of GABAA receptors with the neurosteroid ganaxolone can modulate specific behaviors in Fmr1 knockout mice, emphasizing the therapeutic potential of the receptor. PMID:25790165

  19. Role and therapeutic potential of G-protein coupled receptors in breast cancer progression and metastases.

    PubMed

    Singh, Anukriti; Nunes, Jessica J; Ateeq, Bushra

    2015-09-15

    G-protein-coupled receptors (GPCRs) comprise a large family of cell-surface receptors, which have recently emerged as key players in tumorigenesis, angiogenesis and metastasis. In this review, we discussed our current understanding of the many roles played by GPCRs in general, and particularly Angiotensin II type I receptor (AGTR1), a member of the seven-transmembrane-spanning G-protein coupled receptor superfamily, and its significance in breast cancer progression and metastasis. We have also discussed different strategies for targeting AGTR1, and its ligand Angiotension II (Ang II), which might unravel unique opportunities for breast cancer prevention and treatment. For example, AGTR1 blockers (ARBs) which are already in clinical use for treating hypertension, merit further investigation as a therapeutic strategy for AGTR1-positive cancer patients and may have the potential to prevent Ang II-AGTR1 signalling mediated cancer pathogenesis and metastases. PMID:25981295

  20. Role and therapeutic potential of G-protein coupled receptors in breast cancer progression and metastases

    PubMed Central

    Singh, Anukriti; Nunes, Jessica J.; Ateeq, Bushra

    2015-01-01

    G-protein-coupled receptors (GPCRs) comprise a large family of cell-surface receptors, which have recently emerged as key players in tumorigenesis, angiogenesis and metastasis. In this review, we discussed our current understanding of the many roles played by GPCRs in general, and particularly Angiotensin II type I receptor (AGTR1), a member of the seven-transmembrane-spanning G-protein coupled receptor superfamily, and its significance in breast cancer progression and metastasis. We have also discussed different strategies for targeting AGTR1, and its ligand Angiotension II (Ang II), which might unravel unique opportunities for breast cancer prevention and treatment. For example, AGTR1 blockers (ARBs) which are already in clinical use for treating hypertension, merit further investigation as a therapeutic strategy for AGTR1-positive cancer patients and may have the potential to prevent Ang II-AGTR1 signalling mediated cancer pathogenesis and metastases. PMID:25981295

  1. The Role of Steroid Receptor Coactivators in Hormone Dependent Cancers and Their Potential as Therapeutic Targets.

    PubMed

    Wang, Lei; Lonard, David M; O'Malley, Bert W

    2016-08-01

    Steroid receptor coactivator (SRC) family members (SRC-1, SRC-2, SRC-3) interact with nuclear receptors (NRs) and many transcription factors to enhance target gene transcription. Deregulation of SRCs is widely implicated in NR mediated diseases, especially hormone dependent cancers. By integrating steroid hormone signaling and growth factor pathways, SRC proteins exert multiple modes of oncogenic regulation in cancers and represent emerging targets for cancer therapeutics. Recent work has identified SRC-targeting agents that show promise in blocking tumor growth in vitro and in vivo, and have the potential to function as powerful and broadly encompassing treatments for different cancers. PMID:27125199

  2. Polymodal Transient Receptor Potential Vanilloid Type 1 Nocisensor: Structure, Modulators, and Therapeutic Applications.

    PubMed

    Cui, Minghua; Gosu, Vijayakumar; Basith, Shaherin; Hong, Sunhye; Choi, Sun

    2016-01-01

    Transient receptor potential (TRP) channels belong to a superfamily of sensory-related ion channels responding to a wide variety of thermal, mechanical, or chemical stimuli. In an attempt to comprehend the piquancy and pain mechanism of the archetypal vanilloids, transient receptor potential vanilloid (TRPV) 1 was discovered. TRPV1, a well-established member of the TRP family, is implicated in a range of functions including inflammation, painful stimuli sensation, and mechanotransduction. TRPV1 channels are nonselective cation receptors that are gated by a broad array of noxious ligands. Such polymodal-sensor aspect makes the TRPV1 channel extremely versatile and important for its role in sensing burning pain. Besides ligands, TRPV1 signaling can also be modulated by lipids, secondary messengers, protein kinases, cytoskeleton, and several other proteins. Due to its central role in hyperalgesia transduction and inflammatory processes, it is considered as the primary pharmacological pain target. Moreover, understanding the structural and functional intricacies of the channel is indispensable for the therapeutic intervention of TRPV1 in pain and other pathological disorders. In this chapter, we seek to give a mechanistic outlook on the TRPV1 channel. Specifically, we will explore the TRPV1 structure, activation, modulation, ligands, and its therapeutic targeting. However, the major objective of this review is to highlight the fact that TRPV1 channel can be treated as an effective therapeutic target for treating several pain- and nonpain-related physiological and pathological states. PMID:27038373

  3. A potential role for cannabinoid receptors in the therapeutic action of fenofibrate.

    PubMed

    Priestley, Richard S; Nickolls, Sarah A; Alexander, Stephen P H; Kendall, David A

    2015-04-01

    Cannabinoids are reported to have actions through peroxisome proliferator-activated receptors (PPARs), which led us to investigate PPAR agonists for activity at the cannabinoid receptors. Radio-ligand binding and functional assays were conducted using human recombinant cannabinoid type 1 (CB1) or cannabinoid type 2 (CB2) receptors, as well as the guinea pig isolated ileum, using the full agonist CP55940 as a positive control. The PPAR-α agonist fenofibrate exhibited submicromolar affinity for both receptors (pKi CB1, 6.3 ± 0.1; CB2, 7.7 ± 0.1). Functionally, fenofibrate acted as an agonist at the CB2 receptor (pEC50, 7.7 ± 0.1) and a partial agonist at the CB1 receptor, although with a decrease in functional response at higher concentrations, producing bell-shaped concentration-response curves. High concentrations of fenofibrate were able to increase the dissociation rate constant for [(3)H]-CP55940 at the CB1 receptor, (kfast without: 1.2 ± 0.2/min; with: 3.8 ± 0.1 × 10(-2)/min) and decrease the maximal response to CP55940 (Rmax, 86 ± 2%), which is consistent with a negative allosteric modulator. Fenofibrate also reduced electrically induced contractions in isolated guinea pig ileum via CB1 receptors (pEC50, 6.0 ± 0.4). Fenofibrate is thus identified as an example of a new class of cannabinoid receptor ligand and allosteric modulator, with the potential to interact therapeutically with cannabinoid receptors in addition to its primary PPAR target. PMID:25550466

  4. Novel drugs that target the estrogen-related receptor alpha: their therapeutic potential in breast cancer

    PubMed Central

    May, Felicity EB

    2014-01-01

    The incidence of breast cancer continues to rise: 1.7 million women were diagnosed with and 521,000 women died from breast cancer in 2012. This review considers first current treatment options: surgery; radiotherapy; and systemic endocrine, anti-biological, and cytotoxic therapies. Clinical management includes prevention, early detection by screening, treatment with curative intent, management of chronic disease, and palliative control of advanced breast cancer. Next, the potential of novel drugs that target DNA repair, growth factor dependence, intracellular and intercellular signal transduction, and cell cycle are considered. Estrogen-related receptor alpha has attracted attention as a therapeutic target in triple-negative breast cancers with de novo resistance to, and in breast cancers with acquired resistance to, endocrine therapies such as antiestrogens and aromatase inhibitors. Estrogen-related receptor alpha is an orphan receptor and transcription factor. Its activity is regulated by coregulator proteins and posttranslational modification. It is an energy sensor that controls adaptation to energy demand and may facilitate glycolytic metabolism and mitochondrial oxidative respiration in breast cancer cells. Estrogen-related receptor alpha increases breast cancer cell migration, proliferation, and tumor development. It is expressed at high levels in estrogen receptor-negative tumors, and is proposed to activate estrogen-responsive genes in endocrine-resistant tumors. The structures and functions of the ligand-binding domains of estrogen receptor alpha and estrogen-related receptor alpha, their ability to bind estrogens, phytoestrogens, and synthetic ligands, and the effects of ligand agonists, antagonists, and inverse agonists on biological activity, are evaluated. Synthetic ligands of estrogen-related receptor alpha have activity in preclinical models of metabolic disorders, diabetes, osteoporosis, and oncology. The clinical settings in which these novel

  5. Innate immune receptors in heart failure: Side effect or potential therapeutic target?

    PubMed Central

    Wagner, Katharina B; Felix, Stephan B; Riad, Alexander

    2014-01-01

    Heart failure (HF) is a leading cause of mortality and morbidity in western countries and occasions major expenses for public health systems. Although optimal medical treatment is widely available according to current guidelines, the prognosis of patients with HF is still poor. Despite the etiology of the disease, increased systemic or cardiac activation of the innate immune system is well documented in several types of HF. In some cases there is evidence of an association between innate immune activation and clinical outcome of patients with this disease. However, the few large trials conducted with the use of anti-inflammatory medication in HF have not revealed its benefits. Thus, greater understanding of the relationship between alteration in the immune system and development and progression of HF is urgently necessary: prior to designing therapeutic interventions that target pathological inflammatory processes in preventing harmful cardiac effects of immune modulatory therapy. In this regard, relatively recently discovered receptors of the innate immune system, i.e., namely toll-like receptors (TLRs) and nod-like receptors (NLRs)-are the focus of intense cardiovascular research. These receptors are main up-stream regulators of cytokine activation. This review will focus on current knowledge of the role of TLRs and NLRs, as well as on downstream cytokine activation, and will discuss potential therapeutic implications. PMID:25228958

  6. Peroxisome proliferator-activated receptor α, a potential therapeutic target for alcoholic liver disease

    PubMed Central

    Nan, Yue-Min; Wang, Rong-Qi; Fu, Na

    2014-01-01

    Alcoholic liver injury represents a progressive process with a range of consequences including hepatic steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Targeting key molecular regulators involved in the development of alcoholic liver injury may be of great value in the prevention of liver injury. Peroxisome proliferator-activated receptor α (PPARα) plays a pivotal role in modulation of hepatic lipid metabolism, oxidative stress, inflammatory response and fibrogenesis. As such, PPARα may be a potential therapeutic target for the treatment of alcoholic liver disease. PMID:25009377

  7. Adaptors in toll-like receptor signaling and their potential as therapeutic targets.

    PubMed

    Ve, Thomas; Gay, Nicholas J; Mansell, Ashley; Kobe, Bostjan; Kellie, Stuart

    2012-10-01

    To initiate the innate immune response, Toll-like receptors (TLRs) associate with cytoplasmic adaptor proteins through TIR (Toll/interleukin-1 receptor) domain interactions. The four principal signaling adaptor proteins include MyD88, MAL, TRIF and TRAM, and the fifth protein SARM, involved in negative regulation of TLR pathways, is usually considered a part of the TIR domain-containing adaptor protein group. Other TIR domain-containing proteins have also been shown to regulate these signaling pathways, including ST2 and SIGIRR, as well as several bacterial and viral TIR domain-containing proteins that modulate these pathways as virulence factors. TLR pathways and the adaptor proteins are associated with a number of diseases, including infection, sepsis, inflammatory, allergic and autoimmune diseases and cancer. We review our current understanding of the structure and function of adaptor proteins and their regulatory proteins, their association with disease and their potential as therapeutic targets in human disease. PMID:22664090

  8. Soluble receptor for advanced glycation end products: from disease marker to potential therapeutic target.

    PubMed

    Geroldi, Diego; Falcone, Colomba; Emanuele, Enzo

    2006-01-01

    The receptor for advanced glycation end products (RAGE) is a cell-bound receptor of the immunoglobulin superfamily which may be activated by a variety of proinflammatory ligands including advanced glycoxidation end products, S100/calgranulins, high mobility group box 1, and amyloid beta-peptide. RAGE has a secretory splice isoform, soluble RAGE (sRAGE), that lacks the transmembrane domain and therefore circulates in plasma. By competing with cell-surface RAGE for ligand binding, sRAGE may contribute to the removal/neutralization of circulating ligands thus functioning as a decoy. Clinical studies have recently shown that higher plasma levels of sRAGE are associated with a reduced risk of coronary artery disease, hypertension, the metabolic syndrome, arthritis and Alzheimer's disease. Increasing the production of plasma sRAGE is therefore considered to be a promising therapeutic target that has the potential to prevent vascular damage and neurodegeneration. This review presents the state of the art in the use of sRAGE as a disease marker and discusses the therapeutic potential of targeting sRAGE for the treatment of inflammation-related diseases such as atherosclerosis, arthritis and Alzheimer's disease. PMID:16842191

  9. MT1 and MT2 melatonin receptors: ligands, models, oligomers, and therapeutic potential.

    PubMed

    Zlotos, Darius P; Jockers, Ralf; Cecon, Erika; Rivara, Silvia; Witt-Enderby, Paula A

    2014-04-24

    Numerous physiological functions of the pineal gland hormone melatonin are mediated via activation of two G-protein-coupled receptors, MT1 and MT2. The melatonergic drugs on the market, ramelteon and agomelatine, as well as the most advanced drug candidates under clinical evaluation, tasimelteon and TIK-301, are high-affinity nonselective MT1/MT2 agonists. A great number of MT2-selective ligands and, more recently, several MT1-selective agents have been reported to date. Herein, we review recent advances in the field focusing on high-affinity agonists and antagonists and those displaying selectivity toward MT1 and MT2 receptors. Moreover, the existing models of MT1 and MT2 receptors as well as the current status in the emerging field of melatonin receptor oligomerization are critically discussed. In addition to the already existing indications, such as insomnia, circadian sleep disorders, and depression, new potential therapeutic applications of melatonergic ligands including cardiovascular regulation, appetite control, tumor growth inhibition, and neurodegenerative diseases are presented. PMID:24228714

  10. Modulation of Adult Mesenchymal Stem Cells Activity by Toll-Like Receptors: Implications on Therapeutic Potential

    PubMed Central

    DelaRosa, Olga; Lombardo, Eleuterio

    2010-01-01

    Mesenchymal stem cells (MSCs) are of special interest as therapeutic agents in the settings of both chronic inflammatory and autoimmune diseases. Toll-like receptors (TLR) ligands have been linked with the perpetuation of inflammation in a number of chronic inflammatory diseases due to the permanent exposure of the immune system to TLR-specific stimuli. Therefore, MSCs employed in therapy can be potentially exposed to TLR ligands, which may modulate MSC therapeutic potential in vivo. Recent results demonstrate that MSCs are activated by TLR ligands leading to modulation of the differentiation, migration, proliferation, survival, and immunosuppression capacities. However inconsistent results among authors have been reported suggesting that the source of MSCs, TLR stimuli employed or culture conditions play a role. Notably, activation by TLR ligands has not been reported to modulate the “immunoprivileged” phenotype of MSCs which is of special relevance regarding the use of allogeneic MSC-based therapies. In this review, we discuss the available data on the modulation of MSCs activity through TLR signalling. PMID:20628526

  11. History and perspectives of A2A adenosine receptor antagonists as potential therapeutic agents.

    PubMed

    Preti, Delia; Baraldi, Pier Giovanni; Moorman, Allan R; Borea, Pier Andrea; Varani, Katia

    2015-07-01

    Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as a local regulator in different pathologies. Adenosine is a ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1 , A2A , A2B , and A3 adenosine receptors (ARs). At the present time, the role of A2A ARs is well known in physiological conditions and in a variety of pathologies, including inflammatory tissue damage and neurodegenerative disorders. In particular, the use of selective A2A antagonists has been reported to be potentially useful in the treatment of Parkinson's disease (PD). In this review, A2A AR signal transduction pathways, together with an analysis of the structure-activity relationships of A2A antagonists, and their corresponding pharmacological roles and therapeutic potential have been presented. The initial results from an emerging polypharmacological approach are also analyzed. This approach is based on the optimization of the affinity and/or functional activity of the examined compounds toward multiple targets, such as A1 /A2A ARs and monoamine oxidase-B (MAO-B), both closely implicated in the pathogenesis of PD. PMID:25821194

  12. Allosteric Modulation of Metabotropic Glutamate Receptors: Structural Insights and Therapeutic Potential

    PubMed Central

    Gregory, Karen J.; Dong, Elizabeth N.; Meiler, Jens; Conn, P. Jeffrey

    2010-01-01

    Allosteric modulation of G protein-coupled receptors (GPCRs) represents a novel approach to the development of probes and therapeutics that is expected to enable subtype-specific regulation of central nervous system target receptors. The metabotropic glutamate receptors (mGlus) are class C GPCRs that play important neuromodulatory roles throughout the brain, as such they are attractive targets for therapeutic intervention for a number of psychiatric and neurological disorders including anxiety, depression, Fragile X Syndrome, Parkinson’s disease and schizophrenia. Over the last fifteen years, selective allosteric modulators have been identified for many members of the mGlu family. The vast majority of these allosteric modulators are thought to bind within the transmembrane-spanning domains of the receptors to enhance or inhibit functional responses. A combination of mutagenesis-based studies and pharmacological approaches are beginning to provide a better understanding of mGlu allosteric sites. Collectively, when mapped onto a homology model of the different mGlu subtypes based on the β2-adrenergic receptor, the previous mutagenesis studies suggest commonalities in the location of allosteric sites across different members of the mGlu family. In addition, there is evidence for multiple allosteric binding pockets within the transmembrane region that can interact to modulate one another. In the absence of a class C GPCR crystal structure, this approach has shown promise with respect to the interpretation of mutagenesis data and understanding structure-activity relationships of allosteric modulator pharmacophores. PMID:20637216

  13. Liver receptor homolog-1 (LRH-1): a potential therapeutic target for cancer

    PubMed Central

    Nadolny, Christina; Dong, Xiaoqun

    2015-01-01

    Liver receptor homolog-1 (LRH-1) is a nuclear receptor involved in various biological processes. This nuclear receptor has critical functions in embryonic development as well as in adult homeostasis. Although the physiological functions of LRH-1 in normal breast, pancreas, and intestine have been widely investigated, the dysregulation that occurs during pathological conditions is not well understood. LRH-1 has been implicated in pancreatic, breast, and gastrointestinal cancer, where it exerts its effect of initiation and progression by promoting cell proliferation and metastasis. In addition to mechanistic studies, LRH-1 agonists and antagonists are being explored. Identification and development of endogenous and synthetic ligands has been pursued using computational-based structural analysis. Through ligand identification and a thorough understanding of the pathological roles of LRH-1, new therapeutic avenues for cancer treatment based upon LRH-1 may be a desirable focus for further research. PMID:25951367

  14. Interleukin 6 Receptor Is an Independent Prognostic Factor and a Potential Therapeutic Target of Ovarian Cancer

    PubMed Central

    Isobe, Aki; Sawada, Kenjiro; Kinose, Yasuto; Ohyagi-Hara, Chifumi; Nakatsuka, Erika; Makino, Hiroshi; Ogura, Tomonori; Mizuno, Tomoko; Suzuki, Noriko; Morii, Eiichi; Nakamura, Koji; Sawada, Ikuko; Toda, Aska; Hashimoto, Kae; Mabuchi, Seiji; Ohta, Tsuyoshi; Morishige, Ken-ichirou; Kurachi, Hirohisa; Kimura, Tadashi

    2015-01-01

    Ovarian cancer remains the most lethal gynecologic cancer and new targeted molecular therapies against this miserable disease continue to be challenging. In this study, we analyzed the expressional patterns of Interleukin-6 (IL-6) and its receptor (IL-6R) expression in ovarian cancer tissues, evaluated the impact of these expressions on clinical outcomes of patients, and found that a high-level of IL-6R expression but not IL-6 expression in cancer cells is an independent prognostic factor. In in vitro analyses using ovarian cell lines, while six (RMUG-S, RMG-1, OVISE, A2780, SKOV3ip1 and OVCAR-3) of seven overexpressed IL-6R compared with a primary normal ovarian surface epithelium, only two (RMG-1, OVISE) of seven cell lines overexpressed IL-6, suggesting that IL-6/IL-6R signaling exerts in a paracrine manner in certain types of ovarian cancer cells. Ovarian cancer ascites were collected from patients, and we found that primary CD11b+CD14+ cells, which were predominantly M2-polarized macrophages, are the major source of IL-6 production in an ovarian cancer microenvironment. When CD11b+CD14+ cells were co-cultured with cancer cells, both the invasion and the proliferation of cancer cells were robustly promoted and these promotions were almost completely inhibited by pretreatment with anti-IL-6R antibody (tocilizumab). The data presented herein suggest a rationale for anti-IL-6/IL-6R therapy to suppress the peritoneal spread of ovarian cancer, and represent evidence of the therapeutic potential of anti-IL-6R therapy for ovarian cancer treatment. PMID:25658637

  15. Peroxisome proliferator-activated receptors: potential therapeutic targets in lung disease?

    PubMed

    Denning, Gerene M; Stoll, Lynn L

    2006-01-01

    The peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that play central roles in lipid and glucose homeostasis, cellular differentiation, and the immune/inflammatory response. Growing evidence indicates that changes in expression and activation of PPARs likely modulate conditions as diverse as diabetes, atherosclerosis, cancer, asthma, Parkinson's disease, and Alzheimer's disease. Activation of these receptors by natural or pharmacologic ligands leads to both gene-dependent and gene-independent effects that alter the expression of a wide array of proteins. In the lung, PPARs are expressed by alveolar macrophages, as well as by epithelial, endothelial, and smooth muscle cells. Studies both in vitro and in vivo suggest that PPAR ligands may have anti-inflammatory effects in asthma, pulmonary sarcoidosis, and pulmonary alveolar proteinosis, as well as antiproliferative and antiangiogenic effects in epithelial lung cancers. Further studies to understand the contribution of these receptors to health and disease will be important for determining whether they represent a promising target for therapeutic intervention. PMID:16267824

  16. The Therapeutic Potential of Toll-like Receptor 7 Stimulation in Asthma

    PubMed Central

    Drake, Matthew G.; Kaufman, Elad H.; Fryer, Allison D.; Jacoby, David B.

    2012-01-01

    Asthma is an inflammatory disorder of the airways frequently characterized by an excessive Th2 adaptive immune response. Activation of Toll-like receptor (TLR)-7, a single-stranded viral RNA receptor that is highly expressed in the airways, triggers a rapid innate immune response and favors a subsequent Th1 response. Because of this role in pulmonary immunoregulation, TLR7 has gained considerable interest as a therapeutic target in asthma. Synthetic TLR7 ligands, including the imidazoquinolines imiquimod (R837) and resiquimod (R848), and 8-hydroxyadenine derivatives have been developed for other clinical indications. TLR7 activation prevents ovalbumin-induced airway hyperreactivity, eosinophilic inflammation, goblet cell hyperplasia and airway remodeling in murine models of asthma. TLR7 activation also inhibits viral replication in the lung and prevents virus-induced airway hyperreactivity. Furthermore, it has recently been shown that stimulating TLR7 rapidly relaxes airway smooth muscle, dilating the airways. This bronchodilating effect, which occurs in seconds to minutes and depends on rapid production of nitric oxide, indicates that TLR7 can signal via previously unrecognized pathways. The effects of decreasing the allergic Th2 response, acting as an immediate bronchodilator, and promoting an antiviral immune environment, make TLR7 an attractive drug target. We examine the current understanding of TLR7 as a therapeutic target and its translation to asthma treatment in humans. PMID:23078048

  17. The therapeutic potential of erythropoiesis-stimulating agents for tissue protection: a tale of two receptors.

    PubMed

    Brines, Michael

    2010-01-01

    Erythropoietin (EPO) is a well-known therapeutic protein employed widely in the treatment of anemia. Over the past decade, abundant evidence has shown that in addition to its systemic role in the regulation of plasma pO(2) by modulating erythrocyte numbers, EPO is also a cytoprotective molecule made locally in response to injury or metabolic stress. Many studies have shown beneficial effects of EPO administration in reducing damage caused by ischemia-reperfusion, trauma, cytotoxicity, infection and inflammation in a variety of organs and tissues. Notably, the receptor mediating the nonerythropoietic effects of EPO differs from the one responsible for hematopoiesis. The tissue-protective receptor exhibits a lower affinity for EPO and is a heteromer consisting of EPO receptor monomers in association with the common receptor that is also employed by granulocyte macrophage colony-stimulating factor, interleukin 3, and interleukin 5. This heteromeric receptor is expressed immediately following injury, whereas EPO production is delayed. Thus, early administration of EPO can dramatically reduce the deleterious components of the local inflammatory cascade. However, a high dose of EPO is required and this also stimulates the bone marrow to produce highly reactive platelets and activates the vascular endothelium into a prothrombotic state. To circumvent these undesirable effects, the EPO molecule has been successfully altered to selectively eliminate erythropoietic and prothrombotic potencies, while preserving tissue-protective activities. Very recently, small peptide mimetics have been developed that recapitulate the tissue-protective activities of EPO. Nonerythropoietic tissue-protective molecules hold high promise in a wide variety of acute and chronic diseases. PMID:20093809

  18. Serotonin 5-HT7 receptor agents: structure-activity relationships and potential therapeutic applications in central nervous system disorders

    PubMed Central

    Leopoldo, Marcello; Lacivita, Enza; Berardi, Francesco; Perrone, Roberto; Hedlund, Peter B.

    2010-01-01

    Since its discovery in the 1940s in serum, the mammalian intestinal mucosa, and in the central nervous system, serotonin (5-HT) has been shown to be involved in virtually all cognitive and behavioral human functions, and alterations in its neurochemistry have been implicated in the etiology of a plethora of neuropsychiatric disorders. The cloning of 5-HT receptor subtypes has been of importance in enabling them to be classified as specific protein molecules encoded by specific genes. The 5-HT7 receptor is the most recently classified member of the serotonin receptor family. Since its identification, it has been the subject of intense research efforts driven by its presence in functionally relevant regions of the brain. The availability of some selective antagonists and agonists, in combination with genetically modified mice lacking the 5-HT7 receptor, has allowed for a better understanding of the pathophysiological role of this receptor. This paper reviews data on localization and pharmacological properties of the 5-HT7 receptor, and summarizes the results of structure-activity relationship studies aimed at the discovery of selective 5-HT7 receptor ligands. Additionally, an overview of the potential therapeutic applications of 5-HT7 receptor agonists and antagonists in central nervous system disorders is presented. PMID:20923682

  19. Allosteric and Biased G Protein-Coupled Receptor Signaling Regulation: Potentials for New Therapeutics

    PubMed Central

    Khoury, Etienne; Clément, Stéphanie; Laporte, Stéphane A.

    2014-01-01

    G protein-coupled receptors (GPCRs) are seven-transmembrane proteins that participate in many aspects of the endocrine function and are important targets for drug development. They transduce signals mainly, but not exclusively, via hetero-trimeric G proteins, leading to a diversity of intracellular signaling cascades. Ligands binding at the hormone orthosteric sites of receptors have been classified as agonists, antagonists, and/or inverse agonists based on their ability to mainly modulate G protein signaling. Accumulating evidence also indicates that such ligands, alone or in combination with other ones such as those acting outside the orthosteric hormone binding sites (e.g., allosteric modulators), have the ability to selectively engage subsets of signaling responses as compared to the natural endogenous ligands. Such modes of functioning have been variously referred to as “functional selectivity” or “ligand-biased signaling.” In this review, we provide an overview of the current knowledge regarding GPCR-biased signaling and their functional regulation with a focus on the evolving concept that receptor domains can also be targeted to allosterically bias signaling, and discuss the usefulness of such modes of regulation for the design of more efficient therapeutics. PMID:24847311

  20. Therapeutic potential of targeting group III metabotropic glutamate receptors in the treatment of Parkinson's disease

    PubMed Central

    Duty, Susan

    2010-01-01

    Current drugs used in the treatment of Parkinson's disease (PD), for example, L-DOPA and dopamine agonists, are very effective at reversing the motor symptoms of the disease. However, they do little to combat the underlying degeneration of dopaminergic neurones in the substantia nigra pars compacta (SNc) and their long-term use is associated with the appearance of adverse effects such as L-DOPA-induced dyskinesia. Much emphasis has therefore been placed on finding alternative non-dopaminergic drugs that may circumvent some or all of these problems. Group III metabotropic glutamate (mGlu) receptors were first identified in the basal ganglia a decade ago. One or more of these receptors (mGlu4, mGlu7 or mGlu8) is found on pre-synaptic terminals of basal ganglia pathways whose overactivity is implicated not only in the generation of motor symptoms in PD, but also in driving the progressive SNc degeneration. The finding that drugs which activate group III mGlu receptors can inhibit transmission across these overactive synapses has lead to the proposal that group III mGlu receptors are promising targets for drug discovery in PD. This paper provides a comprehensive review of the role and target potential of group III mGlu receptors in the basal ganglia. Overwhelming evidence obtained from in vitro studies and animal models of PD supports group III mGlu receptors as potentially important drug targets for providing both symptom relief and neuroprotection in PD. PMID:20735415

  1. α7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease

    PubMed Central

    Toyohara, Jun; Hashimoto, Kenji

    2010-01-01

    Accumulating evidence suggests that α7 nicotinic receptors (α7 nAChRs), a subtype of nAChRs, play a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease (AD). A number of psychopharmacological and genetic studies shown that α7 nAChRs play an important role in the deficits of P50 auditory evoked potential in patients with schizophrenia, and that (α nAChR agonists would be potential therapeutic drugs for cognitive impairments associated with P50 deficits in schizophrenia. Furthermore, some studies have demonstrated that α7 nAChRs might play a key role in the amyloid-β (Aβ)-mediated pathology of AD, and that α7 nAChR agonists would be potential therapeutic drugs for Aβ deposition in the brains of patients with AD. Interestingly, the altered expression of α7 nAChRs in the postmortem brain tissues from patients with schizophrenia and AD has been reported. Based on all these findings, selective α7 nAChR agonists can be considered potential therapeutic drugs for cognitive impairments in both schizophrenia and AD. In this article, we review the recent research into the role of α7 nAChRs in the pathophysiology of these diseases and into the potential use of novel α7 nAChR agonists as therapeutic drugs. PMID:21249164

  2. Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential.

    PubMed

    Mony, Laetitia; Kew, James N C; Gunthorpe, Martin J; Paoletti, Pierre

    2009-08-01

    N-methyl-D-aspartate receptors (NMDARs) are ion channels gated by glutamate, the major excitatory neurotransmitter in the mammalian central nervous system (CNS). They are widespread in the CNS and are involved in numerous physiological and pathological processes including synaptic plasticity, chronic pain and psychosis. Aberrant NMDAR activity also plays an important role in the neuronal loss associated with ischaemic insults and major degenerative disorders including Parkinson's and Alzheimer's disease. Agents that target and alter NMDAR function may, thus, have therapeutic benefit. Interestingly, NMDARs are endowed with multiple extracellular regulatory sites that recognize ions or small molecule ligands, some of which are likely to regulate receptor function in vivo. These allosteric sites, which differ from agonist-binding and channel-permeation sites, provide means to modulate, either positively or negatively, NMDAR activity. The present review focuses on allosteric modulation of NMDARs containing the NR2B subunit. Indeed, the NR2B subunit confers a particularly rich pharmacology with distinct recognition sites for exogenous and endogenous allosteric ligands. Moreover, NR2B-containing receptors, compared with other NMDAR subtypes, appear to contribute preferentially to pathological processes linked to overexcitation of glutamatergic pathways. The actions of extracellular H+, Mg2+, Zn2+, of polyamines and neurosteroids, and of the synthetic compounds ifenprodil and derivatives ('prodils') are presented. Particular emphasis is put upon the structural determinants and molecular mechanisms that underlie the effects exerted by these agents. A better understanding of how NR2B-containing NMDARs (and NMDARs in general) operate and how they can be modulated should help define new strategies to counteract the deleterious effects of dysregulated NMDAR activity. PMID:19594762

  3. Therapeutic Potential of 5-HT2C Receptor Agonists for Addictive Disorders.

    PubMed

    Higgins, Guy A; Fletcher, Paul J

    2015-07-15

    The neurotransmitter 5-hydroxytryptamine (5-HT; serotonin) has long been associated with the control of a variety of motivated behaviors, including feeding. Much of the evidence linking 5-HT and feeding behavior was obtained from studies of the effects of the 5-HT releaser (dex)fenfluramine in laboratory animals and humans. Recently, the selective 5-HT2C receptor agonist lorcaserin received FDA approval for the treatment of obesity. This review examines evidence to support the use of selective 5-HT2C receptor agonists as treatments for conditions beyond obesity, including substance abuse (particularly nicotine, psychostimulant, and alcohol dependence), obsessive compulsive, and excessive gambling disorder. Following a brief survey of the early literature supporting a role for 5-HT in modulating food and drug reinforcement, we propose that intrinsic differences between SSRI and serotonin releasers may have underestimated the value of serotonin-based pharmacotherapeutics to treat clinical forms of addictive behavior beyond obesity. We then highlight the critical involvement of the 5-HT2C receptor in mediating the effect of (dex)fenfluramine on feeding and body weight gain and the evidence that 5-HT2C receptor agonists reduce measures of drug reward and impulsivity. A recent report of lorcaserin efficacy in a smoking cessation trial further strengthens the idea that 5-HT2C receptor agonists may have potential as a treatment for addiction. This review was prepared as a contribution to the proceedings of the 11th International Society for Serotonin Research Meeting held in Hermanus, South Africa, July 9-12, 2014. PMID:25870913

  4. Symptomatic treatment of vestibular deficits: therapeutic potential of histamine H4 receptors.

    PubMed

    Wersinger, Eric; Gaboyard-Niay, Sophie; Travo, Cécile; Soto, Enrique; Baez, Adriana; Vega, Rosario; Brugeaud, Aurore; Chabbert, Christian

    2013-01-01

    Vestibular disorders display high prevalence and can severely impact the daily life. However, pharmacological options that would efficiently relieve the vertigo symptoms without side effects are still lacking. In the present review we briefly review the common history of histamine receptor modulation and the pharmacological therapy of vestibular disorders. We also discuss the recent demonstration of Histamine H4 Receptor mRNAs expression in Scarpa's ganglion of mammal and the potential use of specific H4R antagonists as vestibulomodulators. Additional original data confirm the expression of H4R proteins in the rat vestibular primary neurons, the neuromodulatory properties of specific H4R antagonists in vitro (inhibition of vestibular neuron excitability) as well as their efficacy to decrease vestibular deficits induced in different in animal models. PMID:24177347

  5. Interleukin-1 receptor associated kinase inhibitors: potential therapeutic agents for inflammatory- and immune-related disorders.

    PubMed

    Bahia, Malkeet Singh; Kaur, Maninder; Silakari, Pragati; Silakari, Om

    2015-06-01

    The various cells of innate immune system quickly counter-attack invading pathogens, and mount up "first line" defense through their trans-membrane receptors including Toll-like receptors (TLRs) and interleukin receptors (IL-Rs) that result in the secretion of pro-inflammatory cytokines. Albeit such inflammatory responses are beneficial in pathological conditions, their overstimulation may cause severe inflammatory damage; thus, make this defense system a "double edged sword". IRAK-4 has been evaluated as an indispensable element of IL-Rs and TLR pathways that can regulate the abnormal levels of cytokines, and therefore could be employed to manage immune- and inflammation-related disorders. Historically, the identification of selective and potent inhibitors has been challenging; thus, a limited number of small molecule IRAK-4 inhibitors are available in literature. Recently, IRAK-4 achieved great attention, when Ligand® pharmaceutical and Nimbus Discovery® reported the beneficial potentials of IRAK-4 inhibitors in the pre-clinical evaluation for various inflammatory- and immune-related disorders, but not limited to, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, gout, asthma and cancer. PMID:25728511

  6. Therapeutic potential of Takeda-G-protein-receptor-5 (TGR5) agonists. Hope or hype?

    PubMed

    Hodge, R J; Nunez, D J

    2016-05-01

    The gastrointestinal tract regulates glucose and energy metabolism, and there is increasing recognition that bile acids function as key signalling molecules in these processes. For example, bile acid changes that occur after bariatric surgery have been implicated in the effects on satiety, lipid and cholesterol regulation, glucose and energy metabolism, and the gut microbiome. In recent years, Takeda-G-protein-receptor-5 (TGR5), a bile acid receptor found in widely dispersed tissues, has been the target of significant drug discovery efforts in the hope of identifying effective treatments for metabolic diseases including type 2 diabetes, obesity, atherosclerosis, fatty liver disease and cancer. Although the benefits of targeting the TGR5 receptor are potentially great, drug development work to date has identified risks that include histopathological changes, tumorigenesis, gender differences, and questions about the translation of animal data to humans. The present article reviews the noteworthy challenges that must be addressed along the path of development of a safe and effective TGR5 agonist therapy. PMID:26818602

  7. Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks.

    PubMed

    Wong, Gilbert Y; Gavva, Narender R

    2009-04-01

    The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence, both agonists and antagonists of TRPV1 are being evaluated as potential analgesics in clinical trials. Clinical trial results of TRPV1 agonists such as resiniferatoxin in interstitial cystitis, NGX 4010 in post-herpetic neuralgia, and 4975 (Adlea) in osteoarthritis, bunionectomy, and Morton's neuroma have been reported. Similarly, clinical trial results of TRPV1 antagonists such as SB-705498 and AMG 517 have also been published recently. Overall, some molecules (e.g., capsaicin) demonstrated potential analgesia in certain conditions (postsurgical pain, postherpetic neuralgia, pain in diabetic neuropathy, osteoarthritis, bunionectomy, and Morton's neuroma), whereas others fell out of the clinic due to on-target liabilities or failed to demonstrate efficacy. This review summarizes recent advances and setbacks of TRPV1 agonists and antagonists in the clinic and predicts future directions. PMID:19150372

  8. Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease

    PubMed Central

    Xiong, Wei; Chen, Shao-Rui; He, Liming; Cheng, Kejun; Zhao, Yi-Lin; Chen, Hong; Li, De-Pei; Homanics, Gregg E.; Peever, John; Rice, Kenner C.; Wu, Ling-gang; Pan, Hui-Lin; Zhang, Li

    2014-01-01

    While postsynaptic GlyRs as α/β heteromers attract the most research attention, little is known about the role of presynaptic GlyRs, likely α homomers, in diseases. Here, we demonstrate that DH-CBD, a nonpsychoactive cannabinoid, can rescue GlyR functional deficiency and exaggerated acoustic and tactile startle responses in mice bearing the point-mutations in the α1 GlyRs responsible for a hereditary startle/hyperekplexia disease. The GlyRs expressed as α1 homomers either in HEK-293 cells or at presynaptic terminals of the calyceal synapses in auditory brainstem are most vulnerable to hyperekplexia mutation-induced impairment. Homomeric mutants are more sensitive than heteromers to DH-CBD, suggesting presynaptic GlyRs as a primary target. Consistent with this, DH-CBD selectively rescues impaired presynaptic GlyR activity and diminished glycine release in the brainstem and spinal cord of hyperekplexic mutant mice. Thus, presynaptic α GlyRs emerge as a potential therapeutic target for dominant hyperekplexia disease and other diseases with GlyR deficiency. PMID:24390226

  9. Partial adenosine A1 receptor agonism: a potential new therapeutic strategy for heart failure.

    PubMed

    Greene, Stephen J; Sabbah, Hani N; Butler, Javed; Voors, Adriaan A; Albrecht-Küpper, Barbara E; Düngen, Hans-Dirk; Dinh, Wilfried; Gheorghiade, Mihai

    2016-01-01

    Heart failure (HF) represents a global public health and economic problem associated with unacceptable rates of death, hospitalization, and healthcare expenditure. Despite available therapy, HF carries a prognosis comparable to many forms of cancer with a 5-year survival rate of ~50%. The current treatment paradigm for HF with reduced ejection fraction (EF) centers on blocking maladaptive neurohormonal activation and decreasing cardiac workload with therapies that concurrently lower blood pressure and heart rate. Continued development of hemodynamically active medications for stepwise addition to existing therapies carries the risk of limited tolerability and safety. Moreover, this treatment paradigm has thus far failed for HF with preserved EF. Accordingly, development of hemodynamically neutral HF therapies targeting primary cardiac pathologies must be considered. In this context, a partial adenosine A1 receptor (A1R) agonist holds promise as a potentially hemodynamically neutral therapy for HF that could simultaneous improve cardiomyocyte energetics, calcium homeostasis, cardiac structure and function, and long-term clinical outcomes when added to background therapies. In this review, we describe the physiology and pathophysiology of HF as it relates to adenosine agonism, examine the existing body of evidence and biologic rationale for modulation of adenosine A1R activity, and review the current state of drug development of a partial A1R agonist for the treatment of HF. PMID:26701329

  10. Receptor tyrosine kinase (c-Kit) inhibitors: a potential therapeutic target in cancer cells.

    PubMed

    Abbaspour Babaei, Maryam; Kamalidehghan, Behnam; Saleem, Mohammad; Huri, Hasniza Zaman; Ahmadipour, Fatemeh

    2016-01-01

    c-Kit, a receptor tyrosine kinase, is involved in intracellular signaling, and the mutated form of c-Kit plays a crucial role in occurrence of some cancers. The function of c-Kit has led to the concept that inhibiting c-Kit kinase activity can be a target for cancer therapy. The promising results of inhibition of c-Kit for treatment of cancers have been observed in some cancers such as gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, and other tumors, and these results have encouraged attempts toward improvement of using c-Kit as a capable target for cancer therapy. This paper presents the findings of previous studies regarding c-Kit as a receptor tyrosine kinase and an oncogene, as well as its gene targets and signaling pathways in normal and cancer cells. The c-Kit gene location, protein structure, and the role of c-Kit in normal cell have been discussed. Comprehending the molecular mechanism underlying c-Kit-mediated tumorogenesis is consequently essential and may lead to the identification of future novel drug targets. The potential mechanisms by which c-Kit induces cellular transformation have been described. This study aims to elucidate the function of c-Kit for future cancer therapy. In addition, it has c-Kit inhibitor drug properties and their functions have been listed in tables and demonstrated in schematic pictures. This review also has collected previous studies that targeted c-Kit as a novel strategy for cancer therapy. This paper further emphasizes the advantages of this approach, as well as the limitations that must be addressed in the future. Finally, although c-Kit is an attractive target for cancer therapy, based on the outcomes of treatment of patients with c-Kit inhibitors, it is unlikely that Kit inhibitors alone can lead to cure. It seems that c-Kit mutations alone are not sufficient for tumorogenesis, but do play a crucial role in cancer occurrence. PMID:27536065

  11. Receptor tyrosine kinase (c-Kit) inhibitors: a potential therapeutic target in cancer cells

    PubMed Central

    Abbaspour Babaei, Maryam; Kamalidehghan, Behnam; Saleem, Mohammad; Huri, Hasniza Zaman; Ahmadipour, Fatemeh

    2016-01-01

    c-Kit, a receptor tyrosine kinase, is involved in intracellular signaling, and the mutated form of c-Kit plays a crucial role in occurrence of some cancers. The function of c-Kit has led to the concept that inhibiting c-Kit kinase activity can be a target for cancer therapy. The promising results of inhibition of c-Kit for treatment of cancers have been observed in some cancers such as gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, and other tumors, and these results have encouraged attempts toward improvement of using c-Kit as a capable target for cancer therapy. This paper presents the findings of previous studies regarding c-Kit as a receptor tyrosine kinase and an oncogene, as well as its gene targets and signaling pathways in normal and cancer cells. The c-Kit gene location, protein structure, and the role of c-Kit in normal cell have been discussed. Comprehending the molecular mechanism underlying c-Kit-mediated tumorogenesis is consequently essential and may lead to the identification of future novel drug targets. The potential mechanisms by which c-Kit induces cellular transformation have been described. This study aims to elucidate the function of c-Kit for future cancer therapy. In addition, it has c-Kit inhibitor drug properties and their functions have been listed in tables and demonstrated in schematic pictures. This review also has collected previous studies that targeted c-Kit as a novel strategy for cancer therapy. This paper further emphasizes the advantages of this approach, as well as the limitations that must be addressed in the future. Finally, although c-Kit is an attractive target for cancer therapy, based on the outcomes of treatment of patients with c-Kit inhibitors, it is unlikely that Kit inhibitors alone can lead to cure. It seems that c-Kit mutations alone are not sufficient for tumorogenesis, but do play a crucial role in cancer occurrence. PMID:27536065

  12. Scavenger Receptors and Their Potential as Therapeutic Targets in the Treatment of Cardiovascular Disease

    PubMed Central

    Stephen, Sam L.; Freestone, Katie; Dunn, Sarah; Twigg, Michael W.; Homer-Vanniasinkam, Shervanthi; Walker, John H.; Wheatcroft, Stephen B.; Ponnambalam, Sreenivasan

    2010-01-01

    Scavenger receptors act as membrane-bound and soluble proteins that bind to macromolecular complexes and pathogens. This diverse supergroup of proteins mediates binding to modified lipoprotein particles which regulate the initiation and progression of atherosclerotic plaques. In vascular tissues, scavenger receptors are implicated in regulating intracellular signaling, lipid accumulation, foam cell development, and cellular apoptosis or necrosis linked to the pathophysiology of atherosclerosis. One approach is using gene therapy to modulate scavenger receptor function in atherosclerosis. Ectopic expression of membrane-bound scavenger receptors using viral vectors can modify lipid profiles and reduce the incidence of atherosclerosis. Alternatively, expression of soluble scavenger receptors can also block plaque initiation and progression. Inhibition of scavenger receptor expression using a combined gene therapy and RNA interference strategy also holds promise for long-term therapy. Here we review our current understanding of the gene delivery by viral vectors to cells and tissues in gene therapy strategies and its application to the modulation of scavenger receptor function in atherosclerosis. PMID:20981357

  13. DHA, G-protein coupled receptors and melanoma: Is GPR40 a potential therapeutic target?

    PubMed Central

    Nehra, Deepika; Pan, Amy H.; Le, Hau D.; Fallon, Erica M.; Carlson, Sarah J.; Kalish, Brian T.; Puder, Mark

    2014-01-01

    Purpose To determine the effect of docosahexaenoic acid (DHA) on the growth of human melanoma in vitro and in vivo and to better understand the potential role of the G-protein coupled receptors in mediating this effect. Materials and Methods For in vitro studies, human melanoma and control fibroblast cells were treated with DHA and TAK-875 (selective GPR40 agonist) and a cell viability assay was performed to determine cell counts. A murine subcutaneous xenograft model of human melanoma was used to test the effect of dietary treatment with an omega-3 fatty acid (FA) rich diet compared to an omega-6 FA rich diet on the growth of human melanoma in vivo. A similar animal model was used to test the effect of oral TAK-875 on the growth of established melanoma tumors in vivo. Results DHA has an inhibitory effect on the growth of human melanoma both in vitro and in vivo. Tumors from animals on the omega-3 FA rich diet were 69% smaller in weight (P=0.005) and 76% smaller in volume compared to tumors from animals on the omega-6 FA rich diet. TAK-875 has an inhibitory effect on the growth of human melanoma both in vitro and in vivo. Tumors from animals treated with TAK-875 were 46% smaller in weight (P=0.07), 62% smaller in volume (P=0.03) and grew 77% slower (P=0.04) compared to the placebo group. Conclusion DHA and TAK-875 have a profound and selective inhibitory effect on the growth of human melanoma both in vitro and in vivo. PMID:24576779

  14. The therapeutic potential of histamine receptor ligands in inflammatory bowel disease.

    PubMed

    Neumann, Detlef; Seifert, Roland

    2014-09-01

    In the intestine of patients suffering from inflammatory bowel disease concentrations of histamine are increased compared to healthy controls. Genetic ablation of histamine production in mice ameliorates the course of experimentally induced colitis. These observations and first pharmacological studies indicate a function of histamine in the pathogenesis of inflammatory bowel disease. However, a closer examination reveals that available data are highly heterogeneous, limiting the rational design of strategies addressing specific histamine receptor subtypes as possible target for pharmacological interaction. However, very recently first clinical data indicate that antagonism at the histamine receptor subtype H4 provides a beneficial effect in at least the skin. Here, we discuss the available data on histamine effects and histamine receptor subtype functions in inflammatory bowel disease with a special emphasis on the histamine H4-receptor. PMID:24929116

  15. Drug addiction: targeting dynamic neuroimmune receptor interactions as a potential therapeutic strategy.

    PubMed

    Jacobsen, Jonathan Henry W; Hutchinson, Mark R; Mustafa, Sanam

    2016-02-01

    Drug addiction and dependence have proven to be difficult psychiatric disorders to treat. The limited efficacy of neuronally acting medications, such as acamprosate and naltrexone, highlights the need to identify novel targets. Recent research has underscored the importance of the neuroimmune system in many behavioural manifestations of drug addiction. In this review, we propose that our appreciation for complex phenotypes such as drug addiction and dependence will come with a greater understanding that these disorders are the result of intricate, interconnected signalling pathways that are, if only partially, determined at the receptor level. The idea of receptor heteromerisation and receptor mosaics will be introduced to explain cross talk between the receptors and signalling molecules implicated in neuroimmune signalling pathways. PMID:26657076

  16. Sphingosine-1-phosphate receptors: Biology and therapeutic potential in kidney disease

    PubMed Central

    Jo, S-K; Bajwa, A; Awad, AS; Lynch, KR; Okusa, MD

    2008-01-01

    The major sphingolipid metabolite, sphingosine-1-phosphate (S1P), has important biological functions. S1P is the ligand for a family of five G-protein-coupled receptors with distinct signaling pathways that regulate angiogenesis, vascular maturation, immunity, chemotaxis, and other important biological pathways. Recently, clinical trials have targeted S1P receptors (S1PRs) for autoimmune diseases and transplantation and have generated considerable interest in developing additional, more selective compounds. This review summarizes current knowledge on the biology of S1P and S1PRs that forms the basis for future drug development and the treatment of kidney disease. PMID:18322542

  17. The EphB4 Receptor Tyrosine Kinase Promotes Lung Cancer Growth: A Potential Novel Therapeutic Target

    PubMed Central

    Ferguson, Benjamin D.; Liu, Ren; Rolle, Cleo E.; Tan, Yi-Hung Carol; Krasnoperov, Valery; Kanteti, Rajani; Tretiakova, Maria S.; Cervantes, Gustavo M.; Hasina, Rifat; Hseu, Robyn D.; Iafrate, A. John; Karrison, Theodore; Ferguson, Mark K.; Husain, Aliya N.; Faoro, Leonardo; Vokes, Everett E.; Gill, Parkash S.; Salgia, Ravi

    2013-01-01

    Despite progress in locoregional and systemic therapies, patient survival from lung cancer remains a challenge. Receptor tyrosine kinases are frequently implicated in lung cancer pathogenesis, and some tyrosine kinase inhibition strategies have been effective clinically. The EphB4 receptor tyrosine kinase has recently emerged as a potential target in several other cancers. We sought to systematically study the role of EphB4 in lung cancer. Here, we demonstrate that EphB4 is overexpressed 3-fold in lung tumors compared to paired normal tissues and frequently exhibits gene copy number increases in lung cancer. We also show that overexpression of EphB4 promotes cellular proliferation, colony formation, and motility, while EphB4 inhibition reduces cellular viability in vitro, halts the growth of established tumors in mouse xenograft models when used as a single-target strategy, and causes near-complete regression of established tumors when used in combination with paclitaxel. Taken together, these data suggest an important role for EphB4 as a potential novel therapeutic target in lung cancer. Clinical trials investigating the efficacy of anti-EphB4 therapies as well as combination therapy involving EphB4 inhibition may be warranted. PMID:23844053

  18. Histamine H4 receptor: insights into a potential therapeutic target in breast cancer.

    PubMed

    Martinel Lamas, Diego J; Rivera, Elena S; Medina, Vanina A

    2015-01-01

    Breast cancer is the second most common cancer worldwide, and the leading cause of cancer death in women. Several studies underlined the critical role of histamine in breast cancer development and progression. This review addresses the latest evidence regarding the involvement of histamine and histamine receptors in breast cancer, focusing particularly in the histamine H4 receptor (H4R). Histamine concentration in breast cancer tissues was found to be higher than that in normal tissues of healthy controls by means of an increase in the activity of histidine decarboxylase (HDC), the enzyme involved in histamine production. The expression of H4R in different experimental models and human biopsies, the associated biological responses, as well as the in vivo treatment of experimental tumors with H4R ligands is reviewed. Evidence demonstrates that the H4R exhibits a key role in histamine-mediated biological processes such as cell proliferation, senescence and apoptosis in breast cancer. The polymorphisms of the H4R and HDC genes and their association with breast cancer risk and malignancy reinforce the critical (patho)physiological role of H4R in breast cancer. In addition, H4R agonists display anti-tumor effects in vivo in a triple negative breast cancer model. The findings support the exploitation of the H4R as a molecular target for breast cancer drug development. PMID:25961682

  19. Potential therapeutic uses of interleukin 1 receptor antagonists in human diseases

    PubMed Central

    Hallegua, D; Weisman, M

    2002-01-01

    Methods: The National Library of Medicine's PubMed database was searched for articles about pharmaceutical agents that reduce the biological actions of IL1. Results: Fish oils and corticosteroids were identified as non-selective pharmacological interventions that reduce the activity of IL1, whereas a recombinant human IL1 receptor antagonist (anakinra) and a soluble recombinant type I IL1 receptor act selectively. To date, anakinra is the only selective intervention that has been shown in controlled clinical trials to be effective and well tolerated in the treatment of a specific human disorder, RA. In controlled clinical trials, anakinra provided significant clinical improvement and slowed radiographic disease progression in patients with active RA. Moreover, addition of anakinra to existing methotrexate treatment significantly reduced signs and symptoms of active disease. Conclusions: The clinical use of anakinra has been demonstrated in the management of RA, but blocking of IL1 in other human disorders, as well as the safety of the use of these blocking agents in chronic diseases, still needs to be defined by controlled clinical investigations. PMID:12379516

  20. Comparative Analysis of Evolutionarily Conserved Motifs of Epidermal Growth Factor Receptor 2 (HER2) Predicts Novel Potential Therapeutic Epitopes

    PubMed Central

    Deng, Xiaohong; Zheng, Xuxu; Yang, Huanming; Moreira, José Manuel Afonso; Brünner, Nils; Christensen, Henrik

    2014-01-01

    Overexpression of human epidermal growth factor receptor 2 (HER2) is associated with tumor aggressiveness and poor prognosis in breast cancer. With the availability of therapeutic antibodies against HER2, great strides have been made in the clinical management of HER2 overexpressing breast cancer. However, de novo and acquired resistance to these antibodies presents a serious limitation to successful HER2 targeting treatment. The identification of novel epitopes of HER2 that can be used for functional/region-specific blockade could represent a central step in the development of new clinically relevant anti-HER2 antibodies. In the present study, we present a novel computational approach as an auxiliary tool for identification of novel HER2 epitopes. We hypothesized that the structurally and linearly evolutionarily conserved motifs of the extracellular domain of HER2 (ECD HER2) contain potential druggable epitopes/targets. We employed the PROSITE Scan to detect structurally conserved motifs and PRINTS to search for linearly conserved motifs of ECD HER2. We found that the epitopes recognized by trastuzumab and pertuzumab are located in the predicted conserved motifs of ECD HER2, supporting our initial hypothesis. Considering that structurally and linearly conserved motifs can provide functional specific configurations, we propose that by comparing the two types of conserved motifs, additional druggable epitopes/targets in the ECD HER2 protein can be identified, which can be further modified for potential therapeutic application. Thus, this novel computational process for predicting or searching for potential epitopes or key target sites may contribute to epitope-based vaccine and function-selected drug design, especially when x-ray crystal structure protein data is not available. PMID:25192037

  1. The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target.

    PubMed

    Shalaby, Asem; Presneau, Nadège; Ye, Hongtao; Halai, Dina; Berisha, Fitim; Idowu, Bernadine; Leithner, Andreas; Liegl, Bernadette; Briggs, Timothy R W; Bacsi, Krisztian; Kindblom, Lars-Gunnar; Athanasou, Nicholas; Amary, Maria Fernanda; Hogendoorn, Pancras C W; Tirabosco, Roberto; Flanagan, Adrienne M

    2011-02-01

    Chordoma, the molecular hallmark of which is T (brachyury), is a rare malignant bone tumour with a high risk of local recurrence and a tumour from which metastatic disease is a common late event. Currently, there is no effective drug therapy for treating chordomas, although there is evidence that some patients respond to the empirical use of epidermal growth factor receptor (EGFR) antagonists. The aim of this study was to determine the role of EGFR in the pathogenesis of chordoma. Paraffin-embedded material from 173 chordomas from 160 patients [sacro-coccygeal (n = 94), skull-based (n = 50), and mobile spine (n = 16)] was analysed by immunohistochemistry and revealed total EGFR expression in 69% of cases analysed. Of 147 informative chordomas analysed by FISH, 38% revealed high-level EGFR polysomy, 4% high-level polysomy with focal amplification, 18% low-level polysomy, and 39% disomy. Phospho-receptor tyrosine kinase array membranes showed EGFR activation in the chordoma cell line U-CH1 and all of the three chordomas analysed. Direct sequencing of EGFR (exons 18-21), KRAS, NRAS, HRAS (exons 2, 3), and BRAF (exons 11, 15) using DNA from 62 chordomas failed to reveal mutations. PTEN expression was absent by immunohistochemistry in 19 of 147 (13%) analysed chordomas, only one of which revealed high-level polysomy of EGFR. The EGFR inhibitor tyrphostin (AG 1478) markedly inhibited proliferation of the chordoma cell line U-CH1 in vitro and diminished EGFR phosphorylation in a dose-dependant manner, a finding supported by inhibition of phosphorylated Erk1/2. p-Akt was suppressed to a much lesser degree in these experiments. There was no reduction of T as assessed by western blotting. These data implicate aberrant EGFR signalling in the pathogenesis of chordoma. This study provides a strategy for patient stratification for treatment with EGFR antagonists. PMID:21171079

  2. Low-Dose Radiation Potentiates the Therapeutic Efficacy of Folate Receptor-Targeted Hapten Therapy

    SciTech Connect

    Sega, Emanuela I.; Lu Yingjuan; Ringor, Michael; Leamon, Christopher P.; Low, Philip S.

    2008-06-01

    Purpose: Human cancers frequently overexpress a high-affinity cell-surface receptor for the vitamin folic acid. Highly immunogenic haptens can be targeted to folate receptor-expressing cell surfaces by administration of folate-hapten conjugates, rendering the decorated tumor cell surfaces more recognizable by the immune system. Treatment of antihapten-immunized mice with folate-hapten constructs results in elimination of moderately sized tumors by the immune system. However, when subcutaneous tumors exceed 300 mm{sup 3} before initiation of therapy, antitumor activity is significantly decreased. In an effort to enhance the efficacy of folate-targeted hapten immunotherapy (FTHI) against large tumors, we explored the combination of targeted hapten immunotherapy with low-dose radiotherapy. Methods and Materials: Mice bearing 300-mm{sup 3} subcutaneous tumors were treated concurrently with FTHI (500 nmol/kg of folate conjugated to fluorescein isothiocyanate, 20,000 U/dose of interleukin 2, and 25,000 U/dose of interferon {alpha}) and low-dose radiotherapy (3 Gy/dose focused directly on the desired tumor mass). The efficacy of therapy was evaluated by measuring tumor volume. Results: Tumor growth analyses show that radiotherapy synergizes with FTHI in antihapten-immunized mice, thereby allowing for cures of animals bearing tumors greater than 300 mm{sup 3}. More importantly, nonirradiated distal tumor masses in animals containing locally irradiated tumors also showed improved response to hapten immunotherapy, suggesting that not all tumor lesions must be identified and irradiated to benefit from the combination therapy. Conclusions: These results suggest that simultaneous treatment with FTHI and radiation therapy can enhance systemic antitumor activity in tumor-bearing mice.

  3. IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential.

    PubMed

    Zhu, Shu; Qian, Youcun

    2012-06-01

    IL-17 (interleukin-17), a hallmark cytokine of Th17 (T-helper 17) cells, plays critical roles in host defence against bacterial and fungal infections, as well as in the pathogenesis of autoimmune diseases. The present review focuses on current knowledge of the regulation, functional mechanisms and targeting strategies of IL-17 in the context of inflammatory autoimmune diseases. Evidence shows that IL-17 is highly up-regulated at sites of inflammatory tissues of autoimmune diseases and amplifies the inflammation through synergy with other cytokines, such as TNF (tumour necrosis factor) α. Although IL-17 was originally thought to be produced mainly by Th17 cells, a newly defined T-cell subset with a specific differentiation programme and tight regulation, several other cell types (especially innate immune cells) are also found as important sources for IL-17 production. Although IL-17 activates common downstream signalling, including NF-κB (nuclear factor κB), MAPKs (mitogen-activated protein kinases), C/EBPs (CCAAT/enhancer-binding proteins) and mRNA stability, the immediate receptor signalling has been shown to be quite unique and tightly regulated. Mouse genetic studies have demonstrated a critical role for IL-17 in the pathogenesis of variety of inflammatory autoimmune diseases, such as RA (rheumatoid arthritis) and MS (multiple sclerosis). Importantly, promising results have been shown in initial clinical trials of monoclonal antibodies against IL-17 or its receptor (IL-17R) to block IL-17-mediated function in treating autoimmune patients with psoriasis, RA and MS. Therefore targeting IL-17/IL-17R, IL-17-producing pathways or IL-17-mediated signalling pathways can be considered for future therapy in autoimmune diseases. PMID:22324470

  4. Mineralocorticoid receptors are present in skeletal muscle and represent a potential therapeutic target.

    PubMed

    Chadwick, Jessica A; Hauck, J Spencer; Lowe, Jeovanna; Shaw, Jeremiah J; Guttridge, Denis C; Gomez-Sanchez, Celso E; Gomez-Sanchez, Elise P; Rafael-Fortney, Jill A

    2015-11-01

    Early treatment with heart failure drugs lisinopril and spironolactone improves skeletal muscle pathology in Duchenne muscular dystrophy (DMD) mouse models. The angiotensin converting enzyme inhibitor lisinopril and mineralocorticoid receptor (MR) antagonist spironolactone indirectly and directly target MR. The presence and function of MR in skeletal muscle have not been explored. MR mRNA and protein are present in all tested skeletal muscles from both wild-type mice and DMD mouse models. MR expression is cell autonomous in both undifferentiated myoblasts and differentiated myotubes from mouse and human skeletal muscle cultures. To test for MR function in skeletal muscle, global gene expression analysis was conducted on human myotubes treated with MR agonist (aldosterone; EC50 1.3 nM) or antagonist (spironolactone; IC50 1.6 nM), and 53 gene expression differences were identified. Five differences were conserved in quadriceps muscles from dystrophic mice treated with spironolactone plus lisinopril (IC50 0.1 nM) compared with untreated controls. Genes down-regulated more than 2-fold by MR antagonism included FOS, ANKRD1, and GADD45B, with known roles in skeletal muscle, in addition to NPR3 and SERPINA3, bona fide targets of MR in other tissues. MR is a novel drug target in skeletal muscle and use of clinically safe antagonists may be beneficial for muscle diseases. PMID:26178166

  5. Cannabinoid Receptors Are Overexpressed in CLL but of Limited Potential for Therapeutic Exploitation

    PubMed Central

    Le, Trang; Gruber, Michaela; Pausz, Clemens; Staber, Philipp; Jäger, Ulrich; Vanura, Katrina

    2016-01-01

    The cannabinoid receptors 1 and 2 (CNR1&2) are overexpressed in a variety of malignant diseases and cannabinoids can have noteworthy impact on tumor cell viability and tumor growth. Patients diagnosed with chronic lymphocytic leukemia (CLL) present with very heterogeneous disease characteristics translating into highly differential risk properties. To meet the urgent need for refinement in risk stratification at diagnosis and the search for novel therapies we studied CNR expression and response to cannabinoid treatment in CLL. Expression levels of CNR1&2 were determined in 107 CLL patients by real-time PCR and analyzed with regard to prognostic markers and survival. Cell viability of primary CLL cells was determined in suspension and co-culture after incubation in increasing cannabinoid concentrations under normal and reduced serum conditions and in combination with fludarabine. Impact of cannabinoids on migration of CLL cells towards CXCL12 was determined in transwell plates. We found CNR1&2 to be overexpressed in CLL compared to healthy B-cells. Discriminating between high and low expressing subgroups, only high CNR1 expression was associated with two established high risk markers and conferred significantly shorter overall and treatment free survival. Viability of CLL primary cells was reduced in a dose dependent fashion upon incubation with cannabinoids, however, healthy cells were similarly affected. Under serum reduced conditions, no significant differences were observed within suspension and co-culture, respectively, however, the feeder layer contributed significantly to the survival of CLL cells compared to suspension culture conditions. No significant differences were observed when treating CLL cells with cannabinoids in combination with fludarabine. Interestingly, biologic activity of cannabinoids was independent of both CNR1&2 expression. Finally, we did not observe an inhibition of CXCL12-induced migration by cannabinoids. In contrast to other tumor

  6. Impact of pregnancy and oestrogen on psoriasis and potential therapeutic use of selective oestrogen receptor modulators for psoriasis.

    PubMed

    Lin, X; Huang, T

    2016-07-01

    Majority of female patients show improvement of psoriasis during pregnancy. This is demonstrated to be correlated with high levels of oestrogen. Even in male patient, oestrogen level is inversely correlated with the severity of psoriasis. However, a minority of female psoriatic patients still experience worsening during pregnancy. Oestrogen might improve psoriasis by suppressing the T-cell immune response, reducing the keratinocyte (KC) cytokine and chemokine production, restoring the balance of redox and enhancing the skin barrier. However, it might worsen the disease by stimulating KC proliferation and promoting angiogenesis. This complex role of oestrogen in the pathogenesis of psoriasis might explain why the two opposite effects of pregnancy coexist. Data shows that the number of improving patients with psoriasis in pregnancy is double the number of the worsening patients, suggesting that oestrogen may be potentially useful in the treatment of psoriasis. However, oestrogen is not considered suitable as a long-term treatment subject to negative side-effects. This review discusses current studies on taking selective oestrogen receptor mediators as a novel potential therapeutic option for psoriasis. PMID:27072912

  7. Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist

    PubMed Central

    2010-01-01

    Background The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia. Methods First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion. Results Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours. Conclusions Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia. PMID:20932337

  8. Affinity maturation of T-cell receptor-like antibodies for Wilms tumor 1 peptide greatly enhances therapeutic potential

    PubMed Central

    Zhao, Qi; Ahmed, Mahiuddin; Tassev, Dimiter V.; Hasan, Aisha; Kuo, Tzu-Yun; Guo, Hong-fen; O’Reilly, Richard J.; Cheung, Nai-Kong V.

    2016-01-01

    WT1126 (RMFPNAPYL) is a human leukocyte antigen-A2 (HLA-A2) restricted peptide derived from Wilms tumor protein (WT1), which is widely expressed in a broad spectrum of leukemias, lymphomas and solid tumors. A novel T-cell-receptor (TCR)-like single chain variable fragment (scFv) antibody specific for the T cell epitope consisting of the WT1/HLA-A2 complex was isolated from a human scFv phage library. This scFv was affinity-matured by mutagenesis combined with yeast display, and structurally analyzed using a homology model. This monovalent scFv showed a 100-fold affinity improvement (dissociation constant [KD]= 3nM) and exquisite specificity towards its targeted epitope or HLA-A2+/WT1+ tumor cells. Bivalent scFv-huIgG1-Fc fusion protein demonstrated an even higher avidity (KD = 2pM) binding to the T cell epitope and to tumor targets, and was capable of mediating antibody-dependent cell-mediated cytotoxicity or tumor lysis by chimeric antigen receptor (CAR)-expressing human T or NK-92-MI transfected cells. This antibody demonstrated specific and potent cytotoxicity in vivo towards WT1-positive leukemia xenograft that was HLA-A2 restricted. In summary, T cell epitopes can provide novel targets for antibody-based therapeutics. By combining phage and yeast displays and scFv-Fc fusion platforms, a strategy for developing high affinity TCR-like antibodies could be rapidly explored for potential clinical development. PMID:25987253

  9. Targeting the Nicotinic Acetylcholine Receptors (nAChRs) in Astrocytes as a Potential Therapeutic Target in Parkinson's Disease.

    PubMed

    Jurado-Coronel, Juan Camilo; Avila-Rodriguez, Marco; Capani, Francisco; Gonzalez, Janneth; Moran, Valentina Echeverria; Barreto, George E

    2016-01-01

    Parkinson's disease (PD) is a relatively common disorder of the Central Nervous System (CNS), whose etiology is characterized by a selective and progressive degeneration of dopaminergic neurons, and the presence of Lewy bodies in the pars compacta of the substantia nigra, and gaping dopamine depletion in the striatum. Patients with this disease suffer from tremors, slowness of movements, gait instability, and rigidity. These patients may also present functional disability, reduced quality of life, and rapid cognitive decline. It has been shown that nicotine exerts beneficial effects in patients with PD and in in-vitro and in-vivo models of this disease. Astrocytes are an important component in the immune response associated with PD, and that nicotine might be able to inhibit the inflammation-related apoptosis of these cells, being this a potential strategy for PD treatment. This action of nicotine could be due mainly to activation of α7 nicotinic acetylcholine receptors (α7-nAChRs) expressed in glial cells. However, nicotine administration can protect dopaminergic neurons against degeneration by inhibiting astrocytes activation in the substantia nigra pars compacta (SNpc) and therefore reduce inflammation. Owing to the toxicity and capacity of nicotine to induce addiction, analogues of this substance have been designed and tested in various experimental paradigms, and targeting α7-nAChRs expressed in glial cells may be a novel therapeutic strategy for PD treatment. PMID:26972289

  10. The IGF-1 Receptor Identifies a Pool of Human Cardiac Stem Cells with Superior Therapeutic Potential for Myocardial Regeneration

    PubMed Central

    D’Amario, Domenico; Cabral-Da-Silva, Mauricio; Zheng, Hanqiao; Fiorini, Claudia; Goichberg, Polina; Steadman, Elisabeth; Ferreira-Martins, João; Sanada, Fumihiro; Piccoli, Marco; Cappetta, Donato; D’Alessandro, David A.; Michler, Robert E.; Hosoda, Toru; Anastasia, Luigi; Rota, Marcello; Leri, Annarosa; Anversa, Piero; Kajstura, Jan

    2012-01-01

    Rationale Age and coronary artery disease may negatively affect the function of human cardiac stem cells (hCSCs) and their potential therapeutic efficacy for autologous cell transplantation in the failing heart. Objective Insulin-like growth factor 1 (IGF-1) and 2 (IGF-2), and angiotensin II (Ang II) and their receptors, IGF-1R, IGF-2R and AT1R, were characterized in c-kit-positive-hCSCs to establish whether these systems would allow us to separate hCSC classes with different growth reserve in the aging and diseased myocardium. Methods and Results C-kit-positive-hCSCs were collected from myocardial samples obtained from 24 patients, 48 to 86 years of age, undergoing elective cardiac surgery for coronary artery disease. The expression of IGF-1R in hCSCs recognized a young cell phenotype defined by long telomeres, high telomerase activity, enhanced cell proliferation and attenuated apoptosis. In addition to IGF-1, IGF-1R-positive-hCSCs secreted IGF-2 that promoted myocyte differentiation. Conversely, the presence of IGF-2R and AT1R, in the absence of IGF-1R, identified senescent hCSCs with impaired growth reserve and increased susceptibility to apoptosis. The ability of IGF-1R-positive-hCSCs to regenerate infarcted myocardium was then compared with that of unselected c-kit-positive-hCSCs. IGF-1R-positive-hCSCs improved cardiomyogenesis and vasculogenesis. Pretreatment of IGF-1R-positive-hCSCs with IGF-2 resulted in the formation of more mature myocytes and superior recovery of ventricular structure. Conclusions hCSCs expressing only IGF-1R synthesize both IGF-1 and IGF-2, which are potent modulators of stem cell replication, commitment to the myocyte lineage and myocyte differentiation, pointing to this hCSC subset as the ideal candidate cell for the management of human heart failure. PMID:21546606

  11. Anti-IL-31 receptor antibody is shown to be a potential therapeutic option for treating itch and dermatitis in mice

    PubMed Central

    Kasutani, K; Fujii, E; Ohyama, S; Adachi, H; Hasegawa, M; Kitamura, H; Yamashita, N

    2014-01-01

    Background and Purpose IL-31, which is described as a pruritogenic cytokine, is linked to the itching that is associated with allergic and non-allergic eczema, but the precise pruritogenic mechanism of IL-31 and its potential as a therapeutic target for atopic dermatitis (AD) have not been determined. Experimental Approach We investigated the effects of existing drugs on the scratching behaviour induced by an i.v. injection of IL-31 to clarify whether IL-31 induced pruritus indirectly. In addition, we studied the effects of an anti-IL-31 receptor α subunit (anti-IL-31 receptor α) neutralizing antibody on chronic pruritus-inducing dermatitis in an AD-like model to determine whether IL-31 not only induces scratching behaviour, but is also the causative factor in an AD phenotype. Key Results The scratching behaviour induced by an i.v. injection of IL-31 was inhibited by pretreatment with an anti-IL-31 receptor α-neutralizing antibody. In contrast, it was not inhibited significantly by a non-sedative antihistamine (terfenadine), immunosuppressants (dexamethasone and tacrolimus), or a μ-opioid receptor antagonist (naloxone). The anti-IL-31 receptor α-neutralizing antibody reduced the ear swelling and dermatitis score in a chronic pruritus-inducing AD-like model. Moreover, treatment with the anti-IL-31 receptor α-neutralizing antibody showed therapeutic effects on the dermatitis even if it was injected after the disease had developed. Conclusions and Implications Anti-IL-31 receptor α is a potential novel therapeutic approach for escaping from the itch–scratch cycle and also a treatment for dermatitis in AD. PMID:24946165

  12. Bile acids and derivatives, their nuclear receptors FXR, PXR and ligands: role in health and disease and their therapeutic potential.

    PubMed

    Zimber, Amazia; Gespach, Christian

    2008-06-01

    Bile acids, their physiology and metabolism, their role in carcinogenesis and other major human diseases are recently undergoing significant progress. Starting in 1999 when the orphan nuclear receptor FXR was shown to be specifically activated by bile acids, these compounds became part of the arsenal of ligands of the steroid hormone superfamily of nuclear receptors, including receptors of Vitamin D3, retinoids (RAR, RXR), and thyroid hormone. Another decisive discovery pointed later that the pregnane X-receptor (PXR) is activated by the endogenous toxic lithocholic acid, as well as several xenobiotics and drugs. Bile acids have recently emerged as key regulators of their own metabolism, and of lipid and carbohydrate metabolism. They have important role as promoters of esophageal and colon cancers, cholangiocarcinoma, as well as new implications in breast cancer development and metastasis. This Review will emphasize novel aspects of bile acids, FXR and PXR as regulators of interfaces at cell proliferation and differentiation, cell death, survival, invasion, and metastasis during normal development and cancer progression. Signaling pathways controlled by bile acids will be presented and discussed in relation to their impact on gene expression. The biological and pharmacological significance of bile acids and their recently developed synthetic derivatives and conjugates, as well as new development in the design of FXR agonists and antagonists for clinical applications in cancer prevention and therapy, will be evaluated. This part includes advances in the utilization of bile acid transporters in drug resistance, therapeutic targeting and delivery of anticancer drugs, as well as therapeutic combinations using new bile acid derivatives, sequestrating agents and reabsorption inhibitors, and their limitations. PMID:18537536

  13. Therapeutic potential of histamine H4 receptor agonists in triple-negative human breast cancer experimental model

    PubMed Central

    Martinel Lamas, Diego J; Croci, Maximo; Carabajal, Eliana; Crescenti, Ernesto J V; Sambuco, Lorena; Massari, Noelia A; Bergoc, Rosa M; Rivera, Elena S; Medina, Vanina A

    2013-01-01

    Background and Purpose The presence of the histamine H4 receptor (H4R) was previously reported in benign and malignant lesions and cell lines derived from the human mammary gland. The aim of this work was to evaluate the effects of H4R ligands on the survival, tumour growth rate and metastatic capacity of breast cancer in an experimental model. Experimental Approach Xenograft tumours of the highly invasive human breast cancer cell line MDA-MB-231 were established in immune deficient nude mice. The following H4R agonists were employed: histamine (5 mg kg−1), clozapine (1 mg kg−1) and the experimental compound JNJ28610244 (10 mg kg−1). Results Data indicate that developed tumours were highly undifferentiated, expressed H4R and exhibited high levels of histamine content and proliferation marker (PCNA) while displaying low apoptosis. Mice of the untreated group displayed a median survival of 60 days and a tumour doubling time of 7.4 ± 0.6 days. A significant decrease in tumour growth evidenced by an augment of the tumour doubling time was observed in the H4R agonist groups (13.1 ± 1.2, P < 0.01 in histamine group; 15.1 ± 1.1, P < 0.001 in clozapine group; 10.8 ± 0.7, P < 0.01 in JNJ28610244 group). This effect was associated with a decrease in the PCNA expression levels, and also reduced intratumoural vessels in histamine and clozapine treated mice. Histamine significantly increased median survival (78 days; Log rank Mantel-Cox Test, P = 0.0025; Gehan-Breslow-Wilcoxon Test, P = 0.0158) and tumoural apoptosis. Conclusions and Implications Histamine through the H4R exhibits a crucial role in tumour progression. Therefore, H4R ligands offer a novel therapeutic potential as adjuvants for breast cancer treatment. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 PMID:23425150

  14. Interleukin-6 is a potential therapeutic target in interleukin-6 dependent, estrogen receptor-α-positive breast cancer

    PubMed Central

    Casneuf, Tineke; Axel, Amy E; King, Peter; Alvarez, John D; Werbeck, Jillian L; Verhulst, Tinne; Verstraeten, Karin; Hall, Brett M; Sasser, A Kate

    2016-01-01

    engraftment with siltuximab, fulvestrant, or combination therapy. Siltuximab alone was able to blunt MCF-7 engraftment. Similarly, siltuximab alone induced regressions in 90% (9/10) of tumors, which were established in the presence which were established in the presence of hMSC expressing human IL-6 and estrogen. Conclusion Given the established role for IL-6 in ERα-positive breast cancer, these data demonstrate the potential for anti-IL-6 therapeutics in breast cancer. PMID:26893580

  15. The TWEAK Receptor Fn14 is a Potential Cell Surface Portal for Targeted Delivery of Glioblastoma Therapeutics

    PubMed Central

    Perez, Jimena G.; Tran, Nhan L.; Rosenblum, Michael G.; Schneider, Craig S.; Connolly, Nina P.; Kim, Anthony J.; Woodworth, Graeme F.; Winkles, Jeffrey A.

    2016-01-01

    Fibroblast growth factor-inducible 14 (Fn14; TNFRSF12A) is the cell surface receptor for the tumor necrosis factor (TNF) family member TNF-like weak inducer of apoptosis (TWEAK). The Fn14 gene is normally expressed at low levels in healthy tissues but expression is significantly increased after tissue injury and in many solid tumor types, including glioblastoma (GB; formerly referred to as ‘glioblastoma multiforme’ or GBM). GB is the most common and aggressive primary malignant brain tumor, and the current standard-of-care therapeutic regimen has a relatively small impact on patient survival, primarily because glioma cells have an inherent propensity to invade into normal brain parenchyma, which invariably leads to tumor recurrence and patient death. Despite major, concerted efforts to find new treatments, a new GB therapeutic that improves survival has not been introduced since 2005. In this review article, we summarize studies indicating that (i) Fn14 gene expression is low in normal brain tissue but up-regulated in advanced brain cancers and, in particular, in GB tumors exhibiting the mesenchymal molecular subtype, (ii) Fn14 expression can be detected in glioma cells residing in both the tumor core and invasive rim regions, with the maximal levels found in the invading glioma cells located within normal brain tissue, and (iii) TWEAK:Fn14 engagement as well as Fn14 overexpression can stimulate glioma cell migration, invasion, and resistance to chemotherapeutic agents in vitro. We also discuss two new therapeutic platforms that are currently in development that leverage Fn14 overexpression in GB tumors as a way to deliver cytotoxic agents to the glioma cells remaining after surgical resection while sparing normal healthy brain cells. PMID:26300004

  16. Conotoxins: Structure, Therapeutic Potential and Pharmacological Applications.

    PubMed

    Mir, Rafia; Karim, Sajjad; Kamal, Mohammad Amjad; Wilson, Cornelia M; Mirza, Zeenat

    2016-01-01

    Cone snails, also known as marine gastropods, from Conus genus produce in their venom a diverse range of small pharmacologically active structured peptides called conotoxins. The cone snail venoms are widely unexplored arsenal of toxins with therapeutic and pharmacological potential, making them a treasure trove of ligands and peptidic drug leads. Conotoxins are small disulfide bonded peptides, which act as remarkable selective inhibitors and modulators of ion channels (calcium, sodium, potassium), nicotinic acetylcholine receptors, noradrenaline transporters, N-methyl-D-aspartate receptors, and neurotensin receptors. They are highly potent and specific against several neuronal targets making them valuable as research tools, drug leads and even therapeutics. In this review, we discuss their gene superfamily classification, nomenclature, post-translational modification, structural framework, pharmacology and medical applications of the active conopeptides. We aim to give an overview of their structure and therapeutic potential. Understanding these aspects of conopeptides will help in designing more specific peptidic analogues. PMID:26601961

  17. A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases

    PubMed Central

    Arulkumaran, Nishkantha; Unwin, Robert J.; Tam, Frederick W. K.

    2011-01-01

    Introduction The P2X7 receptor (P2X7R) has an important role in inflammation and immunity, but until recently, clinical application has been limited by a lack of specific antagonists. Recent studies using P2X7R knockout (KO) mice and specific receptor antagonists have shown that the P2X7R is an important therapeutic target in inflammatory diseases. Areas covered We have reviewed the current literature on the role of the P2X7R in inflammatory diseases, focusing on potential therapeutic applications of selective P2X7R antagonists as an anti-inflammatory agent. Particular emphasis has been placed on the potential role of P2X7R in common inflammatory diseases. The latest developments in phase I and II clinical trials of P2X7R antagonists are covered. Expert opinion Recent studies using gene KO mice and selective P2X7R antagonists suggest that P2X7R is a viable therapeutic target for inflammatory diseases. However, efficacious P2X7R antagonists for use in clinical studies are still at an early stage of development. Future challenges include: identifying potential toxicity and side effects of treatment, timing of treatment initiation and its duration in chronic inflammatory conditions, optimum dosage, and development of a functional assay for P2X7R that would help to guide treatment. PMID:21510825

  18. Endocannabinoids as regulators of transient receptor potential (TRP) channels: A further opportunity to develop new endocannabinoid-based therapeutic drugs.

    PubMed

    Di Marzo, V; De Petrocellis, L

    2010-01-01

    In the late 1990's, a series of experiments carried out independently in two laboratories led to establish an important connection between the function of the endocannabinoids, which, as exemplified in this special issue, is per se very complex and ubiquitous in animals, and that of the transient receptor potential (TRP) channels, a large family of plasma membrane cation channels involved in several mammalian and non-mammalian physiological and pathological conditions, overlapping only in part with those in which the cannabinoid receptors participate. These experiments were initially based on the observation that the endocannabinoid anandamide and the xenobiotic ligand of TRP channels of V1 type (TRPV1), capsaicin, are somehow chemically similar, both compounds being fatty acid amides, as are also synthetic activators of these channels and inhibitors of anandamide cellular re-uptake. As discussed in this article, the same type of "chemical thoughts" led to the discovery of N-arachidonoyl-dopamine, an endogenous ligand of TRPV1 channels that behaves also an endocannabinoid. The overlap between the ligand recognition properties of some TRP channels and proteins of the endocannabinoid system, namely the cannabinoid receptors and the proteins and enzymes catalyzing anandamide cellular re-uptake and hydrolysis, is being actively explored through the rational design and synthesis of new endocannabinoid-based drugs with multiple mechanisms of action. These aspects are discussed in this review article, together with the possible functional and pharmacological consequences of endocannabinoid-TRP channel interactions. PMID:20166923

  19. Laminin Receptor-Avid Nanotherapeutic EGCg-AuNPs as a Potential Alternative Therapeutic Approach to Prevent Restenosis

    PubMed Central

    Khoobchandani, Menka; Katti, Kavita; Maxwell, Adam; Fay, William P.; Katti, Kattesh V.

    2016-01-01

    In our efforts to develop new approaches to treat and prevent human vascular diseases, we report herein our results on the proliferation and migration of human smooth muscles cells (SMCs) and endothelial cells (ECs) using epigallocatechin-3-gallate conjugated gold nanoparticles (EGCg-AuNPs) as possible alternatives to drug coated stents. Detailed in vitro stability studies of EGCg-AuNPs in various biological fluids, affinity and selectivity towards SMCs and ECs have been investigated. The EGCg-AuNPs showed selective inhibitory efficacy toward the migration of SMCs. However, the endothelial cells remained unaffected under similar experimental conditions. The cellular internalization studies have indicated that EGCg-AuNPs internalize into the SMCs and ECs within short periods of time through laminin receptor mediated endocytosis mode. Favorable toxicity profiles and selective affinity toward SMCs and ECs suggest that EGCg-AuNPs may provide attractive alternatives to drug coated stents and therefore offer new therapeutic approaches in treating cardiovascular diseases. PMID:26938531

  20. Therapeutic potential of cannabinoid medicines.

    PubMed

    Robson, P J

    2014-01-01

    Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines. The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology. In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders. PMID:24006213

  1. Therapeutic potential of conopeptides.

    PubMed

    Schroeder, Christina I; Craik, David J

    2012-06-01

    Conopeptides from the venoms of marine snails have attracted much interest as leads in drug design. Currently, one drug, Prialt(®), is on the market as a treatment for chronic neuropathic pain. Conopeptides target a range of ion channels, receptors and transporters, and are typically small, relatively stable peptides that are generally amenable to production using solid-phase peptide synthesis. With only a small fraction of the predicted diversity of conopeptides examined so far, these peptides represent an exciting and largely untapped resource for drug discovery. Recent efforts at chemically re-engineering conopeptides to improve their biopharmaceutical properties promise to accelerate the translation of these fascinating marine peptides to the clinic. PMID:22800369

  2. Differential expression of hormonal and growth factor receptors in salivary duct carcinomas: biologic significance and potential role in therapeutic stratification of patients.

    PubMed

    Williams, Michelle D; Roberts, Dianna; Blumenschein, George R; Temam, Stephane; Kies, Merrill S; Rosenthal, David I; Weber, Randal S; El-Naggar, Adel K

    2007-11-01

    Salivary duct carcinoma (SDC), a rare malignancy, manifests remarkable morphologic and biologic resemblance to high-grade mammary ductal carcinoma. We contend that, similar to mammary ductal carcinoma, hormones and growth factors may play a role in SDCs. Our aim was to determine the incidence and clinical significance of the expression of several hormone and growth factor receptors and evaluate their potential in therapeutic stratification of SDC patients in the largest cohort studied to date. Eighty-four archived tumor tissue blocks were analyzed immunohistochemically for expression of estrogen receptor-beta (ERbeta), androgen receptor (AR), and proline, glutamic acid, and leucine-rich protein-1 and growth factor receptors HER-2 and epidermal growth factor receptor. The results were correlated with available pathologic, demographic, and clinical data from 59 of 84 cases. Proline, glutamic acid, and leucine-rich protein-1, ERbeta, and AR were expressed individually in 94% (71/76), 73% (57/80), and 67% (56/84) of SDCs, respectively, and coexpressed in 45% (34/75). AR was expressed significantly more often in SDCs of men than in SDCs of women [79% (35/57) vs. 33% (9/27), P<0.001]. Epidermal growth factor receptor and HER-2 were overexpressed individually in 48% (40/83) and 25% (21/84), respectively, and co-overexpressed in 12% (10/83). Survival decreased significantly in patients with lymph node metastasis (P=0.002) and positive surgical margins (P=0.006). Lack of ERbeta expression correlated with increased local and regional recurrence (P=0.05 and P=0.002, respectively). Together, these results indicate that (a) ERbeta down-regulation is associated with adverse clinical features, (b) lymph node and surgical margin status are significant survival factors, and (c) the differential expression of these hormones and growth factor receptors may assist in triaging patients with SDC for novel therapies. PMID:18059220

  3. Transient receptor potential (TRP) channels as a therapeutic target for intervention of respiratory effects and lethality from phosgene.

    PubMed

    Andres, Devon; Keyser, Brian; Benton, Betty; Melber, Ashley; Olivera, Dorian; Holmes, Wesley; Paradiso, Danielle; Anderson, Dana; Ray, Radharaman

    2016-02-26

    Phosgene (CG), a toxic inhalation and industrial hazard, causes bronchoconstriction, vasoconstriction and associated pathological effects that could be life threatening. Ion channels of the transient receptor potential (TRP) family have been identified to act as specific chemosensory molecules in the respiratory tract in the detection, control of adaptive responses and initiation of detrimental signaling cascades upon exposure to various toxic inhalation hazards (TIH); their activation due to TIH exposure may result in broncho- and vasoconstriction. We studied changes in the regulation of intracellular free Ca(2+) concentration ([Ca(2+)]i) in cultures of human bronchial smooth muscle cells (BSMC) and human pulmonary microvascular endothelial cells (HPMEC) exposed to CG (16ppm, 8min), using an air/liquid interface exposure system. CG increased [Ca(2+)]i (p<0.05) in both cell types, The CG-induced [Ca(2+)]i was blocked (p<0.05) by two types of TRP channel blockers, SKF-96365, a general TRP channel blocker, and RR, a general TRPV (vanilloid type) blocker, in both BSMC and HPMEC. These effects correlate with the in vivo efficacies of these compounds to protect against lung injury and 24h lethality from whole body CG inhalation exposure in mice (8-10ppm×20min). Thus the TRP channel mechanism appears to be a potential target for intervention in CG toxicity. PMID:26562769

  4. ADN-1184 a monoaminergic ligand with 5-HT6/7 receptor antagonist activity: pharmacological profile and potential therapeutic utility

    PubMed Central

    Kołaczkowski, M; Mierzejewski, P; Bieńkowski, P; Wesołowska, A; Newman-Tancredi, A

    2014-01-01

    Background and Purpose Many dementia patients exhibit behavioural and psychological symptoms (BPSD) that include psychosis, aggressivity, depression and anxiety. Antipsychotic drugs are frequently prescribed but fail to significantly attenuate mood deficits, may interfere with cognitive function and are associated with motor and cardiac side effects, which are problematic in elderly patients. A need therefore exists for drugs that are better suited for the treatment of BPSD. Experimental Approach We used in vitro cellular and in vivo behavioural tests to characterize ADN-1184, a novel arylsulfonamide ligand with potential utility for treatment of BPSD. Key Results ADN-1184 exhibits substantial 5-HT6/5-HT7/5-HT2A/D2 receptor affinity and antagonist properties in vitro. In tests of antipsychotic-like activity, it reversed MK-801-induced hyperactivity and stereotypies and inhibited conditioned avoidance response (MED = 3 mg·kg−1 i.p.). Remarkably, ADN-1184 also reduced immobility time in the forced swim test at low doses (0.3 and 1 mg·kg−1 i.p.; higher doses were not significantly active). Notably, up to 30 mg·kg−1 ADN-1184 did not impair memory performance in the passive avoidance test or elicit significant catalepsy and only modestly inhibited spontaneous locomotor activity (MED = 30 mg·kg−1 i.p.). Conclusions and Implications ADN-1184 combines antipsychotic-like with antidepressant-like properties without interfering with memory function or locomotion. This profile is better than that of commonly used atypical antipsychotics tested under the same conditions and suggests that it is feasible to identify drugs that improve BPSD, without exacerbating cognitive deficit or movement impairment, which are of particular concern in patients with dementia. PMID:24199650

  5. The therapeutic potential of sigma (σ) receptors for the treatment of central nervous system diseases: evaluation of the evidence.

    PubMed

    Banister, Samuel D; Kassiou, Michael

    2012-01-01

    Since their proposal in 1976, sigma (σ) receptors have been increasingly implicated in the pathophysiology of virtually all major central nervous system (CNS) disorders, including anxiety, depression, schizophrenia, and drug addiction. Due to their involvement in motor function and higher cognitive function,σ receptors have also been implicated in movement disorders (such as Parkinson's disease) and memory deficits (including Alzheimer's disease). In most cases the precise mechanism(s) linking σ receptors to CNS disease are unknown or yet to be fully elucidated. However, many σ ligands have shown promise in pharmacological studies and animal models of the aforementioned diseases, and some have entered clinical trials. This review will assess the validity of receptors as a target for various CNS diseases based on evidence from animal models of human diseases, preclinical studies in humans, and full clinical trials. PMID:22288410

  6. Profile of Steroid Receptors and Increased Aromatase Immunoexpression in Canine Inflammatory Mammary Cancer as a Potential Therapeutic Target.

    PubMed

    De Andrés, P J; Cáceres, S; Clemente, M; Pérez-Alenza, M D; Illera, J C; Peña, L

    2016-04-01

    Canine inflammatory mammary cancer (IMC) has been proposed as a model for the study of human inflammatory breast cancer (IBC). The aims of this study were to compare the immunohistochemical expression of aromatase (Arom) and several hormone receptors [estrogen receptor α (ERα), estrogen receptor β (ERβ), progesterone receptor (PR) and androgen receptor (AR)], in 21 IMC cases vs 19 non-IMC; and to study the possible effect of letrozole on canine IMC and human inflammatory breast cancer (IBC) in vitro using IPC-366 and SUM-149 cell lines. Significant elevations of the means of Arom Total Score (TS), ERβ TS and PR TS were found in the IMC group (p = 0.025, p = 0.038 and p = 0.037, respectively). Secondary IMC tumours expressed higher levels of Arom than primary IMC (p = 0.029). Non-IMC PR- tumours contained higher levels of Arom than non-IMC PR+ tumours (p = 0.007). After the addition of letrozole, the number of IMC and IBC cells dropped drastically. The overexpression of Arom found and the results obtained in vitro further support canine IMC as a model for the study of IBC and future approaches to the treatment of dogs with mammary cancer, and especially IMC, using Arom inhibitors. PMID:26899138

  7. Src Is a Potential Therapeutic Target in Endocrine-Resistant Breast Cancer Exhibiting Low Estrogen Receptor-Mediated Transactivation

    PubMed Central

    Pancholi, Sunil; Nikitorowicz-Buniak, Joanna; Simigdala, Nikiana; Dowsett, Mitch; Johnston, Stephen R.; Martin, Lesley-Ann

    2016-01-01

    Despite the effectiveness of endocrine therapies in estrogen receptor positive (ER+) breast cancer, approximately 40% of patients relapse. Previously, we identified the Focal-adhesion kinase canonical pathway as a major contributor of resistance to estrogen deprivation and cellular-sarcoma kinase (c-src) as a dominant gene in this pathway. Dasatinib, a pan-src inhibitor, has recently been used in clinical trials to treat ER+ patients but has shown mixed success. In the following study, using isogenic cell line models, we provide a potential explanation for these findings and suggest a sub-group that may benefit. A panel of isogenic cell lines modelling resistance to aromatase inhibitors (LTED) and tamoxifen (TAMR) were assessed for response to dasatinib ± endocrine therapy. Dasatinib caused a dose-dependent decrease in proliferation in MCF7-TAMR cells and resensitized them to tamoxifen and fulvestrant but not in HCC1428-TAMR. In contrast, in estrogen-deprived conditions, dasatinib increased the proliferation rate of parental-MCF7 cells and had no effect on MCF7-LTED or HCC1428-LTED. Treatment with dasatinib caused a decrease in src-phosphorylation and inhibition of downstream pathways, including AKT and ERK1/2 in all cell lines tested, but only the MCF7-TAMR showed a concomitant decrease in markers of cell cycle progression. Inhibition of src also caused a significant decrease in cell migration in both MCF7-LTED and MCF7-TAMR cells. Finally, we showed that, in MCF7-TAMR cells, in contrast to tamoxifen sensitive cell lines, ER is expressed throughout the cell rather than being restricted to the nucleus and that treatment with dasatinib resulted in nuclear shuttling of ER, which was associated with an increase in ER-mediated transcription. These data suggest that src has differential effects in endocrine-resistant cell lines, particularly in tamoxifen resistant models, with low ER genomic activity, providing further evidence of the importance of patient selection

  8. Src Is a Potential Therapeutic Target in Endocrine-Resistant Breast Cancer Exhibiting Low Estrogen Receptor-Mediated Transactivation.

    PubMed

    Guest, Stephanie K; Ribas, Ricardo; Pancholi, Sunil; Nikitorowicz-Buniak, Joanna; Simigdala, Nikiana; Dowsett, Mitch; Johnston, Stephen R; Martin, Lesley-Ann

    2016-01-01

    Despite the effectiveness of endocrine therapies in estrogen receptor positive (ER+) breast cancer, approximately 40% of patients relapse. Previously, we identified the Focal-adhesion kinase canonical pathway as a major contributor of resistance to estrogen deprivation and cellular-sarcoma kinase (c-src) as a dominant gene in this pathway. Dasatinib, a pan-src inhibitor, has recently been used in clinical trials to treat ER+ patients but has shown mixed success. In the following study, using isogenic cell line models, we provide a potential explanation for these findings and suggest a sub-group that may benefit. A panel of isogenic cell lines modelling resistance to aromatase inhibitors (LTED) and tamoxifen (TAMR) were assessed for response to dasatinib ± endocrine therapy. Dasatinib caused a dose-dependent decrease in proliferation in MCF7-TAMR cells and resensitized them to tamoxifen and fulvestrant but not in HCC1428-TAMR. In contrast, in estrogen-deprived conditions, dasatinib increased the proliferation rate of parental-MCF7 cells and had no effect on MCF7-LTED or HCC1428-LTED. Treatment with dasatinib caused a decrease in src-phosphorylation and inhibition of downstream pathways, including AKT and ERK1/2 in all cell lines tested, but only the MCF7-TAMR showed a concomitant decrease in markers of cell cycle progression. Inhibition of src also caused a significant decrease in cell migration in both MCF7-LTED and MCF7-TAMR cells. Finally, we showed that, in MCF7-TAMR cells, in contrast to tamoxifen sensitive cell lines, ER is expressed throughout the cell rather than being restricted to the nucleus and that treatment with dasatinib resulted in nuclear shuttling of ER, which was associated with an increase in ER-mediated transcription. These data suggest that src has differential effects in endocrine-resistant cell lines, particularly in tamoxifen resistant models, with low ER genomic activity, providing further evidence of the importance of patient selection

  9. The immunopharmacologic potential of Semaxanib and new generation directed therapeutic drugs: Receptor tyrosine kinase regulation with anti-tumorigenensis/angiogenesis properties

    PubMed Central

    Haddad, John J.

    2011-01-01

    Molecular signaling of messages emanating from cellular membranes through receptor tyrosine kinases (RTKs) is a major mechanism for intercellular communication and transduction during development and metabolism, as well as in disease-associated processes. The phosphorylation status and signaling activity of RTKs are determined by a dynamic equilibrium of the activity of both RTKs and protein tyrosine phosphatases (PTPs). RTKs are essentially a class of cell-surface receptors for growth factors and other extracellular ligands, the most conspicuous perhaps are members of the vascular endothelial growth factor (VEGF) gene family, which plays a fundamental role in the growth and differentiation of vascular, as well as lymphatic endothelial cells. In particular, VEGF is a major regulator of normal (physiologic) and abnormal (cancerous) angiogenesis, including that associated with tumors and cancer. Blockers/inhibitors and regulators of RTKs are indeed promising cancer interventions, their specific mechanisms are yet to be unraveled. In this cutting-edge synopsis, I elaborate on breakthroughs/advances and current concepts of RTK regulation, further shedding light on exploring the role of potential regulators, particularly the RTK inhibitor Semaxanib, and the mechanisms associated with tumorigenesis in an effort to understand a potentially alleviating pharmacologic therapeutic intervention. This survey also tackles the loopholes and shortcomings of the aforementioned inhibitory role of Semaxanib, especially its inefficacy and ultimate discontinuation of relevant clinical trials. PMID:23960782

  10. AMPA Receptors as Therapeutic Targets for Neurological Disorders.

    PubMed

    Lee, Kevin; Goodman, Lucy; Fourie, Chantelle; Schenk, Susan; Leitch, Beulah; Montgomery, Johanna M

    2016-01-01

    Almost every neurological disease directly or indirectly affects synapse function in the brain. However, these diseases alter synapses through different mechanisms, ultimately resulting in altered synaptic transmission and/or plasticity. Glutamate is the major neurotransmitter that mediates excitatory synaptic transmission in the brain through activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. These receptors have therefore been identified as a target for the development of therapeutic treatments for neurological disorders including epilepsy, neurodegenerative diseases, autism, and drug addiction. The fact that AMPA receptors play a dominant role throughout the brain raises the significant challenge of selectively targeting only those regions affected by disease, and clinical trials have raised doubt regarding the feasibility of specifically targeting AMPA receptors for new therapeutic options. Benzamide compounds that act as positive allosteric AMPA receptor modulators, known as AMPAkines, can act on specific brain regions and were initially proposed to revolutionize the treatment of cognitive deficits associated with neurological disorders. Their therapeutic potential has since declined due to inconsistent results in clinical trials. However, recent advances in basic biomedical research are significantly increasing our knowledge of AMPA receptor structure, binding sites, and interactions with auxiliary proteins. In particular, the large complex of postsynaptic proteins that interact with AMPA receptor subunits have been shown to control AMPA receptor insertion, location, pharmacology, synaptic transmission, and plasticity. These proteins are now being considered as alternative therapeutic target sites for modulating AMPA receptors in neurological disorders. PMID:26920691

  11. Eph Receptors and Ephrins: Therapeutic Opportunities

    PubMed Central

    Barquilla, Antonio; Pasquale, Elena B.

    2015-01-01

    The Eph receptor tyrosine kinase family plays important roles in developmental processes, adult tissue homeostasis and various diseases. Interaction with ephrin ligands on the surface of neighboring cells triggers Eph receptor kinase-dependent signaling. The ephrins can also transmit signals, leading to bidirectional cell contact-dependent communication. Moreover, Eph receptors and ephrins can function independently of each other, through interplay with other signaling systems. Given their involvement in many pathological conditions ranging from neurological disorders to cancer and viral infections, Eph receptors and ephrins are increasingly recognized as attractive therapeutic targets and a variety of strategies are being explored to modulate their expression and function. Eph receptor/ephrin upregulation in cancer cells, the angiogenic vasculature, and injured or diseased tissues also offers opportunities for Eph/ephrin-based targeted drug delivery and imaging. Thus, despite the challenges presented by the complex biology of the Eph receptor/ephrin system, exciting possibilities exist for therapies exploiting these molecules. PMID:25292427

  12. Unprecedented Therapeutic Potential with a Combination of A2A/NR2B Receptor Antagonists as Observed in the 6-OHDA Lesioned Rat Model of Parkinson's Disease

    PubMed Central

    Michel, Anne; Downey, Patrick; Nicolas, Jean-Marie; Scheller, Dieter

    2014-01-01

    In Parkinson's disease, the long-term use of dopamine replacing agents is associated with the development of motor complications; therefore, there is a need for non-dopaminergic drugs. This study evaluated the potential therapeutic impact of six different NR2B and A2A receptor antagonists given either alone or in combination in unilateral 6-OHDA-lesioned rats without (monotherapy) or with (add-on therapy) the co-administration of L-Dopa: Sch-58261+ Merck 22; Sch-58261+Co-101244; Preladenant + Merck 22; Preladenant + Radiprodil; Tozadenant + Radiprodil; Istradefylline + Co-101244. Animals given monotherapy were assessed on distance traveled and rearing, whereas those given add-on therapy were assessed on contralateral rotations. Three-way mixed ANOVA were conducted to assess the main effect of each drug separately and to determine whether any interaction between two drugs was additive or synergistic. Additional post hoc analyses were conducted to compare the effect of the combination with the effect of the drugs alone. Motor activity improved significantly and was sustained for longer when the drugs were given in combination than when administered separately at the same dose. Similarly, when tested as add-on treatment to L-Dopa, the combinations resulted in higher levels of contralateral rotation in comparison to the single drugs. Of special interest, the activity observed with some combinations could not be described by a simplistic additive effect and involved more subtle synergistic pharmacological interactions. The combined administration of A2A/NR2B-receptor antagonists improved motor behaviour in 6-OHDA rats. Given the proven translatability of this model such a combination may be expected to be effective in improving motor symptoms in patients. PMID:25513815

  13. A Small-Animal Pharmacokinetic/Pharmacodynamic PET Study of Central Serotonin 1A Receptor Occupancy by a Potential Therapeutic Agent for Overactive Bladder

    PubMed Central

    Nakatani, Yosuke; Suzuki, Michiyuki; Tokunaga, Masaki; Maeda, Jun; Sakai, Miyuki; Ishihara, Hiroki; Yoshinaga, Takashi; Takenaka, Osamu; Zhang, Ming-Rong; Suhara, Tetsuya; Higuchi, Makoto

    2013-01-01

    Serotonin 1A (5-HT1A) receptors have been mechanistically implicated in micturition control, and there has been a need for an appropriate biomarker surrogating the potency of a provisional drug acting on this receptor system for developing a new therapeutic approach to overactive bladder (OAB). Here, we analyzed the occupancy of 5-HT1A receptors in living Sprague-Dawley rat brains by a novel candidate drug for OAB, E2110, using positron emission tomography (PET) imaging, and assessed the utility of a receptor occupancy (RO) assay to establish a pharmacodynamic index translatable between animals and humans. The plasma concentrations inducing 50% RO (EC50) estimated by both direct and effect compartment models were in good agreement. Dose-dependent therapeutic effects of E2110 on dysregulated micturition in different rat models of pollakiuria were also consistently explained by achievement of 5-HT1A RO by E2110 in a certain range (≥ 60%). Plasma drug concentrations inducing this RO range and EC50 would accordingly be objective indices in comparing pharmacokinetics-RO relationships between rats and humans. These findings support the utility of PET RO and plasma pharmacokinetic assays with the aid of adequate mathematical models in determining the in vivo characteristics of a drug acting on 5-HT1A receptors and thereby counteracting OAB. PMID:24086433

  14. Neurosteroids, stress and depression: Potential therapeutic opportunities

    PubMed Central

    Zorumski, Charles F.; Paul, Steven M.; Izumi, Yukitoshi; Covey, Douglas F.; Mennerick, Steven

    2012-01-01

    Neurosteroids are potent and effective neuromodulators that are synthesized from cholesterol in the brain. These agents and their synthetic derivatives influence the function of multiple signaling pathways including receptors for γ-aminobutyric acid (GABA) and glutamate, the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS). Increasing evidence indicates that dysregulation of neurosteroid production plays a role in the pathophysiology of stress and stress-related psychiatric disorders, including mood and anxiety disorders. In this paper, we review the mechanisms of neurosteroid action in brain with an emphasis on those neurosteroids that potently modulate the function of GABAA receptors. We then discuss evidence indicating a role for GABA and neurosteroids in stress and depression, and focus on potential strategies that can be used to manipulate CNS neurosteroid synthesis and function for therapeutic purposes. PMID:23085210

  15. Therapeutic antibodies against CGRP or its receptor

    PubMed Central

    Bigal, Marcelo E; Walter, Sarah; Rapoport, Alan M

    2015-01-01

    CGRP is an extensively studied neuropeptide that has been implicated in the pathophysiology of migraine. While a number of small molecule antagonists against the CGRP receptor have demonstrated that targeting this pathway is a valid and effective way of treating migraine, off-target hepatoxicity and formulation issues have hampered the development for regulatory approval of any therapeutic in this class. The development of monoclonal antibodies to CGRP or its receptor as therapeutic agents has allowed this pathway to be re-investigated. Herein we review why CGRP is an ideal target for the prevention of migraine and describe four monoclonal antibodies against either CGRP or its receptor that are in clinical development for the treatment of both episodic and chronic migraine. We describe what has been publically disclosed about their clinical trials and future clinical development plans. PMID:25614243

  16. The therapeutic potential of a C-X-C chemokine receptor type 4 (CXCR-4) antagonist on hypertrophic scarring in vivo.

    PubMed

    Ding, Jie; Ma, Zengshuan; Liu, Hongbin; Kwan, Peter; Iwashina, Takashi; Shankowsky, Heather A; Wong, Donald; Tredget, Edward E

    2014-01-01

    Effective prevention and treatment of hypertrophic scars (HTSs), a dermal form of fibrosis that frequently occurs following thermal injury to deep dermis, are unsolved significant clinical problems. Previously, we have found that stromal cell-derived factor 1/CXCR4 signaling is up-regulated during wound healing in burn patients and HTS tissue after thermal injury. We hypothesize that blood-borne mononuclear cells are recruited into wound sites after burn injury through the chemokine pathway of stromal cell-derived factor 1 and its receptor CXCR4. Deep dermal injuries to the skin are often accompanied by prolonged inflammation, which leads to chemotaxis of mononuclear cells into the wounds by chemokine signaling where fibroblast activation occurs and ultimately HTS are formed. Blocking mononuclear cell recruitment and fibroblast activation, CXCR4 antagonism is expected to reduce or minimize scar formation. In this study, the inhibitory effect of CXCR4 antagonist CTCE-9908 on dermal fibrosis was determined in vivo using a human HTS-like nude mouse model, in which split-thickness human skin is transplanted into full-thickness dorsal excisional wounds in athymic mice, where these wounds subsequently develop fibrotic scars that resemble human HTS as previously described. CTCE-9908 significantly attenuated scar formation and contraction, reduced the accumulation of macrophages and myofibroblasts, enhanced the remodeling of collagen fibers, and down-regulated the gene and protein expression of fibrotic growth factors in the human skin tissues. These findings support the potential therapeutic value of CXCR4 antagonist in dermal fibrosis and possibly other fibroproliferative disorders. PMID:25139227

  17. Advanced Glycation End-Products and Their Receptors: Related Pathologies, Recent Therapeutic Strategies, and a Potential Model for Future Neurodegeneration Studies.

    PubMed

    Pinkas, Adi; Aschner, Michael

    2016-05-16

    Advanced glycation end products (AGEs) are the result of a nonenzymatic reaction between sugars and proteins, lipids, or nucleic acids. AGEs are both consumed and endogenously formed; their accumulation is accelerated under hyperglycemic and oxidative stress conditions, and they are associated with the onset and complication of many diseases, such as cardiovascular diseases, diabetes, and Alzheimer's disease. AGEs exert their deleterious effects by either accumulating in the circulation and tissues or by receptor-mediated signal transduction. Several receptors bind AGEs: some are specific and contribute to clearance of AGEs, whereas others, like the RAGE receptor, are nonspecific, associated with inflammation and oxidative stress, and considered to be mediators of the aforementioned AGE-related diseases. Although several anti-AGE compounds have been studied, understanding the underlying mechanisms of RAGE and targeting it as a therapeutic strategy is becoming increasingly desirable. For achieving these goals efficiently and expeditiously, the C. elegans model has been suggested. This model is already used for studying several human diseases and, by expressing RAGE, could also be used to study RAGE-related pathways and pathologies to facilitate the development of novel therapeutic strategies. PMID:27054356

  18. Leucine-rich repeat-containing G-protein-coupled receptor 5 is associated with invasion, metastasis, and could be a potential therapeutic target in human gastric cancer

    PubMed Central

    Xi, H Q; Cai, A Z; Wu, X S; Cui, J X; Shen, W S; Bian, S B; Wang, N; Li, J Y; Lu, C R; Song, Z; Wei, B; Chen, L

    2014-01-01

    Background: Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5), which is identified as a novel intestinal stem cell marker, is overexpressed in various tumours. In this study, we explore Lgr5 expression in gastric carcinoma and analyse its role in invasion, metastasis, and prognosis in carcinoma. Methods: A combination of immunohistochemistry, western blotting, and quantitative reverse transcription–polymerase chain reaction were used to detect mRNA and protein expression levels of Lgr5 and matrix metalloproteinase 2 (MMP2). Small interfering RNA against Lgr5 was designed, synthesised, and transfected into AGS cells. The effects of Lgr5 siRNA on cell invasion were detected by transwell invasion chamber assay and wound healing assay. Results: Leucine-rich repeat-containing G-protein-coupled receptor 5 expression was significantly higher in gastric carcinomas than in normal mucosa. Leucine-rich repeat-containing G-protein-coupled receptor 5 expression positively correlated with the depth of invasion, lymph node metastasis, distance of metastasis, and MMP2 expression levels. Multivariate analysis showed that Lgr5 had an independent effect on survival, and that it positively correlated with MMP2. Leucine-rich repeat-containing G-protein-coupled receptor 5 siRNAs inhibited Lgr5 mRNA and protein expression. Transwell assays indicated that these siRNAs resulted in significantly fewer cells migrating through the polycarbonate membrane, and wound healing assay also indicated that siRNAs decreased the migration of cells. Inhibition of Lgr5 resulted in a significant decrease in MMP2 and β-catenin levels compared with those in controls. Conclusions: Leucine-rich repeat-containing G-protein-coupled receptor 5 was correlated with invasion and metastasis. Leucine-rich repeat-containing G-protein-coupled receptor 5 inhibition could serve as a novel therapeutic approach. PMID:24594994

  19. Thymoquinone and its therapeutic potentials.

    PubMed

    Darakhshan, Sara; Bidmeshki Pour, Ali; Hosseinzadeh Colagar, Abasalt; Sisakhtnezhad, Sajjad

    2015-01-01

    Herbal medicine has attracted great attention in the recent years and is increasingly used as alternatives to chemical drugs. Several lines of evidence support the positive impact of medicinal plants in the prevention and cure of a wide range of diseases. Thymoquinone (TQ) is the most abundant constituent of the volatile oil of Nigella sativa seeds and most properties of N sativa are mainly attributed to TQ. A number of pharmacological actions of TQ have been investigated including anti-oxidant, anti-inflammatory, immunomodulatory, anti-histaminic, anti-microbial and anti-tumor effects. It has also gastroprotective, hepatoprotective, nephroprotective and neuroprotective activities. In addition, positive effects of TQ in cardiovascular disorders, diabetes, reproductive disorders and respiratory ailments, as well as in the treatment of bone complications as well as fibrosis have been shown. In addition, a large body of data shows that TQ has very low adverse effects and no serious toxicity. More recently, a great deal of attention has been given to this dietary phytochemical with an increasing interest to investigate it in pre-clinical and clinical researches for assessing its health benefits. Here we report on and analyze numerous properties of the active ingredient of N. sativa seeds, TQ, in the context of its therapeutic potentials for a wide range of illnesses. We also summarize the drug's possible mechanisms of action. The evidence reported sugests that TQ should be developed as a novel drug in clinical trials. PMID:25829334

  20. Neurosteroids and potential therapeutics: Focus on pregnenolone.

    PubMed

    Vallée, Monique

    2016-06-01

    Considerable evidence from preclinical and clinical studies shows that steroids and in particular neurosteroids are important endogenous modulators of several brain-related functions. In this context, it remains to be elucidated whether neurosteroids may serve as biomarkers in the diagnosis of disorders and might have therapeutic potential for the treatment of these disorders. Pregnenolone (PREG) is the main steroid synthesized from cholesterol in mammals and invertebrates. PREG has three main sources of synthesis, the gonads, adrenal glands and brain and is submitted to various metabolizing pathways which are modulated depending on various factors including species, steroidogenic tissues and steroidogenic enzymes. Looking at the whole picture of steroids, PREG is often known as the precursor to other steroids and not as an active steroid per se. Actually, physiological and brain functions have been studied mainly for steroids that are very active either binding to specific intracellular receptors, or modulating with high affinity the abundant membrane receptors, GABAA or NMDA receptors. However, when high sensitive and specific methodological approaches were available to analyze low concentrations of steroids and then match endogenous levels of different steroid metabolomes, several studies have reported more significant alterations in PREG than in other steroids in extraphysiological or pathological conditions, suggesting that PREG could play a functional role as well. Additionally, several molecular targets of PREG were revealed in the mammalian brain and beneficial effects of PREG have been demonstrated in preclinical and clinical studies. On this basis, this review will be divided into three parts. The first provides a brief overview of the molecular targets of PREG and the pharmacological effects observed in animal and human studies. The second will focus on the possible functional role of PREG with an outline of the modulation of PREG levels in animal and in

  1. Nuclear receptor coregulators as a new paradigm for therapeutic targeting

    PubMed Central

    Hsia, Elaine Y.; Goodson, Michael L.; Zou, June X.; Privalsky, Martin L.; Chen, Hong-Wu

    2012-01-01

    The complex function and regulation of nuclear receptors cannot be fully understood without a thorough knowledge of the receptor-associated coregulators that either enhance (coactivators) or inhibit (corepressors) transcription. While nuclear receptors themselves have garnered much attention as therapeutic targets, the clinical and etiological relevance of the coregulators to human diseases is increasingly recognized. Aberrant expression or function of coactivators and corepressors has been associated with malignant and metabolic disease development. Many of them are key epigenetic regulators and utilize enzymatic activities to modify chromatin through histone acetylation/deacetylation, histone methylation/demethylation or chromatin remodeling. In this review, we showcase and evaluate coregulators with the most promising therapeutic potential based on their physiological roles and involvement in various diseases that are revealed thus far. We also describe the structural features of the coactivator and corepressor functional domains and highlight areas that can be further explored for molecular targeting. PMID:20933027

  2. The Pharmacology of TUG-891, a Potent and Selective Agonist of the Free Fatty Acid Receptor 4 (FFA4/GPR120), Demonstrates Both Potential Opportunity and Possible Challenges to Therapeutic Agonism

    PubMed Central

    Hudson, Brian D.; Shimpukade, Bharat; Mackenzie, Amanda E.; Butcher, Adrian J.; Pediani, John D.; Christiansen, Elisabeth; Heathcote, Helen; Tobin, Andrew B.; Ulven, Trond

    2013-01-01

    TUG-891 [3-(4-((4-fluoro-4′-methyl-[1,1′-biphenyl]-2-yl)methoxy)phenyl)propanoic acid] was recently described as a potent and selective agonist for the long chain free fatty acid (LCFA) receptor 4 (FFA4; previously G protein–coupled receptor 120, or GPR120). Herein, we have used TUG-891 to further define the function of FFA4 and used this compound in proof of principle studies to indicate the therapeutic potential of this receptor. TUG-891 displayed similar signaling properties to the LCFA α-linolenic acid at human FFA4 across various assay end points, including stimulation of Ca2+ mobilization, β-arrestin-1 and β-arrestin-2 recruitment, and extracellular signal-regulated kinase phosphorylation. Activation of human FFA4 by TUG-891 also resulted in rapid phosphorylation and internalization of the receptor. While these latter events were associated with desensitization of the FFA4 signaling response, removal of TUG-891 allowed both rapid recycling of FFA4 back to the cell surface and resensitization of the FFA4 Ca2+ signaling response. TUG-891 was also a potent agonist of mouse FFA4, but it showed only limited selectivity over mouse FFA1, complicating its use in vivo in this species. Pharmacologic dissection of responses to TUG-891 in model murine cell systems indicated that activation of FFA4 was able to mimic many potentially beneficial therapeutic properties previously reported for LCFAs, including stimulating glucagon-like peptide-1 secretion from enteroendocrine cells, enhancing glucose uptake in 3T3-L1 adipocytes, and inhibiting release of proinflammatory mediators from RAW264.7 macrophages, which suggests promise for FFA4 as a therapeutic target for type 2 diabetes and obesity. Together, these results demonstrate both potential but also significant challenges that still need to be overcome to therapeutically target FFA4. PMID:23979972

  3. The pharmacology of TUG-891, a potent and selective agonist of the free fatty acid receptor 4 (FFA4/GPR120), demonstrates both potential opportunity and possible challenges to therapeutic agonism.

    PubMed

    Hudson, Brian D; Shimpukade, Bharat; Mackenzie, Amanda E; Butcher, Adrian J; Pediani, John D; Christiansen, Elisabeth; Heathcote, Helen; Tobin, Andrew B; Ulven, Trond; Milligan, Graeme

    2013-11-01

    TUG-891 [3-(4-((4-fluoro-4'-methyl-[1,1'-biphenyl]-2-yl)methoxy)phenyl)propanoic acid] was recently described as a potent and selective agonist for the long chain free fatty acid (LCFA) receptor 4 (FFA4; previously G protein-coupled receptor 120, or GPR120). Herein, we have used TUG-891 to further define the function of FFA4 and used this compound in proof of principle studies to indicate the therapeutic potential of this receptor. TUG-891 displayed similar signaling properties to the LCFA α-linolenic acid at human FFA4 across various assay end points, including stimulation of Ca²⁺ mobilization, β-arrestin-1 and β-arrestin-2 recruitment, and extracellular signal-regulated kinase phosphorylation. Activation of human FFA4 by TUG-891 also resulted in rapid phosphorylation and internalization of the receptor. While these latter events were associated with desensitization of the FFA4 signaling response, removal of TUG-891 allowed both rapid recycling of FFA4 back to the cell surface and resensitization of the FFA4 Ca²⁺ signaling response. TUG-891 was also a potent agonist of mouse FFA4, but it showed only limited selectivity over mouse FFA1, complicating its use in vivo in this species. Pharmacologic dissection of responses to TUG-891 in model murine cell systems indicated that activation of FFA4 was able to mimic many potentially beneficial therapeutic properties previously reported for LCFAs, including stimulating glucagon-like peptide-1 secretion from enteroendocrine cells, enhancing glucose uptake in 3T3-L1 adipocytes, and inhibiting release of proinflammatory mediators from RAW264.7 macrophages, which suggests promise for FFA4 as a therapeutic target for type 2 diabetes and obesity. Together, these results demonstrate both potential but also significant challenges that still need to be overcome to therapeutically target FFA4. PMID:23979972

  4. [Therapeutic potential of optogenetic neuromodulation].

    PubMed

    Vandecasteele, Marie; Senova, Yann-Suhan; Palfi, Stéphane; Dugué, Guillaume P

    2015-04-01

    Optogenetic neuromodulation techniques, which have emerged during the last 15 years, have considerably enhanced our ability to probe the functioning of neural circuits by allowing the excitation and inhibition of genetically-defined neuronal populations using light. Having gained tremendous popularity in the field of fundamental neuroscience, these techniques are now opening new therapeutic avenues. Optogenetic neuromodulation is a method of choice for studying the physiopathology of neurological and neuropsychiatric disorders in a range of animal models, and could accelerate the discovery of new therapeutic strategies. New therapeutic protocols employing optogenetic neuromodulation may also emerge in the near future, offering promising alternative approaches for disorders which lack appropriate treatments, such as pharmacoresistant epilepsy and inherited retinal degeneration. PMID:25958759

  5. Therapeutic potential of atmospheric neutrons

    PubMed Central

    Voyant, Cyril; Roustit, Rudy; Tatje, Jennifer; Biffi, Katia; Leschi, Delphine; Briançon, Jérome; Marcovici, Céline Lantieri

    2010-01-01

    Background Glioblastoma multiform (GBM) is the most common and most aggressive type of primary brain tumour in humans. It has a very poor prognosis despite multi-modality treatments consisting of open craniotomy with surgical resection, followed by chemotherapy and/or radiotherapy. Recently, a new treatment has been proposed – Boron Neutron Capture Therapy (BNCT) – which exploits the interaction between Boron-10 atoms (introduced by vector molecules) and low energy neutrons produced by giant accelerators or nuclear reactors. Methods The objective of the present study is to compute the deposited dose using a natural source of neutrons (atmospheric neutrons). For this purpose, Monte Carlo computer simulations were carried out to estimate the dosimetric effects of a natural source of neutrons in the matter, to establish if atmospheric neutrons interact with vector molecules containing Boron-10. Results The doses produced (an average of 1 μGy in a 1 g tumour) are not sufficient for therapeutic treatment of in situ tumours. However, the non-localised yet specific dosimetric properties of 10B vector molecules could prove interesting for the treatment of micro-metastases or as (neo)adjuvant treatment. On a cellular scale, the deposited dose is approximately 0.5 Gy/neutron impact. Conclusion It has been shown that BNCT may be used with a natural source of neutrons, and may potentially be useful for the treatment of micro-metastases. The atmospheric neutron flux is much lower than that utilized during standard NBCT. However the purpose of the proposed study is not to replace the ordinary NBCT but to test if naturally occurring atmospheric neutrons, considered to be an ionizing pollution at the Earth's surface, can be used in the treatment of a disease such as cancer. To finalize this study, it is necessary to quantify the biological effects of the physically deposited dose, taking into account the characteristics of the incident particles (alpha particle and Lithium

  6. Potential new therapeutic targets for pathological pruritus.

    PubMed

    Kuraishi, Yasushi

    2013-01-01

    Very few approved medications are indicated for the treatment of pruritus, and drug development for pruritic diseases is awaited. During the past two decades, progress has been made in understanding the molecular basis of the physiology and pathophysiology of pruritus. Newly identified potential targets for pathological pruritus include receptors (histamine H4 receptor, leukotriene B4 receptors, interleukin-31 receptor A, bombesin BB2 receptor, toll-like receptor 3, α-adrenoceptor, and opioid μ- and κ-receptors), channels (transient receptor potential (TRP) V3 and TRPA1 channels), and enzymes (histidine decarboxylase, sphingomyelin glucosylceramide deacylase, 5-lipoxygenase, leukotriene A4 hydrolase, and autotaxin). The development of specific, effective blockers and agonists/antagonists of these targets is awaited. PMID:23902965

  7. TRAIL death receptors and cancer therapeutics

    SciTech Connect

    Huang Ying Sheikh, M. Saeed

    2007-11-01

    Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) also known as Apo2L is an apoptotic molecule that belongs to the tumor necrosis factor superfamily of cytokines. It mediates its apoptotic effects via its cognate death receptors including DR4 and DR5. Agonistic monoclonal antibodies have also been developed that selectively activate TRAIL death receptors to mediate apoptosis. Multiple clinically relevant agents also upregulate the expression of TRAIL death receptors, and cooperate with TRAIL as well as DR4 and DR5-specific agonistic antibodies to exhibit tumor cell killing. TRAIL is currently in phase I clinical trials, whereas DR4 and DR5-specific agonistic antibodies have been tested in phase I and II studies. Thus, TRAIL has clearly distinguished itself from the other family members including TNF-alpha and FasL both of which could not make it to the clinic due to their toxic nature. It is therefore, evident that the future of TRAIL-based therapeutic approaches looks brighter.

  8. Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis.

    PubMed

    Macrez, Richard; Ortega, Maria C; Bardou, Isabelle; Mehra, Anupriya; Fournier, Antoine; Van der Pol, Susanne M A; Haelewyn, Benoit; Maubert, Eric; Lesept, Flavie; Chevilley, Arnaud; de Castro, Fernando; De Vries, Helga E; Vivien, Denis; Clemente, Diego; Docagne, Fabian

    2016-09-01

    Multiple sclerosis is among the most common causes of neurological disability in young adults. Here we provide the preclinical proof of concept of the benefit of a novel strategy of treatment for multiple sclerosis targeting neuroendothelial N-methyl-D-aspartate glutamate receptors. We designed a monoclonal antibody against N-methyl-D-aspartate receptors, which targets a regulatory site of the GluN1 subunit of N-methyl-D-aspartate receptor sensitive to the protease tissue plasminogen activator. This antibody reverted the effect of tissue plasminogen activator on N-methyl-D-aspartate receptor function without affecting basal N-methyl-D-aspartate receptor activity (n = 21, P < 0.01). This antibody bound N-methyl-D-aspartate receptors on the luminal surface of neurovascular endothelium in human tissues and in mouse, at the vicinity of tight junctions of the blood-spinal cord barrier. Noteworthy, it reduced human leucocyte transmigration in an in vitro model of the blood-brain barrier (n = 12, P < 0.05). When injected during the effector phase of MOG-induced experimental autoimmune encephalomyelitis (n = 24), it blocked the progression of neurological impairments, reducing cumulative clinical score (P < 0.001) and mean peak score (P < 0.001). This effect was observed in wild-type animals but not in tissue plasminogen activator knock-out animals (n = 10). This therapeutic effect was associated to a preservation of the blood-spinal cord barrier (n = 6, P < 0.001), leading to reduced leucocyte infiltration (n = 6, P < 0.001). Overall, this study unveils a critical function of endothelial N-methyl-D-aspartate receptor in multiple sclerosis, and highlights the therapeutic potential of strategies targeting the protease-regulated site of N-methyl-D-aspartate receptor. PMID:27435092

  9. The Serotonin-6 Receptor as a Novel Therapeutic Target

    PubMed Central

    Yun, Hyung-Mun

    2011-01-01

    Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that is found in both the central and peripheral nervous systems. 5-HT mediates its diverse physiological responses through 7 different 5-HT receptor families: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors. Among them, the 5-HT6 receptor (5-HT6R) is the most recently cloned serotonin receptor and plays important roles in the central nervous system (CNS) and in the etiology of neurological diseases. Compared to other 5-HT receptors, the 5-HT6R has been considered as an attractive CNS therapeutic target because it is expressed exclusively in the CNS and has no known isoforms. This review evaluates in detail the role of the 5-HT6R in the physiology and pathophysiology of the CNS and the potential usefulness of 5-HT6R ligands in the development of therapeutic strategies for the treatment of CNS disorders. Preclinical studies provide support for the use of 5-HT6R ligands as promising medications to treat the cognitive dysfunction associated with Alzheimer's disease, obesity, depression, and anxiety. PMID:22355260

  10. TAM Receptors in Leukemia: Expression, Signaling, and Therapeutic Implications

    PubMed Central

    Brandão, Luis; Migdall-Wilson, Justine; Eisenman, Kristen; Graham, Douglas K.

    2016-01-01

    In the past 30 years there has been remarkable progress in the treatment of leukemia and lymphoma. However, current treatments are largely ineffective against relapsed leukemia and, in the case of pediatric patients, are often associated with severe long-term toxicities. Thus, there continues to be a critical need for the development of effective biologically targeted therapies. The TAM family of receptor tyrosine kinases—Tyro3, Axl, and Mer—plays an important role in normal hematopoiesis, including natural killer cell maturation, macrophage function, and platelet activation and signaling. Furthermore, TAM receptor activation leads to upregulation of pro-survival and proliferation signaling pathways, and aberrant TAM receptor expression contributes to cancer development, including myeloid and lymphoid leukemia. This review summarizes the role of TAM receptors in leukemia. We outline TAM receptor expression patterns in different forms of leukemia, describe potential mechanisms leading to their overexpression, and delineate the signaling pathways downstream of receptor activation that have been implicated in leukemogenesis. Finally, we discuss the current research focused on inhibitors against these receptors in an effort to develop new therapeutic strategies for leukemia. PMID:22150307

  11. Anticancer therapeutic potential of soy isoflavone, genistein.

    PubMed

    Ravindranath, Mepur H; Muthugounder, Sakunthala; Presser, Naftali; Viswanathan, Subramanian

    2004-01-01

    to recombinant EGF to target cancers overexpressing the EGF receptor. Although genistein has many potentially therapeutic actions against cancer, its biphasic bioactivity (inhibitory at high concentrations and activating at low concentrations) requires caution in determining therapeutic doses of genistein alone or in combination with chemotherapy, radiation therapy, and/or immunotherapies. Of the more than 4500 genistein studies in peer-reviewed primary publications, almost one fifth pertain to its antitumor capabilities and more than 400 describe its mechanism of action in normal and malignant human and animal cells, animal models, in vitro experiments, or phase I/II clinical trials. Several biotechnological firms in Japan, Australia and in the United States (e.g., Nutrilite) manufacture genistein as a natural supplement under quality controlled and assured conditions. PMID:15584372

  12. The autotaxin-lysophosphatidic acid-lysophosphatidic acid receptor cascade: proposal of a novel potential therapeutic target for treating glioblastoma multiforme.

    PubMed

    Tabuchi, Sadaharu

    2015-01-01

    Glioblastoma multiforme (GBM) is the most malignant tumor of the central nervous system (CNS). Its prognosis is one of the worst among all cancer types, and it is considered a fatal malignancy, incurable with conventional therapeutic strategies. As the bioactive multifunctional lipid mediator lysophosphatidic acid (LPA) is well recognized to be involved in the tumorigenesis of cancers by acting on G-protein-coupled receptors, LPA receptor (LPAR) antagonists and LPA synthesis inhibitors have been proposed as promising drugs for cancer treatment. Six LPARs, named LPA1-6, are currently recognized. Among them, LPA1 is the dominant LPAR in the CNS and is highly expressed in GBM in combination with the overexpression of autotaxin (ATX), the enzyme (a phosphodiesterase, which is a potent cell motility-stimulating factor) that produces LPA.Invasion is a defining hallmark of GBM. LPA is significantly related to cell adhesion, cell motility, and invasion through the Rho family GTPases Rho and Rac. LPA1 is responsible for LPA-driven cell motility, which is attenuated by LPA4. GBM is among the most vascular human tumors. Although anti-angiogenic therapy (through the inhibition of vascular endothelial growth factor (VEGF)) was established, sufficient results have not been obtained because of the increased invasiveness triggered by anti-angiogenesis. As both ATX and LPA play a significant role in angiogenesis, similar to VEGF, inhibition of the ATX/LPA axis may be beneficial as a two-pronged therapy that includes anti-angiogenic and anti-invasion therapy. Conventional approaches to GBM are predominantly directed at cell proliferation. Recurrent tumors regrow from cells that have invaded brain tissues and are less proliferative, and are thus quite resistant to conventional drugs and radiation, which preferentially kill rapidly proliferating cells. A novel approach that targets this invasive subpopulation of GBM cells may improve the prognosis of GBM. Patients with GBM that

  13. Ligand regulation of retinoic acid receptor-related orphan receptors: implications for development of novel therapeutics

    PubMed Central

    Solt, Laura A.; Griffin, Patrick R.; Burris, Thomas P.

    2016-01-01

    Purpose of review In the late 1980s, the cloning of several nuclear receptors led to the intense search and isolation of new members of this superfamily. Despite their identification, many of these receptors were dubbed ‘orphan’ receptors, as their physiological ligands remained unknown. Recent reports have presented evidence for one family of orphan receptors, the retinoic acid receptor-related orphan receptors (RORs), in several pathologies, including osteoporosis, several autoimmune diseases, asthma, cancer, diabetes and obesity. The present review summarizes the studies identifying ligands for the RORs and evaluates their role as targets for potential therapeutics. Recent findings Significant progress was made in the initial identification of ligands for the RORs when X-ray crystallographic studies identified several molecules within the ligand-binding pockets of RORα and RORβ. Recently, we identified endogenous and synthetic ligands for RORα and RORγ, thereby solidifying their function as ligand-dependent transcription factors. Summary Recent studies have established roles for the RORs in physiological development and the advent of disease. Identification of ligands for the RORs, both endogenous and synthetic, has established these receptors as attractive new therapeutic targets for the treatment of ROR-related diseases. PMID:20463469

  14. Therapeutic potential of the dual peroxisome proliferator activated receptor (PPAR)α/γ agonist aleglitazar in attenuating TNF-α-mediated inflammation and insulin resistance in human adipocytes.

    PubMed

    Massaro, Marika; Scoditti, Egeria; Pellegrino, Mariangela; Carluccio, Maria Annunziata; Calabriso, Nadia; Wabitsch, Martin; Storelli, Carlo; Wright, Matthew; De Caterina, Raffaele

    2016-05-01

    Adipose tissue inflammation is a mechanistic link between obesity and its related sequelae, including insulin resistance and type 2 diabetes. Dual ligands of peroxisome proliferator activated receptor (PPAR)α and γ, combining in a single molecule the metabolic and inflammatory-regulatory properties of α and γ agonists, have been proposed as a promising therapeutic strategy to antagonize adipose tissue inflammation. Here we investigated the effects of the dual PPARα/γ agonist aleglitazar on human adipocytes challenged with inflammatory stimuli. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were treated with aleglitazar or - for comparison - the selective agonists for PPARα or γ fenofibrate or rosiglitazone, respectively, for 24h before stimulation with TNF-α. Aleglitazar, at concentrations as low as 10nmol/L, providing the half-maximal transcriptional activation of both PPARα and PPARγ, reduced the stimulated expression of several pro-inflammatory mediators including interleukin (IL)-6, the chemokine CXC-L10, and monocyte chemoattractant protein (MCP)-1. Correspondingly, media from adipocytes treated with aleglitazar reduced monocyte migration, consistent with suppression of MCP-1 secretion. Under the same conditions, aleglitazar also reversed the TNF-α-mediated suppression of insulin-stimulated ser473 Akt phosphorylation and decreased the TNF-α-induced ser312 IRS1 phosphorylation, two major switches in insulin-mediated metabolic activities, restoring glucose uptake in insulin-resistant adipocytes. Such effects were similar to those obtainable with a combination of single PPARα and γ agonists. In conclusion, aleglitazar reduces inflammatory activation and dysfunction in insulin signaling in activated adipocytes, properties that may benefit diabetic and obese patients. The effect of aleglitazar was consistent with dual PPARα and γ agonism, but with no evidence of synergism. PMID:26976796

  15. Pharmacology of nociceptin and its receptor: a novel therapeutic target

    PubMed Central

    Calo', Girolamo; Guerrini, Remo; Rizzi, Anna; Salvadori, Severo; Regoli, Domenico

    2000-01-01

    Nociceptin (NC), alias Orphanin FQ, has been recently identified as the endogenous ligand of the opioid receptor-like 1 receptor (OP4). This new NC/OP4 receptor system belongs to the opioid family and has been characterized pharmacologically with functional and binding assays on native (mouse, rat, guinea-pig) and recombinant (human) receptors, by using specific and selective agonists (NC, NC(1–13)NH2) and a pure and competitive antagonist, [Nphe1]NC(1–13)NH2. The similar order of potency of agonists and affinity values of the antagonist indicate that the same receptor is present in the four species. OP4 is expressed in neurons, where it reduces activation of adenylyl cyclase and Ca2+ channels while activating K+ channels in a manner similar to opioids. In this way, OP4 mediates inhibitory effects in the autonomic nervous system, but its activities in the central nervous system can be either similar or opposite to those of opioids. In vivo experiments have demonstrated that NC modulates a variety of biological functions ranging from nociception to food intake, from memory processes to cardiovascular and renal functions, from spontaneous locomotor activity to gastrointestinal motility, from anxiety to the control of neurotransmitter release at peripheral and central sites. These actions have been demonstrated using NC and various pharmacological tools, as antisense oligonucleotides targeting OP4 or the peptide precursor genes, antibodies against NC, an OP4 receptor selective antagonist and with data obtained from animals in which the receptor or the peptide precursor genes were knocked out. These new advances have contributed to better understanding of the pathophysiological role of the NC/OP4 system, and ultimately will help to identify the therapeutic potential of new OP4 receptor ligands. PMID:10742280

  16. Molecular pathways: targeting resistance in the androgen receptor for therapeutic benefit.

    PubMed

    Mostaghel, Elahe A; Plymate, Stephen R; Montgomery, Bruce

    2014-02-15

    Androgen receptor signaling is critical in the development and progression of prostate cancer, leading to intensive efforts to elucidate all potential points of inflection for therapeutic intervention. These efforts have revealed new mechanisms of resistance and raise the possibility that known mechanisms may become even more relevant in the context of effective androgen receptor suppression. These mechanisms include tumoral appropriation of alternative androgen sources, alterations in androgen receptor expression, androgen receptor mutations, truncated androgen receptor variants, alterations and cross-talk in recruitment of cofactors to androgen receptor binding sites in the genome, and androgen receptor-driven oncogenic gene fusions. New agents such as enzalutamide, EPI-001, androgen receptor-specific peptidomimetics, novel HSP90 inhibitors, and PARP inhibitors, as well as new approaches to cotargeting the androgen receptor pathway, point to the potential for more complete and durable control of androgen receptor-mediated growth. PMID:24305618

  17. Therapeutic potential of monoacylglycerol lipase inhibitors.

    PubMed

    Mulvihill, Melinda M; Nomura, Daniel K

    2013-03-19

    Marijuana and aspirin have been used for millennia to treat a wide range of maladies including pain and inflammation. Both cannabinoids, like marijuana, that exert anti-inflammatory action through stimulating cannabinoid receptors, and cyclooxygenase (COX) inhibitors, like aspirin, that suppress pro-inflammatory eicosanoid production have shown beneficial outcomes in mouse models of neurodegenerative diseases and cancer. Both cannabinoids and COX inhibitors, however, have untoward effects that discourage their chronic usage, including cognitive deficits and gastrointestinal toxicity, respectively. Recent studies have uncovered that the serine hydrolase monoacylglycerol lipase (MAGL) links the endocannabinoid and eicosanoid systems together through hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG) to provide the major arachidonic acid (AA) precursor pools for pro-inflammatory eicosanoid synthesis in specific tissues. Studies in recent years have shown that MAGL inhibitors elicit anti-nociceptive, anxiolytic, and anti-emetic responses and attenuate precipitated withdrawal symptoms in addiction paradigms through enhancing endocannabinoid signaling. MAGL inhibitors have also been shown to exert anti-inflammatory action in the brain and protect against neurodegeneration through lowering eicosanoid production. In cancer, MAGL inhibitors have been shown to have anti-cancer properties not only through modulating the endocannabinoid-eicosanoid network, but also by controlling fatty acid release for the synthesis of protumorigenic signaling lipids. Thus, MAGL serves as a critical node in simultaneously coordinating multiple lipid signaling pathways in both physiological and disease contexts. This review will discuss the diverse (patho)physiological roles of MAGL and the therapeutic potential of MAGL inhibitors in treating a vast array of complex human diseases. PMID:23142242

  18. The Pregnane X Receptor in Tuberculosis Therapeutics

    PubMed Central

    Shehu, Amina I.; Li, Guangming; Xie, Wen; Ma, Xiaochao

    2016-01-01

    Introduction Among the infectious diseases, tuberculosis (TB) remains the second cause of death after HIV. TB treatment requires the combination of multiple drugs including the rifamycin class. However, rifamycins are activators of human pregnane X receptor (PXR), a transcription factor that regulates drug metabolism, drug resistance, energy metabolism, and immune response. Rifamycin-mediated PXR activation may affect the outcome of TB therapy. Areas covered This review describes the role of PXR in modulating metabolism, efficacy, toxicity, and resistance to anti-TB drugs; as well as polymorphisms of PXR that potentially affect TB susceptibility. Expert opinion The wide range of PXR functions aside mediating drug metabolism and toxicity in TB therapy is underappreciated and thus understudied. Further studies are needed to determine the overall impact of PXR activation on the outcome of TB therapy. PMID:26592418

  19. Therapeutic potential of curcumin in gastrointestinal diseases.

    PubMed

    Rajasekaran, Sigrid A

    2011-02-15

    Curcumin, also known as diferuloylmethane, is derived from the plant Curcuma longa and is the active ingredient of the spice turmeric. The therapeutic activities of curcumin for a wide variety of diseases such as diabetes, allergies, arthritis and other chronic and inflammatory diseases have been known for a long time. More recently, curcumin's therapeutic potential for preventing and treating various cancers is being recognized. As curcumin's therapeutic promise is being explored more systematically in various diseases, it has become clear that, due to its increased bioavailability in the gastrointestinal tract, curcumin may be particularly suited to be developed to treat gastrointestinal diseases. This review summarizes some of the current literature of curcumin's anti-inflammatory, anti-oxidant and anti-cancer potential in inflammatory bowel diseases, hepatic fibrosis and gastrointestinal cancers. PMID:21607160

  20. Rapastinel (GLYX-13) has therapeutic potential for the treatment of post-traumatic stress disorder: Characterization of a NMDA receptor-mediated metaplasticity process in the medial prefrontal cortex of rats.

    PubMed

    Burgdorf, Jeffrey; Kroes, Roger A; Zhang, Xiao-lei; Gross, Amanda L; Schmidt, Mary; Weiss, Craig; Disterhoft, John F; Burch, Ronald M; Stanton, Patric K; Moskal, Joseph R

    2015-11-01

    Rapastinel (GLYX-13) is a NMDA receptor modulator with glycine-site partial agonist properties. It is a robust cognitive enhancer and shows rapid and long-lasting antidepressant properties in both animal models and in humans. Contextual fear extinction (CFE) in rodents has been well characterized and used extensively as a model to study the neurobiological mechanisms of post-traumatic stress disorder (PTSD). Since CFE is NMDA receptor modulated and neural circuitry in the medial prefrontal cortex (MPFC) regulates both depression and PTSD, studies were undertaken to examine the effects of rapastinel for its therapeutic potential in PTSD and to use rapastinel as a tool to study its underlying glutamatergic mechanisms. A 21-day chronic mild unpredictable stress (CUS) rat model was used to model depression and PTSD. The effects of CUS alone compared to No CUS controls, and the effects of rapastinel (3 mg/kg IV) on CUS-treated animals were examined. The effect of rapastinel was first assessed using CUS-treated rats in three depression models, Porsolt, sucrose preference, and novelty-induced hypophagia tests, and found to produce a complete reversal of the depressive-like state in each model. Rapastinel was then assessed in a MPFC-dependent positive emotional learning paradigm and in CFE and again a reversal of the impairments induced by CUS treatment was observed. Both synaptic plasticity and metaplasticity, as measured by the induction of long-term potentiation in rat MPFC slice preparations, was found to be markedly impaired in CUS-treated animals. This impairment was reversed when CUS-treated rats were administered rapastinel and tested 24 h later. Transcriptomic analysis of MPFC mRNA expression in CUS-treated rats corroborated the link between rapastinel's behavioral effects and synaptic plasticity. A marked enrichment in both the LTP and LTD connectomes in rapastinel-treated CUS rats was observed compared to CUS-treated controls. The effects of rapastinel on

  1. Prostanoid receptor antagonists: development strategies and therapeutic applications

    PubMed Central

    Jones, RL; Giembycz, MA; Woodward, DF

    2009-01-01

    Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP1, EP2 …) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP1, TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP2). While some antagonists are structurally related to the natural agonist, most recent compounds are ‘non-prostanoid’ (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD2 (acting on DP1 and DP2 receptors) and PGE2 (on EP1 and EP4 receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage. PMID:19624532

  2. Tumour vasculature--a potential therapeutic target.

    PubMed Central

    Baillie, C. T.; Winslet, M. C.; Bradley, N. J.

    1995-01-01

    The tumour vasculature is vital for the establishment, growth and metastasis of solid tumours. Its physiological properties limit the effectiveness of conventional anti-cancer strategies. Therapeutic approaches directed at the tumour vasculature are reviewed, suggesting the potential of anti-angiogenesis and the targeting of vascular proliferation antigens as cancer treatments. PMID:7543770

  3. Transferrin: structure, function and potential therapeutic actions.

    PubMed

    Gomme, Peter T; McCann, Karl B; Bertolini, Joseph

    2005-02-15

    There are many proteins that can multi-task. Transferrin, widely known as an iron-binding protein, is one such example of a multi-tasking protein. In this review, the multiple biological actions of transferrin, including its growth and cytoprotective activities, are discussed with the view of highlighting the potential therapeutic applications of this protein. PMID:15708745

  4. Ubiquitylation of Nuclear Receptors: New Linkages and Therapeutic Implications

    PubMed Central

    Helzer, Kyle T.; Hooper, Christopher; Miyamoto, Shigeki; Alarid, Elaine T.

    2015-01-01

    The nuclear receptor superfamily is a group of transcriptional regulators that control multiple aspects of both physiology and pathology, and are broadly recognized as viable therapeutic targets. While receptor-modulating drugs have been successful in many cases, the discovery of new drug targets is still an active area of research, because resistance to nuclear receptor-targeting therapies remains a significant clinical challenge. Many successful targeted therapies have harnessed the control of receptor activity by targeting events within the nuclear receptor signaling pathway. In this review, we explore the role of nuclear receptor ubiquitylation and discuss how the expanding roles of ubiquitin might be leveraged to identify additional entry points to control receptor function for future therapeutic development. PMID:25943391

  5. Use of heteropolymeric monoclonal antibodies to attach antigens to the C3b receptor of human erythrocytes: A potential therapeutic treatment

    SciTech Connect

    Taylor, R.P.; Sutherland, W.M.; Reist, C.J.; Webb, D.J.; Wright, E.L.; Labuguen, R.H. )

    1991-04-15

    The authors prepared bispecific, cross-linked monoclonal antibodies (heteropolymers) with specificity for both targeted antigens and the human erythrocyte (RBC) complement receptor. These heteropolymers facilitate binding of target antigens (human IgG and dinitrophenylated bovine {gamma} globulin) to human RBCs under conditions that either allow or preclude complement activation. Radioimmuno-assay analyses of this binding agree well with the number of complement receptors per RBC. In vitro whole-blood model experiments indicate heteropolymer-facilitated binding of antigens to RBCs is rapid and stable at 37C. It may be possible to extend these prototype experiments to the in vivo situation and use heteropolymer-attached RBCs for the safe and rapid binding, neutralization, and removal from the circulation of pathogenic antigens associated with infectious disease.

  6. Testing NMDA receptor block as a therapeutic strategy for reducing ischaemic damage to CNS white matter.

    PubMed

    Bakiri, Yamina; Hamilton, Nicola B; Káradóttir, Ragnhildur; Attwell, David

    2008-01-15

    Damage to oligodendrocytes caused by glutamate release contributes to mental or physical handicap in periventricular leukomalacia, spinal cord injury, multiple sclerosis, and stroke, and has been attributed to activation of AMPA/kainate receptors. However, glutamate also activates unusual NMDA receptors in oligodendrocytes, which can generate an ion influx even at the resting potential in a physiological [Mg2+]. Here, we show that the clinically licensed NMDA receptor antagonist memantine blocks oligodendrocyte NMDA receptors at concentrations achieved therapeutically. Simulated ischaemia released glutamate which activated NMDA receptors, as well as AMPA/kainate receptors, on mature and precursor oligodendrocytes. Although blocking AMPA/kainate receptors alone during ischaemia had no effect, combining memantine with an AMPA/kainate receptor blocker, or applying the NMDA blocker MK-801 alone, improved recovery of the action potential in myelinated axons after the ischaemia. These data suggest NMDA receptor blockers as a potentially useful treatment for some white matter diseases and define conditions under which these blockers may be useful therapeutically. Our results highlight the importance of developing new antagonists selective for oligodendrocyte NMDA receptors based on their difference in subunit structure from most neuronal NMDA receptors. PMID:18046734

  7. Harnessing Fc receptor biology in the design of therapeutic antibodies.

    PubMed

    Sondermann, Peter; Szymkowski, David E

    2016-06-01

    The antibody Fc domain engages the small family of Fc receptors, expressed on cells of the immune system and beyond, to stimulate a rich diversity of positive and negative cell-mediated effector functions. The emergence of monoclonal antibodies for the treatment of various pathologic conditions has provided additional insights into Fc receptor biology, and has suggested new strategies to exploit Fc receptor interactions to create improved therapeutics. While most therapeutic IgGs approved to date have retained a native IgG Fc domain, the knowledge gained over the last decades has provided the opportunity to design tailored and more efficacious immunotherapies exhibiting fewer side effects and longer half-life. This review summarizes recent advances made in the design of biologics that modulate or exploit Fc receptor-IgG interactions, and describes innovative drugs currently under investigation in clinical trials that have been precisely tuned to achieve a desired therapeutic effect. PMID:27038127

  8. Therapeutic potential of cannabis-related drugs.

    PubMed

    Alexander, Stephen P H

    2016-01-01

    In this review, I will consider the dual nature of Cannabis and cannabinoids. The duality arises from the potential and actuality of cannabinoids in the laboratory and clinic and the 'abuse' of Cannabis outside the clinic. The therapeutic areas currently best associated with exploitation of Cannabis-related medicines include pain, epilepsy, feeding disorders, multiple sclerosis and glaucoma. As with every other medicinal drug of course, the 'trick' will be to maximise the benefit and minimise the cost. After millennia of proximity and exploitation of the Cannabis plant, we are still playing catch up with an understanding of its potential influence for medicinal benefit. PMID:26216862

  9. Orexin Receptors: Pharmacology and Therapeutic Opportunities

    PubMed Central

    Scammell, Thomas E.; Winrow, Christopher J.

    2011-01-01

    Orexin-A and -B (also known as hypocretin-1 and -2) are neuropeptides produced in the lateral hypothalamus that promote many aspects of arousal through the OX1 and OX2 receptors. In fact, they are necessary for normal wakefulness, as loss of the orexin-producing neurons causes narcolepsy in humans and rodents. This has generated considerable interest in developing small-molecule orexin receptor antagonists as a novel therapy for the treatment of insomnia. Orexin antagonists, especially those that block OX2 or both OX1 and OX2 receptors, clearly promote sleep in animals, and clinical results are encouraging: Several compounds are in Phase III trials. As the orexin system mainly promotes arousal, these new compounds will likely improve insomnia without incurring many of the side effects encountered with current medications. PMID:21034217

  10. Novel bifunctional natriuretic peptides as potential therapeutics.

    PubMed

    Dickey, Deborah M; Burnett, John C; Potter, Lincoln R

    2008-12-12

    Synthetic atrial natriuretic peptide (carperitide) and B-type natriuretic peptide (BNP; nesiritide) are used to treat congestive heart failure. However, despite beneficial cardiac unloading properties, reductions in renal perfusion pressures limit their clinical effectiveness. Recently, CD-NP, a chimeric peptide composed of C-type natriuretic peptide (CNP) fused to the C-terminal tail of Dendroaspis natriuretic peptide (DNP), was shown to be more glomerular filtration rate-enhancing than BNP in dogs. However, the molecular basis for the increased responsiveness was not determined. Here, we show that the DNP tail has a striking effect on CNP, converting it from a non-agonist to a partial agonist of natriuretic peptide receptor (NPR)-A while maintaining the ability to activate NPR-B. This effect is specific for human receptors because CD-NP was only a slightly better activator of rat NPR-A due to the promiscuous nature of CNP in this species. Interesting, the DNP tail alone had no effect on any NPR even though it is effective in vivo. To further increase the potency of CD-NP for NPR-A, we converted two different triplet sequences within the CNP ring to their corresponding residues in BNP. Both variants demonstrated increased affinity and full agonist activity for NPR-A, whereas one was as potent as any NPR-A activator known. In contrast to a previous report, we found that DNP binds the natriuretic peptide clearance receptor (NPR-C). However, none of the chimeric peptides bound NPR-C with significantly higher affinity than endogenous ligands. We suggest that bifunctional chimeric peptides represent a new generation of natriuretic peptide therapeutics. PMID:18940797

  11. Novel Bifunctional Natriuretic Peptides as Potential Therapeutics*

    PubMed Central

    Dickey, Deborah M.; Burnett, John C.; Potter, Lincoln R.

    2008-01-01

    Synthetic atrial natriuretic peptide (carperitide) and B-type natriuretic peptide (BNP; nesiritide) are used to treat congestive heart failure. However, despite beneficial cardiac unloading properties, reductions in renal perfusion pressures limit their clinical effectiveness. Recently, CD-NP, a chimeric peptide composed of C-type natriuretic peptide (CNP) fused to the C-terminal tail of Dendroaspis natriuretic peptide (DNP), was shown to be more glomerular filtration rate-enhancing than BNP in dogs. However, the molecular basis for the increased responsiveness was not determined. Here, we show that the DNP tail has a striking effect on CNP, converting it from a non-agonist to a partial agonist of natriuretic peptide receptor (NPR)-A while maintaining the ability to activate NPR-B. This effect is specific for human receptors because CD-NP was only a slightly better activator of rat NPR-A due to the promiscuous nature of CNP in this species. Interesting, the DNP tail alone had no effect on any NPR even though it is effective in vivo. To further increase the potency of CD-NP for NPR-A, we converted two different triplet sequences within the CNP ring to their corresponding residues in BNP. Both variants demonstrated increased affinity and full agonist activity for NPR-A, whereas one was as potent as any NPR-A activator known. In contrast to a previous report, we found that DNP binds the natriuretic peptide clearance receptor (NPR-C). However, none of the chimeric peptides bound NPR-C with significantly higher affinity than endogenous ligands. We suggest that bifunctional chimeric peptides represent a new generation of natriuretic peptide therapeutics. PMID:18940797

  12. Antioxidants as potential therapeutics for neuropsychiatric disorders

    PubMed Central

    Pandya, Chirayu D; Howell, Kristy R; Pillai, Anilkumar

    2012-01-01

    Oxidative stress has been implicated in the pathophysiology of many neuropsychiatric disorders such as schizophrenia, bipolar disorder, major depression etc. Both genetic and nongenetic factors have been found to cause increased cellular levels of reactive oxygen species beyond the capacity of antioxidant defense mechanism in patients of psychiatric disorders. These factors trigger oxidative cellular damage to lipids, proteins and DNA, leading to abnormal neural growth and differentiation. Therefore, novel therapeutic strategies such as supplementation with antioxidants can be effective for long-term treatment management of neuropsychiatric disorders. The use of antioxidants and PUFAs as supplements in the treatment of neuropsychiatric disorders has provided some promising results. At the same time, one should be cautious with the use of antioxidants since excessive antioxidants could dangerously interfere with some of the protective functions of reactive oxygen species. The present article will give an overview of the potential strategies and outcomes of using antioxidants as therapeutics in psychiatric disorders. PMID:23123357

  13. Recent advances in molecular pharmacology of the histamine systems: physiology and pharmacology of histamine H3 receptor: roles in feeding regulation and therapeutic potential for metabolic disorders.

    PubMed

    Tokita, Shigeru; Takahashi, Kazuhiko; Kotani, Hidehito

    2006-05-01

    Histamine H3 receptors (H3Rs) are autoreceptors that negatively regulate the release of histamine and other neurotransmitters such as norepinephrine, dopamine, and acetylcholine in the central nervous system (CNS). Consistent with the wide-spread projection of histaminergic neurons from the lateral hypothalamus, H3Rs are widely distributed in the CNS and are believed to play a variety of physiological roles, including regulation of feeding, arousal, cognition, pain, and endocrine systems. To further understand the physiological roles of H3Rs in vivo, we produced H3R knockout (H3R-/-) mice and found that H3R-/- mice displayed hyperphagia and late-onset obesity associated with hyperinsulinemia and leptinemia, the fundamental marks of metabolic syndromes. A series of non-imidazole H3R antagonists/inverse agonists with improved selectivity and potency have been developed and were found to regulate feeding and body weight gain in laboratory animals. Taken together, these observations suggest that H3Rs are involved in the regulation of feeding behavior and body weight. Several H3R inverse agonists targeting cognitive disorders and dementia have entered clinical trials. These trials will give critical information about the physiological functions of H3Rs in humans. PMID:16648667

  14. Inflammation and hypertension: new understandings and potential therapeutic targets.

    PubMed

    De Miguel, Carmen; Rudemiller, Nathan P; Abais, Justine M; Mattson, David L

    2015-01-01

    Research studying the role of inflammation in hypertension and cardiovascular disease has flourished in recent years; however, the exact mechanisms by which the activated immune cells lead to the development and maintenance of hypertension remain to be elucidated. The objectives of this brief review are to summarize and discuss the most recent findings in the field, with special emphasis on potential therapeutics to treat or prevent hypertension. This review will cover novel immune cell subtypes recently associated to the disease including the novel role of cytokines, toll-like receptors, and inflammasomes in hypertension. PMID:25432899

  15. Cannabidiol and epilepsy: Rationale and therapeutic potential.

    PubMed

    Leo, Antonio; Russo, Emilio; Elia, Maurizio

    2016-05-01

    Despite the introduction of new antiepileptic drugs (AEDs), the quality of life and therapeutic response for patients with epilepsy remains still poor. Unfortunately, besides several advantages, these new AEDs have not satisfactorily reduced the number of refractory patients. Therefore, the need for different other therapeutic options to manage epilepsy is still a current issue. To this purpose, emphasis has been given to phytocannabinoids, which have been medicinally used since ancient time in the treatment of neurological disorders including epilepsy. In particular, the nonpsychoactive compound cannabidiol (CBD) has shown anticonvulsant properties, both in preclinical and clinical studies, with a yet not completely clarified mechanism of action. However, it should be made clear that most phytocannabinoids do not act on the endocannabinoid system as in the case of CBD. In in vivo preclinical studies, CBD has shown significant anticonvulsant effects mainly in acute animal models of seizures, whereas restricted data exist in chronic models of epilepsy as well as in animal models of epileptogenesis. Likewise, clinical evidence seems to indicate that CBD is able to manage epilepsy both in adults and children affected by refractory seizures, with a favourable side effect profile. However, to date, clinical trials are both qualitatively and numerically limited, thus yet inconsistent. Therefore, further preclinical and clinical studies are undoubtedly needed to better evaluate the potential therapeutic profile of CBD in epilepsy, although the actually available data is promising. PMID:26976797

  16. Biopharmaceutics and Therapeutic Potential of Engineered Nanomaterials

    PubMed Central

    Liang, Xing-Jie; Chen, Chunying; Zhao, Yuliang; Jia, Lee; Wang, Paul C.

    2009-01-01

    Engineered nanomaterials are at the leading edge of the rapidly developing nanosciences and are founding an important class of new materials with specific physicochemical properties different from bulk materials with the same compositions. The potential for nanomaterials is rapidly expanding with novel applications constantly being explored in different areas. The unique size-dependent properties of nanomaterials make them very attractive for pharmaceutical applications. Investigations of physical, chemical and biological properties of engineered nanomaterials have yielded valuable information. Cytotoxic effects of certain engineered nanomaterials towards malignant cells form the basis for one aspect of nanomedicine. It is inferred that size, three dimensional shape, hydrophobicity and electronic configurations make them an appealing subject in medicinal chemistry. Their unique structure coupled with immense scope for derivatization forms a base for exciting developments in therapeutics. This review article addresses the fate of absorption, distribution, metabolism and excretion (ADME) of engineered nanoparticles in vitro and in vivo. It updates the distinctive methodology used for studying the biopharmaceutics of nanoparticles. This review addresses the future potential and safety concerns and genotoxicity of nanoparticle formulations in general. It particularly emphasizes the effects of nanoparticles on metabolic enzymes as well as the parenteral or inhalation administration routes of nanoparticle formulations. This paper illustrates the potential of nanomedicine by discussing biopharmaceutics of fullerene derivatives and their suitability for diagnostic and therapeutic purposes. Future direction is discussed as well. PMID:18855608

  17. [Lactoferrin - a glycoprotein of great therapeutic potentials].

    PubMed

    Lauterbach, Ryszard; Kamińska, Ewa; Michalski, Piotr; Lauterbach, Jan Paweł

    2016-01-01

    Lactoferrin is an iron-binding glycoprotein, which is present in most biological fluids with particularly high levels in colostrum and in mammalian milk. Bovine lactoferrin is more than 70% homologous with human lactoferrin. Most of the clinical trials have used bovine lactoferrin for supplementation. This review summarizes the recent advances in explaining the mechanisms, which are responsible for the multifunctional roles of lactoferrin, and presents its potential prophylactic and therapeutic applications. On the ground of the results of preliminary clinical observations, authors suggest beneficial effect of lactoferrin supplementation on the prevalence of necrotizing enterocolitis in infants with birth weight below 1250 grams. PMID:27442696

  18. Therapeutic potential of icatibant (HOE-140, JE-049).

    PubMed

    Cruden, Nicholas L M; Newby, David E

    2008-09-01

    There is now a substantial body of work implicating bradykinin, an endogenous peptide neurohormone, in the pathophysiology of a variety of inflammatory conditions in man. Icatibant (HOE-140, JE-049), a highly selective antagonist at the bradykinin B2 receptor, blocks the vasodilatation and increased vascular permeability associated with exogenous bradykinin administration both in experimental models and in vivo in man. Recent attention has focused on the therapeutic potential of icatibant in a number of human disease states. The most promising of these is hereditary angioedema in which Phase III clinical trials have recently been completed and regulatory approval is currently being sought in Europe and the USA. A therapeutic role for icatibant has also been proposed in several other human conditions including drug-induced angioedema, airways disease, thermal injury, refractory ascites in patients with liver cirrhosis, and acute pancreatitis, although this work remains largely experimental. PMID:18710362

  19. Phytochemical and therapeutic potential of cucumber.

    PubMed

    Mukherjee, Pulok K; Nema, Neelesh K; Maity, Niladri; Sarkar, Birendra K

    2013-01-01

    Cucumber (Cucumis sativus L.) is a member of the Cucurbitaceae family like melon, squash and pumpkins. It is a popular vegetable crop used in Indian traditional medicine since ancient times. This vegetable is very high in water content and very low in calories. It has potential antidiabetic, lipid lowering and antioxidant activity. Cucumber has a cleansing action within the body by removing accumulated pockets of old waste materials and chemical toxins. Fresh fruit juice is used for nourishing the skin. It gives a soothing effect against skin irritations and reduces swelling. Cucumber also has the power to relax and alleviate the sunburn's pain. The fruit is refrigerant, haemostatic, tonic and useful in hyperdipsia, thermoplegia etc. The seeds also have a cooling effect on the body and they are used to prevent constipation. Several bioactive compounds have been isolated from cucumber including cucurbitacins, cucumegastigmanes I and II, cucumerin A and B, vitexin, orientin, isoscoparin 2″-O-(6‴-(E)-p-coumaroyl) glucoside, apigenin 7-O-(6″-O-p-coumaroylglucoside) etc. Despite huge exploration of cucumber in agricultural field, comparatively very few studies have been published about its chemical profile and its therapeutic potential. This article reviews the therapeutic application, pharmacological and phytochemical profile of different parts of C. sativus. In this review we have explored the current phytochemical and pharmacological knowledge available with this well known plant and several promising aspects for research on cucumber. PMID:23098877

  20. Toll-like receptor signalling and their therapeutic targeting in colorectal cancer.

    PubMed

    Moossavi, Shirin; Rezaei, Nima

    2013-06-01

    Intestinal homeostasis is dependent on the proper host/microbiota interaction via pattern recognition receptors. Toll-like receptors are a specialised group of membrane receptors which detect pathogen-associated conserved structures. They are present in the intestinal tract and are required for intestinal homeostasis. Dysregulation in the Toll-like receptor signalling can conceivably result in a dysregulated immune response which could contribute to major intestinal pathologies including colorectal cancer. Evidence for the role of microbiota and toll-like receptors in colorectal cancer is emerging. In this report the evidence for the contribution of toll-like receptors to the pathogenesis of colorectal cancer; potential mechanisms affecting toll-like receptor signalling; and their therapeutic targeting in colorectal cancer are reviewed. PMID:23602501

  1. Comparative Expression Study of the Endo–G Protein Coupled Receptor (GPCR) Repertoire in Human Glioblastoma Cancer Stem-like Cells, U87-MG Cells and Non Malignant Cells of Neural Origin Unveils New Potential Therapeutic Targets

    PubMed Central

    Lennon, Sarah; Carapito, Christine; Dong, Jihu; Van Dorsselaer, Alain; Junier, Marie-Pierre; Chneiweiss, Hervé; Cianférani, Sarah; Haiech, Jacques; Kilhoffer, Marie-Claude

    2014-01-01

    Glioblastomas (GBMs) are highly aggressive, invasive brain tumors with bad prognosis and unmet medical need. These tumors are heterogeneous being constituted by a variety of cells in different states of differentiation. Among these, cells endowed with stem properties, tumor initiating/propagating properties and particularly resistant to chemo- and radiotherapies are designed as the real culprits for tumor maintenance and relapse after treatment. These cells, termed cancer stem-like cells, have been designed as prominent targets for new and more efficient cancer therapies. G-protein coupled receptors (GPCRs), a family of membrane receptors, play a prominent role in cell signaling, cell communication and crosstalk with the microenvironment. Their role in cancer has been highlighted but remains largely unexplored. Here, we report a descriptive study of the differential expression of the endo-GPCR repertoire in human glioblastoma cancer stem-like cells (GSCs), U-87 MG cells, human astrocytes and fetal neural stem cells (f-NSCs). The endo-GPCR transcriptome has been studied using Taqman Low Density Arrays. Of the 356 GPCRs investigated, 138 were retained for comparative studies between the different cell types. At the transcriptomic level, eight GPCRs were specifically expressed/overexpressed in GSCs. Seventeen GPCRs appeared specifically expressed in cells with stem properties (GSCs and f-NSCs). Results of GPCR expression at the protein level using mass spectrometry and proteomic analysis are also presented. The comparative GPCR expression study presented here gives clues for new pathways specifically used by GSCs and unveils novel potential therapeutic targets. PMID:24662753

  2. Garlic: a review of potential therapeutic effects

    PubMed Central

    Bayan, Leyla; Koulivand, Peir Hossain; Gorji, Ali

    2014-01-01

    Throughout history, many different cultures have recognized the potential use of garlic for prevention and treatment of different diseases. Recent studies support the effects of garlic and its extracts in a wide range of applications. These studies raised the possibility of revival of garlic therapeutic values in different diseases. Different compounds in garlic are thought to reduce the risk for cardiovascular diseases, have anti-tumor and anti-microbial effects, and show benefit on high blood glucose concentration. However, the exact mechanism of all ingredients and their long-term effects are not fully understood. Further studies are needed to elucidate the pathophysiological mechanisms of action of garlic as well as its efficacy and safety in treatment of various diseases. PMID:25050296

  3. Potential and effective meaning in therapeutic ritual.

    PubMed

    McCreery, J L

    1979-03-01

    Anthropologists who accept the functionalist dogma that everything in a culture is related to everything else can easily demonstrate from their own point of view that any ritual is richly meaningful. If, then, the healing power of therapeutic ritual depends on making illness meaningful, any ritual, if seen from this perspective, should be efficacious. We must distinguish, however, between potential and effective meaning, i.e. what a ritual might mean and what it does mean to participants in it who generally lack an anthropologist's global view of their culture. Effective meaning can be assessed by examining a ritual's relevance to the situation in which it occurs and factors which facilitate or hinder communication of what it might mean to particular persons. This argument is illustrated by analyzing the meaning of a Chinese healing ritual in two different situations in which it occurs. PMID:498802

  4. Therapeutic antibodies directed at G protein-coupled receptors

    PubMed Central

    Hutchings, Catherine J; Koglin, Markus

    2010-01-01

    G protein-coupled receptors (GPCRs) are one of the most important classes of targets for small molecule drug discovery, but many current GPCRs of interest are proving intractable to small molecule discovery and may be better approached with bio-therapeutics. GPCRs are implicated in a wide variety of diseases where antibody therapeutics are currently used. These include inflammatory diseases such as rheumatoid arthritis and Crohn disease, as well as metabolic disease and cancer. Raising antibodies to GPCRs has been difficult due to problems in obtaining suitable antigen because GPCRs are often expressed at low levels in cells and are very unstable when purified. A number of new developments in overexpressing receptors, as well as formulating stable pure protein, are contributing to the growing interest in targeting GPCRs with antibodies. This review discusses the opportunities for targeting GPCRs with antibodies using these approaches and describes the therapeutic antibodies that are currently in clinical development. PMID:20864805

  5. Chemical modulators of sphingosine-1-phosphate receptors as barrier-oriented therapeutic molecules

    PubMed Central

    Marsolais, David; Rosen, Hugh

    2015-01-01

    Biological barriers regulate the passage of cells, pathogens, fluids, nutrients, ions and signalling molecules between anatomical compartments during homeostasis and disease. Yet strategies that allow for reversible therapeutic modulation of these barriers are still in their infancy. The enhancement or protection of natural barriers is desirable in conditions such as acute respiratory distress syndrome or ischaemia–reperfusion injuries, whereas a temporary disruption could facilitate the penetration of drugs across such barriers. This Review discusses the role of sphingosine-1-phosphate receptors in the regulation and protection of biological barriers, and the potential of therapeutic strategies that target this receptor family. PMID:19300460

  6. Cannabinoids and Schizophrenia: Risks and Therapeutic Potential.

    PubMed

    Manseau, Marc W; Goff, Donald C

    2015-10-01

    A convergence of evidence shows that use of Cannabis sativa is associated with increased risk of developing psychotic disorders, including schizophrenia, and earlier age at which psychotic symptoms first manifest. Cannabis exposure during adolescence is most strongly associated with the onset of psychosis amongst those who are particularly vulnerable, such as those who have been exposed to child abuse and those with family histories of schizophrenia. Schizophrenia that develops after cannabis use may have a unique clinical phenotype, and several genetic polymorphisms may modulate the relationship between cannabis use and psychosis. The endocannabinoid system has been implicated in psychosis both related and unrelated to cannabis exposure, and studying this system holds potential to increase understanding of the pathophysiology of schizophrenia. Anandamide signaling in the central nervous system may be particularly important. Δ(9)-Tetrahydrocannabinol in cannabis can cause symptoms of schizophrenia when acutely administered, and cannabidiol (CBD), another compound in cannabis, can counter many of these effects. CBD may have therapeutic potential for the treatment of psychosis following cannabis use, as well as schizophrenia, possibly with better tolerability than current antipsychotic treatments. CBD may also have anti-inflammatory and neuroprotective properties. Establishing the role of CBD and other CBD-based compounds in treating psychotic disorders will require further human research. PMID:26311150

  7. Cyclic depsipeptides as potential cancer therapeutics.

    PubMed

    Kitagaki, Jirouta; Shi, Genbin; Miyauchi, Shizuka; Murakami, Shinya; Yang, Yili

    2015-03-01

    Cyclic depsipeptides are polypeptides in which one or more amino acid is replaced by a hydroxy acid, resulting in the formation of at least one ester bond in the core ring structure. Many natural cyclic depsipeptides possessing intriguing structural and biological properties, including antitumor, antifungal, antiviral, antibacterial, anthelmintic, and anti-inflammatory activities, have been identified from fungi, plants, and marine organisms. In particular, the potent effects of cyclic depsipeptides on tumor cells have led to a number of clinical trials evaluating their potential as chemotherapeutic agents. Although many of the trials have not achieved the desired results, romidepsin (FK228), a bicyclic depsipeptide that inhibits histone deacetylase, has been shown to have clinical efficacy in patients with refractory cutaneous T-cell lymphoma and has received Food and Drug Administration approval for use in treatment. In this review, we discuss antitumor cyclic depsipeptides that have undergone clinical trials and focus on their structural features, mechanisms, potential applications in chemotherapy, and pharmacokinetic and toxicity data. The results of this study indicate that cyclic depsipeptides could be a rich source of new cancer therapeutics. PMID:25419631

  8. Therapeutic potential of chalcones as cardiovascular agents.

    PubMed

    Mahapatra, Debarshi Kar; Bharti, Sanjay Kumar

    2016-03-01

    Cardiovascular diseases are the leading cause of death affecting 17.3 million people across the globe and are estimated to affect 23.3 million people by year 2030. In recent years, about 7.3 million people died due to coronary heart disease, 9.4 million deaths due to high blood pressure and 6.2 million due to stroke, where obesity and atherosclerotic progression remain the chief pathological factors. The search for newer and better cardiovascular agents is the foremost need to manage cardiac patient population across the world. Several natural and (semi) synthetic chalcones deserve the credit of being potential candidates to inhibit various cardiovascular, hematological and anti-obesity targets like angiotensin converting enzyme (ACE), cholesteryl ester transfer protein (CETP), diacylglycerol acyltransferase (DGAT), acyl-coenzyme A: cholesterol acyltransferase (ACAT), pancreatic lipase (PL), lipoprotein lipase (LPL), calcium (Ca(2+))/potassium (K(+)) channel, COX-1, TXA2 and TXB2. In this review, a comprehensive study of chalcones, their therapeutic targets, structure activity relationships (SARs), mechanisms of actions (MOAs) have been discussed. Chemically diverse chalcone scaffolds, their derivatives including structural manipulation of both aryl rings, replacement with heteroaryl scaffold(s) and hybridization through conjugation with other pharmacologically active scaffold have been highlighted. Chalcones which showed promising activity and have a well-defined MOAs, SARs must be considered as prototype for the design and development of potential anti-hypertensive, anti-anginal, anti-arrhythmic and cardioprotective agents. With the knowledge of these molecular targets, structural insights and SARs, this review may be helpful for (medicinal) chemists to design more potent, safe, selective and cost effective chalcone derivatives as potential cardiovascular agents. PMID:26876916

  9. Estrogen receptor beta is a novel therapeutic target for photoaging.

    PubMed

    Chang, Ken C N; Wang, Yihe; Oh, Inn Gyung; Jenkins, Susan; Freedman, Leonard P; Thompson, Catherine C; Chung, Jin Ho; Nagpal, Sunil

    2010-05-01

    One of the many harmful factors faced by the skin is solar UV radiation, which damages skin by inducing chronic low-grade inflammation through increased expression of proinflammatory cytokines, metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). Estrogen receptors (ERs) alpha and beta are ligand-dependent transcription factors that are expressed in skin, and an ERbeta agonist has previously shown efficacy in vivo in models of pain and inflammation. Because ERbeta does not carry the breast and uterine proliferation liabilities of ERalpha, we decided to explore the possibility of using ERbeta as a target for photoaging. We show that ERbeta-selective compounds suppressed the expression of cytokines and MMPs in activated keratinocytes and fibroblast-based in vitro models of photoaging. Furthermore, in activated dermal fibroblasts, ERbeta-selective compounds also inhibited COX-2. These activities of ERbeta ligands in skin cells correlated with the expression levels of ERbeta and showed reversal by treatment with a potent synthetic ER antagonist. Furthermore, the pharmacology of ERbeta-selective compound was observed in wild-type but not in skin cells obtained from ERbeta knockout mice. Finally, we demonstrate that a synthetic ERbeta agonist inhibited UV-induced photodamage and skin wrinkle formation in a murine model of photoaging. Therefore, the potential of an ERbeta ligand to regulate multiple pathways underlying the cause of photoaging suggests ERbeta to be a novel therapeutic target for the prevention and treatment of photoaging. PMID:20110405

  10. Therapeutic uses of anti-interleukin-6 receptor antibody.

    PubMed

    Kang, Sujin; Tanaka, Toshio; Kishimoto, Tadamitsu

    2015-01-01

    Cytokine-targeted therapy has generated a paradigm shift in the treatment of several immune-mediated diseases. Interleukin-6 (IL-6), which was initially identified as B-cell stimulatory factor 2, is a prototypical cytokine with wide-ranging biological effects on immune cells such as B and T cells, on hepatocytes, hematopoietic cells, vascular endothelial cells and on many others. IL-6 is thus crucially involved in the regulation of immune responses, hematopoiesis and inflammation. When infections and tissue injuries occur, IL-6 is promptly synthesized and performs a protective role in host defense against such stresses and traumas. However, excessive production of IL-6 during this emergent process induces potentially fatal complications, including systemic inflammatory response syndrome (SIRS), and dysregulated, persistently high expression of IL-6 causes the onset or development of various chronic immune-mediated disorders. For these reasons, IL-6 blockade was expected to become a novel therapeutic strategy for various diseases characterized by IL-6 overproduction. Indeed, worldwide clinical trials of tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, have successfully proved its outstanding efficacy against rheumatoid arthritis, juvenile idiopathic arthritis and Castleman disease, leading to the approval of tocilizumab for the treatment of these diseases. Moreover, various reports regarding off-label use of tocilizumab strongly suggest that it will be widely applicable for acute, severe complications such as SIRS and cytokine-release syndrome and other refractory chronic immune-mediated diseases. PMID:25142313

  11. Therapeutic potential of monoamine transporter substrates.

    PubMed

    Rothman, Richard B; Baumann, Michael H

    2006-01-01

    Monoamine transporter proteins are targets for many psychoactive compounds, including therapeutic and abused stimulant drugs. This paper reviews recent work from our laboratory investigating the interaction of stimulants with transporters in brain tissue. We illustrate how determining the precise mechanism of stimulant drug action (uptake inhibitor vs. substrate) can provide unique opportunities for medication discovery. An important lesson learned from this work is that drugs which display equipotent substrate activity at dopamine (DA) and serotonin (5-HT) transporters have minimal abuse liability and few stimulant side-effects, yet are able to suppress ongoing drug-seeking behavior. As a specific example, we describe the development of PAL-287 (alpha-methylnapthylethylamine), a dual DA/5-HT releasing agent that suppresses cocaine self-administration in rhesus monkeys, without the adverse effects associated with older phenylethylamine 5-HT releasers (e.g., fenfluramine) and DA releasers (e.g., amphetamine). Our findings demonstrate the feasibility of developing non-amphetamine releasing agents as potential treatments for substance abuse disorders and other psychiatric conditions. PMID:17017961

  12. Therapeutic potential of berberine against neurodegenerative diseases.

    PubMed

    Jiang, WenXiao; Li, ShiHua; Li, XiaoJiang

    2015-06-01

    Berberine (BBR) is an organic small molecule isolated from various plants that have been used in traditional Chinese medicine. Isolation of this compound was its induction into modern medicine, and its usefulness became quickly apparent as seen in its ability to combat bacterial diarrhea, type 2 diabetes, hypercholesterolemia, inflammation, heart diseases, and more. However, BBR's effects on neurodegenerative diseases remained relatively unexplored until its ability to stunt Alzheimer's disease (AD) progression was characterized. In this review, we will delve into the multi-faceted defensive capabilities and bio-molecular pathways of BBR against AD, Parkinson's disease (PD), and trauma-induced neurodegeneration. The multiple effects of BBR, some of which enhance neuro-protective factors/pathways and others counteract targets that induce neurodegeneration, suggest that there are many more branches to the diverse capabilities of BBR that have yet to be uncovered. The promising results seen provide a convincing and substantial basis to support further scientific exploration and development of the therapeutic potential of BBR against neurodegenerative diseases. PMID:25749423

  13. Canonical transient receptor potential 5.

    PubMed

    Beech, D J

    2007-01-01

    Canonical transient receptor potential 5 TRPC5 (also TrpC5, trp-5 or trp5) is one of the seven mammalian TRPC proteins. Its known functional property is that of a mixed cationic plasma membrane channel with calcium permeability. It is active alone or as a heteromultimeric assembly with TRPC1; TRPC4 and TRPC3 may also be involved. Multiple activators of TRPC5 are emerging, including various G protein-coupled receptor agonists, lysophospholipids, lanthanide ions and, in some contexts, calcium store depletion. Intracellular calcium has complex impact on TRPC5, including a permissive role for other activators, as well as inhibition at high concentrations. Protein kinase C is inhibitory and mediates desensitisation following receptor activation. Tonic TRPC5 activity is detected and may reflect the presence of constitutive activation signals. The channel has voltage dependence but the biological significance of this is unknown; it is partially due to intracellular magnesium blockade at aspartic acid residue 633. Protein partners include calmodulin, CaBP1, enkurin, Na(+)-H+ exchange regulatory factor (NHERF) and stathmin. TRPC5 is included in local vesicular trafficking regulated by growth factors through phosphatidylinositol (PI)-3-kinase, Rac1 and PIP-5-kinase. Inhibition of myosin light chain kinase suppresses TRPC5, possibly via an effect on trafficking. Biological roles of TRPC5 are emerging but more reports on this aspect are needed. One proposed role is as a mediator of calcium entry and excitation in smooth muscle, another as an inhibitor of neuronal growth cone extension. The latter is intriguing in view of the original cloning of the human TRPC5 gene from a region of the X chromosome linked to mental retardation. TRPC5 is a broadly expressed calcium channel with capability to act as an integrator of extracellular and intracellular signals at the level of calcium entry. PMID:17217053

  14. Transferrin receptors and the targeted delivery of therapeutic agents against cancer

    PubMed Central

    Daniels, Tracy R.; Bernabeu, Ezequiel; Rodríguez, José A.; Patel, Shabnum; Kozman, Maggie; Chiappetta, Diego A.; Holler, Eggehard; Ljubimova, Julia Y.; Helguera, Gustavo; Penichet, Manuel L.

    2012-01-01

    Background Traditional cancer therapy can be successful in destroying tumors, but can also cause dangerous side effects. Therefore, many targeted therapies are in development. The transferrin receptor (TfR) functions in cellular iron uptake through its interaction with transferrin. This receptor is an attractive molecule for the targeted therapy of cancer since it is upregulated on the surface of many cancer types and is efficiently internalized. This receptor can be targeted in two ways: 1) for the delivery of therapeutic molecules into malignant cells or 2) to block the natural function of the receptor leading directly to cancer cell death. Scope of review In the present article we discuss the strategies used to target the TfR for the delivery of therapeutic agents into cancer cells. We provide a summary of the vast types of anti-cancer drugs that have been delivered into cancer cells employing a variety of receptor binding molecules including Tf, anti-TfR antibodies, or TfR-binding peptides alone or in combination with carrier molecules including nanoparticles and viruses. Major conclusions Targeting the TfR has been shown to be effective in delivering many different therapeutic agents and causing cytotoxic effects in cancer cells in vitro and in vivo. General significance The extensive use of TfR for targeted therapy attests to the versatility of targeting this receptor for therapeutic purposes against malignant cells. More advances in this area are expected to further improve the therapeutic potential of targeting the TfR for cancer therapy leading to an increase in the number of clinical trials of molecules targeting this receptor. PMID:21851850

  15. Peroxisome Proliferator-Activated Receptor Ligands and Their Role in Chronic Myeloid Leukemia: Therapeutic Strategies.

    PubMed

    Yousefi, Bahman; Samadi, Nasser; Baradaran, Behzad; Shafiei-Irannejad, Vahid; Zarghami, Nosratollah

    2016-07-01

    Imatinib therapy remains the gold standard for treatment of chronic myeloid leukemia; however, the acquired resistance to this therapeutic agent in patients has urged the scientists to devise modalities for overcoming this chemoresistance. For this purpose, initially therapeutic agents with higher tyrosine kinase activity were introduced, which had the potential for inhibiting even mutant forms of Bcr-Abl. Furthermore, coupling imatinib with peroxisome proliferator-activated receptor ligands also showed beneficial effects in chronic myeloid leukemia cell proliferation. These combination protocols inhibited cell growth and induced apoptosis as well as differentiation in chronic myeloid leukemia cell lines. In addition, peroxisome proliferator-activated receptors ligands increased imatinib uptake by upregulating the expression of human organic cation transporter 1. Taken together, peroxisome proliferator-activated receptors ligands are currently being considered as novel promising therapeutic candidates for chronic myeloid leukemia treatment, because they can synergistically enhance the efficacy of imatinib. In this article, we reviewed the potential of peroxisome proliferator-activated receptors ligands for use in chronic myeloid leukemia treatment. The mechanism of action of these therapeutics modalities are also presented in detail. PMID:26841308

  16. MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective.

    PubMed

    Liu, Jiabei; Clough, Shannon J; Hutchinson, Anthony J; Adamah-Biassi, Ekue B; Popovska-Gorevski, Marina; Dubocovich, Margarita L

    2016-01-01

    Melatonin, or 5-methoxy-N-acetyltryptamine, is synthesized and released by the pineal gland and locally in the retina following a circadian rhythm, with low levels during the day and elevated levels at night. Melatonin activates two high-affinity G protein-coupled receptors, termed MT1 and MT2, to exert beneficial actions in sleep and circadian abnormality, mood disorders, learning and memory, neuroprotection, drug abuse, and cancer. Progress in understanding the role of melatonin receptors in the modulation of sleep and circadian rhythms has led to the discovery of a novel class of melatonin agonists for treating insomnia, circadian rhythms, mood disorders, and cancer. This review describes the pharmacological properties of a slow-release melatonin preparation (i.e., Circadin®) and synthetic ligands (i.e., agomelatine, ramelteon, tasimelteon), with emphasis on identifying specific therapeutic effects mediated through MT1 and MT2 receptor activation. Discovery of selective ligands targeting the MT1 or the MT2 melatonin receptors may promote the development of novel and more efficacious therapeutic agents. PMID:26514204

  17. Receptor-mediated endocytosis and brain delivery of therapeutic biologics.

    PubMed

    Xiao, Guangqing; Gan, Liang-Shang

    2013-01-01

    Transport of macromolecules across the blood-brain-barrier (BBB) requires both specific and nonspecific interactions between macromolecules and proteins/receptors expressed on the luminal and/or the abluminal surfaces of the brain capillary endothelial cells. Endocytosis and transcytosis play important roles in the distribution of macromolecules. Due to the tight junction of BBB, brain delivery of traditional therapeutic proteins with large molecular weight is generally not possible. There are multiple pathways through which macromolecules can be taken up into cells through both specific and nonspecific interactions with proteins/receptors on the cell surface. This review is focused on the current knowledge of receptor-mediated endocytosis/transcytosis and brain delivery using the Angiopep-2-conjugated system and the molecular Trojan horses. In addition, the role of neonatal Fc receptor (FcRn) in regulating the efflux of Immunoglobulin G (IgG) from brain to blood, and approaches to improve the pharmacokinetics of therapeutic biologics by generating Fc fusion proteins, and increasing the pH dependent binding affinity between Fc and FcRn, are discussed. PMID:23840214

  18. Receptor-Mediated Endocytosis and Brain Delivery of Therapeutic Biologics

    PubMed Central

    Xiao, Guangqing

    2013-01-01

    Transport of macromolecules across the blood-brain-barrier (BBB) requires both specific and nonspecific interactions between macromolecules and proteins/receptors expressed on the luminal and/or the abluminal surfaces of the brain capillary endothelial cells. Endocytosis and transcytosis play important roles in the distribution of macromolecules. Due to the tight junction of BBB, brain delivery of traditional therapeutic proteins with large molecular weight is generally not possible. There are multiple pathways through which macromolecules can be taken up into cells through both specific and nonspecific interactions with proteins/receptors on the cell surface. This review is focused on the current knowledge of receptor-mediated endocytosis/transcytosis and brain delivery using the Angiopep-2-conjugated system and the molecular Trojan horses. In addition, the role of neonatal Fc receptor (FcRn) in regulating the efflux of Immunoglobulin G (IgG) from brain to blood, and approaches to improve the pharmacokinetics of therapeutic biologics by generating Fc fusion proteins, and increasing the pH dependent binding affinity between Fc and FcRn, are discussed. PMID:23840214

  19. Therapeutic aptamers: developmental potential as anticancer drugs

    PubMed Central

    Lee, Ji Won; Kim, Hyun Jung; Heo, Kyun

    2015-01-01

    Aptamers, composed of single-stranded DNA or RNA oligonucleotides that interact with target molecules through a specific three-dimensional structure, are selected from pools of combinatorial oligonucleotide libraries. With their high specificity and affinity for target proteins, ease of synthesis and modification, and low immunogenicity and toxicity, aptamers are considered to be attractive molecules for development as anticancer therapeutics. Two aptamers - one targeting nucleolin and a second targeting CXCL12 - are currently undergoing clinical trials for treating cancer patients, and many more are under study. In this mini-review, we present the current clinical status of aptamers and aptamer-based cancer therapeutics. We also discuss advantages, limitations, and prospects for aptamers as cancer therapeutics. [BMB Reports 2015; 48(4): 234-237] PMID:25560701

  20. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor.

    PubMed

    Wu, Chia-Yung; Roybal, Kole T; Puchner, Elias M; Onuffer, James; Lim, Wendell A

    2015-10-16

    There is growing interest in using engineered cells as therapeutic agents. For example, synthetic chimeric antigen receptors (CARs) can redirect T cells to recognize and eliminate tumor cells expressing specific antigens. Despite promising clinical results, these engineered T cells can exhibit excessive activity that is difficult to control and can cause severe toxicity. We designed "ON-switch" CARs that enable small-molecule control over T cell therapeutic functions while still retaining antigen specificity. In these split receptors, antigen-binding and intracellular signaling components assemble only in the presence of a heterodimerizing small molecule. This titratable pharmacologic regulation could allow physicians to precisely control the timing, location, and dosage of T cell activity, thereby mitigating toxicity. This work illustrates the potential of combining cellular engineering with orthogonal chemical tools to yield safer therapeutic cells that tightly integrate cell-autonomous recognition and user control. PMID:26405231

  1. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor

    PubMed Central

    Wu, Chia-Yung; Roybal, Kole T.; Puchner, Elias M.; Onuffer, James; Lim, Wendell A.

    2016-01-01

    There is growing promise in using engineered cells as therapeutic agents. For example, synthetic Chimeric Antigen Receptors (CARs) can redirect T cells to recognize and eliminate tumor cells expressing specific antigens. Despite promising clinical results, excessive activity and poor control over such engineered T cells can cause severe toxicities. We present the design of “ON-switch” CARs that enable small molecule-control over T cell therapeutic functions, while still retaining antigen specificity. In these split receptors, antigen binding and intracellular signaling components only assemble in the presence of a heterodimerizing small molecule. This titratable pharmacologic regulation could allow physicians to precisely control the timing, location, and dosage of T cell activity, thereby mitigating toxicity. This work illustrates the potential of combining cellular engineering with orthogonal chemical tools to yield safer therapeutic cells that tightly integrate both cell autonomous recognition and user control. PMID:26405231

  2. Immune repertoire: A potential biomarker and therapeutic for hepatocellular carcinoma.

    PubMed

    Han, Yingxin; Li, Hongmei; Guan, Yanfang; Huang, Jian

    2016-09-01

    The immune repertoire (IR) refers to the sum of B cells and T cells with functional diversity in the circulatory system of one individual at any given time. Immune cells, which reside within microenvironments and are responsible for protecting the human body, include T cells, B cells, macrophages, and dendritic cells. These dedicated immune cells have a characteristic structure and function. T and B cells are the main lymphocytes and are responsible for cellular immunity and humoral immunity, respectively. The T cell receptor (TCR) and B cell receptor (BCR) are composed of multiple peptide chains with antigen specificity. The amino acid composition and sequence order are more diverse in the complementarity-determining regions (including CDR1, CDR2 and CDR3) of each peptide chain, allowing a vast library of TCRs and BCRs. IR research is becoming increasingly focused on the study of CDR3 diversity. Deep profiling of CDR3s using high-throughput sequencing is a powerful approach for elucidating the composition and distribution of the CDR3s in a given sample, with in-depth information at the sequence level. Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world. To identify novel biomarkers for diagnosis and drug targets for therapeutic interventions, several groups attempted to describe immune repertoire characteristics of the liver in the physiological environment or/and pathological conditions. This paper reviews the recent progress in IR research on human diseases, including hepatocellular carcinoma, attempting to depict the relationships between hepatocellular carcinogenesis and the IR, and discusses the possibility of IR as a potential biomarker and therapeutic for hepatocellular carcinoma. PMID:26188280

  3. Physiological effects and therapeutic potential of proinsulin C-peptide

    PubMed Central

    Maric-Bilkan, Christine; Luppi, Patrizia; Wahren, John

    2014-01-01

    Connecting Peptide, or C-peptide, is a product of the insulin prohormone, and is released with and in amounts equimolar to those of insulin. While it was once thought that C-peptide was biologically inert and had little biological significance beyond its role in the proper folding of insulin, it is now known that C-peptide binds specifically to the cell membranes of a variety of tissues and initiates specific intracellular signaling cascades that are pertussis toxin sensitive. Although it is now clear that C-peptide is a biologically active molecule, controversy still remains as to the physiological significance of the peptide. Interestingly, C-peptide appears to reverse the deleterious effects of high glucose in some tissues, including the kidney, the peripheral nerves, and the vasculature. C-peptide is thus a potential therapeutic agent for the treatment of diabetes-associated long-term complications. This review addresses the possible physiologically relevant roles of C-peptide in both normal and disease states and discusses the effects of the peptide on sensory nerve, renal, and vascular function. Furthermore, we highlight the intracellular effects of the peptide and present novel strategies for the determination of the C-peptide receptor(s). Finally, a hypothesis is offered concerning the relationship between C-peptide and the development of microvascular complications of diabetes. PMID:25249503

  4. A Novel Glucagon-like Peptide-1 (GLP-1)/Glucagon Hybrid Peptide with Triple-acting Agonist Activity at Glucose-dependent Insulinotropic Polypeptide, GLP-1, and Glucagon Receptors and Therapeutic Potential in High Fat-fed Mice*

    PubMed Central

    Gault, Victor A.; Bhat, Vikas K.; Irwin, Nigel; Flatt, Peter R.

    2013-01-01

    Glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon bind to related members of the same receptor superfamily and exert important effects on glucose homeostasis, insulin secretion, and energy regulation. The present study assessed the biological actions and therapeutic utility of novel GIP/glucagon/GLP-1 hybrid peptides. Nine novel peptides were synthesized and exhibited complete DPP-IV resistance and enhanced in vitro insulin secretion. The most promising peptide, [dA2]GLP-1/GcG, stimulated cAMP production in GIP, GLP-1, and glucagon receptor-transfected cells. Acute administration of [dA2]GLP-1/GcG in combination with glucose significantly lowered plasma glucose and increased plasma insulin in normal and obese diabetic (ob/ob) mice. Furthermore, [dA2]GLP-1/GcG elicited a protracted glucose-lowering and insulinotropic effect in high fat-fed mice. Twice daily administration of [dA2]GLP-1/GcG for 21 days decreased body weight and nonfasting plasma glucose and increased circulating plasma insulin concentrations in high fat-fed mice. Furthermore, [dA2]GLP-1/GcG significantly improved glucose tolerance and insulin sensitivity by day 21. Interestingly, locomotor activity was increased in [dA2]GLP-1/GcG mice, without appreciable changes in aspects of metabolic rate. Studies in knock-out mice confirmed the biological action of [dA2]GLP-1/GcG via multiple targets including GIP, GLP-1, and glucagon receptors. The data suggest significant promise for novel triple-acting hybrid peptides as therapeutic options for obesity and diabetes. PMID:24165127

  5. Acyl-CoA synthetase-4, a new regulator of mTOR and a potential therapeutic target for enhanced estrogen receptor function in receptor-positive and -negative breast cancer

    PubMed Central

    Dattilo, Melina A.; Solano, Angela R.; Maloberti, Paula M.; Podesta, Ernesto J.

    2015-01-01

    Although the role of acyl-CoA synthetase 4 (ACSL4) in mediating an aggressive phenotype is well accepted, there is little evidence as to the early steps through which ACSL4 increases tumor growth and progression. In this study, and by means of the stable transfection of MCF-7 cells with ACSL4 using the tetracycline Tet-Off system (MCF-7 Tet-Off/ACSL4), we identify the mTOR pathway as one of the main specific signatures of ACSL4 expression and demonstrate the partial involvement of the lipoxygenase pathway in the activation of mTOR. The specificity of ACSL4 action on mTOR signaling is also determined by doxycycline inhibition of ACSL4 expression in MCF-7 Tet-Off/ACSL4 cells, by the expression of ACSL4 in the non-aggressive T47D breast cancer cell line and by knocking down this enzyme expression in the MDA-MB-231 breast cancer cells, which constitutively express ACSL4. ACSL4 regulates components of the two complexes of the mTOR pathway (mTORC1/2), along with upstream regulators and substrates. We show that mTOR inhibitor rapamycin and ACSL4 inhibitor rosiglitazone can act in combination to inhibit cell growth. In addition, we demonstrate a synergistic effect on cell growth inhibition by the combination of rosiglitazone and tamoxifen, an estrogen receptor α (ERα) inhibitor. Remarkably, this synergistic effect is also evident in the triple negative MDA-MB-231 cells in vitro and in vivo. These results suggest that ACSL4 could be a target to restore tumor hormone dependence in tumors with poor prognosis for disease-free and overall survival, in which no effective specifically targeted therapy is readily available. PMID:26536660

  6. Therapeutic Potential of Non-Psychotropic Cannabidiol in Ischemic Stroke

    PubMed Central

    Hayakawa, Kazuhide; Mishima, Kenichi; Fujiwara, Michihiro

    2010-01-01

    Cannabis contains the psychoactive component delta9-tetrahydrocannabinol (delta9-THC), and the non-psychoactive components cannabidiol (CBD), cannabinol, and cannabigerol. It is well-known that delta9-THC and other cannabinoid CB1 receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta9-THC also mediates psychological effects through the activation of the CB1 receptor in the central nervous system. In addition to the CB1 receptor agonists, cannabis also contains therapeutically active components which are CB1 receptor independent. Of the CB1 receptor-independent cannabis, the most important is CBD. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD. In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson’s disease, Alzheimer’s disease, and rheumatoid arthritis. The cerebroprotective action of CBD is CB1 receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke.

  7. Adrenomedullin: A potential therapeutic target for retinochoroidal disease.

    PubMed

    Iesato, Yasuhiro; Yuda, Kentaro; Chong, Kelvin Teo Yi; Tan, Xue; Murata, Toshinori; Shindo, Takayuki; Yanagi, Yasuo

    2016-05-01

    Adrenomedullin (AM) is a 52-amino acid peptide with anti-inflammatory, anti-apoptotic, and anti-oxidative properties discovered in a human pheochromocytoma. It is a member of the calcitonin peptide superfamily, and its signal is mediated by calcitonin receptor-like receptor (CLR). CLR interacts with receptor activity-modifying proteins (RAMPs), among which RAMP-2 and RAMP-3 carry CLR from the endoplasmic reticulum to the cellular membrane to confer high affinity for AM. In addition to being implicated in a variety of systemic diseases, AM is a critical contributor to the pathogenesis of retinochoroidal disease. It is robustly upregulated in retinochoroidal disease models of oxygen-induced retinopathy (OIR) and laser-induced choroidal neovascularisation (CNV) as well as in human patients with retinochoroidal diseases. In this review, we discuss the most salient recent findings that strongly illustrate the role of AM in retinochoroidal disease. In the OIR model, AM was identified as a key angiogenic mediator of retinal vascularisation, and AM inhibition suppressed only pathological angiogenesis, not physiological angiogenesis. On the contrary, lesion size was larger in AM(+/-) CNV model mice, presumably due to the anti-inflammatory function of AM. Despite the success of anti-vascular endothelial growth factor agents for the treatment of retinochoroidal disease, therapeutic shortcomings remain. Finding ways to modulate AM activity will provide new treatment avenues. Potential treatment strategies modulating the action of AM and its signaling pathway have been studied extensively. AM and its signaling molecules are intriguing future treatment targets for retinochoroidal disease. PMID:26791747

  8. Engineering therapeutic antibodies targeting G-protein–coupled receptors

    PubMed Central

    Jo, Migyeong; Jung, Sang Taek

    2016-01-01

    G-protein–coupled receptors (GPCRs) are one of the most attractive therapeutic target classes because of their critical roles in intracellular signaling and their clinical relevance to a variety of diseases, including cancer, infection and inflammation. However, high conformational variability, the small exposed area of extracellular epitopes and difficulty in the preparation of GPCR antigens have delayed both the isolation of therapeutic anti-GPCR antibodies as well as studies on the structure, function and biochemical mechanisms of GPCRs. To overcome the challenges in generating highly specific anti-GPCR antibodies with enhanced efficacy and safety, various forms of antigens have been successfully designed and employed for screening with newly emerged systems based on laboratory animal immunization and high-throughput-directed evolution. PMID:26846450

  9. Therapeutic potential of cannabinoid-based drugs.

    PubMed

    Klein, Thomas W; Newton, Catherine A

    2007-01-01

    Cannabinoid-based drugs modeled on cannabinoids originally isolated from marijuana are now known to significantly impact the functioning of the endocannabinoid system of mammals. This system operates not only in the brain but also in organs and tissues in the periphery including the immune system. Natural and synthetic cannabinoids are tricyclic terpenes, whereas the endogenous physiological ligands are eicosanoids. Several receptors for these compounds have been extensively described, CB1 and CB2, and are G protein-coupled receptors; however, cannabinoid-based drugs are also demonstrated to function independently of these receptors. Cannabinoids regulate many physiological functions and their impact on immunity is generally antiinflammatory as powerful modulators of the cytokine cascade. This anti-inflammatory potency has led to the testing of these drugs in chronic inflammatory laboratory paradigms and even in some human diseases. Psychoactive and nonpsychoactive cannabinoid-based drugs such as Delta9-tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Furthermore, although clinical trials are not yet reported, preclinical data with cannabinoid-based drugs suggest efficacy in other inflammatory diseases such as inflammatory bowel disease, Alzheimer's disease, atherosclerosis, and osteoporosis. PMID:17713029

  10. Therapeutic applications of TRAIL receptor agonists in cancer and beyond.

    PubMed

    Amarante-Mendes, Gustavo P; Griffith, Thomas S

    2015-11-01

    TRAIL/Apo-2L is a member of the TNF superfamily first described as an apoptosis-inducing cytokine in 1995. Similar to TNF and Fas ligand, TRAIL induces apoptosis in caspase-dependent manner following TRAIL death receptor trimerization. Because tumor cells were shown to be particularly sensitive to this cytokine while normal cells/tissues proved to be resistant along with being able to synthesize and release TRAIL, it was rapidly appreciated that TRAIL likely served as one of our major physiologic weapons against cancer. In line with this, a number of research laboratories and pharmaceutical companies have attempted to exploit the ability of TRAIL to kill cancer cells by developing recombinant forms of TRAIL or TRAIL receptor agonists (e.g., receptor-specific mAb) for therapeutic purposes. In this review article we will describe the biochemical pathways used by TRAIL to induce different cell death programs. We will also summarize the clinical trials related to this pathway and discuss possible novel uses of TRAIL-related therapies. In recent years, the physiological importance of TRAIL has expanded beyond being a tumoricidal molecule to one critical for a number of clinical settings - ranging from infectious disease and autoimmunity to cardiovascular anomalies. We will also highlight some of these conditions where modulation of the TRAIL/TRAIL receptor system may be targeted in the future. PMID:26343199

  11. Pathological potential of astroglial purinergic receptors.

    PubMed

    Franke, Heike; Illes, Peter

    2014-01-01

    Acute brain injury and neurodegenerative disorders may result in astroglial activation. Astrocytes are able to determine the progression and outcome of these neuropathologies in a beneficial or detrimental way. Nucleotides, e.g. adenosine 5'-triphosphate (ATP), released after acute or chronic neuronal injury, are important mediators of glial activation and astrogliosis.Acute injury may cause significant changes in ATP balance, resulting in (1) a decline of intracellular ATP levels and (2) an increase in extracellular ATP concentrations via efflux from the intracellular space. The released ATP may have trophic effects, but can also act as a proinflammatory mediator or cytotoxic factor, inducing necrosis/apoptosis as a universal "danger" signal. Furthermore, ATP, primarily released from astrocytes, is a means of communication between neurons, glial cells, and intracerebral blood vessels.Astrocytes express a heterogeneous battery of purinergic ionotropic and metabotropic receptors (P2XRs and P2YRs, respectively) to respond to extracellular nucleotides.In this chapter, we summarize the contemporary knowledge on the pathological potential of P2Rs in relation to changes of astrocytic functions, determined by distinct molecular signaling cascades, in a variety of diseases. We discuss specific aspects of reactive astrogliosis, with respect to the involvement of prominent receptor subtypes, such as the P2X7 and P2Y1/2Rs. Examples of purinergic signaling of microglia, oligodendrocytes, and blood vessels under pathophysiological conditions will also be presented.The understanding of the pathological potential of purinergic signaling in "controlling and fine-tuning" of astrocytic responses is important for identifying possible therapeutic principles to treat acute and chronic central nervous system diseases. PMID:25236731

  12. Vasopressin receptors and pharmacological chaperones: from functional rescue to promising therapeutic strategies.

    PubMed

    Mouillac, Bernard; Mendre, Christiane

    2014-05-01

    Conformational diseases result from protein misfolding and/or aggregation and constitute a major public health problem. Congenital Nephrogenic Diabetes Insipidus is a typical conformational disease. In most of the cases, it is associated to inactivating mutations of the renal arginine-vasopressin V2 receptor gene leading to misfolding and intracellular retention of the receptor, causing the inability of patients to concentrate their urine in response to the antidiuretic hormone. Cell-permeable pharmacological chaperones have been successfully challenged to restore plasma membrane localization of the receptor mutants and to rescue their function. Interestingly, different classes of specific ligands such as antagonists (vaptans), agonists as well as biased agonists of the V2 receptor have proven their usefulness as efficient pharmacochaperones. These compounds represent a potential therapeutic treatment of this X-linked genetic pathology. PMID:24239889

  13. The potential therapeutic effects of THC on Alzheimer's disease.

    PubMed

    Cao, Chuanhai; Li, Yaqiong; Liu, Hui; Bai, Ge; Mayl, Jonathan; Lin, Xiaoyang; Sutherland, Kyle; Nabar, Neel; Cai, Jianfeng

    2014-01-01

    The purpose of this study was to investigate the potential therapeutic qualities of Δ9-tetrahydrocannabinol (THC) with respect to slowing or halting the hallmark characteristics of Alzheimer's disease. N2a-variant amyloid-β protein precursor (AβPP) cells were incubated with THC and assayed for amyloid-β (Aβ) levels at the 6-, 24-, and 48-hour time marks. THC was also tested for synergy with caffeine, in respect to the reduction of the Aβ level in N2a/AβPPswe cells. THC was also tested to determine if multiple treatments were beneficial. The MTT assay was performed to test the toxicity of THC. Thioflavin T assays and western blots were performed to test the direct anti-Aβ aggregation significance of THC. Lastly, THC was tested to determine its effects on glycogen synthase kinase-3β (GSK-3β) and related signaling pathways. From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin's enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer's disease through multiple functions and pathways. PMID:25024327

  14. The therapeutic potential of regulated hypothermia.

    PubMed

    Gordon, C J

    2001-03-01

    Reducing body temperature of rodents has been found to improve their survival to ischaemia, hypoxia, chemical toxicants, and many other types of insults. Larger species, including humans, may also benefit from a lower body temperature when recovering from CNS ischaemia and other traumatic insults. Rodents subjected to these insults undergo a regulated hypothermic response (that is, decrease in set point temperature) characterised by preference for cooler ambient temperatures, peripheral vasodilatation, and reduced metabolic rate. However, forced hypothermia (that is, body temperature forced below set point) is the only method used in the study and treatment of human pathological insults. The therapeutic efficacy of the hypothermic treatment is likely to be influenced by the nature of the reduction in body temperature (that is, forced versus regulated). Homeostatic mechanisms counter forced reductions in body temperature resulting in physiological stress and decreased efficacy of the hypothermic treatment. On the other hand, regulated hypothermia would seem to be the best means of achieving a therapeutic benefit because thermal homeostatic systems mediate a controlled reduction in core temperature. PMID:11300205

  15. Therapeutic potential of curcumin in digestive diseases

    PubMed Central

    Dulbecco, Pietro; Savarino, Vincenzo

    2013-01-01

    Curcumin is a low-molecular-weight hydrophobic polyphenol that is extracted from turmeric, which possesses a wide range of biological properties including anti-inflammatory, anti-oxidant, anti-proliferative and anti-microbial activities. Despite its diverse targets and substantial safety, clinical applications of this molecule for digestive disorders have been largely limited to case series or small clinical trials. The poor bioavailability of curcumin is likely the major hurdle for its more widespread use in humans. However, complexation of curcumin into phytosomes has recently helped to bypass this problem, as it has been demonstrated that this new lecithin formulation enables increased absorption to a level 29-fold higher than that of traditional curcuminoid products. This allows us to achieve much greater tissue substance delivery using significantly lower doses of curcumin than have been used in past clinical studies. As curcumin has already been shown to provide good therapeutic results in some small studies of both inflammatory and neoplastic bowel disorders, it is reasonable to anticipate an even greater efficacy with the advent of this new technology, which remarkably improves its bioavailability. These features are very promising and may represent a novel and effective therapeutic approach to both functional and organic digestive diseases. PMID:24409053

  16. Therapeutic potential of curcumin in digestive diseases.

    PubMed

    Dulbecco, Pietro; Savarino, Vincenzo

    2013-12-28

    Curcumin is a low-molecular-weight hydrophobic polyphenol that is extracted from turmeric, which possesses a wide range of biological properties including anti-inflammatory, anti-oxidant, anti-proliferative and anti-microbial activities. Despite its diverse targets and substantial safety, clinical applications of this molecule for digestive disorders have been largely limited to case series or small clinical trials. The poor bioavailability of curcumin is likely the major hurdle for its more widespread use in humans. However, complexation of curcumin into phytosomes has recently helped to bypass this problem, as it has been demonstrated that this new lecithin formulation enables increased absorption to a level 29-fold higher than that of traditional curcuminoid products. This allows us to achieve much greater tissue substance delivery using significantly lower doses of curcumin than have been used in past clinical studies. As curcumin has already been shown to provide good therapeutic results in some small studies of both inflammatory and neoplastic bowel disorders, it is reasonable to anticipate an even greater efficacy with the advent of this new technology, which remarkably improves its bioavailability. These features are very promising and may represent a novel and effective therapeutic approach to both functional and organic digestive diseases. PMID:24409053

  17. Lipoic acid - biological activity and therapeutic potential.

    PubMed

    Gorąca, Anna; Huk-Kolega, Halina; Piechota, Aleksandra; Kleniewska, Paulina; Ciejka, Elżbieta; Skibska, Beata

    2011-01-01

    α-Lipoic acid (LA; 5-(1,2-dithiolan-3-yl)pentanoic acid) was originally isolated from bovine liver by Reed et al. in 1951. LA was once considered a vitamin. Subsequently, it was found that LA is not a vitamin and is synthesized by plants and animals. LA is covalently bound to the ε-amino group of lysine residues and functions as a cofactor for mitochondrial enzymes by catalyzing the oxidative decarboxylation of pyruvate, α-ketoglutarate and branched-chain α-keto acids. LA and its reduced form - dihydrolipoic acid (DHLA), meet all the criteria for an ideal antioxidant because they can easily quench radicals, can chelate metals, have an amphiphlic character and they do not exhibit any serious side effects. They interact with other antioxidants and can regenerate them. For this reason, LA is called an antioxidant of antioxidants. LA has an influence on the second messenger nuclear factor κB (NF-κB) and attenuates the release of free radicals and cytotoxic cytokines. The therapeutic action of LA is based on its antioxidant properties. Current studies support its use in the ancillary treatment of many diseases, such as diabetes, cardiovascular, neurodegenerative, autoimmune diseases, cancer and AIDS. This review was undertaken to gather the most recent information regarding the therapeutic properties of LA and its possible utility in disease treatment. PMID:22001972

  18. CB2 Cannabinoid Receptor As Potential Target against Alzheimer's Disease

    PubMed Central

    Aso, Ester; Ferrer, Isidro

    2016-01-01

    The CB2 receptor is one of the components of the endogenous cannabinoid system, a complex network of signaling molecules and receptors involved in the homeostatic control of several physiological functions. Accumulated evidence suggests a role for CB2 receptors in Alzheimer's disease (AD) and indicates their potential as a therapeutic target against this neurodegenerative disease. Levels of CB2 receptors are significantly increased in post-mortem AD brains, mainly in microglia surrounding senile plaques, and their expression levels correlate with the amounts of Aβ42 and β-amyloid plaque deposition. Moreover, several studies on animal models of AD have demonstrated that specific CB2 receptor agonists, which are devoid of psychoactive effects, reduce AD-like pathology, resulting in attenuation of the inflammation associated with the disease but also modulating Aβ and tau aberrant processing, among other effects. CB2 receptor activation also improves cognitive impairment in animal models of AD. This review discusses available data regarding the role of CB2 receptors in AD and the potential usefulness of specific agonists of these receptors against AD. PMID:27303261

  19. Harnessing the Therapeutic Potential of Th17 Cells

    PubMed Central

    Bystrom, Jonas; Taher, Taher E.; Muhyaddin, M. Sherwan; Clanchy, Felix I.; Mangat, Pamela; Jawad, Ali S.; Williams, Richard O.; Mageed, Rizgar A.

    2015-01-01

    Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and RORγt while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferon γ (IFNγ). In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since RORγt is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases. PMID:26101460

  20. Minireview: From the Bench, Toward the Clinic: Therapeutic Opportunities for Cannabinoid Receptor Modulation

    PubMed Central

    Picone, Robert P.

    2015-01-01

    The effects of cannabinoids have been known for centuries and over the past several decades two G protein-coupled receptors, CB1 and CB2, that are responsible for their activity have been identified. Endogenous lipid-derived cannabinergic agents have been found, biosynthetic and catabolic machinery has been characterized, and synthetic agents have been designed to modulate these receptors. Selective agents including agonists, antagonists, inverse agonists, and novel allosteric modulators targeting either CB1 or CB2 have been developed to inhibit or augment their basal tone. As a result, the role these receptors play in human physiology and their potential therapeutic applications in disease states are being elucidated. The CB1 receptor, although ubiquitous, is densely expressed in the brain, and CB2 is largely found on cells of immune origin. This minireview highlights the role of CB1 in excitotoxic assaults in the brain and its potential to limit addiction liability. In addition, it will examine the relationship between receptor activity and stimulation of insulin release from pancreatic β-cells, insulin resistance, and feeding behavior leading toward obesity. The roles of CB2 in the neuropathology of amyotrophic lateral sclerosis and in the central manifestations of chronic HIV infection potentially converge at inflammatory cell activation, thereby providing an opportunity for intervention. Last, CB2 modulation is discussed in the context of an experimental model of postmenopausal osteoporosis. Achieving exquisite receptor selectivity and elucidating the mechanisms underlying receptor inhibition and activation will be essential for the development of the next generation of cannabinergic-based therapeutic agents. PMID:25866875

  1. Natriuretic peptides and their therapeutic potential.

    PubMed

    Cho, Y; Somer, B G; Amatya, A

    1999-01-01

    Natriuretic peptides are a group of naturally occurring substances that act in the body to oppose the activity of the renin-angiotensin system. There are three major natriuretic peptides: atrial natriuretic peptide (ANP), which is synthesized in the atria; brain natriuretic peptide (BNP), which is synthesized in the ventricles; and C-type natriuretic peptide (CNP), which is synthesized in the brain. Both ANP and BNP are released in response to atrial and ventricular stretch, respectively, and will cause vasorelaxation, inhibition of aldosterone secretion in the adrenal cortex, and inhibition of renin secretion in the kidney. Both ANP and BNP will cause natriuresis and a reduction in intravascular volume, effects amplified by antagonism of antidiuretic hormone (ADH). The physiologic effects of CNP are different from those of ANP and BNP. CNP has a hypotensive effect, but no significant diuretic or natriuretic actions. Three natriuretic peptide receptors (NPRs) have been described that have different binding capacities for ANP, BNP, and CNP. Removal of the natriuretic peptides from the circulation is affected mainly by binding to clearance receptors and enzymatic degradation in the circulation. Increased blood levels of natriuretic peptides have been found in certain disease states, suggesting a role in the pathophysiology of those diseases, including congestive heart failure (CHF), systemic hypertension, and acute myocardial infarction. The natriuretic peptides also serve as disease markers and indicators of prognosis in various cardiovascular conditions. The natriuretic peptides have been used in the treatment of disease, with the most experience with intravenous BNP in the treatment of CHF. Another pharmacologic approach being used is the inhibition of natriuretic peptide metabolism by neutral endopeptidase (NEP) inhibitor drugs. The NEP inhibitors are currently being investigated as treatments for CHF and systemic hypertension. PMID:11720638

  2. Combination therapy of potential gene to enhance oral cancer therapeutic effect

    NASA Astrophysics Data System (ADS)

    Yeh, Chia-Hsien; Hsu, Yih-Chih

    2015-03-01

    The epidermal growth factor receptor (EGFR) over-regulation related to uncontrolled cell division and promotes progression in tumor. Over-expression of human epidermal growth factor receptor (EGFR) has been detected in oral cancer cells. EGFR-targeting agents are potential therapeutic modalities for treating oral cancer based on our in vitro study. Liposome nanotechnology is used to encapsulate siRNA and were modified with target ligand to receptors on the surface of tumor cells. We used EGFR siRNA to treat oral cancer in vitro.

  3. Telomerase and its potential for therapeutic intervention

    PubMed Central

    Phatak, P; Burger, A M

    2007-01-01

    Telomerase and telomeres are attractive targets for anticancer therapy. This is supported by the fact that the majority of human cancers express the enzyme telomerase which is essential to maintain their telomere length and thus, to ensure indefinite cell proliferation – a hallmark of cancer. Tumours have relatively shorter telomeres compared to normal cell types, opening the possibility that human cancers may be considerably more susceptible to killing by agents that inhibit telomere replication than normal cells. Advances in the understanding of the regulation of telomerase activity and the telomere structure, as well as the identification of telomerase and telomere associated binding proteins have opened new avenues for therapeutic intervention. Here, we review telomere and telomerase biology and the various approaches which have been developed to inhibit the telomere/telomerase complex over the past decade. They include inhibitors of the enzyme catalytic subunit and RNA component, agents that target telomeres, telomerase vaccines and drugs targeting binding proteins. The emerging role of telomerase in cancer stem cells and the implications for cancer therapy are also discussed. PMID:17603541

  4. Therapeutic Potential of Cannabinoids in Psychosis.

    PubMed

    Leweke, F Markus; Mueller, Juliane K; Lange, Bettina; Rohleder, Cathrin

    2016-04-01

    Over recent years, the interest in the endocannabinoid system (ECS) as a new target for the treatment of schizophrenia has evolved. The ECS represents one of the most relevant neurotransmitter systems in the brain and mainly fulfills a homeostatic role in terms of neurotransmission but also with respect to inflammatory processes. Two main approaches to the modulation of endocannabinoid functioning have been chosen so far. First, the selective blockade or inverse agonism of the type 1 cannabinoid receptor has been tested for the improvement of acute psychotic symptoms, as well as for the improvement of cognitive functions in schizophrenia. This was not effective in either case. Second, the modulation of endocannabinoid levels by use of the phytocannabinoid cannabidiol and selective fatty acid amide hydrolase inhibitors has been proposed, and the antipsychotic properties of cannabidiol are currently being investigated in humans. Unfortunately, for most of these trials that have focused on psychopathological and cognitive effects of cannabidiol, no published data are available. However, there is first evidence that cannabidiol may ameliorate psychotic symptoms with a superior side-effect profile compared with established antipsychotics. In conclusion, several clinical trials targeting the ECS in acute schizophrenia have either been completed or are underway. Although publicly available results are currently limited, preliminary data indicate that selected compounds modulating the ECS may be effective in acute schizophrenia. Nevertheless, so far, sample sizes of patients investigated are not sufficient to come to a final judgment, and no maintenance studies are available to ensure long-term efficacy and safety. PMID:26852073

  5. Chaperoning G Protein-Coupled Receptors: From Cell Biology to Therapeutics

    PubMed Central

    Conn, P. Michael

    2014-01-01

    G protein-coupled receptors (GPCRs) are membrane proteins that traverse the plasma membrane seven times (hence, are also called 7TM receptors). The polytopic structure of GPCRs makes the folding of GPCRs difficult and complex. Indeed, many wild-type GPCRs are not folded optimally, and defects in folding are the most common cause of genetic diseases due to GPCR mutations. Both general and receptor-specific molecular chaperones aid the folding of GPCRs. Chemical chaperones have been shown to be able to correct the misfolding in mutant GPCRs, proving to be important tools for studying the structure-function relationship of GPCRs. However, their potential therapeutic value is very limited. Pharmacological chaperones (pharmacoperones) are potentially important novel therapeutics for treating genetic diseases caused by mutations in GPCR genes that resulted in misfolded mutant proteins. Pharmacoperones also increase cell surface expression of wild-type GPCRs; therefore, they could be used to treat diseases that do not harbor mutations in GPCRs. Recent studies have shown that indeed pharmacoperones work in both experimental animals and patients. High-throughput assays have been developed to identify new pharmacoperones that could be used as therapeutics for a number of endocrine and other genetic diseases. PMID:24661201

  6. Immunoactive effects of cannabinoids: considerations for the therapeutic use of cannabinoid receptor agonists and antagonists.

    PubMed

    Greineisen, William E; Turner, Helen

    2010-05-01

    The active constituents of Cannabis sativa have been used for centuries as recreational drugs and medicinal agents. Today, marijuana is the most prevalent drug of abuse in the United States and, conversely, therapeutic use of marijuana constituents are gaining mainstream clinical and political acceptance. Given the documented contributions of endocannabinoid signaling to a range of physiological systems, including cognitive function, and the control of eating behaviors, it is unsurprising that cannabinoid receptor agonists and antagonists are showing significant clinical potential. In addition to the neuroactive effects of cannabinoids, an emerging body of data suggests that both endogenous and exogenous cannabinoids are potently immunoactive. The central premise of this review article is that the immunological effects of cannabinoids should be considered in the context of each prescribing decision. We present evidence that the immunological effects of cannabinoid receptor agonists and antagonists are highly relevant to the spectrum of disorders for which cannabinoid therapeutics are currently offered. PMID:20219697

  7. CB2 Cannabinoid Receptors as a Therapeutic Target—What Does the Future Hold?

    PubMed Central

    Dhopeshwarkar, Amey

    2014-01-01

    The past decades have seen an exponential rise in our understanding of the endocannabinoid system, comprising CB1 and CB2 cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes that synthesize and degrade endocannabinoids. The primary focus of this review is the CB2 receptor. CB2 receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential for treating various pathologies while avoiding the adverse psychotropic effects that can accompany CB1 receptor–based therapies. With the appreciation that CB2-selective ligands show marked functional selectivity, there is a renewed opportunity to explore this promising area of research from both a mechanistic as well as a therapeutic perspective. In this review, we summarize our present knowledge of CB2 receptor signaling, localization, and regulation. We discuss the availability of genetic tools (and their limitations) to study CB2 receptors and also provide an update on preclinical data on CB2 agonists in pain models. Finally, we suggest possible reasons for the failure of CB2 ligands in clinical pain trials and offer possible ways to move the field forward in a way that can help reconcile the inconsistencies between preclinical and clinical data. PMID:25106425

  8. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities.

    PubMed

    Pertwee, Roger G

    2012-12-01

    Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ(9)-tetrahydrocannabinol (Δ(9)-THC)) and Sativex (Δ(9)-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive 'multi-targeting'. PMID:23108552

  9. G protein-coupled receptors as oncogenic signals in glioma: emerging therapeutic avenues

    PubMed Central

    Cherry, Allison E; Stella, Nephi

    2014-01-01

    Gliomas are the most common malignant intracranial tumors. Newly developed targeted therapies for these cancers aim to inhibit oncogenic signals, many of which emanate from receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR). Unfortunately, the first generation treatments targeting these oncogenic signals provide little survival benefit in both mouse xenograft models and human patients. The search for new treatment options has uncovered several G protein-coupled receptor (GPCR) candidates and generated a growing interest in this class of proteins as alternative therapeutic targets for the treatment of various cancers, including GBM. GPCRs constitute a large family of membrane receptors that influence oncogenic pathways through canonical and non-canonical signaling. Accordingly, evidence indicates that GPCRs display a unique ability to crosstalk with receptor tyrosine kinases, making them important molecular components controlling tumorigenesis. This review summarizes the current research on GPCR functionality in gliomas and explores the potential of modulating these receptors to treat this devastating disease. PMID:25158675

  10. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

    PubMed Central

    Pertwee, Roger G.

    2012-01-01

    Human tissues express cannabinoid CB1 and CB2 receptors that can be activated by endogenously released ‘endocannabinoids’ or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB1/CB2 receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Δ9-tetrahydrocannabinol (Δ9-THC)) and Sativex (Δ9-THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB2 receptors, and/or (v) adjunctive ‘multi-targeting’. PMID:23108552

  11. Targeting CBLB as a potential therapeutic approach for disseminated candidiasis.

    PubMed

    Xiao, Yun; Tang, Juan; Guo, Hui; Zhao, Yixia; Tang, Rong; Ouyang, Song; Zeng, Qiuming; Rappleye, Chad A; Rajaram, Murugesan V S; Schlesinger, Larry S; Tao, Lijian; Brown, Gordon D; Langdon, Wallace Y; Li, Belinda T; Zhang, Jian

    2016-08-01

    Disseminated candidiasis has become one of the leading causes of hospital-acquired blood stream infections with high mobility and mortality. However, the molecular basis of host defense against disseminated candidiasis remains elusive, and treatment options are limited. Here we report that the E3 ubiquitin ligase CBLB directs polyubiquitination of dectin-1 and dectin-2, two key pattern-recognition receptors for sensing Candida albicans, and their downstream kinase SYK, thus inhibiting dectin-1- and dectin-2-mediated innate immune responses. CBLB deficiency or inactivation protects mice from systemic infection with a lethal dose of C. albicans, and deficiency of dectin-1, dectin-2, or both in Cblb(-/-) mice abrogates this protection. Notably, silencing the Cblb gene in vivo protects mice from lethal systemic C. albicans infection. Our data reveal that CBLB is crucial for homeostatic control of innate immune responses mediated by dectin-1 and dectin-2. Our data also indicate that CBLB represents a potential therapeutic target for protection from disseminated candidiasis. PMID:27428899

  12. New vitamin D analogs as potential therapeutics in melanoma

    PubMed Central

    Szyszka, Paulina; Zmijewski, Michal A; Slominski, Andrzej T

    2012-01-01

    Extensive evidence shows that the active form of vitamin D3 – 1α,25-dihydroxyvitamin D3 – plays an important role in cancer prevention, has tumorostatic activity and may potentially be used in therapy for melanoma. Vitamin D3 and its analogs (secosteroids) exert multiple effects on cancer cells, including inhibition of cell growth and induction of differentiation. Activity of secosteroids depends on multiple cellular factors, including expression of the vitamin D receptor. Despite its endogenous origin, the key drawback for the use of pharmacologically effective doses of 1α,25-dihydroxyvitamin D3 is its hypercalcemic effect leading to profound toxicity. The solution may lie in properties of vitamin D3 analogs with modified side chains, which demonstrate low calcemic activity but conserve the anti-tumor properties. Noncalcemic vitamin D compounds were found to be potent in multiple studies that mandate further clinical testing. Finally, recent studies revealed alternative metabolic pathways for secosteroids and new targets in the cells, which opens up new therapeutic possibilities. PMID:22594894

  13. The therapeutic potential of milk thistle in diabetes.

    PubMed

    Kazazis, Christos E; Evangelopoulos, Angelos A; Kollas, Aris; Vallianou, Natalia G

    2014-01-01

    Milk thistle has been known for more than 2.000 years as a herbal remedy for a variety of disorders. It has mainly been used to treat liver and gallbladder diseases. Silibum marianum, the Latin term for the plant, and its seeds contain a whole family of natural compounds, called flavonolignans. Silimarin is a dry mixture of these compounds; it is extracted after processing with ethanol, methanol, and acetone. Silimarin contains mainly silibin A, silibin B, taxifolin, isosilibin A, isosilibin B, silichristin A, silidianin, and other compounds in smaller concentrations. Apart from its use in liver and gallbladder disorders, milk thistle has recently gained attention due to its hypoglycemic and hypolipidemic properties. Recently, a substance from milk thistle has been shown to possess peroxisome proliferator-activated receptor γ (PPARγ) agonist properties. PPARγ is the molecular target of thiazolidinediones, which are used clinically as insulin sensitizers to lower blood glucose levels in diabetes type 2 patients. The thiazolidinedione type of PPARγ ligands is an agonist with a very high binding affinity. However, this ligand type demonstrates a range of undesirable side effects, thus necessitating the search for new effective PPARγ agonists. Interestingly, studies indicate that partial agonism of PPARγ induces promising activity patterns by retaining the positive effects attributed to the full agonists, with reduced side effects. In this review, the therapeutic potential of milk thistle in the management of diabetes and its complications are discussed. PMID:25396404

  14. Glucocorticoid analogues: potential therapeutic alternatives for treating inflammatory muscle diseases.

    PubMed

    Reeves, Erica K M; Rayavarapu, Sree; Damsker, Jesse M; Nagaraju, Kanneboyina

    2012-03-01

    Glucocorticoids (GCs) have been prescribed to treat a variety of diseases, including inflammatory myopathies and Duchenne muscular dystrophy for over 50 years. However, their prescription remains controversial due to the significant side effects associated with the chronic treatment. It is a common belief that the clinical efficacy of GCs is due to their transrepression of pro-inflammatory genes through inhibition of inflammatory transcription factors (i.e. NF-κB, AP-1) whereas the adverse side effects are attributed to the glucocorticoid receptor (GR)-mediated transcription of target genes (transactivation). The past decade has seen an increased interest in the development of GR modulators that maintain the effective anti-inflammatory properties but lack the GR-dependent transcriptional response as a safe alternative to traditional GCs. Many of these analogues or "dissociative" compounds show potential promise in in vitro studies but fail to reach human clinical trials. In this review, we discuss molecular effects of currently prescribed GCs on skeletal muscle and also discuss the current state of development of GC analogues as alternative therapeutics for inflammatory muscle diseases. PMID:22214335

  15. The Therapeutic Potential of Milk Thistle in Diabetes

    PubMed Central

    Kazazis, Christos E.; Evangelopoulos, Angelos A.; Kollas, Aris; Vallianou, Natalia G.

    2014-01-01

    Milk thistle has been known for more than 2.000 years as a herbal remedy for a variety of disorders. It has mainly been used to treat liver and gallbladder diseases. Silibum marianum, the Latin term for the plant, and its seeds contain a whole family of natural compounds, called flavonolignans. Silimarin is a dry mixture of these compounds; it is extracted after processing with ethanol, methanol, and acetone. Silimarin contains mainly silibin A, silibin B, taxifolin, isosilibin A, isosilibin B, silichristin A, silidianin, and other compounds in smaller concentrations. Apart from its use in liver and gallbladder disorders, milk thistle has recently gained attention due to its hypoglycemic and hypolipidemic properties. Recently, a substance from milk thistle has been shown to possess peroxisome proliferator-activated receptor γ (PPARγ) agonist properties. PPARγ is the molecular target of thiazolidinediones, which are used clinically as insulin sensitizers to lower blood glucose levels in diabetes type 2 patients. The thiazolidinedione type of PPARγ ligands is an agonist with a very high binding affinity. However, this ligand type demonstrates a range of undesirable side effects, thus necessitating the search for new effective PPARγ agonists. Interestingly, studies indicate that partial agonism of PPARγ induces promising activity patterns by retaining the positive effects attributed to the full agonists, with reduced side effects. In this review, the therapeutic potential of milk thistle in the management of diabetes and its complications are discussed. PMID:25396404

  16. Cellular Functions of Transient Receptor Potential channels

    PubMed Central

    Dadon, Daniela; Minke, Baruch

    2010-01-01

    Transient Receptor Potential channels are polymodal cellular sensors involved in a wide variety of cellular processes, mainly by increasing cellular Ca2+. In this review we focus on the roles of these channels in: i) cell death ii) proliferation and differentiation and iii) synaptic vesicle release. Cell death Ca2+ influx participates in apoptotic and necrotic cell death. The Ca2+ permeability and high sensitivity of part of these channels to oxidative/metabolic stress make them important participants in cell death. Several examples are given. Transient Receptor Potential Melastatin 2 is activated by H2O2, inducing cell death through an increase in cellular Ca2+ and activation of Poly ADP-Ribose Polymerase. Exposure of cultured cortical neurons to oxygen-glucose deprivation, in vitro, causes cell death via cation influx, mediated by Transient Receptor Potential Melastatin 7. Metabolic stress constitutively activates the Ca2+ permeable Transient Receptor Potential channels of Drosophila photoreceptor in the dark, potentially leading to retinal degeneration. Similar sensitivity to metabolic stress characterizes several mammalian Transient Receptor Potential Canonical channels. Proliferation and differentiation The rise in cytosolic Ca2+ induces cell growth, differentiation and proliferation via activation of several transcription factors. Activation a variety of store operated and Transient Receptor Potential channels cause a rise in cytosolic Ca2+, making these channels components involved in proliferation and differentiation. Synaptic vesicle release Transient Receptor Potential Melastatin 7 channels reside in synaptic vesicles and regulate neurotransmitter release by a mechanism that is not entirely clear. All the above features of Transient Receptor Potential channels make them crucial components in important, sometimes conflicting, cellular processes that still need to be explored. PMID:20399884

  17. The Therapeutic Potential of Medicinal Foods

    PubMed Central

    Ramalingum, Nelvana; Mahomoodally, M. Fawzi

    2014-01-01

    Pharmaceutical and nutritional sciences have recently witnessed a bloom in the scientific literature geared towards the use of food plants for their diversified health benefits and potential clinical applications. Health professionals now recognize that a synergism of drug therapy and nutrition might confer optimum outcomes in the fight against diseases. The prophylactic benefits of food plants are being investigated for potential use as novel medicinal remedies due to the presence of pharmacologically active compounds. Although the availability of scientific data is rapidly growing, there is still a paucity of updated compilation of data and concerns about the rationale of these health-foods still persist in the literature. This paper attempts to congregate the nutritional value, phytochemical composition, traditional uses, in vitro and in vivo studies of 10 common medicinal food plants used against chronic noncommunicable and infectious diseases. Food plants included were based on the criteria that they are consumed as a common food in a typical diet as either fruit or vegetable for their nutritive value but have also other parts which are in common use in folk medicine. The potential challenges of incorporating these medicinal foods in the diet which offers prospective opportunities for future drug development are also discussed. PMID:24822061

  18. Heteromers of μ-δ opioid receptors: new pharmacology and novel therapeutic possibilities

    PubMed Central

    Fujita, Wakako; Gomes, Ivone; Devi, Lakshmi A

    2015-01-01

    Several studies suggest that heteromerization between μ (MOP) and δ (DOP) opioid receptors modulates the signalling properties of the individual receptors. For example, whereas activation of MOP receptors by an agonist induces G protein-mediated signalling, the same agonist induces β-arrestin-mediated signalling in the context of the MOP-DOP receptor heteromer. Moreover, heteromer-mediated signalling is allosterically modulated by a combination of MOP and DOP receptor ligands. This has implications in analgesia given that morphine-induced antinociception can be potentiated by DOP receptor ligands. Recently reagents selectively targeting the MOP-DOP receptor heteromer such as bivalent ligands, antibodies or membrane permeable peptides have been generated; these reagents are enabling studies to elucidate the contribution of endogenously expressed heteromers to analgesia as well as to the development of side-effects associated with chronic opioid use. Recent advances in drug screening technology have led to the identification of a MOP-DOP receptor heteromer-biased agonist that activates both G protein-mediated and β-arrestin-mediated signalling. Moreover, this heteromer-biased agonist exhibits potent antinociceptive activity but with reduced side-effects, suggesting that ligands targeting the MOP-DOP receptor heteromer form a basis for the development of novel therapeutics for the treatment of pain. In this review, we summarize findings regarding the biological and functional characteristics of the MOP-DOP receptor heteromer and the in vitro and in vivo properties of heteromer-selective ligands. LINKED ARTICLES This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2 PMID:24571499

  19. Tyrosine Kinase Receptor Landscape in Lung Cancer: Therapeutical Implications.

    PubMed

    Quintanal-Villalonga, A; Paz-Ares, Luis; Ferrer, Irene; Molina-Pinelo, S

    2016-01-01

    Lung cancer is a heterogeneous disease responsible for the most cases of cancer-related deaths. The majority of patients are clinically diagnosed at advanced stages, with a poor survival rate. For this reason, the identification of oncodrivers and novel biomarkers is decisive for the future clinical management of this pathology. The rise of high throughput technologies popularly referred to as "omics" has accelerated the discovery of new biomarkers and drivers for this pathology. Within them, tyrosine kinase receptors (TKRs) have proven to be of importance as diagnostic, prognostic, and predictive tools and, due to their molecular nature, as therapeutic targets. Along this review, the role of TKRs in the different lung cancer histologies, research on improvement of anti-TKR therapy, and the current approaches to manage anti-TKR resistance will be discussed. PMID:27528792

  20. Tyrosine Kinase Receptor Landscape in Lung Cancer: Therapeutical Implications

    PubMed Central

    Quintanal-Villalonga, A.; Paz-Ares, Luis

    2016-01-01

    Lung cancer is a heterogeneous disease responsible for the most cases of cancer-related deaths. The majority of patients are clinically diagnosed at advanced stages, with a poor survival rate. For this reason, the identification of oncodrivers and novel biomarkers is decisive for the future clinical management of this pathology. The rise of high throughput technologies popularly referred to as “omics” has accelerated the discovery of new biomarkers and drivers for this pathology. Within them, tyrosine kinase receptors (TKRs) have proven to be of importance as diagnostic, prognostic, and predictive tools and, due to their molecular nature, as therapeutic targets. Along this review, the role of TKRs in the different lung cancer histologies, research on improvement of anti-TKR therapy, and the current approaches to manage anti-TKR resistance will be discussed. PMID:27528792

  1. Therapeutic Potential of Resveratrol in Lymphoid Malignancies.

    PubMed

    Khan, Omar S; Bhat, Ajaz A; Krishnankutty, Roopesh; Mohammad, Ramzi M; Uddin, Shahab

    2016-01-01

    Natural products have always been sought as a dependable source for the cure of many fatal diseases including cancer. Resveratrol (RSV), a naturally occurring plant polyphenol, has been of recent research interest and is being investigated for its beneficial biological properties that include antioxidant, anti-inflammatory, proapoptotic, and growth inhibitory activities. These effects are mainly mediated by cell cycle arrest, upregulation of proapoptotic proteins, loss of mitochondrial potential, and generation of reactive oxygen species. Among the beneficial properties of RSV, the anticancer property has been of the prime focus and extensively explored during the last few years. Although reports exist on the chemopreventive role of RSV in many solid tumors, limited information is available on the antiproliferative activity of RSV in human lymphoma cells and experimental models. Potential mechanisms for its antiproliferative effect include induction of cell differentiation, apoptosis, and inhibition of DNA synthesis. In this review, the different kinds of lymphoid malignancies and the main mechanisms of cell death induced by resveratrol are discussed. The challenges are limiting in vivo experimental studies involving resveratrol. An attempt for the translation of this compound into a clinical drug also forms a part of this review. PMID:27028800

  2. The therapeutic potential of stem cells

    PubMed Central

    Watt, Fiona M.; Driskell, Ryan R.

    2010-01-01

    In recent years, there has been an explosion of interest in stem cells, not just within the scientific and medical communities but also among politicians, religious groups and ethicists. Here, we summarize the different types of stem cells that have been described: their origins in embryonic and adult tissues and their differentiation potential in vivo and in culture. We review some current clinical applications of stem cells, highlighting the problems encountered when going from proof-of-principle in the laboratory to widespread clinical practice. While some of the key genetic and epigenetic factors that determine stem cell properties have been identified, there is still much to be learned about how these factors interact. There is a growing realization of the importance of environmental factors in regulating stem cell behaviour and this is being explored by imaging stem cells in vivo and recreating artificial niches in vitro. New therapies, based on stem cell transplantation or endogenous stem cells, are emerging areas, as is drug discovery based on patient-specific pluripotent cells and cancer stem cells. What makes stem cell research so exciting is its tremendous potential to benefit human health and the opportunities for interdisciplinary research that it presents. PMID:20008393

  3. MERTK receptor tyrosine kinase is a therapeutic target in melanoma

    PubMed Central

    Schlegel, Jennifer; Sambade, Maria J.; Sather, Susan; Moschos, Stergios J.; Tan, Aik-Choon; Winges, Amanda; DeRyckere, Deborah; Carson, Craig C.; Trembath, Dimitri G.; Tentler, John J.; Eckhardt, S. Gail; Kuan, Pei-Fen; Hamilton, Ronald L.; Duncan, Lyn M.; Miller, C. Ryan; Nikolaishvili-Feinberg, Nana; Midkiff, Bentley R.; Liu, Jing; Zhang, Weihe; Yang, Chao; Wang, Xiaodong; Frye, Stephen V.; Earp, H. Shelton; Shields, Janiel M.; Graham, Douglas K.

    2013-01-01

    Metastatic melanoma is one of the most aggressive forms of cutaneous cancers. Although recent therapeutic advances have prolonged patient survival, the prognosis remains dismal. C-MER proto-oncogene tyrosine kinase (MERTK) is a receptor tyrosine kinase with oncogenic properties that is often overexpressed or activated in various malignancies. Using both protein immunohistochemistry and microarray analyses, we demonstrate that MERTK expression correlates with disease progression. MERTK expression was highest in metastatic melanomas, followed by primary melanomas, while the lowest expression was observed in nevi. Additionally, over half of melanoma cell lines overexpressed MERTK compared with normal human melanocytes; however, overexpression did not correlate with mutations in BRAF or RAS. Stimulation of melanoma cells with the MERTK ligand GAS6 resulted in the activation of several downstream signaling pathways including MAPK/ERK, PI3K/AKT, and JAK/STAT. MERTK inhibition via shRNA reduced MERTK-mediated downstream signaling, reduced colony formation by up to 59%, and diminished tumor volume by 60% in a human melanoma murine xenograft model. Treatment of melanoma cells with UNC1062, a novel MERTK-selective small-molecule tyrosine kinase inhibitor, reduced activation of MERTK-mediated downstream signaling, induced apoptosis in culture, reduced colony formation in soft agar, and inhibited invasion of melanoma cells. This work establishes MERTK as a therapeutic target in melanoma and provides a rationale for the continued development of MERTK-targeted therapies. PMID:23585477

  4. Pregnane xenobiotic receptor in cancer pathogenesis and therapeutic response

    PubMed Central

    Pondugula, Satyanarayana R.; Mani, Sridhar

    2012-01-01

    Pregnane xenobiotic receptor (PXR) is an orphan nuclear receptor that regulates the metabolism of endobiotics and xenobiotics. PXR is promiscuous and unique in that it is activated by a diverse group of xenochemicals, including therapeutic anticancer drugs and naturally-occurring endocrine disruptors. PXR has been predominantly studied to understand its regulatory role in xenobiotic clearance in liver and intestine via induction of drug metabolizing enzymes and drug transporters. PXR, however, is widely expressed and has functional implications in other normal and malignant tissues, including breast, prostate, ovary, endometrium and bone. The differential expression of PXR and its target genes in cancer tissues has been suggested to determine the prognosis of chemotherapeutic outcome. In addition, the emerging evidence points to the implications of PXR in regulating apoptotic and antiapoptotic as well as growth factor signaling that promote tumor proliferation and metastasis. In this review, we highlight the recent progress made in understanding the role of PXR in cancer, discuss the future directions to further understand the mechanistic role of PXR in cancer, and conclude with the need to identify novel selective PXR modulators. PMID:22939994

  5. Therapeutic Potential of Dietary Phenolic Acids

    PubMed Central

    Saibabu, Venkata; Fatima, Zeeshan; Khan, Luqman Ahmad; Hameed, Saif

    2015-01-01

    Although modern lifestyle has eased the quality of human life, this lifestyle's related patterns have imparted negative effects on health to acquire multiple diseases. Many synthetic drugs are invented during the last millennium but most if not all of them possess several side effects and proved to be costly. Convincing evidences have established the premise that the phytotherapeutic potential of natural compounds and need of search for novel drugs from natural sources are of high priority. Phenolic acids (PAs) are a class of secondary metabolites spread throughout the plant kingdom and generally involved in plethora of cellular processes involved in plant growth and reproduction and also produced as defense mechanism to sustain various environmental stresses. Extensive research on PAs strongly suggests that consumption of these compounds hold promise to offer protection against various ailments in humans. This paper focuses on the naturally derived PAs and summarizes the action mechanisms of these compounds during disease conditions. Based on the available information in the literature, it is suggested that use of PAs as drugs is very promising; however more research and clinical trials are necessary before these bioactive molecules can be made for treatment. Finally this review provides greater awareness of the promise that natural PAs hold for use in the disease prevention and therapy. PMID:26442119

  6. Pseudomonas aeruginosa biofilm: potential therapeutic targets.

    PubMed

    Sharma, Garima; Rao, Saloni; Bansal, Ankiti; Dang, Shweta; Gupta, Sanjay; Gabrani, Reema

    2014-01-01

    Pseudomonas aeruginosa is a gram-negative pathogen that has become an important cause of infection, especially in patients with compromised host defense mechanisms. It is frequently related to nosocomial infections such as pneumonia, urinary tract infections (UTIs) and bacteremia. The biofilm formed by the bacteria allows it to adhere to any surface, living or non-living and thus Pseudomonal infections can involve any part of the body. Further, the adaptive and genetic changes of the micro-organisms within the biofilm make them resistant to all known antimicrobial agents making the Pseudomonal infections complicated and life threatening. Pel, Psl and Alg operons present in P. aeruginosa are responsible for the biosynthesis of extracellular polysaccharide which plays an important role in cell-cell and cell-surface interactions during biofilm formation. Understanding the bacterial virulence which depends on a large number of cell-associated and extracellular factors is essential to know the potential drug targets for future studies. Current novel methods like small molecule based inhibitors, phytochemicals, bacteriophage therapy, photodynamic therapy, antimicrobial peptides, monoclonal antibodies and nanoparticles to curtail the biofilm formed by P. aeruginosa are being discussed in this review. PMID:24309094

  7. PEI-g-PEG-RGD/Small Interference RNA Polyplex-Mediated Silencing of Vascular Endothelial Growth Factor Receptor and Its Potential as an Anti-Angiogenic Tumor Therapeutic Strategy

    PubMed Central

    Kim, Jihoon; Kim, Sung Wan

    2011-01-01

    Tumor angiogenesis appears to be achieved by the expression of vascular endothelial growth factor (VEGF) within solid tumors that stimulate host vascular endothelial cell mitogenesis and possibly chemotaxis. VEGF's angiogenic actions are mediated through its high-affinity binding to 2 endothelium-specific receptor tyrosine kinase, Flt-1 (VEGFR1), and Flk-1/KDR (VEGFR2). RNA interference-mediated knockdown of protein expression at the messenger RNA level provides a new therapeutic strategy to overcome various diseases. To achieve high efficacy in RNA interference-mediated therapy, it is critical to develop an efficient delivering system to deliver small interference RNA (siRNA) into tissues or cells site-specifically. We previously reported an angiogenic endothelial cell-targeted polymeric gene carrier, PEI-g-PEG-RGD. This targeted carrier was developed by the conjugation of the ανβ3/ανβ5 integrin-binding RGD peptide (ACDCRGDCFC) to the cationic polymer, branched polyethylenimine, with a hydrophilic polyethylene glycol (PEG) spacer. In this study, we used PEI-g-PEG-RGD to deliver siRNA against VEGFR1 into tumor site. The physicochemical properties of PEI-g-PEG-RGD/siRNA complexes was evaluated. Further, tumor growth profile was also investigated after systemic administration of PEI-g-PEG-RGD/siRNA complexes. PMID:21375397

  8. Positive allosteric modulators as an approach to nicotinic acetylcholine receptor- targeted therapeutics: advantages and limitations

    PubMed Central

    Williams, Dustin K.; Wang, Jingyi; Papke, Roger L.

    2011-01-01

    Neuronal nicotinic acetylcholine receptors (nAChR), recognized targets for drug development in cognitive and neuro-degenerative disorders, are allosteric proteins with dynamic interconversions between multiple functional states. Activation of the nAChR ion channel is primarily controlled by the binding of ligands (agonists, partial agonists, competitive antagonists) at conventional agonist binding sites, but is also regulated in either negative or positive ways by the binding of ligands to other modulatory sites. In this review, we discuss models for the activation and desensitization of nAChR, and the discovery of multiple types of ligands that influence those processes in both heteromeric nAChR, such as the high affinity nicotine receptors of the brain, and homomeric α7-type receptors. In recent years, α7 nAChRs have been identified as a potential target for therapeutic indications leading to the development of α7-selective agonists and partial agonists. However, unique properties of α7 nAChR, including low probability of channel opening and rapid desensitization, may limit the therapeutic usefulness of ligands binding exclusively to conventional agonist binding sites. New enthusiasm for the therapeutic targeting of α7 has come from the identification of α7-selective positive allosteric modulators (PAMs) that work effectively on the intrinsic factors that limit α7 ion channel activation. While these new drugs appear promising for therapeutic development, we also consider potential caveats and possible limitations for their use, including PAM-insensitive forms of desensitization and cytotoxicity issues. PMID:21575610

  9. Myostatin/activin pathway antagonism: molecular basis and therapeutic potential.

    PubMed

    Han, H Q; Zhou, Xiaolan; Mitch, William E; Goldberg, Alfred L

    2013-10-01

    Muscle wasting is associated with a wide range of catabolic diseases. This debilitating loss of muscle mass and functional capacity reduces the quality of life and increases the risks of morbidity and mortality. Major progress has been made in understanding the biochemical mechanisms and signaling pathways regulating muscle protein balance under normal conditions and the enhanced protein loss in atrophying muscles. It is now clear that activation of myostatin/activin signaling is critical in triggering the accelerated muscle catabolism that causes muscle loss in multiple disease states. Binding of myostatin and activin to the ActRIIB receptor complex on muscle cell membrane leads to activation of Smad2/3-mediated transcription, which in turn stimulates FoxO-dependent transcription and enhanced muscle protein breakdown via ubiquitin-proteasome system and autophagy. In addition, Smad activation inhibits muscle protein synthesis by suppressing Akt signaling. Pharmacological blockade of the myostatin/activin-ActRIIB pathway has been shown to prevent or reverse the loss of muscle mass and strength in various disease models including cancer cachexia and renal failure. Moreover, it can markedly prolong the lifespan of animals with cancer-associated muscle loss. Furthermore, inhibiting myostatin/activin actions also improves insulin sensitivity, reduces excessive adiposity, attenuates systemic inflammation, and accelerates bone fracture healing in disease models. Based on these exciting advances, the potential therapeutic benefits of myostatin/activin antagonism are now being tested in multiple clinical settings. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID:23721881

  10. The Emerging Role of HMGB1 in Neuropathic Pain: A Potential Therapeutic Target for Neuroinflammation.

    PubMed

    Wan, Wenbin; Cao, Lan; Khanabdali, Ramin; Kalionis, Bill; Tai, Xiantao; Xia, Shijin

    2016-01-01

    Neuropathic pain (NPP) is intolerable, persistent, and specific type of long-term pain. It is considered to be a direct consequence of pathological changes affecting the somatosensory system and can be debilitating for affected patients. Despite recent progress and growing interest in understanding the pathogenesis of the disease, NPP still presents a major diagnostic and therapeutic challenge. High mobility group box 1 (HMGB1) mediates inflammatory and immune reactions in nervous system and emerging evidence reveals that HMGB1 plays an essential role in neuroinflammation through receptors such as Toll-like receptors (TLR), receptor for advanced glycation end products (RAGE), C-X-X motif chemokines receptor 4 (CXCR4), and N-methyl-D-aspartate (NMDA) receptor. In this review, we present evidence from studies that address the role of HMGB1 in NPP. First, we review studies aimed at determining the role of HMGB1 in NPP and discuss the possible mechanisms underlying HMGB1-mediated NPP progression where receptors for HMGB1 are involved. Then we review studies that address HMGB1 as a potential therapeutic target for NPP. PMID:27294160

  11. The Emerging Role of HMGB1 in Neuropathic Pain: A Potential Therapeutic Target for Neuroinflammation

    PubMed Central

    Wan, Wenbin; Cao, Lan; Khanabdali, Ramin; Kalionis, Bill; Tai, Xiantao; Xia, Shijin

    2016-01-01

    Neuropathic pain (NPP) is intolerable, persistent, and specific type of long-term pain. It is considered to be a direct consequence of pathological changes affecting the somatosensory system and can be debilitating for affected patients. Despite recent progress and growing interest in understanding the pathogenesis of the disease, NPP still presents a major diagnostic and therapeutic challenge. High mobility group box 1 (HMGB1) mediates inflammatory and immune reactions in nervous system and emerging evidence reveals that HMGB1 plays an essential role in neuroinflammation through receptors such as Toll-like receptors (TLR), receptor for advanced glycation end products (RAGE), C-X-X motif chemokines receptor 4 (CXCR4), and N-methyl-D-aspartate (NMDA) receptor. In this review, we present evidence from studies that address the role of HMGB1 in NPP. First, we review studies aimed at determining the role of HMGB1 in NPP and discuss the possible mechanisms underlying HMGB1-mediated NPP progression where receptors for HMGB1 are involved. Then we review studies that address HMGB1 as a potential therapeutic target for NPP. PMID:27294160

  12. Regulation of therapeutic resistance in cancers by receptor tyrosine kinases

    PubMed Central

    Chen, Mei-Kuang; Hung, Mien-Chie

    2016-01-01

    In response to DNA damage lesions due to cellular stress, DNA damage response (DDR) pathways are activated to promote cell survival and genetic stability or unrepaired lesion-induced cell death. Current cancer treatments predominantly utilize DNA damaging agents, such as irradiation and chemotherapy drugs, to inhibit cancer cell proliferation and induce cell death through the activation of DDR. However, a portion of cancer patients is reported to develop therapeutic resistance to these DDR-inducing agents. One significant resistance mechanism in cancer cells is oncogenic kinase overexpression, which promotes cell survival by enhancing DNA damage repair pathways and evading cell cycle arrest. Among the oncogenic kinases, overexpression of receptor tyrosine kinases (RTKs) is reported in many of solid tumors, and numerous clinical trials targeting RTKs are currently in progress. As the emerging trend in cancer treatment combines DNA damaging agents and RTK inhibitors, it is important to understand the substrates of RTKs relative to the DDR pathways. In addition, alteration of RTK expression and their phosphorylated substrates can serve as biomarkers to stratify patients for combination therapies. In this review, we summarize the deleterious effects of RTKs on the DDR pathways and the emerging biomarkers for personalized therapy. PMID:27186434

  13. Transgenic silkworms expressing human insulin receptors for evaluation of therapeutically active insulin receptor agonists.

    PubMed

    Matsumoto, Yasuhiko; Ishii, Masaki; Ishii, Kenichi; Miyaguchi, Wataru; Horie, Ryo; Inagaki, Yoshinori; Hamamoto, Hiroshi; Tatematsu, Ken-ichiro; Uchino, Keiro; Tamura, Toshiki; Sezutsu, Hideki; Sekimizu, Kazuhisa

    2014-12-12

    We established a transgenic silkworm strain expressing the human insulin receptor (hIR) using the GAL4/UAS system. Administration of human insulin to transgenic silkworms expressing hIR decreased hemolymph sugar levels and facilitated Akt phosphorylation in the fat body. The decrease in hemolymph sugar levels induced by injection of human insulin in the transgenic silkworms expressing hIR was blocked by co-injection of wortmannin, a phosphoinositide 3-kinase inhibitor. Administration of bovine insulin, an hIR ligand, also effectively decreased sugar levels in the transgenic silkworms. These findings indicate that functional hIRs that respond to human insulin were successfully induced in the transgenic silkworms. We propose that the humanized silkworm expressing hIR is useful for in vivo evaluation of the therapeutic activities of insulin receptor agonists. PMID:25449269

  14. Targeted D4 dopamine receptors: implications for drug discovery and therapeutic development.

    PubMed

    Ptáček, Radek; Kuželová, Hana; Stefano, George B; Raboch, Jiri; Kream, Richard M

    2013-04-01

    A wealth of preclinical and clinical literature has established functional associations of CNS dopamine (DA) and its multiple G protein-coupled receptor (GPCR) types in the integration of key neurological processes linked to complex behavioral activities. Conversely, an equivalent vast literature supports the role of aberrant CNS DA expression and DA receptor signaling in the etiology and persistence of major psychiatric illnesses and has established selective targeting of DA-ergic systems as a cornerstone of pharmacotherapeutic intervention and current neuroleptic drug development. The present short review focuses on potential functional/behavioral alterations linked to polymorphisms in the primary DNA sequence of the DA receptor type 4 (DRD4) gene in reference to major psychiatric illnesses. The potential clinical relevance of major polymorphisms of the DRD4 gene are discussed within the context of practical aspects of typical and atypical neuroleptic drug usage within afflicted populations of psychiatric patients. It is anticipated that additional complementary molecular, biochemical, and behavioral studies of DRD4 gene polymorphisms will provide essential information for selective targeting of heterogeneous populations of CNS D4 receptors and advance drug discovery and therapeutic development efforts for highly efficacious treatment of psychiatric illnesses. PMID:23469923

  15. The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination.

    PubMed

    Hussain, Rashad; Ghoumari, Abdel M; Bielecki, Bartosz; Steibel, Jérôme; Boehm, Nelly; Liere, Philippe; Macklin, Wendy B; Kumar, Narender; Habert, René; Mhaouty-Kodja, Sakina; Tronche, François; Sitruk-Ware, Regine; Schumacher, Michael; Ghandour, M Said

    2013-01-01

    Myelin regeneration is a major therapeutic goal in demyelinating diseases, and the failure to remyelinate rapidly has profound consequences for the health of axons and for brain function. However, there is no efficient treatment for stimulating myelin repair, and current therapies are limited to anti-inflammatory agents. Males are less likely to develop multiple sclerosis than females, but often have a more severe disease course and reach disability milestones at an earlier age than females, and these observations have spurred interest in the potential protective effects of androgens. Here, we demonstrate that testosterone treatment efficiently stimulates the formation of new myelin and reverses myelin damage in chronic demyelinated brain lesions, resulting from the long-term administration of cuprizone, which is toxic for oligodendrocytes. In addition to the strong effect of testosterone on myelin repair, the number of activated astrocytes and microglial cells returned to low control levels, indicating a reduction of neuroinflammatory responses. We also identify the neural androgen receptor as a novel therapeutic target for myelin recovery. After the acute demyelination of cerebellar slices in organotypic culture, the remyelinating actions of testosterone could be mimicked by 5α-dihydrotestosterone, a metabolite that is not converted to oestrogens, and blocked by the androgen receptor antagonist flutamide. Testosterone treatment also failed to promote remyelination after chronic cuprizone-induced demyelination in mice with a non-functional androgen receptor. Importantly, testosterone did not stimulate the formation of new myelin sheaths after specific knockout of the androgen receptor in neurons and macroglial cells. Thus, the neural brain androgen receptor is required for the remyelination effect of testosterone, whereas the presence of the receptor in microglia and in peripheral tissues is not sufficient to enhance remyelination. The potent synthetic

  16. Selective Modulators of α5-Containing GABAA Receptors and their Therapeutic Significance.

    PubMed

    Soh, Ming Shiuan; Lynch, Joseph W

    2015-01-01

    GABAA receptors containing the α5 subunit (5GABAARs) are found mainly in the hippocampus where they mediate a tonic chloride leak current and contribute a slow component to GABAergic inhibitory synaptic currents. Their inhibitory effect on the excitability of hippocampal neurons at least partly explains why changes in the level of activity of 5GABAARs affect cognition, learning and memory. These receptors have been implicated as potential therapeutic targets for a range of clinical conditions including age-related dementia, stroke, schizophrenia, Down syndrome and anesthetic- induced amnesia. Accordingly, a range of pharmacological modulators that selectively target 5GABAARs, as either inhibitors or allosteric enhancers, have been developed. Although many of these compounds show therapeutic effects in animal models of the above clinical disorders, none has been marketed yet due to unsuccessful clinical trials and toxicity in humans. These experiments have also revealed paradoxical effects of 5GABAAR modulation (e.g., cognitive impairments can be reversed by both positive and negative modulation), suggesting that our knowledge of the physiological roles of 5GABAARs is incomplete. This review highlights the various positive and negative modulators for 5GABAARs that have been developed, key findings concerning their effects in behavioral studies, and their importance across a number of therapeutic fields. It also highlights some of the gaps in our knowledge of the physiological and pathological roles of α5GABAARs. PMID:25751008

  17. MicroRNAs as potential therapeutic targets in kidney disease

    PubMed Central

    Gomez, Ivan G; Grafals, Monica; Portilla, Didier; Duffield, Jeremy S

    2014-01-01

    One cornerstone of Chronic Kidney Disease (CKD) is fibrosis, as kidneys are susceptible due to their high vascularity and predisposition to ischemia. Presently, only therapies targeting the angiotensin receptor are used in clinical practice to retard the progression of CKD. Thus, there is a pressing need for new therapies designed to treat the damaged kidney. Several independent laboratories have identified a number of microRNAs that are dysregulated in human and animal models of CKD. We will explore the evidence suggesting that by blocking the activity of such dysregulated microRNAs, new therapeutics could be developed to treat the progression of CKD. PMID:23660218

  18. Self-Assembly into Nanoparticles Is Essential for Receptor Mediated Uptake of Therapeutic Antisense Oligonucleotides.

    PubMed

    Ezzat, Kariem; Aoki, Yoshitsugu; Koo, Taeyoung; McClorey, Graham; Benner, Leif; Coenen-Stass, Anna; O'Donovan, Liz; Lehto, Taavi; Garcia-Guerra, Antonio; Nordin, Joel; Saleh, Amer F; Behlke, Mark; Morris, John; Goyenvalle, Aurelie; Dugovic, Branislav; Leumann, Christian; Gordon, Siamon; Gait, Michael J; El-Andaloussi, Samir; Wood, Matthew J A

    2015-07-01

    Antisense oligonucleotides (ASOs) have the potential to revolutionize medicine due to their ability to manipulate gene function for therapeutic purposes. ASOs are chemically modified and/or incorporated within nanoparticles to enhance their stability and cellular uptake, however, a major challenge is the poor understanding of their uptake mechanisms, which would facilitate improved ASO designs with enhanced activity and reduced toxicity. Here, we study the uptake mechanism of three therapeutically relevant ASOs (peptide-conjugated phosphorodiamidate morpholino (PPMO), 2'Omethyl phosphorothioate (2'OMe), and phosphorothioated tricyclo DNA (tcDNA) that have been optimized to induce exon skipping in models of Duchenne muscular dystrophy (DMD). We show that PPMO and tcDNA have high propensity to spontaneously self-assemble into nanoparticles. PPMO forms micelles of defined size and their net charge (zeta potential) is dependent on the medium and concentration. In biomimetic conditions and at low concentrations, PPMO obtains net negative charge and its uptake is mediated by class A scavenger receptor subtypes (SCARAs) as shown by competitive inhibition and RNAi silencing experiments in vitro. In vivo, the activity of PPMO was significantly decreased in SCARA1 knockout mice compared to wild-type animals. Additionally, we show that SCARA1 is involved in the uptake of tcDNA and 2'OMe as shown by competitive inhibition and colocalization experiments. Surface plasmon resonance binding analysis to SCARA1 demonstrated that PPMO and tcDNA have higher binding profiles to the receptor compared to 2'OMe. These results demonstrate receptor-mediated uptake for a range of therapeutic ASO chemistries, a mechanism that is dependent on their self-assembly into nanoparticles. PMID:26042553

  19. Repurposing antipsychotics as glioblastoma therapeutics: Potentials and challenges

    PubMed Central

    LEE, JIN-KU; NAM, DO-HYUN; LEE, JEONGWU

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and most lethal primary brain tumor, with tragically little therapeutic progress over the last 30 years. Surgery provides a modest benefit, and GBM cells are resistant to radiation and chemotherapy. Despite significant development of the molecularly targeting strategies, the clinical outcome of GBM patients remains dismal. The challenges inherent in developing effective GBM treatments have become increasingly clear, and include resistance to standard treatments, the blood-brain barrier, resistance of GBM stem-like cells, and the genetic complexity and molecular adaptability of GBM. Recent studies have collectively suggested that certain antipsychotics harbor antitumor effects and have potential utilities as anti-GBM therapeutics. In the present review, the anti-tumorigenic effects and putative mechanisms of antipsychotics, and the challenges for the potential use of antipsychotic drugs as anti-GBM therapeutics are reviewed. PMID:26893731

  20. The Emerging Role of the Thrombin Receptor (PAR-1) in Melanoma Metastasis - a Possible Therapeutic Target

    PubMed Central

    Villares, Gabriel J.; Zigler, Maya; Bar-Eli, Menashe

    2011-01-01

    Melanoma remains as the deadliest form of skin cancer with limited and inefficient treatment options available for patients with metastatic disease. Within the last decade, the thrombin receptor, Protease Activated Receptor-1, has been described as an essential gene involved in the progression of human melanoma. PAR-1 is known to activate adhesive, invasive and angiogenic factors to promote melanoma metastasis. It is overexpressed not only in metastatic melanoma cell lines but is also highly expressed in metastatic lesions as compared to primary nevi and normal skin. Recently, PAR-1 has been described to regulate the gap junction protein Connexin 43 and the tumor suppressor gene Maspin to promote the metastatic melanoma phenotype. Herein, we review the role of PAR-1 in the progression of melanoma as well as utilizing PAR-1-regulated genes as potential therapeutic targets for melanoma treatment. PMID:21378407

  1. Orexin Receptor Antagonists: New Therapeutic Agents for the Treatment of Insomnia.

    PubMed

    Roecker, Anthony J; Cox, Christopher D; Coleman, Paul J

    2016-01-28

    Since its discovery in 1998, the orexin system, composed of two G-protein coupled receptors, orexins 1 and 2, and two neuropeptide agonists, orexins A and B, has captured the attention of the scientific community as a potential therapeutic target for the treatment of obesity, anxiety, and sleep/wake disorders. Genetic evidence in rodents, dogs, and humans was revealed between 1999 and 2000, demonstrating a causal link between dysfunction or deletion of the orexin system and narcolepsy, a disorder characterized by hypersomnolence during normal wakefulness. These findings encouraged efforts to discover agonists to treat narcolepsy and, alternatively, antagonists to treat insomnia. This perspective will focus on the discovery and development of structurally diverse orexin antagonists suitable for preclinical pharmacology studies and human clinical trials. The work described herein culminated in the 2014 FDA approval of suvorexant as a first-in-class dual orexin receptor antagonist for the treatment of insomnia. PMID:26317591

  2. Pharmacological and Therapeutic Effects of A3 Adenosine Receptor (A3AR) Agonists

    PubMed Central

    Fishman, Pnina; Bar-Yehuda, Sara; Liang, Bruce T.; Jacobson, Kenneth A.

    2011-01-01

    The Gi-coupled A3 adenosine receptor (A3AR) mediates anti-inflammatory, anticancer and anti-ischemic protective effects. The receptor is overexpressed in inflammatory and cancer cells, while low expression is found in normal cells, rendering the A3AR as a potential therapeutic target. Highly selective A3AR agonists have been synthesized and molecular recognition in the binding site has been characterized. The present review summarizes preclinical and clinical human studies demonstrating that A3AR agonists induce specific anti-inflammatory and anticancer effects via a molecular mechanism that entails modulation of the Wnt and the NF-κB signal transduction pathways. Currently, A3AR agonists are being developed for the treatment of inflammatory diseases including rheumatoid arthritis and psoriasis; ophthalmic diseases such as dry eye syndrome and glaucoma; liver diseases such as hepatocellular carcinoma and hepatitis. PMID:22033198

  3. Assessing the therapeutic potential of lab-made hepatocytes.

    PubMed

    Rezvani, Milad; Grimm, Andrew A; Willenbring, Holger

    2016-07-01

    Hepatocyte transplantation has potential as a bridge or even alternative to whole-organ liver transplantation. Because donor livers are scarce, realizing this potential requires the development of alternative cell sources. To be therapeutically effective, surrogate hepatocytes must replicate the complex function and ability to proliferate of primary human hepatocytes. Ideally, they are also autologous to eliminate the need for immune suppression, which can have severe side effects and may not be sufficient to prevent rejection long term. In the past decade, several methods have been developed to generate hepatocytes from other readily and safely accessible somatic cells. These lab-made hepatocytes show promise in animal models of liver diseases, supporting the feasibility of autologous liver cell therapies. Here, we review recent preclinical studies exemplifying different types of lab-made hepatocytes that can potentially be used in autologous liver cell therapies. To define the therapeutic efficacy of current lab-made hepatocytes, we compare them to primary human hepatocytes, focusing on engraftment efficiency and posttransplant proliferation and function. In addition to summarizing published results, we discuss animal models and assays effective in assessing therapeutic efficacy. This analysis underscores the therapeutic potential of current lab-made hepatocytes, but also highlights deficiencies and uncertainties that need to be addressed in future studies aimed at developing liver cell therapies with lab-made hepatocytes. (Hepatology 2016;64:287-294). PMID:27014802

  4. ERα-Negative and Triple Negative Breast Cancer: Molecular Features and Potential Therapeutic Approaches

    PubMed Central

    Chen, Jin-Qiang; Russo, Jose

    2010-01-01

    Triple negative breast cancer (TNBC) is a type of aggressive breast cancer lacking the expression of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor-2 (HER-2). TNBC patients account for approximately 15% of total breast cancer patients and are more prevalent among young African, African-American and Latino women patients. The currently available ER-targeted and Her-2-based therapies are not effective for treating TNBC. Recent studies have revealed a number of novel features of TNBC. In the present work, we comprehensively addressed these features and discussed potential therapeutic approaches based on these features for TNBC, with particular focus on: 1) the pathological features of TNBC/basal-like breast cancer; 2) E2/ERβ – mediated signaling pathways; 3) G-protein coupling receptor-30/epithelial growth factor receptor (GPCR-30/EGFR) signaling pathway; 4) interactions of ERβ with breast cancer 1/2 (BRCA1/2); 5) chemokine CXCL8 and related chemokines; 6) altered microRNA signatures and suppression of ERα expression/ERα-signaling by micro-RNAs; 7) altered expression of several pro-oncongenic and tumor suppressor proteins; and 8) genotoxic effects caused by oxidative estrogen metabolites. Gaining better insights into these molecular pathways in TNBC may lead to identification of novel biomarkers and targets for development of diagnostic and therapeutic approaches for prevention and treatment of TNBC. PMID:19527773

  5. Ursolic acid (UA): A metabolite with promising therapeutic potential.

    PubMed

    Kashyap, Dharambir; Tuli, Hardeep Singh; Sharma, Anil K

    2016-02-01

    Plants are known to produce a variety of bioactive metabolites which are being used to cure various life threatening and chronic diseases. The molecular mechanism of action of such bioactive molecules, may open up new avenues for the scientific community to develop or improve novel therapeutic approaches to tackle dreadful diseases such as cancer and cardiovascular and neurodegenerative disorders. Ursolic acid (UA) is one among the categories of such plant-based therapeutic metabolites having multiple intracellular and extracellular targets that play role in apoptosis, metastasis, angiogenesis and inflammatory processes. Moreover, the synthetic derivatives of UA have also been seen to be involved in a range of pharmacological applications, which are associated with prevention of diseases. Evidences suggest that UA could be used as a potential candidate to develop a comprehensive competent strategy towards the treatment and prevention of health disorders. The review article herein describes the possible therapeutic effects of UA along with putative mechanism of action. PMID:26775565

  6. Autophagy: a potential therapeutic target in lung diseases

    PubMed Central

    Nakahira, Kiichi

    2013-01-01

    Macroautophagy (hereafter referred to as autophagy) is an evolutionally conserved intracellular process to maintain cellular homeostasis by facilitating the turnover of protein aggregates, cellular debris, and damaged organelles. During autophagy, cytosolic constituents are engulfed into double-membrane-bound vesicles called “autophagosomes,” which are subsequently delivered to the lysosome for degradation. Accumulated evidence suggests that autophagy is critically involved not only in the basal physiological states but also in the pathogenesis of various human diseases. Interestingly, a diverse variety of clinically approved drugs modulate autophagy to varying extents, although they are not currently utilized for the therapeutic purpose of manipulating autophagy. In this review, we highlight the functional roles of autophagy in lung diseases with focus on the recent progress of the potential therapeutic use of autophagy-modifying drugs in clinical medicine. The purpose of this review is to discuss the merits, and the pitfalls, of modulating autophagy as a therapeutic strategy in lung diseases. PMID:23709618

  7. Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation.

    PubMed

    Rom, Slava; Persidsky, Yuri

    2013-06-01

    An accumulating body of evidence suggests that endocannabinoids and cannabinoid receptors type 1 and 2 (CB(1), CB(2)) play a significant role in physiologic and pathologic processes, including cognitive and immune functions. While the addictive properties of marijuana, an extract from the Cannabis plant, are well recognized, there is growing appreciation of the therapeutic potential of cannabinoids in multiple pathologic conditions involving chronic inflammation (inflammatory bowel disease, arthritis, autoimmune disorders, multiple sclerosis, HIV-1 infection, stroke, Alzheimer's disease to name a few), mainly mediated by CB(2) activation. Development of CB(2) agonists as therapeutic agents has been hampered by the complexity of their intracellular signaling, relative paucity of highly selective compounds and insufficient data regarding end effects in the target cells and organs. This review attempts to summarize recent advances in studies of CB(2) activation in the setting of neuroinflammation, immunomodulation and HIV-1 infection. PMID:23471521

  8. Cannabinoid receptor 2: Potential role in immunomodulation and neuroinflammation Review

    PubMed Central

    Rom, Slava; Persidsky, Yuri

    2013-01-01

    An accumulating body of evidence suggests that endocannabinoids and cannabinoid receptors type 1 and 2 (CB1, CB2) play a significant role in physiologic and pathologic processes, including cognitive and immune functions. While the addictive properties of marijuana, an extract from the Cannabis plant, are well recognized, there is growing appreciation of the therapeutic potential of cannabinoids in multiple pathologic conditions involving chronic inflammation (inflammatory bowel disease, arthritis, autoimmune disorders, multiple sclerosis, HIV-1 infection, stroke, Alzheimer’s disease to name a few), mainly mediated by CB2 activation. Development of CB2 agonists as therapeutic agents has been hampered by the complexity of their intracellular signaling, relative paucity of highly selective compounds and insufficient data regarding end effects in the target cells and organs. This review attempts to summarize recent advances in studies of CB2 activation in the setting of neuroinflammation, immunomodulation and HIV-1 infection. PMID:23471521

  9. Protein Engineering for Cardiovascular Therapeutics: Untapped Potential for Cardiac Repair

    PubMed Central

    Jay, Steven M.; Lee, Richard T.

    2013-01-01

    Numerous new and innovative approaches for repairing damaged myocardium are currently under investigation, with several encouraging results. In addition to the progression of stem cell-based approaches and gene therapy/silencing methods, evidence continues to emerge that protein therapeutics may be used to directly promote cardiac repair and even regeneration. However, proteins are often limited in their therapeutic potential by short local half-lives and insufficient bioavailability and/or bioactivity, and many academic laboratories studying cardiovascular diseases are more comfortable with molecular and cellular biology compared with protein biochemistry. Protein engineering has been employed broadly to overcome weaknesses traditionally associated with protein therapeutics and has the potential to specifically enhance the efficacy of molecules for cardiac repair. Yet protein engineering as a strategy has not yet been employed in the development of cardiovascular therapeutics to the degree that it has in other fields. In this review, we discuss the role of engineered proteins in cardiovascular therapies to date. Further, we address the promise of applying emerging protein engineering technologies to cardiovascular medicine and the barriers that must be overcome to enable the ultimate success of this approach. PMID:24030023

  10. The therapeutic potential of cannabinoids for movement disorders.

    PubMed

    Kluger, Benzi; Triolo, Piera; Jones, Wallace; Jankovic, Joseph

    2015-03-01

    There is growing interest in the therapeutic potential of marijuana (cannabis) and cannabinoid-based chemicals within the medical community and, particularly, for neurological conditions. This interest is driven both by changes in the legal status of cannabis in many areas and increasing research into the roles of endocannabinoids within the central nervous system and their potential as symptomatic and/or neuroprotective therapies. We review basic science as well as preclinical and clinical studies on the therapeutic potential of cannabinoids specifically as it relates to movement disorders. The pharmacology of cannabis is complex, with over 60 neuroactive chemicals identified to date. The endocannabinoid system modulates neurotransmission involved in motor function, particularly within the basal ganglia. Preclinical research in animal models of several movement disorders have shown variable evidence for symptomatic benefits, but more consistently suggest potential neuroprotective effects in several animal models of Parkinson's (PD) and Huntington's disease (HD). Clinical observations and clinical trials of cannabinoid-based therapies suggests a possible benefit of cannabinoids for tics and probably no benefit for tremor in multiple sclerosis or dyskinesias or motor symptoms in PD. Data are insufficient to draw conclusions regarding HD, dystonia, or ataxia and nonexistent for myoclonus or RLS. Despite the widespread publicity about the medical benefits of cannabinoids, further preclinical and clinical research is needed to better characterize the pharmacological, physiological, and therapeutic effects of this class of drugs in movement disorders. PMID:25649017

  11. The Therapeutic Potential of Cannabinoids for Movement Disorders

    PubMed Central

    Kluger, Benzi; Triolo, Piera; Jones, Wallace; Jankovic, Joseph

    2014-01-01

    Background There is growing interest in the therapeutic potential of marijuana (cannabis) and cannabinoid-based chemicals within the medical community and particularly for neurologic conditions. This interest is driven both by changes in the legal status of cannabis in many areas and increasing research into the roles of endocannabinoids within the central nervous system and their potential as symptomatic and/or neuroprotective therapies. We review basic science, preclinical and clinical studies on the therapeutic potential of cannabinoids specifically as it relates to movement disorders. Results The pharmacology of cannabis is complex with over 60 neuroactive chemicals identified to date. The endocannabinoid system modulates neurotransmission involved in motor function, particularly within the basal ganglia. Preclinical research in animal models of several movement disorders have shown variable evidence for symptomatic benefits but more consistently suggest potential neuroprotective effects in several animal models of Parkinson’s (PD) and Huntington’s disease (HD). Clinical observations and clinical trials of cannabinoid-based therapies suggests a possible benefit of cannabinoids for tics and probably no benefit for tremor in multiple sclerosis or dyskinesias or motor symptoms in PD. Data are insufficient to draw conclusions regarding HD, dystonia or ataxia and nonexistent for myoclonus or restless legs syndrome. Conclusions Despite the widespread publicity about the medical benefits of cannabinoids, further preclinical and clinical research is needed to better characterize the pharmacological, physiological and therapeutic effects of this class of drugs in movement disorders. PMID:25649017

  12. Application potential of toll-like receptors in cancer immunotherapy

    PubMed Central

    Shi, Ming; Chen, Xi; Ye, Kangruo; Yao, Yuanfei; Li, Yu

    2016-01-01

    Abstract Toll-like receptors (TLRs), as the most important pattern recognition receptors in innate immunity, play a pivotal role in inducing immune response through recognition of microbial invaders or specific agonists. Recent studies have suggested that TLRs could serve as important regulators in the development of a variety of cancer. However, increasing evidences have shown that TLRs may display quite opposite outcomes in cancer development. Although several potential therapeutic Toll-like receptor ligands have been found, the mechanism and therapy prospect of TLRs in cancer development has to be further elucidated to accelerate the clinical application. By performing a systematic review of the present findings on TLRs in cancer immunology, we attempted to evaluate the therapeutic potential of TLRs in cancer therapy and elucidate the potential mechanism of cancer progress regulated by TLR signaling and the reported targets on TLRs for clinical application. An electronic databases search was conducted in PubMed, Chinese Scientific Journal Database, and Chinese Biomedical Literature Database from their inception to February 1, 2016. The following keywords were used to search the databases: Toll-like receptors, cancer therapy, therapeutic target, innate immunity. Of 244 studies that were identified, 97 nonrelevant studies were excluded. In total, 147 full-text articles were assessed, and from these, 54 were excluded as they did not provide complete key information. Thus, 93 studies were considered eligible and included in the analysis. According to the data from the included trials, 14 TLR ligands (77.8%) from 82 studies have been demonstrated to display antitumor property in various cancers, whereas 4 ligands (22.2%) from 11 studies promote tumors. Among them, only 3 TLR ligands have been approved for cancer therapy, and 9 ligands were in clinical trials. In addition, the potential mechanism of recently reported targets on TLRs for clinical application was also

  13. Latest advances in novel cannabinoid CB2 ligands for drug abuse and their therapeutic potential

    PubMed Central

    Yang, Peng; Wang, Lirong; Xie, Xiang-Qun

    2012-01-01

    The field of cannabinoid (CB) drug research is experiencing a challenge as the CB1 antagonist Rimonabant, launched in 2006 as an anorectic/anti-obesity drug, was withdrawn from the European market due to the complications of suicide and depression as side effects. There is interest in developing CB2 drugs without CB1 psychotropic side effects for drug-abuse treatment and therapeutic medication. The CB1 receptor was discovered predominantly in the brain, whereas the CB2 is mainly expressed in peripheral cells and tissues, and is involved in immune signal transduction. Conversely, the CB2 receptor was recently detected in the CNS, for example, in the microglial cells and the neurons. While the CB2 neurons activity remains controversial, the CB2 receptor is an attractive therapeutic target for neuropathic pain, immune system, cancer and osteoporosis without psychoactivity. This review addresses CB drug abuse and therapeutic potential with a focus on the most recent advances on new CB2 ligands from the literature as well as patents. PMID:22300098

  14. eQTL and receptor pharmacology implicate Arg1 and the GABA-A receptor as therapeutic targets in neuroblastoma

    PubMed Central

    Hackett, Christopher S.; Quigley, David A.; Wong, Robyn A.; Chen, Justin; Cheng, Christine; Song, Young K.; Wei, Jun S.; Pawlikowska, Ludmila; Bao, Yun; Goldenberg, David D.; Nguyen, Kim; Gustafson, W. Clay; Rallapalli, Sundari K.; Cho, Yoon-Jae; Cook, James M.; Kozlov, Serguei; Mao, Jian-Hua; Van Dyke, Terry; Kwok, Pui-Yan; Khan, Javed; Balmain, Allan; Fan, QiWen; Weiss, William A.

    2014-01-01

    SUMMARY The development of targeted therapeutics for neuroblastoma, the third most common tumor in children, has been limited by a poor understanding of growth signaling mechanisms unique to the peripheral nerve precursors from which tumors arise. In this study, we combined genetics with gene expression analysis in the peripheral sympathetic nervous system to implicate arginase 1 and GABA signaling in tumor formation in vivo. In human neuroblastoma cells, either blockade of ARG1 or benzodiazepine-mediated activation of GABA-A receptors induced apoptosis and inhibited mitogenic signaling through AKT and MAPK. These results suggest that ARG1 and GABA influence both neural development and neuroblastoma, and that benzodiazepines in clinical use may have potential for neuroblastoma therapy. PMID:25437558

  15. P2Y nucleotide receptors: Promise of therapeutic applications

    PubMed Central

    Jacobson, Kenneth A.; Boeynaems, Jean-Marie

    2010-01-01

    Extracellular nucleotides, such as ATP and UTP, have distinct signaling roles through a class of G protein-coupled receptors, termed P2Y. However, the receptor ligands are typically charged molecules of low bioavailability and stability in vivo. Recent progress in the development of selective agonists and antagonists for P2Y receptors and study of knockout mice have led to new drug concepts based on these receptors. The rapidly accelerating progress in this field has already resulted in drug candidates for cystic fibrosis, dry eye disease, and thrombosis. On the horizon are novel treatments of cardiovascular diseases, inflammatory diseases, and neurodegeneration. PMID:20594935

  16. Orphan nuclear receptors in breast cancer pathogenesis and therapeutic response.

    PubMed

    Riggins, Rebecca B; Mazzotta, Mary M; Maniya, Omar Z; Clarke, Robert

    2010-09-01

    Nuclear receptors comprise a large family of highly conserved transcription factors that regulate many key processes in normal and neoplastic tissues. Most nuclear receptors share a common, highly conserved domain structure that includes a carboxy-terminal ligand-binding domain. However, a subgroup of this gene family is known as the orphan nuclear receptors because to date there are no known natural ligands that regulate their activity. Many of the 25 nuclear receptors classified as orphan play critical roles in embryonic development, metabolism, and the regulation of circadian rhythm. Here, we review the emerging role(s) of orphan nuclear receptors in breast cancer, with a particular focus on two of the estrogen-related receptors (ERRalpha and ERRgamma) and several others implicated in clinical outcome and response or resistance to cytotoxic or endocrine therapies, including the chicken ovalbumin upstream promoter transcription factors, nerve growth factor-induced B, DAX-1, liver receptor homolog-1, and retinoic acid-related orphan receptor alpha. We also propose that a clearer understanding of the function of orphan nuclear receptors in mammary gland development and normal mammary tissues could significantly improve our ability to diagnose, treat, and prevent breast cancer. PMID:20576803

  17. Mesenchymal stem cell subpopulations: phenotype, property and therapeutic potential.

    PubMed

    Mo, Miaohua; Wang, Shan; Zhou, Ying; Li, Hong; Wu, Yaojiong

    2016-09-01

    Mesenchymal stem cells (MSC) are capable of differentiating into cells of multiple cell lineages and have potent paracrine effects. Due to their easy preparation and low immunogenicity, MSC have emerged as an extremely promising therapeutic agent in regenerative medicine for diverse diseases. However, MSC are heterogeneous with respect to phenotype and function in current isolation and cultivation regimes, which often lead to incomparable experimental results. In addition, there may be specific stem cell subpopulations with definite differentiation capacity toward certain lineages in addition to stem cells with multi-differentiation potential. Recent studies have identified several subsets of MSC which exhibit distinct features and biological activities, and enhanced therapeutic potentials for certain diseases. In this review, we give an overview of these subsets for their phenotypic, biological and functional properties. PMID:27141940

  18. The pharmacology and therapeutic potential of (−)-huperzine A

    PubMed Central

    Tun, Maung Kyaw Moe; Herzon, Seth B

    2012-01-01

    (−)-Huperzine A (1) is an alkaloid isolated from a Chinese club moss. Due to its potent neuroprotective activities, it has been investigated as a candidate for the treatment of neurodegenerative diseases, including Alzheimer’s disease. In this review, we will discuss the pharmacology and therapeutic potential of (−)-huperzine A (1). Synthetic studies of (−)-huperzine A (1) aimed at enabling its development as a pharmaceutical will be described.

  19. Aquaporin 1, a potential therapeutic target for migraine with aura

    PubMed Central

    2010-01-01

    The pathophysiology of migraine remains largely unknown. However, evidence regarding the molecules participating in the pathophysiology of migraine has been accumulating. Water channel proteins, known as aquaporins (AQPs), notably AQP-1 and AQP-4, appears to be involved in the pathophysiology of several neurological diseases. This review outlines newly emerging evidence indicating that AQP-1 plays an important role in pain signal transduction and migraine and could therefore serve as a potential therapeutic target for these diseases. PMID:20969805

  20. The therapeutic potential of RORγ modulators in the treatment of human disease

    PubMed Central

    Chang, Mi Ra; Goswami, Devrishi; Mercer, Becky A; Griffin, Patrick R

    2012-01-01

    Nuclear receptors (NR) are ligand-regulated transcription factors that bind DNA in proximity to their target genes and exert their effects as a result of binding by small molecule ligands such as sterols, lipids, fatty acids, retinoids, and steroid hormones. The retinoic acid receptor-related orphan receptors or RORs (NR1F1–NR1F3) are nuclear receptors that regulate multiple cellular processes, including metabolism, cellular differentiation, and apoptosis, in a range of tissues and organs. These receptors bind as monomers to ROR response elements commonly called ROREs present in promoter regions of target genes and tether chromatin remodeling enzymes, facilitating recruitment of transcription machinery. Several recent reports have highlighted the potential role for RORs in human disease, and more importantly, studies have demonstrated that these receptors can be modulated by exogenous synthetic ligands, paving the way for development of novel therapeutics. Here we review the current status of synthetic ligand development as well as the structural aspects governing modulation of ROR signaling pathways as they relate to metabolic diseases and autoimmune disorders. PMID:27186126

  1. Potential therapeutic value of TRPV1 and TRPA1 in diabetes mellitus and obesity.

    PubMed

    Derbenev, Andrei V; Zsombok, Andrea

    2016-05-01

    Diabetes mellitus and obesity, which is a major risk factor in the development of type 2 diabetes mellitus, have reached epidemic proportions worldwide including the USA. The current statistics and forecasts, both short- and long-term, are alarming and predict severe problems in the near future. Therefore, there is a race for developing new compounds, discovering new receptors, or finding alternative solutions to prevent and/or treat the symptoms and complications related to obesity and diabetes mellitus. It is well demonstrated that members of the transient receptor potential (TRP) superfamily play a crucial role in a variety of biological functions both in health and disease. In the recent years, transient receptor potential vanilloid type 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) were shown to have beneficial effects on whole body metabolism including glucose homeostasis. TRPV1 and TRPA1 have been associated with control of weight, pancreatic function, hormone secretion, thermogenesis, and neuronal function, which suggest a potential therapeutic value of these channels. This review summarizes recent findings regarding TRPV1 and TRPA1 in association with whole body metabolism with emphasis on obese and diabetic conditions. PMID:26403087

  2. Imaging Diagnostic and Therapeutic Targets - Steroid Receptors in Breast Cancer

    PubMed Central

    Fowler, Amy M.; Clark, Amy S.; Katzenellenbogen, John A; Linden, Hannah M.; Dehdashti, Farrokh

    2016-01-01

    Estrogen receptor-alpha (ERα) and progesterone receptor (PR) are important steroid hormone receptor biomarkers used to determine prognosis and predict benefit from endocrine therapies for breast cancer patients. Receptor expression is routinely measured in biopsy specimens using immunohistochemistry, although such testing can be challenging particularly in the setting of metastatic disease. ERα and PR can be quantitatively assayed non-invasively with positron emission tomography (PET). This approach provides the opportunity to assess receptor expression and function in “real-time”, within the entire tumor, and across distant sites of metastatic disease. This article reviews the current evidence of ERα and PR PET imaging as predictive and early response biomarkers for endocrine therapy. PMID:26834106

  3. Bitropic D3 Dopamine Receptor Selective Compounds s Potential Antipsychotics.

    PubMed

    Luedtke, Robert R; Rangel-Barajas, Claudia; Malik, Mahinder; Reichert, David E; Mach, R H

    2015-01-01

    Neuropsychiatric disorders represent a substantial social and health care issue. The National Institutes of Health estimates that greater than 2 million adults suffer from neuropsychiatric disorders in the USA. These individuals experience symptoms that can include auditory hallucinations, delusions, unrealistic beliefs and cognitive dysfunction. Although antipsychotic medications are available, suboptimal therapeutic responses are observed for approximately one-third of patients. Therefore, there is still a need to explore new pharmacotherapeutic strategies for the treatment of neuropsychiatric disorders. Many of the medications that are used clinically to treat neuropsychiatric disorders have a pharmacological profile that includes being an antagonist at D2-like (D2, D3 and D4) dopamine receptor subtypes. However, dopamine receptor subtypes are involved in a variety of neuronal circuits that include movement coordination, cognition, emotion, affect, memory and the regulation of prolactin. Consequently, antagonism at D2-like receptors can also contribute to some of the adverse side effects associated with the long-term use of antipsychotics including the a) adverse extrapyramidal symptoms associated with the use of typical antipsychotics and b) metabolic side effects (weight gain, hyperglycemia, increased risk of diabetes mellitus, dyslipidemia and gynecomastia) associated with atypical antipsychotic use. Preclinical studies suggest that D3 versus D2 dopamine receptor selective compounds might represent an alternative strategy for the treatment of the symptoms of schizophrenia. In this review we discuss a) how bitropic Nphenylpiperazine D3 dopamine receptor selective compounds have been developed by modification of the primary (orthosteric) and secondary (allosteric or modulatory) pharmacophores to optimize D3 receptor affinity and D2/D3 binding selectivity ratios and b) the functional selectivity of these compounds. Examples of how these compounds might be

  4. COGNITION AS A THERAPEUTIC TARGET IN LATE-LIFE DEPRESSION: POTENTIAL FOR NICOTINIC THERAPEUTICS

    PubMed Central

    Zurkovsky, Lilia; Taylor, Warren D.; Newhouse, Paul A.

    2013-01-01

    Depression is associated with impairments to cognition and brain function at any age, but such impairments in the elderly are particularly problematic because of the additional burden of normal cognitive aging and in some cases, structural brain pathology. Individuals with late-life depression exhibit impairments in cognition and brain structural integrity, alongside mood dysfunction. Antidepressant treatment improves symptoms in some but not all patients, and those who benefit may not return to the cognitive and functional level of nondepressed elderly. Thus, for comprehensive treatment of late-life depression, it may be necessary to address both the affective and cognitive deficits. In this review, we propose a model for the treatment of late-life depression in which nicotinic stimulation is used to improve cognitive performance and improve the efficacy of an antidepressant treatment of the syndrome of late-life depression. The cholinergic system is well-established as important to cognition. Although muscarinic stimulation may exacerbate depressive symptoms, nicotinic stimulation may improve cognition and neural functioning without a detriment to mood. While some studies of nicotinic subtype specific receptor agonists have shown promise in improving cognitive performance, less is known regarding how nicotinic receptor stimulation affects cognition in depressed elderly patients. Late-life depression thus represents a new therapeutic target for the development of nicotinic agonist drugs and parallel treatment of cognitive dysfunction along with medical and psychological approaches to treating mood dysfunction may be necessary to ensure full resolution of depressive illness in aging. PMID:23933385

  5. The Natural Flavonoid Pinocembrin: Molecular Targets and Potential Therapeutic Applications.

    PubMed

    Lan, Xi; Wang, Wenzhu; Li, Qiang; Wang, Jian

    2016-04-01

    Pinocembrin is a natural flavonoid compound extracted from honey, propolis, ginger roots, wild marjoram, and other plants. In preclinical studies, it has shown anti-inflammatory and neuroprotective effects as well as the ability to reduce reactive oxygen species, protect the blood-brain barrier, modulate mitochondrial function, and regulate apoptosis. Considering these pharmaceutical characteristics, pinocembrin has potential as a drug to treat ischemic stroke and other clinical conditions. In this review, we summarize its pharmacologic characteristics and discuss its mechanisms of action and potential therapeutic applications. PMID:25744566

  6. Immunohistochemical detection of a potential molecular therapeutic target for canine hemangiosarcoma

    PubMed Central

    ADACHI, Mami; HOSHINO, Yuki; IZUMI, Yusuke; TAKAGI, Satoshi

    2015-01-01

    Canine hemangiosarcoma (HSA) is a progressive malignant neoplasm of dogs for which there is currently no effective treatment. A recent study suggested that receptor tyrosine kinases (RTKs), the PI3K/Akt/m-TOR and MAPK pathways are all activated in canine and human HSA. The aim of the present study was to investigate the overexpression of these proteins by immunohistochemistry in canine splenic HSA to identify potential molecular therapeutic targets. A total of 10 splenic HSAs and two normal splenic samples surgically resected from dogs were sectioned and stained with hematoxylin and eosin for histological diagnosis or analyzed using immunohistochemistry. The expression of RTKs, c-kit, VEGFR-2 and PDGFR-2, as well as PI3K/Akt/m-TOR and MEK was higher in canine splenic HSAs compared to normal spleens. These proteins may therefore be potential therapeutic targets in canine splenic HSA. PMID:26685984

  7. Immunohistochemical detection of a potential molecular therapeutic target for canine hemangiosarcoma.

    PubMed

    Adachi, Mami; Hoshino, Yuki; Izumi, Yusuke; Takagi, Satoshi

    2016-05-01

    Canine hemangiosarcoma (HSA) is a progressive malignant neoplasm of dogs for which there is currently no effective treatment. A recent study suggested that receptor tyrosine kinases (RTKs), the PI3K/Akt/m-TOR and MAPK pathways are all activated in canine and human HSA. The aim of the present study was to investigate the overexpression of these proteins by immunohistochemistry in canine splenic HSA to identify potential molecular therapeutic targets. A total of 10 splenic HSAs and two normal splenic samples surgically resected from dogs were sectioned and stained with hematoxylin and eosin for histological diagnosis or analyzed using immunohistochemistry. The expression of RTKs, c-kit, VEGFR-2 and PDGFR-2, as well as PI3K/Akt/m-TOR and MEK was higher in canine splenic HSAs compared to normal spleens. These proteins may therefore be potential therapeutic targets in canine splenic HSA. PMID:26685984

  8. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders.

    PubMed

    Campos, Alline Cristina; Moreira, Fabricio Araújo; Gomes, Felipe Villela; Del Bel, Elaine Aparecida; Guimarães, Francisco Silveira

    2012-12-01

    Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ(9)-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca(2+)) increase, etc.), on CBD behavioural effects. PMID:23108553

  9. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders

    PubMed Central

    Campos, Alline Cristina; Moreira, Fabricio Araújo; Gomes, Felipe Villela; Del Bel, Elaine Aparecida; Guimarães, Francisco Silveira

    2012-01-01

    Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ9-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca2+) increase, etc.), on CBD behavioural effects. PMID:23108553

  10. Therapeutic potential of mGluR5 targeting in Alzheimer's disease

    PubMed Central

    Kumar, Anil; Dhull, Dinesh K.; Mishra, Pooja S.

    2015-01-01

    Decades of research dedicated toward Alzheimer's disease (AD) has culminated in much of the current understanding of the neurodegeneration associated with disease. However, delineating the pathophysiology and finding a possible cure for the disease is still wanting. This is in part due to the lack of knowledge pertaining to the connecting link between neurodegenerative and neuroinflammatory pathways. Consequently, the inefficacy and ill-effects of the drugs currently available for AD encourage the need for alternative and safe therapeutic intervention. In this review we highlight the potential of mGluR5, a metabotropic glutamatergic receptor, in understanding the mechanism underlying the neuronal death and neuroinflammation in AD. We also discuss the role of mGlu5 receptor in mediating the neuron-glia interaction in the disease. Finally, we discuss the potential of mGluR5 as target for treating AD. PMID:26106290