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  • A BAG's life: Every connection matters in cancer
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2020-01-27
    Elena Mariotto; Giampietro Viola; Carlo Zanon; Sanja Aveic

    The members of the BCL-2 associated athanogene (BAG) family participate in the regulation of a variety of interrelated physiological processes, such as autophagy, apoptosis, and protein homeostasis. Under normal circumstances, the six BAG members described in mammals (BAG1-6) principally assist the 70 kDa heat-shock protein (HSP70) in protein folding; however, their role as oncogenes is becoming increasingly evident. Deregulation of the BAG multigene family has been associated with cell transformation, tumor recurrence, and drug resistance. In addition to BAG overexpression, BAG members are also involved in many oncogenic protein–protein interactions (PPIs). As such, either the inhibition of overloading BAGs or of specific BAG–client protein interactions could have paramount therapeutic value. In this review, we will examine the role of each BAG family member in different malignancies, focusing on their modular structure, which enables interaction with a variety of proteins to exert their pro-tumorigenic role. Lastly, critical remarks on the unmet needs for proposing effective BAG inhibitors will be pointed out.

    更新日期:2020-01-27
  • Role of Rad51 and DNA repair in cancer: A molecular perspective
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2020-01-27
    Erik Laurini; Domenico Marson; Alice Fermeglia; Suzana Aulic; Maurizio Fermeglia; Sabrina Pricl

    The maintenance of genome integrity is essential for any organism survival and for the inheritance of traits to offspring. To the purpose, cells have developed a complex DNA repair system to defend the genetic information against both endogenous and exogenous sources of damage. Accordingly, multiple repair pathways can be aroused from the diverse forms of DNA lesions, which can be effective per se or via crosstalk with others to complete the whole DNA repair process. Deficiencies in DNA healing resulting in faulty repair and/or prolonged DNA damage can lead to genes mutations, chromosome rearrangements, genomic instability, and finally carcinogenesis and/or cancer progression. Although it might seem paradoxical, at the same time such defects in DNA repair pathways may have therapeutic implications for potential clinical practice. Here we provide an overview of the main DNA repair pathways, with special focus on the role played by homologous repair and the RAD51 recombinase protein in the cellular DNA damage response. We next discuss the recombinase structure and function per se and in combination with all its principal mediators and regulators. Finally, we conclude with an analysis of the manifold roles that RAD51 plays in carcinogenesis, cancer progression and anticancer drug resistance, and conclude this work with a survey of the most promising therapeutic strategies aimed at targeting RAD51 in experimental oncology.

    更新日期:2020-01-27
  • Berberine in the treatment of metabolism-related chronic diseases: A drug cloud (dCloud) effect to target multifactorial disorders
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2020-01-27
    Wei-Jia Kong; Claudio Vernierib; Marco Foiani; Jian-Dong Jiang

    Berberine (BBR) is a multi-target drug (MTD) that has proven effective in the treatment of metabolism-related chronic diseases (CDs). However, the mode of action (MOA) of BBR remains to be clarified. At a cellular level, the inhibitory effect of BBR on mitochondrial enzymes is probably responsible for many of its biological activities, including the activation of low-density lipoprotein receptor (LDLR), AMP-activated protein kinase (AMPK) and insulin receptor (InsR); these biological activities contribute to ameliorate peripheral blood metabolic profiles, e.g. by reducing plasma lipids and glucose levels, thus improving signs and symptoms of metabolic disorders. In this perspective, BBR acts as a targeted therapy. However, it also exerts pleiotropic systemic activities on some root causes of CDs that include antioxidant / anti-inflammatory effects and modifications of gut microbiota composition and metabolism, which may also contribute to its disease-modifying effects. After reviewing the different MOA of BBR, here we propose that BBR acts through a drug-cloud (dCloud) mechanism, as different to a drug-target effect. The dCloud here is defined as a group of terminal molecular events induced by the drug (or/and related metabolites), as well as the network connections among them. In this scenario, the therapeutic efficacy of BBR is the result of its dCloud effect acting on symptoms/signs as well as on root causes of the diseases. The dCloud concept is applicable to other established MTDs, such as aspirin, metformin, statins as well as to nutrient starvation, thus providing a novel instrument for the design of effective therapies against multifactorial metabolism-related CDs.

    更新日期:2020-01-27
  • Endozepines and their receptors: Structure, functions and pathophysiological significance
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-07-05
    Marie-Christine Tonon; Hubert Vaudry; Julien Chuquet; Florent Guillebaud; Jinjiang Fan; Olfa Masmoudi-Kouki; David Vaudry; Damien Lanfray; Fabrice Morin; Vincent Prevot; Vassilios Papadopoulos; Jean-Denis Troadec; Jérôme Leprince

    The existence of specific binding sites for benzodiazepines (BZs) in the brain has prompted the search for endogenous BZ receptor ligands designated by the generic term « endozepines ». This has led to the identification of an 86-amino acid polypeptide capable of displacing [3H]diazepam binding to brain membranes, thus called diazepam-binding inhibitor (DBI). It was subsequently found that the sequence of DBI is identical to that of a lipid carrier protein termed acyl-CoA-binding protein (ACBP). The primary structure of DBI/ACBP has been well preserved, suggesting that endozepines exert vital functions. The DBI/ACBP gene is expressed by astroglial cells in the central nervous system, and by various cell types in peripheral organs. Endoproteolytic cleavage of DBI/ACBP generates several bioactive peptides including a triakontatetraneuropeptide that acts as a selective ligand of peripheral BZ receptors/translocator protein (PBR/TSPO), and an octadecaneuropeptide that activates a G protein-coupled receptor and behaves as an allosteric modulator of the GABAAR. Although DBI/ACBP is devoid of a signal peptide, endozepines are released by astrocytes in a regulated manner. Consistent with the diversity and wide distribution of BZ-binding sites, endozepines appear to exert a large array of biological functions and pharmacological effects. Thus, intracerebroventricular administration of DBI or derived peptides induces proconflict and anxiety-like behaviors, and reduces food intake. Reciprocally, the expression of DBI/ACBP mRNA is regulated by stress and metabolic signals. In vitro, endozepines stimulate astrocyte proliferation and protect neurons and astrocytes from apoptotic cell death. Endozepines also regulate neurosteroid biosynthesis and neuropeptide expression, and promote neurogenesis. In peripheral organs, endozepines activate steroid hormone production, stimulate acyl chain ceramide synthesis and trigger pro-inflammatory cytokine secretion. The expression of the DBI/ACBP gene is enhanced in addiction/withdrawal animal models, in patients with neurodegenerative disorders and in various types of tumors. We review herein the current knowledge concerning the various actions of endozepines and discusses the physiopathological implications of these regulatory gliopeptides.

    更新日期:2020-01-27
  • A hypothesis of monoamine (5-HT) – Glutamate/GABA long neural circuit: Aiming for fast-onset antidepressant discovery
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2020-01-25
    Yun-Feng Li

    Major depressive disorder has become a global public health problem of serious concern. Most of the clinical antidepressants are developed under the classic “monoamine hypothesis (strategy)”. These drugs generally have such deficiencies including slow onset and limited efficiency, cognitive impairment and suicidal tendency. Therefore, it is the direction to break through the classic monoamine strategy framework for developing antidepressants that have fast-acting, lower side effects, and cognitive enhancement, to satisfy the major clinical needs. In 2019, the launch of fast-acting antidepressants such as S-ketamine(S-Ket) and brexanolone into market by FDA has opened up new prospects for non-monoamine strategy mainly based on the N-methyl-d-aspartate (NMDA) and γ-aminobutyric acid type A (GABAA) receptors. There are two main trends in the development of fast-onset antidepressants: the optimized multi-target monoamine strategy (modern monoamine strategy) and the non-monoamine strategy based on glutamate(Glu)-GABA balance modulation. Based to the research conducted by foreign peers and our lab, we propose a hypothesis of “monoamine (5-HT)- Glu/GABA long neural circuit”, which holds the view that both monoaminergic mechanisms (such as 5-HT neurons located in raphe nucleus) and non-monoaminergic mechanisms (Glu/GABA neurons located in prefrontal cortex) are all part of the rapid-acting antidepressant mechanisms, and both of them form a long neural circuit mediating the fast synaptogenesis of the brain regions including prefrontal cortex. Based on this, it is proposed that fast launch and activation of this circuit may be an important mechanism for fast-onset of antidepressant, in which Glu/GABA (excitation/ inhibition, E/I) rebalance should be the critical rate-limiting step for the onset speed. Therefore, five potential strategies are proposed for fast-acting antidepressant based on this circuit: 1) Achieve the rapid E/I balance by relieving the inhibition of GABA interneurons on glutamatergic pyramidal neurons or directly activating pyramidal neurons; 2) Simultaneously modulate 5-HT neuronal activity and Glu/GABA balance by 5-HT transporter combining with some receptors such as 5-HT1A/1B (namely simultaneous enhancement of the 5-HT and Glu/GABA links); 3) Directly activate mammalian rapamycin target protein complex 1 (mTORC1) and rapidly enhance brain-derived neurotrophic factor (BDNF) -mTOR pathway; 4) Stimulate rapid release of BDNF in the brain; 5) Positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. It is hoped that these ideas will provide possible strategies for the further development of a new generation of antidepressants and provide a useful reference for the further discovery of fast-onset antidepressant candidate targets.

    更新日期:2020-01-26
  • Pharmacology and perspectives in erectile dysfunction in man
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2020-01-25
    Emma Mitidieri; Giuseppe Cirino; Roberta d’Emmanuele di Villa Bianca; Raffaella Sorrentino

    Penile erection is a perfect example of microcirculation modulated by psychological factors and hormonal status. It is the result of a complex neurovascular process that involves the integrative synchronized action of vascular endothelium; smooth muscle; and psychological, neuronal, and hormonal systems. Therefore, the fine coordination of these events is essential to maintain penile flaccidity or allow erection; an alteration of these events leads to erectile dysfunction (ED). ED is defined as the consistent or recurrent inability of a man to attain and/or maintain a penile erection sufficient for sexual activity. A great boost to this research field was given by commercialization of phosphodiesterase-5 (PDE5) inhibitors. Indeed, following the discovery of sildenafil, research on the mechanisms underlying penile erection has had an enormous boost, and many preclinical and clinical papers have been published in the last 10 years. This review is structured to provide an overview of the mediators and peripheral mechanism(s) involved in penile function in men, the drugs used in therapy, and the future prospective in the management of ED. Indeed, 30% of patients affected by ED are classified as “nonresponders,” and there is still an unmet need for therapeutic alternatives. A flowchart suggesting the guidelines for ED evaluation and the ED pharmacological treatment is also provided.

    更新日期:2020-01-26
  • Natural products-based polypharmacological modulation of the peripheral immune system for the treatment of neuropsychiatric disorders
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2020-01-21
    Simon Wing-Fai Mok; Vincent Kam-Wai Wong; Hang-Hong Lo; Ivo Ricardo de Seabra Rodrigues Dias; Elaine Lai-Han Leung; Betty Yuen-Kwan Law; Liang Liu

    Chronic inflammation of the central nervous system (CNS) is critical to the pathogenesis of neuropsychiatric disorders (NPDs) that affect the global population. Current therapeutics for NPDs are limited to relieving symptoms and induce many adverse effects. Therefore, the discovery of novel therapeutic agents from natural sources is urgently needed. Intriguingly, the immune responses of peripheral organs are closely linked through the molecular communication between resident and blood-borne cellular components, which shape the neuroinflammatory phenotypes of NPDs. Since the gut and spleen are the two largest immunological organs of the body, the brain–gut microbiome and brain–spleen axes have been implicated in the connection between the CNS and the peripheral immune system. Accordingly, it has been proposed that the local CNS inflammation observed in NPDs is regulated via the manipulation of the systemic immune system by targeting the gut and spleen. Additionally, the complexity of the signalling network underlying the communication between the CNS and the systemic immune system suggests a strong potential for treating NPDs through a polypharmacological approach. The close association between systemic immunity and the homeostasis of the CNS points to the concept of repurposing interventions for systemic immune disorders to treat NPDs. Notably, natural products represent a promising source of such effective compounds due to both their pharmacological potency and safety. This review discusses the complex implications of dysregulated systemic immunity mediated by the brain–spleen and brain–gut microbiome axes in NPDs, such as Alzheimer’s disease, Parkinson’s disease, schizophrenia and major depressive disorder. In addition, the potential of repurposing natural product-based bioactive compounds for treating NPDs via modulating systemic immune disorders is intensively discussed.

    更新日期:2020-01-21
  • Antifungal effects of statins
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2020-01-15
    Alireza Tavakkoli; Thomas P. Johnston; Amirhossein Sahebkar

    Fungal infections are estimated to be responsible for 1.5 million deaths annually. Global anti-microbial resistance is also observed for fungal pathogens, and scientists are looking for new antifungal agents to address this challenge. One potential strategy is to evaluate currently available drugs for their possible antifungal activity. One of the suggested drug classes are statins, which are commonly used to decrease plasma cholesterol and reduce cardiovascular risk associated with low density lipoprotein cholesterol (LDL-c). Statins are postulated to possess pleiotropic effects beyond cholesterol lowering; improving endothelial function, modulating inflammation, and potentially exerting anti-microbial effects. In this study, we reviewed in-vitro and in-vivo studies, as well as clinical reports pertaining to the antifungal efficacy of statins. In addition, we have addressed various modulators of statin anti-fungal activity and the potential mechanisms responsible for their anti-fungal effects. In general, statins do possess anti-fungal activity, targeting a broad spectrum of fungal organisms including human opportunistic pathogens such as Candida spp. and Zygomycetes, Dermatophytes, alimentary toxigenic species such as Aspergillus spp., and fungi found in device implants such as Saccharomyces cerevisiae. Statins have been shown to augment a number of antifungal drug classes, for example, the azoles and polyenes. Synthetic statins are generally considered more potent than the first generation of fungal metabolites. Fluvastatin is considered the most effective statin with the broadest and most potent fungal inhibitory activity, including fungicidal and/or fungistatic properties. This has been demonstrated with plasma concentrations that can easily be achieved in a clinical setting. Additionally, statins can potentiate the efficacy of available antifungal drugs in a synergistic fashion. Although only a limited number of animal and human studies have been reported to date, observational cohort studies have confirmed that patients using statins have a reduced risk of candidemia-related complications. Further studies are warranted to confirm our findings and expand current knowledge of the anti-fungal effects of statins.

    更新日期:2020-01-15
  • Make your best BET the emerging role of BET inhibitor treatment in malignant tumors
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2020-01-11
    Oliver Bechter; Patrick Schöffski

    Bromodomains are protein-protein interaction modules with a great diversity in terms of number of proteins and their function. The bromodomain and extraterminal protein (BET) represents a distinct subclass of bromodomain proteins mainly involved in transcriptional regulation via their interaction with acetylated chromatin. In cancer cells BET proteins are found to be altered in many ways such as overexpression, mutations and fusions of BET proteins or their interference with cancer relevant signaling pathways and transcriptional programs in order to sustain cancer growth and viability. Blocking BET protein function with small molecules is associated with therapeutic activity. Consequently, a variety of small molecules have been developed and a number of phase I clinical trials have explored their tolerability and efficacy in patients with solid tumors and hematological malignancies. We will review the rational for applying BET inhibitors in the clinic and we will discuss the toxicity profile as well as efficacy of this new class of protein inhibitors. We will also highlight the emerging problem of treatment resistance and the potential these drugs might have when combined with other anti-cancer therapies.

    更新日期:2020-01-13
  • Immunotherapy in sepsis - brake or accelerate?
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2020-01-10
    Folkert Steinhagen; Susanne Schmidt; Jens-Christian Schewe; Konrad Peukert; Dennis M. Klinman; Christian Bode

    Sepsis, a life threating syndrome characterized by organ failure after infection, is the most common cause of death in hospitalized patients. The treatment of sepsis is generally supportive in nature, involving the administration of intravenous fluids, vasoactive substances and oxygen plus antibiotics to eliminate the pathogen. No drugs have been approved specifically for the treatment of sepsis, and clinical trials of potential therapies have failed to reduce mortality - suggesting that new approaches are needed. Abnormalities in the immune response elicited by the pathogen, ranging from excessive inflammation to immunosuppression, contribute to disease pathogenesis. Although hundreds of immunomodulatory agents are potentially available, it remains unclear which patient benefits from which immune therapy at a given time point. Results indicate the importance of personalized therapy, specifically the need to identify the type of intervention required by each individual patient at a given point in the disease process. To address this issue will require using biomarkers to stratify patients based on their individual immune status. This article reviews recent and ongoing clinical investigations using immunostimulatory or immunosuppressive therapies against sepsis including non-pharmacological and novel preclinical approaches.

    更新日期:2020-01-10
  • In situ imaging of monoamine localization and dynamics
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2020-01-10
    Eiji Sugiyama; Ashwin N. Skelly; Makoto Suematsu; Yuki Sugiura

    Recent advances in sample preparation protocols and instrumentation allow current imaging mass spectrometry (IMS) to enable the visualization of small molecule tissue localization, including that of monoamine neurotransmitters, such as serotonin, dopamine, and norepinephrine. Although monoamine-producing neurons, and their projections and synaptic connections, have been thoroughly characterized, in situ monoamine localization within these circuits remains unclear. Moreover, studying the fluctuations in local monoamine concentration in response to physiological stimuli, drug administration, and neurodegenerative disease progression is worthwhile, which can be achieved by analyzing the in situ concentration maps afforded by coupling IMS with on-tissue derivatization protocols. Recent reports have shown that monoamines localize within cell bodies and also translocate to distant nerve terminals, indicating active transport along axons and/or local synthesis at the terminals. Moreover, IMS can reveal regionally segregated monoamine fluctuations, such as, rapid dopamine fluctuation within the nucleus accumbens (NAcc) subregion during pain sensation. Furthermore, since exogenous drug pharmacokinetics can also be visualized by IMS, it could provide powerful methodologies enabling the simultaneous imaging of monoamines and drugs that selectively regulate monoamine signaling, such as serotonin reuptake inhibitors (SSRIs). Therefore, IMS could reveal where SSRIs administered over the long-term accumulate and how they affect local monoamine metabolism.

    更新日期:2020-01-10
  • Hyperthermia induced by transient receptor potential vanilloid-1 (TRPV1) antagonists in human clinical trials: Insights from mathematical modeling and meta-analysis
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2020-01-09
    Andras Garami; Yury P. Shimansky; Zoltan Rumbus; Robson C.L. Vizin; Nelli Farkas; Judit Hegyi; Zsolt Szakacs; Margit Solymar; Alexandra Csenkey; Dan A. Chiche; Ram Kapil; Donald J. Kyle; Wade D. Van Horn; Peter Hegyi; Andrej A. Romanovsky

    Antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel alter body temperature (Tb) in laboratory animals and humans: most cause hyperthermia; some produce hypothermia; and yet others have no effect. TRPV1 can be activated by capsaicin (CAP), protons (low pH), and heat. First-generation (polymodal) TRPV1 antagonists potently block all three TRPV1 activation modes. Second-generation (mode-selective) TRPV1 antagonists potently block channel activation by CAP, but exert different effects (e.g., potentiation, no effect, or low-potency inhibition) in the proton mode, heat mode, or both. Based on our earlier studies in rats, only one mode of TRPV1 activation – by protons – is involved in thermoregulatory responses to TRPV1 antagonists. In rats, compounds that potently block, potentiate, or have no effect on proton activation cause hyperthermia, hypothermia, or no effect on Tb, respectively. A Tb response occurs when a TRPV1 antagonist blocks (in case of hyperthermia) or potentiates (hypothermia) the tonic TRPV1 activation by protons somewhere in the trunk, perhaps in muscles, and – via the acido-antithermogenic and acido-antivasoconstrictor reflexes – modulates thermogenesis and skin vasoconstriction. In this work, we used a mathematical model to analyze Tb data from human clinical trials of TRPV1 antagonists. The analysis suggests that, in humans, the hyperthermic effect depends on the antagonist’s potency to block TRPV1 activation not only by protons, but also by heat, while the CAP activation mode is uninvolved. Whereas in rats TRPV1 drives thermoeffectors by mediating pH signals from the trunk, but not Tb signals, our analysis suggests that TRPV1 mediates both pH and thermal signals driving thermoregulation in humans. Hence, in humans (but not in rats), TRPV1 is likely to serve as a thermosensor of the thermoregulation system. We also conducted a meta-analysis of Tb data from human trials and found that polymodal TRPV1 antagonists (ABT-102, AZD1386, and V116517) increase Tb, whereas the mode-selective blocker NEO6860 does not. Several strategies of harnessing the thermoregulatory effects of TRPV1 antagonists in humans are discussed.

    更新日期:2020-01-10
  • The therapeutic potential of second and third generation CB1R antagonists
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2020-01-09
    Resat Cinar; Malliga R. Iyer; George Kunos

    Endocannabinoids acting via CB1 receptors (CB1R) play a critical role in regulating energy homeostasis, which was the rationale for the pharmaceutical development of CB1R antagonists for the treatment of obesity. Although the first-in-class CB1R antagonist rimonabant proved to be effective in mitigating obesity and its multiple cardiometabolic complications, it was withdrawn from clinical use due to CNS-mediated neuropsychiatric side effects, which halted the further therapeutic development of the whole class of these compounds. Compared to the brain, CB1Rs are expressed at low yet functional levels in peripheral organs involved in regulating energy homeostasis, including liver, skeletal muscle, adipose tissue and endocrine pancreas. In recent preclinical studies, selective targeting of these receptors by ‘second generation’ peripherally restricted CB1R antagonists replicated the metabolic benefits of rimonabant in rodent models of obesity and diabetes without causing CNS-mediated side effects. Increased CB1R activity also contributes to complex, multifactorial disorders such as various forms of tissue fibrosis, treatment of which may benefit from simultaneous engagement of more than one therapeutic target. Accordingly, novel ‘third generation’ hybrid inhibitors of peripheral CB1R and inducible NO synthase were tested in mouse models of liver and pulmonary fibrosis where their antifibrotic efficacy was found to exceed the efficacy of drugs that inhibit only one of these targets. In this review, we will discuss the challenges and opportunities offered by second and third generation CB1R antagonists and their potential therapeutic uses.

    更新日期:2020-01-09
  • Cyclic nucleotide phosphodiesterases: New targets in the metabolic syndrome?
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2020-01-09
    Claire Lugnier; Alain Meyer; Samy Talha; Bernard Geny

    Metabolic diseases have a tremendous impact on human morbidity and mortality. Numerous targets regulating adenosine monophosphate kinase (AMPK) have been identified for treating the metabolic syndrome (MetS), and many compounds are being used or developed to increase AMPK activity. In parallel, the cyclic nucleotide phosphodiesterase families (PDEs) have emerged as new therapeutic targets in cardiovascular diseases, as well as in non-resolved pathologies. Since some PDE subfamilies inactivate cAMP into 5′-AMP, while the beneficial effects in MetS are related to 5′-AMP-dependent activation of AMPK, an analysis of the various controversial relationships between PDEs and AMPK in MetS appears interesting. The present review will describe the various PDE families, AMPK and molecular mechanisms in the MetS and discuss the PDEs/PDE modulators related to the tissues involved, thus supporting the discovery of original molecules and the design of new therapeutic approaches in MetS.

    更新日期:2020-01-09
  • Recent advances in bone-targeted therapy
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2020-01-08
    Chen Shi; Tingting Wu; Yu He; Yu Zhang; Dehao Fu

    The coordination between bone resorption and bone formation plays an essential role in keeping the mass and microstructure integrity of the bone in a steady state. However, this balance can be disturbed in many pathological conditions of the bone. Nowadays, the classical modalities for treating bone-related disorders are being challenged by severe obstacles owing to low tissue selectivity and considerable safety concerns. Moreover, as a highly mineralized tissue, the bone shows innate rigidity, low permeability, and reduced blood flow, features that further hinder the effective treatment of bone diseases. With the development of bone biology and precision medicine, one novel concept of bone-targeted therapy appears to be promising, with improved therapeutic efficacy and minimized systematic toxicity. Here we focus on the recent advances in bone-targeted treatment based on the unique biology of bone tissues. We summarize commonly used bone targeting moieties, with an emphasis on bisphosphonates, tetracyclines, and biomimetic bone-targeting moieties. We also introduce potential bone-targeting strategies aimed at the bone matrix and major cell types in the bone. Based on these bone-targeting moieties and strategies, we discussed the potential applications of targeted therapy to treat bone diseases. We expect that this review will put together useful insights to help with the search for therapeutic efficacy in bone-related conditions.

    更新日期:2020-01-09
  • Cancer immunotherapy with immunoadjuvants, nanoparticles, and checkpoint inhibitors: Recent progress and challenges in treatment and tracking response to immunotherapy
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-12-19
    Michael-Joseph Gorbet; Ashish Ranjan

    Chemotherapy, surgery, and radiation are accepted as the preferred treatment modalities against cancer, but in recent years the use of immunotherapeutic approaches has gained prominence as the fourth treatment modality in cancer patients. In this approach, a patient’s innate and adaptive immune systems are activated to achieve clearance of occult cancerous cells. In this review, we discuss the preclinical and clinical immunotherapeutic (e.g., immunoadjuvants (in-situ vaccines, oncolytic viruses, CXC antagonists, device activated agents), organic and inorganic nanoparticles, checkpoint blockade etc.) that are under investigation for cancer therapy and diagnostics. Additionally, the innovations in imaging of immune cells for tracking therapeutic responses and limitations (e.g., toxicity, inefficient immunomodulation, etc.) are described. Existing data suggest that if immune therapy is optimized, it can be a real and potentially paradigm-shifting cancer treatment frontier.

    更新日期:2019-12-19
  • Metal homeostasis disturbances in neurodegenerative disorders, with special emphasis on Creutzfeldt-Jakob disease – Potential pathogenetic mechanism and therapeutic implications
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-12-19
    Yutaka Nakagawa; Shizuo Yamada

    Creutzfeldt-Jakob disease (CJD) is characterized by a rapidly progressive dementia often accompanied by myoclonus and other signs of brain dysfunction, relying on the conversion of the normal cellular form of the prion protein (PrPC) to a misfolded form (PrPSc). The neuropathological changes include spongiform degeneration, neuronal loss, astrogliosis, and deposition of PrPSc. It is still unclear how these pathological changes correlate with the development of CJD symptoms because few patients survive beyond 2 years after diagnosis. Inasmuch as the symptoms of CJD overlap some of those observed in Alzheimer’s, Parkinson’s, and Huntington’s diseases, there may be some underlying pathologic mechanisms associated with CJD that may contribute to the symptoms of non-prion neurodegenerative diseases as well. Data suggest that imbalance of metals, including copper, zinc, iron, and manganese, induces abnormalities in processing and degradation of prion proteins that are accompanied by self-propagation of PrPSc. These events appear to be responsible for glutamatergic synaptic dysfunctions, neuronal death, and PrPSc aggregation. Given that the prodromal symptoms of CJD such as sleep disturbances and mood disorders are associated with brain stem and limbic system dysfunction, the pathological changes may initially occur in these brain regions, then spread throughout the entire brain. Alterations in cerebrospinal fluid homeostasis, which may be linked to imbalance of these metals, seem to be more important than neuroinflammation in causing the cell death. It is proposed that metal dyshomeostasis could be responsible for the initiation and progression of the pathological changes associated with symptoms of CJD and other neurodegenerative disorders.

    更新日期:2019-12-19
  • Sphingosine kinase and sphingosine-1-phosphate receptor signaling pathway in inflammatory gastrointestinal disease and cancers: A novel therapeutic target
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-12-18
    Olga A. Sukocheva; Hideki Furuya; Mei Li Ng; Markus Friedemann; Mario Menschikowski; Vadim V. Tarasov; Vladimir N. Chubarev; Sergey G. Klochkov; Margarita E. Neganova; Arduino A. Mangoni; Gjumrakch Aliev; Anupam Bishayee

    Inflammatory gastrointestinal (GI) diseases and malignancies are associated with growing morbidity and cancer-related mortality worldwide. GI tumor and inflammatory cells contain activated sphingolipid-metabolizing enzymes, including sphingosine kinase 1 (SphK1) and SphK2, that generate sphingosine-1-phosphate (S1P), a highly bioactive compound. Many inflammatory responses, including lymphocyte trafficking, are directed by circulatory S1P, present in high concentrations in both the plasma and the lymph of cancer patients. High fat and sugar diet, disbalanced intestinal flora, and obesity have recently been linked to activation of inflammation and SphK/S1P/S1P receptor (S1PR) signaling in various GI pathologies, including cancer. SphK1 overexpression and activation facilitate and enhance the development and progression of esophageal, gastric, and colon cancers. SphK/S1P axis, a mediator of inflammation in the tumor microenvironment, has recently been defined as a target for the treatment of GI disease states, including inflammatory bowel disease and colitis. Several SphK1 inhibitors and S1PR antagonists have been developed as novel anti-inflammatory and anticancer agents. In this review, we analyze the mechanisms of SphK/S1P signaling in GI tissues and critically appraise recent studies on the role of SphK/S1P/S1PR in inflammatory GI disorders and cancers. The potential role of SphK/S1PR inhibitors in the prevention and treatment of inflammation-mediated GI diseases, including GI cancer, is also evaluated.

    更新日期:2019-12-19
  • The past, present and future perspectives of matrix metalloproteinase inhibitors
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-12-18
    Kang Li; Franklin R. Tay; Cynthia Kar Yung Yiu

    Matrix metalloproteinases (MMPs) are a large family of enzymes that degrade the extracellular matrix (ECM). Under pathologic conditions, overexpression of MMPs or insufficient control by tissue inhibitors of MMPs (TIMPs) results in the dysregulation of tissue remodeling and causes a variety of diseases such as encephalomyelitis, rheumatoid arthritis, Alzheimer's disease and tumors. Therefore, the high affinity of MMPs for biomolecules renders them attractive targets for inhibition when homeostasis breaks down in the ECM. There are 4 generations of MMP inhibitors (MMPIs), ranging from small molecules or peptides to antibodies and protein-engineered inhibitors of metalloproteinase. Although a plethora of MMPIs has been synthesized, most of them have failed in clinical trials or are still in the laboratory stage of development. The present review summarizes the development of MMPIs, their associated problems and discusses future directions for the development of the future generations of MMPIs.

    更新日期:2019-12-19
  • Circulating tumor DNA as an early cancer detection tool
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-12-18
    Andrea Campos-Carrillo; Jeffrey N. Weitzel; Prativa Sahoo; Russell Rockne; Janet V. Mokhnatkin; Muhammed Murtaza; Stacy W. Gray; Laura Goetz; Ajay Goel; Nicholas Schork; Thomas P. Slavin

    Circulating tumor DNA holds substantial promise as an early detection biomarker, particularly for cancers that do not have currently accepted screening methodologies, such as ovarian, pancreatic, and gastric cancers. Many features intrinsic to ctDNA analysis may be leveraged to enhance its use as an early cancer detection biomarker: including ctDNA fragment lengths, DNA copy number variations, and associated patient phenotypic information. Furthermore, ctDNA testing may be synergistically used with other multi-omic biomarkers to enhance early detection. For instance, assays may incorporate early detection proteins (i.e., CA-125), epigenetic markers, circulating tumor RNA, nucleosomes, exosomes, and associated immune markers. Many companies are currently competing to develop a marketable early cancer detection test that leverages ctDNA. Although some hurdles (like early stage disease assay accuracy, high implementation costs, confounding from clonal hematopoiesis, and lack of clinical utility studies) need to be addressed before integration into healthcare, ctDNA assays hold substantial potential as an early cancer screening test.

    更新日期:2019-12-19
  • Lipid-modifying therapy in chronic kidney disease: Pathophysiological and clinical considerations
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-12-18
    Gunnar H. Heine; Kathrin Eller; Julia T. Stadler; Kyrill S. Rogacev; Gunther Marsche

    Chronic kidney disease (CKD), which affects >10% of the population worldwide, is associated with a dramatically increased rate of cardiovascular disease (CVD). More people with CKD will die from CVD than develop end-stage renal disease with dialysis-dependency. However, the contribution of classical atherosclerotic cardiovascular risk factors is less evident than in the general population. Particularly, the relationship between dyslipidemia and CVD morbidity and mortality in CKD patients is not as evident as in the general population. While LDL cholesterol-lowering drugs such as statins significantly reduce the rate of cardiovascular events in the general population, their role in patients with end-stage renal disease has been questioned. This could be caused by a shift from atherosclerotic to non-atherosclerotic CVD in patients with advanced CKD, which cannot be effectively prevented by lipid-lowering drugs. In addition, many lines of evidence suggest that impaired renal function directly affects the metabolism, composition and functionality of lipoproteins, which may affect their responsiveness to pharmacological interventions. In this review, we highlight the challenges for the therapeutic application of lipid-lowering treatment strategies in CKD and discuss why treatment strategies used in the general population cannot be applied uncritically to CKD patients.

    更新日期:2019-12-19
  • Therapeutic potential of targeting mixed lineage kinases in cancer and inflammation
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-12-18
    Kathleen A. Gallo; Edmund Ellsworth; Hayden Stoub; Susan E. Conrad

    Dysregulation of intracellular signaling pathways is a key attribute of diseases associated with chronic inflammation, including cancer. Mitogen activated protein kinases have emerged as critical conduits of intracellular signal transmission, yet due to their ubiquitous roles in cellular processes, their direct inhibition may lead to undesired effects, thus limiting their usefulness as therapeutic targets. Mixed lineage kinases (MLKs) are mitogen-activated protein kinase kinase kinases (MAP3Ks) that interact with scaffolding proteins and function upstream of p38, JNK, ERK, and NF-kappaB to mediate diverse cellular signals. Studies involving gene silencing, genetically engineered mouse models, and small molecule inhibitors suggest that MLKs are critical in tumor progression as well as in inflammatory processes. Recent advances indicate that they may be useful targets in some types of cancer and in diseases driven by chronic inflammation including neurodegenerative diseases and metabolic diseases such as nonalcoholic steatohepatitis. This review describes existing MLK inhibitors, the roles of MLKs in various aspects of tumor progression and in the control of inflammatory processes, and the potential for therapeutic targeting of MLKs.

    更新日期:2019-12-19
  • Time-dependent enzyme inactivation: Numerical analyses of in vitro data and prediction of drug-drug interactions
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-12-11
    Jaydeep Yadav, Erickson Paragas, Ken Korzekwa, Swati Nagar

    Cytochrome P450 (CYP) enzyme kinetics often do not conform to Michaelis-Menten assumptions, and time-dependent inactivation (TDI) of CYPs displays complexities such as multiple substrate binding, partial inactivation, quasi-irreversible inactivation, and sequential metabolism. Additionally, in vitro experimental issues such as lipid partitioning, enzyme concentrations, and inactivator depletion can further complicate the parameterization of in vitro TDI. The traditional replot method used to analyze in vitro TDI datasets is unable to handle complexities in CYP kinetics, and numerical approaches using ordinary differential equations of the kinetic schemes offer several advantages. Improvement in the parameterization of CYP in vitro kinetics has the potential to improve prediction of clinical drug-drug interactions (DDIs). This manuscript discusses various complexities in TDI kinetics of CYPs, and numerical approaches to model these complexities. The extrapolation of CYP in vitro TDI parameters to predict in vivo DDIs with static and dynamic modeling is discussed, along with a discussion on current gaps in knowledge and future directions to improve the prediction of DDI with in vitro data for CYP catalyzed drug metabolism.

    更新日期:2019-12-11
  • Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-12-11
    Tom Malone, Lea Schӓfer, Nathalie Simon, Susan Heavey, Sinead Cuffe, Stephen Finn, Gillian Moore, Kathy Gately

    PIM kinases are a class of serine/threonine kinases that play a role in several of the hallmarks of cancer including cell cycle progression, metabolism, inflammation and immune evasion. Their constitutively active nature and unique catalytic structure has led them to be an attractive anticancer target through the use of small molecule inhibitors. This review highlights the enhanced activity of PIM kinases in cancer that can be driven by hypoxia in the tumour microenvironment and the important role that aberrant PIM kinase activity plays in resistance mechanisms to chemotherapy, radiotherapy, anti-angiogenic therapies and targeted therapies. We highlight an interaction of PIM kinases with numerous major oncogenic players, including but not limited to, stabilisation of p53, synergism with c-Myc, and notable parallel signalling with PI3K/Akt. We provide a comprehensive overview of PIM kinase's role as an escape mechanism to targeted therapies including PI3K/mTOR inhibitors, MET inhibitors, anti-HER2/EGFR treatments and the immunosuppressant rapamycin, providing a rationale for co-targeting treatment strategies for a more durable patient response. The current status of PIM kinase inhibitors and their use as a combination therapy with other targeted agents, in addition to the development of novel multi-molecularly targeted single therapeutic agents containing a PIM kinase targeting moiety are discussed.

    更新日期:2019-12-11
  • Adeno-associated viral vector-mediated immune responses: Understanding barriers to gene delivery
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-12-11
    Natalie F. Nidetz, Michael C. McGee, Longping V. Tse, Chengwen Li, Le Cong, Yunxing Li, Weishan Huang

    Adeno-associated viral (AAV) vectors have emerged as the leading gene delivery platform for gene therapy and vaccination. Three AAV-based gene therapy drugs, Glybera, LUXTURNA, and ZOLGENSMA were approved between 2012 and 2019 by the European Medicines Agency and the United States Food and Drug Administration as treatments for genetic diseases hereditary lipoprotein lipase deficiency (LPLD), inherited retinal disease (IRD), and spinal muscular atrophy (SMA), respectively. Despite these therapeutic successes, clinical trials have demonstrated that host anti-viral immune responses can prevent the long-term gene expression of AAV vector-encoded genes. Therefore, it is critical that we understand the complex relationship between AAV vectors and the host immune response. This knowledge could allow for the rational design of optimized gene transfer vectors capable of either subverting host immune responses in the context of gene therapy applications, or stimulating desirable immune responses that generate protective immunity in vaccine applications to AAV vector-encoded antigens. This review provides an overview of our current understanding of the AAV-induced immune response and discusses potential strategies by which these responses can be manipulated to improve AAV vector-mediated gene transfer.

    更新日期:2019-12-11
  • Unraveling cancer lineage drivers in squamous cell carcinomas
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-12-11
    Yinglu Guan, Guan Wang, Danielle Fails, Priyadharsini Nagarajan, Yejing Ge

    Cancer hijacks embryonic development and adult wound repair mechanisms to fuel malignancy. Cancer frequently originates from de-regulated adult stem cells or progenitors, which are otherwise essential units for postnatal tissue remodeling and repair. Cancer genomics studies have revealed convergence of multiple cancers across organ sites, including squamous cell carcinomas (SCCs), a common group of cancers arising from the head and neck, esophagus, lung, cervix and skin. In this review, we summarize our current knowledge on the molecular drivers of SCCs, including these five major organ sites. We especially focus our discussion on lineage dependent driver genes and pathways, in the context of squamous development and stratification. We then use skin as a model to discuss the notion of field cancerization during SCC carcinogenesis, and cancer as a wound that never heals. Finally, we turn to the idea of context dependency widely observed in cancer driver genes, and outline literature support and possible explanations for their lineage specific functions. Through these discussions, we aim to provide an up-to-date summary of molecular mechanisms driving tumor plasticity in squamous cancers. Such basic knowledge will be helpful to inform the clinics for better stratifying cancer patients, revealing novel drug targets and providing effective treatment options.

    更新日期:2019-12-11
  • Targeting ATR as Cancer Therapy: A new era for synthetic lethality and synergistic combinations?
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-12-11
    Alice Bradbury, Sally Hall, Nicola Curtin, Yvette Drew

    The DNA damage response (DDR) machinery is responsible for detecting DNA damage, pausing the cell cycle and initiating DNA repair. Ataxia telangiectasia and Rad3-related (ATR) protein is a key kinase at the heart of the DDR, responsible for sensing replication stress (RS) and signalling it to S and G2/M checkpoints to facilitate repair. In cancer, loss of G1 checkpoint control and activation of oncogenes that drive replication, result in cancer cells more likely to enter S phase with increased RS. These cancer cells become more reliant on their S and G2/M checkpoints, making this an attractive anti-cancer target. Targeting ATR is the focus of many oncology drug pipelines with a number of potent, selective ATR inhibitors developed, four (M6620, M4344, AZD6738 and BAY1895344) are currently in clinical development. Here we summarise the pre-clinical data supporting the use of ATR inhibitors as monotherapy and in combination with chemotherapy, radiotherapy and novel targeted agents such as PARP inhibitors. We discuss the current clinical trial data and the challenges of taking ATR inhibitors into the clinic and of identifying biomarkers to aid patient selection.

    更新日期:2019-12-11
  • 更新日期:2019-12-11
  • Lactate/GPR81 signaling and proton motive force in cancer: Role in angiogenesis, immune escape, nutrition, and Warburg phenomenon
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-12-10
    Timothy Brown, Vadivel Ganapathy

    Reprogramming of biochemical pathways is a hallmark of cancer cells, and generation of lactic acid from glucose/glutamine represents one of the consequences of such metabolic alterations. Cancer cells export lactic acid out to prevent intracellular acidification, not only increasing lactate levels but also creating an acidic pH in extracellular milieu. Lactate and protons in tumor microenvironment are not innocuous bystander metabolites but have special roles in promoting tumor-cell proliferation and growth. Lactate functions as a signaling molecule by serving as an agonist for the G-protein-coupled receptor GPR81, involving both autocrine and paracrine mechanisms. In the autocrine pathway, cancer cell-generated lactate activates GPR81 on cancer cells; in the paracrine pathway, cancer cell-generated lactate activates GPR81 on immune cells, endothelial cells, and adipocytes present in tumor stroma. The end result of GPR81 activation is promotion of angiogenesis, immune evasion, and chemoresistance. The acidic pH creates an inwardly directed proton gradient across the cancer-cell plasma membrane, which provides driving force for proton-coupled transporters in cancer cells to enhance supply of selective nutrients. There are several molecular targets in the pathways involved in the generation of lactic acid by cancer cells and its role in tumor promotion for potential development of novel anticancer therapeutics.

    更新日期:2019-12-11
  • 5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-11-19
    Sona Vodenkova, Tomas Buchler, Klara Cervena, Veronika Veskrnova, Pavel Vodicka, Veronika Vymetalkova

    5-Fluorouracil (5-FU) is an essential component of systemic chemotherapy for colorectal cancer (CRC) in the palliative and adjuvant settings. Over the past four decades, several modulation strategies including the implementation of 5-FU-based combination regimens and 5-FU pro-drugs have been developed and tested to increase the anti-tumor activity of 5-FU and to overcome the clinical resistance. Despite the encouraging progress in CRC therapy to date, the patients' response rates to therapy continue to remain low and the patients' benefit from 5-FU-based therapy is frequently compromised by the development of chemoresistance. Inter-individual differences in the treatment response in CRC patients may originate in the unique genetic and epigenetic make-up of each individual. The critical element in the current trend of personalized medicine is the proper comprehension of causes and mechanisms contributing to the low or lack of sensitivity of tumor tissue to 5-FU-based therapy. The identification and validation of predictive biomarkers for existing 5-FU-based and new targeted therapies for CRC treatment will likely improve patients' outcomes in the future. Herein we present a comprehensive review summarizing options of CRC treatment and the mechanisms of 5-FU action at the molecular level, including both anabolic and catabolic ways. The main part of this review comprises the currently known molecular mechanisms underlying the chemoresistance in CRC patients. We also focus on various 5-FU pro-drugs developed to increase the amount of circulating 5-FU and to limit toxicity. Finally, we propose future directions of personalized CRC therapy according to the latest published evidence.

    更新日期:2019-11-20
  • Look before you leap: Looking into PARP inhibition from bench to bedside and back
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-11-19
    Giovanni Grignani, Alessandra Merlini, Dario Sangiolo, Lorenzo D'Ambrosio, Ymera Pignochino

    With the ever-expanding therapeutic indications and ongoing clinical trials with Poly(adenosine diphosphate-ribose) Polymerase (PARP) inhibitors, it is of outmost importance to stop and rethink what we know and still do not know concerning one of the major revolutions in target therapies in the last decades. Indeed, many PARP inhibitors (PARPi) are able to bind multiple targets, with a plethora of potential interactions with cancer cell signaling, metabolism and the tumor microenvironment (TME). These interactions can mediate both response and resistance to PARPi, but also represent an opportunity for sequential and/or combinatorial therapies. Here we advocate a “look before you leap” approach in reviewing available clinical and preclinical evidence concerning PARPi, delving into this complex entanglement, trying to unravel the potential for innovative therapeutic strategies revolving on PARP inhibition.

    更新日期:2019-11-20
  • ATM in DNA repair in cancer
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-07-09
    Mei Hua Jin, Do-Youn Oh

    Alterations in DNA damage response (DDR) pathways are hallmarks of cancer. Incorrect repair of DNA lesions often leads to genomic instability. Ataxia telangiectasia mutated (ATM), a core component of the DNA repair system, is activated to enhance the homologous recombination (HR) repair pathway upon DNA double-strand breaks. Although ATM signaling has been widely studied in different types of cancer, its research is still lacking compared with other DDR-involved molecules such as PARP and ATR. There is still a vast research opportunity for the development of ATM inhibitors as anticancer agents. Here, we focus on the recent findings of ATM signaling in DNA repair of cancer. Previous studies have identified several partners of ATM, some of which promote ATM signaling, while others have the opposite effect. ATM inhibitors, including KU-55933, KU-60019, KU-59403, CP-466722, AZ31, AZ32, AZD0156, and AZD1390, have been evaluated for their antitumor effects. It has been revealed that ATM inhibition increases a cancer cell's sensitivity to radiotherapy. Moreover, the combination with PARP or ATR inhibitors has synergistic lethality in some cancers. Of note, among these ATM inhibitors, AZD0156 and AZD1390 achieve potent and highly selective ATM kinase inhibition and have an excellent ability to penetrate the blood-brain barrier. Currently, AZD0156 and AZD1390 are under investigation in phase I clinical trials. Taken together, targeting ATM may be a promising strategy for cancer treatment. Hence, further development of ATM inhibitors is urgently needed in cancer research.

    更新日期:2019-11-18
  • Cancer the‘RBP’eutics–RNA-binding proteins as therapeutic targets for cancer
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-07-11
    Shakur Mohibi, Xinbin Chen, Jin Zhang

    RNA-binding proteins (RBPs) play a critical role in the regulation of various RNA processes, including splicing, cleavage and polyadenylation, transport, translation and degradation of coding RNAs, non-coding RNAs and microRNAs. Recent studies indicate that RBPs not only play an instrumental role in normal cellular processes but have also emerged as major players in the development and spread of cancer. Herein, we review the current knowledge about RNA binding proteins and their role in tumorigenesis as well as the potential to target RBPs for cancer therapeutics.

    更新日期:2019-11-18
  • The endothelial mineralocorticoid receptor: Contributions to sex differences in cardiovascular disease
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-07-02
    M. Elizabeth Moss, Brigett Carvajal, Iris Z. Jaffe

    Cardiovascular disease remains the leading cause of death for both men and women. The observation that premenopausal women are protected from cardiovascular disease relative to age-matched men, and that this protection is lost with menopause, has led to extensive study of the role of sex steroid hormones in the pathogenesis of cardiovascular disease. However, the molecular basis for sex differences in cardiovascular disease is still not fully understood, limiting the ability to tailor therapies to male and female patients. Therefore, there is a growing need to investigate molecular pathways outside of traditional sex hormone signaling to fully understand sex differences in cardiovascular disease. Emerging evidence points to the mineralocorticoid receptor (MR), a steroid hormone receptor activated by the adrenal hormone aldosterone, as one such mediator of cardiovascular disease risk, potentially serving as a sex-dependent link between cardiovascular risk factors and disease. Enhanced activation of the MR by aldosterone is associated with increased risk of cardiovascular disease. Emerging evidence implicates the MR specifically within the endothelial cells lining the blood vessels in mediating some of the sex differences observed in cardiovascular pathology. This review summarizes the available clinical and preclinical literature concerning the role of the MR in the pathophysiology of endothelial dysfunction, hypertension, atherosclerosis, and heart failure, with a special emphasis on sex differences in the role of endothelial-specific MR in these pathologies. The available data regarding the molecular mechanisms by which endothelial-specific MR may contribute to sex differences in cardiovascular disease is also summarized. A paradigm emerges from synthesis of the literature in which endothelial-specific MR regulates vascular function in a sex-dependent manner in response to cardiovascular risk factors to contribute to disease. Limitations in this field include the relative paucity of women in clinical trials and, until recently, the nearly exclusive use of male animals in preclinical investigations. Enhanced understanding of the sex-specific roles of endothelial MR could lead to novel mechanistic insights underlying sex differences in cardiovascular disease incidence and outcomes and could identify additional therapeutic targets to effectively treat cardiovascular disease in men and women.

    更新日期:2019-11-18
  • Dopamine outside the brain: The eye, cardiovascular system and endocrine pancreas
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-07-09
    Claudio Bucolo, Gian Marco Leggio, Filippo Drago, Salvatore Salomone

    Dopamine (DA) and DA receptors (DR) have been extensively studied in the central nervous system (CNS), but their role in the periphery is still poorly understood. Here we summarize data on DA and DRs in the eye, cardiovascular system and endocrine pancreas, three districts where DA and DA-related drugs have been studied and the expression of DR documented. In the eye, DA modulates ciliary blood flow and aqueous production, which impacts on intraocular pressure and glaucoma. In the cardiovascular system, DA increases blood pressure and heart activity, mostly through a stimulation of adrenoceptors, and induces vasodilatation in the renal circulation, possibly through D1R stimulation. In pancreatic islets, beta cells store DA and co-release it with insulin. D1R is mainly expressed in beta cells, where it stimulates insulin release, while D2R is expressed in both beta and delta cells (in the latter at higher level), where it inhibits, respectively, insulin and somatostatin release. The formation of D2R-somatostatin receptor 5 heteromers (documented in the CNS), might add complexity to the system. DA may exert both direct autocrine effects on beta cells, and indirect paracrine effects through delta cells and somatostatin. Bromocriptine, an FDA approved drug for diabetes, endowed with both D1R (antagonistic) and D2R (agonistic) actions, may exert complex effects, resulting from the integration of direct effects on beta cells and paracrine effects from delta cells. A full comprehension of peripheral DA signaling deserves further studies that may generate innovative therapeutic drugs to manage conditions such as glaucoma, cardiovascular diseases and diabetes.

    更新日期:2019-11-18
  • Long non-coding RNAs as new regulators of cardiac electrophysiology and arrhythmias: Molecular mechanisms, therapeutic implications and challenges
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-07-02
    Yong Zhang, Weijie Du, Baofeng Yang

    Long non-coding RNAs (lncRNAs or lncRs) as a new class of regulatory transcripts have been intensively studied for their roles in cardiovascular biology in the past decade. We now know that lncRNAs are significantly implicated in diverse cardiovascular conditions and associated risk factors, including myocardial infarction, coronary heart disease, atherosclerosis/coronary artery disease, vascular disease, cardiac hypertrophy, heart failure, etc. Though in its early stage, research on control of cardiac electrophysiology by lncRNAs has generated some interesting observations and mechanistic insight of significant relevance to translational medicine. This review article focuses on lncRNA regulation of cardiac electrophysiology and arrhythmias with brief discussion on some fundamental aspects of relevant background information for better understanding of the subject. It provides critical analysis of published studies in the literature together with unpublished observations from our own laboratories. In addition to discuss the phenotypes associated with deregulation of lncRNAs, we also try to dissect out the cellular and molecular mechanisms for lncRNAs as regulators of arrhythmogenesis. This review then further touches on the therapeutic implications of lncRNAs and potential strategies for the development of lncRNA-based drugs. Finally, future directions to lncRNA research on cardiac electrophysiology and arrhythmias are anticipated.

    更新日期:2019-11-18
  • Progress in the development of antiplatelet agents: Focus on the targeted molecular pathway from bench to clinic
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-07-26
    Qian Xiang, Xiaocong Pang, Zhenming Liu, Guoping Yang, Weikang Tao, Qi Pei, Yimin Cui

    Antiplatelet drugs serve as a first-line antithrombotic therapy for the management of acute ischemic events and the prevention of secondary complications in vascular diseases. Numerous antiplatelet therapies have been developed; however, currently available agents are still associated with inadequate efficacy, risk of bleeding, and variability in individual response. Understanding the mechanisms of platelet involvement in thrombosis and the clinical development process of antiplatelet agents is critical for the discovery of novel agents. The functions of platelets in thrombosis are regulated by two major mechanisms: the interaction between surface receptors and their ligands, and the downstream intracellular signaling pathways. Recently, most of the progress made in antiplatelet drug development has been achieved with P2Y receptor antagonists. Additionally, the usage of GP IIb/IIIa receptor antagonists has decreased, because it is associated with a higher risk of bleeding and thrombocytopenia. Agents targeting other platelet surface receptors such as PARs, TP receptor, EP3 receptor, GPIb-IX-V receptor, P-selectin, as well as intracellular signaling factors, such as PI3Kβ, have been evaluated in an attempt to develop the next generation of antiplatelet drugs, reduce or eliminate interpatient variability of drug efficacy and significantly lower the risk of drug-induced bleeding. The aim of this review is to describe the pathways of platelet activation in thrombosis, and summarize the development process of antiplatelet agents, as well as the preclinical and clinical evaluations performed on these agents.

    更新日期:2019-11-18
  • Ursodeoxycholic acid and cancer: From chemoprevention to chemotherapy
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-07-26
    Jean-François Goossens, Christian Bailly

    Ursodeoxycholic acid (UDCA) is a secondary bile acid issued from the transformation of (cheno)deoxycholic acid by intestinal bacteria, acting as a key regulator of the intestinal barrier integrity and essential for lipid metabolism. UDCA is also a long-established drug, largely used for the dissolution of cholesterol gallstones, the treatment of primary biliary cholangitis and other hepatobiliary disorders. The history of UDCA is briefly retraced here as well as its multifactorial mechanism of action, based on its anti-inflammatory, antioxidant and cytoprotective activities. The present review is centred around the anticancer properties of UDCA and synthetic antitumor derivatives designed over the past 20 years. Paradoxically, depending on the conditions, UDCA exhibits both pro- and anti-apoptotic properties toward different cell types. In particular, the UDCA drug can protect epithelial cells from damages and apoptosis while inducing inhibition of proliferation and apoptotic and/or autophagic death of cancer cells. The effects of UDCA on cancer cell migration, cancer stem cells and drug-induced dysbiosis are also evoked. The drug has revealed modest activities against colon and gastric cancers but may be useful to improve treatments of hepatocellular carcinoma, notably in combination with other drugs such as sorafenib. UDCA can also protect from damages induced by cancer chemotherapeutic agents. The potential of UDCA in cancer, as a chemo-protecting or chemotherapeutic agent, is highlighted here as well as the design of tumour-active derivatives, including UDCA-drug conjugates. A repurposing of UDCA in oncology should be further considered.

    更新日期:2019-11-18
  • Machine learning and data mining frameworks for predicting drug response in cancer: An overview and a novel in silico screening process based on association rule mining
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-07-30
    Konstantinos Vougas, Theodore Sakellaropoulos, Athanassios Kotsinas, George-Romanos P. Foukas, Andreas Ntargaras, Filippos Koinis, Alexander Polyzos, Vassilios Myrianthopoulos, Hua Zhou, Sonali Narang, Vassilis Georgoulias, Leonidas Alexopoulos, Iannis Aifantis, Paul A. Townsend, Petros Sfikakis, Rebecca Fitzgerald, Dimitris Thanos, Jiri Bartek, Vassilis G. Gorgoulis

    A major challenge in cancer treatment is predicting the clinical response to anti-cancer drugs on a personalized basis. The success of such a task largely depends on the ability to develop computational resources that integrate big “omic” data into effective drug-response models. Machine learning is both an expanding and an evolving computational field that holds promise to cover such needs. Here we provide a focused overview of: 1) the various supervised and unsupervised algorithms used specifically in drug response prediction applications, 2) the strategies employed to develop these algorithms into applicable models, 3) data resources that are fed into these frameworks and 4) pitfalls and challenges to maximize model performance. In this context we also describe a novel in silico screening process, based on Association Rule Mining, for identifying genes as candidate drivers of drug response and compare it with relevant data mining frameworks, for which we generated a web application freely available at: https://compbio.nyumc.org/drugs/. This pipeline explores with high efficiency large sample-spaces, while is able to detect low frequency events and evaluate statistical significance even in the multidimensional space, presenting the results in the form of easily interpretable rules. We conclude with future prospects and challenges of applying machine learning based drug response prediction in precision medicine.

    更新日期:2019-11-18
  • Roles of chitinase 3-like 1 in the development of cancer, neurodegenerative diseases, and inflammatory diseases
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-07-26
    In Jun Yeo, Chong-Kil Lee, Sang-Bae Han, Jaesuk Yun, Jin Tae Hong

    Chitinase 3-like 1 (CHI3L1) is a secreted glycoprotein that mediates inflammation, macrophage polarization, apoptosis, and carcinogenesis. The expression of CHI3L1 is strongly increased by various inflammatory and immunological conditions, including rheumatoid arthritis, multiple sclerosis, Alzheimer’s disease, and several cancers. However, its physiological and pathophysiological roles in the development of cancer and neurodegenerative and inflammatory diseases remain unclear. Several studies have reported that CHI3L1 promotes cancer proliferation, inflammatory cytokine production, and microglial activation, and that multiple receptors, such as advanced glycation end product, syndecan-1/αVβ3, and IL-13Rα2, are involved. In addition, the pro-inflammatory action of CHI3L1 may be mediated via the protein kinase B and phosphoinositide-3 signaling pathways and responses to various pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, interleukin-6, and interferon-γ. Therefore, CHI3L1 could contribute to a vast array of inflammatory diseases. In this article, we review recent findings regarding the roles of CHI3L1 and suggest therapeutic approaches targeting CHI3L1 in the development of cancers, neurodegenerative diseases, and inflammatory diseases.

    更新日期:2019-11-18
  • Clinical investigation of CAR T cells for solid tumors: Lessons learned and future directions
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-10-16
    Stephen J. Bagley, Donald M. O’Rourke

    Chimeric antigen receptor (CAR) T cells are a form of autologous immunotherapy that has changed the therapeutic landscape of hematologic malignancies. CAR T cell therapy involves collection of a patient’s T cells by apheresis, ex vivo genetic modification of the T cells to encode a synthetic receptor that binds a specific tumor antigen, and infusion of the T cells back into the patient. With the unprecedented success of CAR T cells in leukemia and lymphoma, a growing number of preclinical studies and clinical trials have focused on translating this treatment to solid tumors. In non-hematologic malignancies, however, response rates have been much less favorable. Some of the most significant challenges for CAR T cell immunotherapy in solid cancers include a paucity of unique tumor target antigens, limited CAR T cell trafficking to tumor sites, tumor heterogeneity and antigen loss, and the severely immunosuppressive tumor microenvironment. This review article provides an update on completed and ongoing clinical trials of CAR T cells for solid tumors, as well as an overview of strategies to improve CAR T cell efficacy in non-hematologic malignancies.

    更新日期:2019-11-18
  • Lorcaserin: A review of its preclinical and clinical pharmacology and therapeutic potential
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-10-16
    Guy A. Higgins, Paul J. Fletcher, William R. Shanahan

    The selective 5-HT2C receptor agonist lorcaserin, in conjunction with lifestyle modification, was approved by the FDA in 2012 for weight management. It has been marketed in the US as Belviq® since 2013. This article provides a review of the preclinical and clinical pharmacology of lorcaserin, including its pharmacokinetic and safety profiles. Preclinical studies with lorcaserin initially focused on simple measures of food intake and body weight gain, but have now expanded to include studies on its effects on appetitive aspects of feeding behaviour and models of binge-eating. A significant number of studies have also shown that lorcaserin alters behaviours related to drug use and addiction, in rodents and non-human primates. Potential clinically-relevant effects of lorcaserin have also been reported in models of pain and seizure-like activity. Not surprisingly, the majority of clinical work with lorcaserin has focused on its effects on weight gain, and on physiological processes related to energy intake. However, results of clinical trials and experimental laboratory studies involving lorcaserin are now appearing which describe effects on a range of other behaviours and physiological functions. These include smoking cessation, cocaine self-administration, and behavioural and brain responses to food cues. All of this work suggests that lorcaserin may have therapeutic potential for a variety of disorders and conditions beyond obesity. Based on clinical experience, including the outcomes from several, large, well-powered clinical obesity trials at the approved 10 mg BID dose both pre and post approval, a priori concerns about cardiac valvulopathy have largely been allayed. However, as with any recently approved first-in-class pharmacotherapy, there may be yet-unknown risks, as well as benefits, associated with use of lorcaserin. Nonetheless, the current safety profile and an expanding post approval safety data base should encourage further experimental laboratory-based and clinical trial-based research with lorcaserin in targeted populations to investigate its full therapeutic potential.

    更新日期:2019-11-18
  • The role of DNA-demethylating agents in cancer therapy
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-10-15
    Parinaz Mehdipour, Tracy Murphy, Daniel D. De Carvalho

    DNA methylation patterns are frequently altered in cancer cells as compared to normal cells. A large body of research associates these DNA methylation aberrations with cancer initiation and progression. Moreover, cancer cells seem to depend upon these aberrant DNA methylation profiles to thrive. Finally, DNA methylation modifications are reversible, highlighting the potential to target the global methylation patterns for cancer therapy. In this review, we will discuss the scientific and clinical aspects of DNA methylation in cancer. We will review the limited success of targeting DNA methylation in the clinic, the associated clinical challenges, the impact of novel DNA methylation inhibitors and how combination therapies are improving patient outcomes.

    更新日期:2019-11-18
  • Use of glucocorticoids in the critical care setting: Science and clinical evidence
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-10-15
    Edward D. Chan, Michael M. Chan, Mallory M. Chan, Paul E. Marik

    Glucocorticoids (GC) in all its various forms and formulations are likely one of the most commonly used pharmacologic agents in medicine. Their use can be profoundly therapeutic but are also associated with a myriad of acute and chronic side effects. It is fairly well-accepted in the medical community that GC can be life-saving when used in critically ill patients with severe exacerbations of asthma and chronic obstructive pulmonary disease, HIV-associated pneumocystosis, and systemic vasculitides. However, the adjunctive role of GC is much more controversial in acute respiratory distress syndrome (ARDS), septic shock, community-acquired pneumonia, and several other serious medical conditions. Despite such controversies, GC should at least be considered for patients with fulminant manifestations of the following conditions as there is equipoise to indicate that GC may improve outcome with acceptable risks: (i) severe ARDS with refractory hypoxemia despite one to two weeks of state-of-the-art management, (ii) recalcitrant, vasopressor-dependent septic shock, (iii) non-influenza, severe community-acquired pneumonia, and (iv) severe alcoholic hepatitis. The bases for these controversies is likely due to both host factors (e.g., differences in GC resistance and susceptibility to adverse effects) and different phenotypes of any one disease state; e.g., different pathogenesis and pathogens under the rubric of “sepsis.” Elucidation of better biomarkers to determine the underlying pathogenic phenotype will significantly advance our understanding and prediction of which critically ill patients will benefit from GC and who would experience a deleterious effect from its use.

    更新日期:2019-11-18
  • Targeting miRNAs by histone deacetylase inhibitors (HDACi): Rationalizing epigenetics-based therapies for breast cancer
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-11-09
    Meran Keshawa Ediriweera, Somi Kim Cho

    MicroRNAs (miRNAs) belong to a group of short RNA molecules of ~22 nucleotides that play a significant role in the regulation of gene expression through post-transcriptional regulatory mechanisms. They can directly interact with their target mRNA molecules and induce target gene silencing. Many investigations over the past decade have revealed the involvement of different miRNAs in essential biological events. The expression of a considerable number of miRNAs is tightly regulated through epigenetic events such as histone modifications and DNA methylation. Notably, irregularities in these epigenetic events are associated with aberrant expression of miRNAs in a range of diseases including cancer. Impaired epigenetic events associated with aberrant expression of miRNAs can be pharmacologically modified using chromatin modifying drugs. Numerous pre-clinical and clinical data demonstrate that histone deacetylase inhibitors (HDACi) can re-establish the expression of aberrantly expressed miRNAs in a range of cancer types, rationalizing miRNAs as potential drug targets. This review highlights evidence from investigations assessing the effects of different classes of HDACi on miRNA expression in breast cancer (BC).

    更新日期:2019-11-11
  • Drug resistance to targeted therapeutic strategies in non-small cell lung cancer
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-11-09
    Wen-juan Liu, Yue Du, Ru Wen, Ming Yang, Jian Xu

    Rapidly developing molecular biology techniques have been employed to identify cancer driver genes in specimens from patients with non-small cell lung cancer (NSCLC). Inhibitors and antibodies that specifically target driver gene-mediated signaling pathways to suppress tumor growth and progression are expected to extend the survival time and further improve the quality of life of patients. However, the health of patients with advanced and metastatic NSCLC presents significant challenges due to treatment resistance, mediated by cancer driver gene alteration, epigenetic alteration, and tumor heterogeneity. In this review, we discuss two different resistance mechanisms in NSCLC targeted therapies, namely changes in the targeted oncogenes (on-target resistance) and changes in other related signaling pathways (off-target resistance) in tumor cells. We highlight the conventional mechanisms of drug resistance elicited by the complex heterogeneous microenvironment of NSCLC during targeted therapy, including mutations in epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), the receptor tyrosine kinase ROS proto-oncogene 1 (ROS1), and the serine/threonine-protein kinase BRAF (v-Raf murine sarcoma viral oncogene homolog B). We also discuss the mechanism of action of less common oncoproteins, as in-depth understanding of these molecular mechanisms is important for optimizing treatment strategies.

    更新日期:2019-11-11
  • Therapeutic strategy for atherosclerosis based on bone-vascular axis hypothesis
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-11-09
    Jeong-Min Kim, Wang-Soo Lee, Jaetaek Kim

    As the world's older population grows, the disease burden of atherosclerosis is rapidly increasing, causing significant morbidity and mortality worldwide. Despite recent improvements in the control of vascular risk factors, a significant number of patients still suffer from vascular events and the progression of atherosclerosis. Aging also results in decreased bone mineral density. Since bones are a home for hematopoietic stem cells as well as reservoirs of the minerals required for vascular integrity, it is conceivable that a novel therapeutic strategy for atherosclerosis treatment can be developed by focusing on the complex interplay between bones and blood vessels. The correction of mineral dyshomeostasis, disrupted bone marrow microenvironments, and triggered inflammatory cell production provide potential therapeutic options against the atherosclerotic process. This review highlights recent advances in our understanding of the bone-vascular link and discusses new insights into treatment targets for atherosclerosis.

    更新日期:2019-11-11
  • Adolescent Neurodevelopment and Substance Use: Receptor Expression and Behavioral Consequences
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-11-07
    Hayley H.A. Thorpe, Shahnaza Hamidullah, Bryan W. Jenkins, Jibran Y. Khokhar

    Adolescence is the transitional period between childhood and adulthood, during which extensive brain development occurs. Since this period also overlaps with the initiation of drug use, it is important to consider how substance use during this time might produce long-term neurobiological alterations, especially against the backdrop of developmental changes in neurotransmission. Alcohol, cannabis, nicotine, and opioids all produce marked changes in the expression and function of the neurotransmitter and receptor systems with which they interact. These acute and chronic alterations also contribute to behavioral consequences ranging from increased addiction risk to cognitive or neuropsychiatric behavioral dysfunctions. The current review provides an in-depth overview and update of the developmental changes in neurotransmission during adolescence, as well as the impact of drug exposure during this neurodevelopmental window. While most of these factors have been studied in animal models, which are the focus of this review, future longitudinal studies in humans that assess neural function and behavior will help to confirm pre-clinical findings. Furthermore, the neural changes induced by each drug should also be considered in the context of other contributing factors, such as sex. Further understanding of these consequences can help in the identification of novel approaches for preventing and reversing the neurobiological effects of adolescent substance use.

    更新日期:2019-11-08
  • Intravital multiphoton microscopy as a novel tool in the field of immunopharmacology
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2019-11-02
    Akito Morimoto, Junichi Kikuta, Masaru Ishii

    Intravital microscopy with multiphoton excitation is a recently developed optical imaging technique for deep tissue imaging without fixation or sectioning, which permits examination of fundamental concepts regarding the dynamic nature of cells under physiological and pathological conditions in living animals. This novel technique also offers exciting opportunities for pharmacological research by providing new platforms for the study of cellular dynamics in response to drugs in vivo. Moreover, fluorescent chemical probes for functional or molecular analysis in single cells in vivo play important roles in pharmacology. For example, we have recently revealed the pharmacodynamic actions of different biological agents for the treatment of rheumatoid arthritis (RA) in vivo by directly visualizing drug-induced cellular behaviors and functions of osteoclasts on bone surfaces. This review focuses on the principles and advantages of intravital imaging for the dissection of pharmacological mechanisms, and discusses how such imaging can contribute to the drug development process, introducing recent trials that evaluated the in vivo pharmacological effects of various agents.

    更新日期:2019-11-04
  • Siglec-8 as a drugable target to treat eosinophil and mast cell-associated conditions.
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2012-07-04
    Takumi Kiwamoto,Norihito Kawasaki,James C Paulson,Bruce S Bochner

    Siglecs (sialic acid immunoglobulin-like lectins) are members of the immunoglobulin gene family that contain sialoside binding N-terminal domains. They are cell surface proteins found predominantly on cells of the immune system. Among them, Siglec-8 is uniquely expressed by human eosinophils and mast cells, as well as basophils. Engaging this structure with antibodies or glycan ligands results in apoptosis in human eosinophils and inhibition of release of preformed and newly generated mediators from human mast cells without affecting their survival. Pro-apoptotic effects are also seen when its closest functional paralog, Siglec-F, on mouse eosinophils is similarly engaged in vitro, and beneficial effects are observed after administration of Siglec-F antibody using models of eosinophilic pulmonary and gastrointestinal inflammation in vivo. Siglec-8 targeting may thus provide a means to specifically inhibit or deplete these cell types. Cell-directed therapies are increasingly sought after by the pharmaceutical industry for their potential to reduce side effects and increase safety. The challenge is to identify suitable targets on the cell type of interest, and selectively deliver a therapeutic agent. By targeting Siglec-8, monoclonal antibodies and glycan ligand-conjugated nanoparticles may be ideally suited for treatment of eosinophil and mast cell-related diseases, such as asthma, chronic rhinosinusitis, chronic urticaria, hypereosinophilic syndromes, mast cell and eosinophil malignancies and eosinophilic gastrointestinal disorders.

    更新日期:2019-11-01
  • MicroRNAs: Meta-controllers of gene expression in synaptic activity emerge as genetic and diagnostic markers of human disease.
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2011-01-25
    Stephanie Ceman,Julie Saugstad

    MicroRNAs are members of the non-protein-coding family of RNAs. They serve as regulators of gene expression by modulating the translation and/or stability of messenger RNA targets. The discovery of microRNAs has revolutionized the field of cell biology, and has permanently altered the prevailing view of a linear relationship between gene and protein expression. The increased complexity of gene regulation is both exciting and daunting, as emerging evidence supports a pervasive role for microRNAs in virtually every cellular process. This review briefly describes microRNA processing and formation of RNA-induced silencing complexes, with a focus on the role of RNA binding proteins in this process. We also discuss mechanisms for microRNA-mediated regulation of translation, particularly in dendritic spine formation and function, and the role of microRNAs in synaptic plasticity. We then discuss the evidence for altered microRNA function in cognitive brain disorders, and the effect of gene mutations revealed by single nucleotide polymorphism analysis on altered microRNA function and human disease. Further, we present evidence that altered microRNA expression in circulating fluids such as plasma/serum can correlate with, and serve as, novel diagnostic biomarkers of human disease.

    更新日期:2019-11-01
  • Integration of molecular targeted therapy with radiation in head and neck cancer.
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2013-11-28
    Yu Du,Noah D Peyser,Jennifer R Grandis

    Approximately 600,000 new cases of head and neck cancer arise worldwide each year. Of these, a large majority are head and neck squamous cell carcinomas (HNSCC). Conventional treatments, including surgical excision followed by radiation and/or chemoradiotherapy have limited efficacy and are associated with substantial toxicity. To date, key targets for molecular targeted therapy in HNSCC are epidermal growth factor receptors and angiogenesis-related factors. Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) and it is the only targeted therapy approved by the United States Food and Drug Administration for the treatment of HNSCC. Cetuximab in combination with radiotherapy represents a standard approach for newly diagnosed patients who are unable to tolerate platinum chemotherapy. Despite efficacy in preclinical HNSCC models, cetuximab is only effective in a subset of HNSCC patients, most likely due to the high heterogeneity of this cancer. Additional targets under active investigation include the PI3K/Akt pathway, the Ras-MAPK-ERK pathway and the JAK/STAT pathway, among others. Combining molecular targeted therapies and radiation may allow for deintensification of radiotherapy thereby reducing radiation toxicities and improving treatment outcomes. Here we review the preclinical and clinical data in support of treatment strategies that combined targeted therapy with radiation in HNSCC.

    更新日期:2019-11-01
  • The therapeutic potential of novel cannabinoid receptors.
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2009-03-03
    Faith R Kreitzer,Nephi Stella

    Cannabinoids produce a plethora of biological effects, including the modulation of neuronal activity through the activation of CB(1) receptors and of immune responses through the activation of CB(2) receptors. The selective targeting of either of these two receptor subtypes has clear therapeutic value. Recent evidence indicates that some of the cannabinomimetic effects previously thought to be produced through CB(1) and/or CB(2) receptors, be they on neuronal activity, on the vasculature tone or immune responses, still persist despite the pharmacological blockade or genetic ablation of CB(1) and/or CB(2) receptors. This suggests that additional cannabinoid and cannabinoid-like receptors exist. Here we will review this evidence in the context of their therapeutic value and discuss their true belonging to the endocannabinoid signaling system.

    更新日期:2019-11-01
  • Insight into SUCNR1 (GPR91) structure and function.
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2016-01-26
    Julie Gilissen,François Jouret,Bernard Pirotte,Julien Hanson

    SUCNR1 (or GPR91) belongs to the family of G protein-coupled receptors (GPCR), which represents the largest group of membrane proteins in human genome. The majority of marketed drugs targets GPCRs, directly or indirectly. SUCNR1 has been classified as an orphan receptor until a landmark study paired it with succinate, a citric acid cycle intermediate. According to the current paradigm, succinate triggers SUCNR1 signaling pathways to indicate local stress that may affect cellular metabolism. SUCNR1 implication has been well documented in renin-induced hypertension, ischemia/reperfusion injury, inflammation and immune response, platelet aggregation and retinal angiogenesis. In addition, the SUCNR1-induced increase of blood pressure may contribute to diabetic nephropathy or cardiac hypertrophy. The understanding of SUCNR1 activation, signaling pathways and functions remains largely elusive, which calls for deeper investigations. SUCNR1 shows a high potential as an innovative drug target and is probably an important regulator of basic physiology. In order to achieve the full characterization of this receptor, more specific pharmacological tools such as small-molecules modulators will represent an important asset. In this review, we describe the structural features of SUCNR1, its current ligands and putative binding pocket. We give an exhaustive overview of the known and hypothetical signaling partners of the receptor in different in vitro and in vivo systems. The link between SUCNR1 intracellular pathways and its pathophysiological roles are also extensively discussed.

    更新日期:2019-11-01
  • Tumor regulation of the tissue environment in the liver.
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2017-02-09
    Tobias Eggert,Tim F Greten

    The tumor microenvironment (TME) in the liver plays an important role in primary and metastatic liver tumor formation and tumor growth promotion. Cellular and non-cellular components of the TME significantly influence tumor development, growth, metastatic spread, anti-tumor immunity and response to tumor therapy. The cellular components of the TME in the liver not only consist of infiltrating immune cells, but also of liver-resident cells such as liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC), which promote tumor growth by negatively regulating tumor-associated immune responses. In this review, we characterize cells of the TME with pro- and anti-tumor function in primary and metastatic liver tumors. Furthermore, we summarize mechanisms that permit growth of hepatic tumors despite the occurrence of spontaneous anti-tumor immune responses and how novel therapeutic approaches targeting the TME could unleash tumor-specific immune responses to improve survival of liver cancer patients.

    更新日期:2019-11-01
  • Pharmacological and immunological targeting of tumor mesenchymalization.
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2016-12-06
    Justin M David,Charli Dominguez,Claudia Palena

    Controlling the spread of carcinoma cells to distant organs is the foremost challenge in cancer treatment, as metastatic disease is generally resistant to therapy and is ultimately incurable for the majority of patients. The plasticity of tumor cell phenotype, in which the behaviors and functions of individual tumor cells differ markedly depending upon intrinsic and extrinsic factors, is now known to be a central mechanism in cancer progression. Our expanding knowledge of epithelial and mesenchymal phenotypic states in tumor cells, and the dynamic nature of the transitions between these phenotypes has created new opportunities to intervene to better control the behavior of tumor cells. There are now a variety of innovative pharmacological approaches to preferentially target tumor cells that have acquired mesenchymal features, including cytotoxic agents that directly kill these cells, and inhibitors that block or revert the process of mesenchymalization. Furthermore, novel immunological strategies have been developed to engage the immune system in seeking out and destroying mesenchymalized tumor cells. This review highlights the relevance of phenotypic plasticity in tumor biology, and discusses recently developed pharmacological and immunological means of targeting this phenomenon.

    更新日期:2019-11-01
  • The functional interplay between systemic cancer and the hematopoietic stem cell niche.
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2016-09-07
    Amber J Giles,Christopher D Chien,Caitlin M Reid,Terry J Fry,Deric M Park,Rosandra N Kaplan,Mark R Gilbert

    Hematopoietic cells are increasingly recognized as playing key roles in tumor growth and metastatic progression. Although many studies have focused on the functional interaction of hematopoietic cells with tumor cells, few have examined the regulation of hematopoiesis by the hematopoietic stem cell (HSC) niche in the setting of cancer. Hematopoiesis occurs primarily in the bone marrow, and processes including expansion, mobilization, and differentiation of hematopoietic progenitors are tightly regulated by the specialized stem cell niche. Loss of niche components or the ability of stem cells to localize to the stem cell niche relieves HSCs of the restrictions imposed under normal homeostasis. In this review, we discuss how tumor-derived factors and therapeutic interventions disrupt structural and regulatory properties of the stem cell niche, resulting in niche invasion by hematopoietic malignancies, extramedullary hematopoiesis, myeloid skewing by peripheral tissue microenvironments, and lymphopenia. The key regulatory roles played by the bone marrow niche in hematopoiesis has implications for therapy-related toxicity and the successful development of immune-based therapies for cancer.

    更新日期:2019-11-01
  • Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders.
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2014-06-20
    David S Goldstein,Irwin J Kopin,Yehonatan Sharabi

    Several neurodegenerative diseases involve loss of catecholamine neurons-Parkinson disease is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are vulnerable in PD and related disorders has been mysterious. Accumulating evidence supports the concept of "autotoxicity"-inherent cytotoxicity of catecholamines and their metabolites in the cells in which they are produced. According to the "catecholaldehyde hypothesis" for the pathogenesis of Parkinson disease, long-term increased build-up of 3,4-dihydroxyphenylacetaldehyde (DOPAL), the catecholaldehyde metabolite of dopamine, causes or contributes to the eventual death of dopaminergic neurons. Lewy bodies, a neuropathologic hallmark of PD, contain precipitated alpha-synuclein. Bases for the tendency of alpha-synuclein to precipitate in the cytoplasm of catecholaminergic neurons have also been mysterious. Since DOPAL potently oligomerizes and aggregates alpha-synuclein, the catecholaldehyde hypothesis provides a link between alpha-synucleinopathy and catecholamine neuron loss in Lewy body diseases. The concept developed here is that DOPAL and alpha-synuclein are nodes in a complex nexus of interacting homeostatic systems. Dysfunctions of several processes, including decreased vesicular sequestration of cytoplasmic catecholamines, decreased aldehyde dehydrogenase activity, and oligomerization of alpha-synuclein, lead to conversion from the stability afforded by negative feedback regulation to the instability, degeneration, and system failure caused by induction of positive feedback loops. These dysfunctions result from diverse combinations of genetic predispositions, environmental exposures, stress, and time. The notion of catecholamine autotoxicity has several implications for treatment, disease modification, and prevention. Conversely, disease modification clinical trials would provide key tests of the catecholaldehyde hypothesis.

    更新日期:2019-11-01
  • Circulating tumor cells: advances in isolation and analysis, and challenges for clinical applications.
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2013-10-19
    Ramdane Harouaka,Zhigang Kang,Si-Yang Zheng,Liang Cao

    Circulating tumor cells (CTCs) are rare cancer cells released from tumors into the bloodstream that are thought to have a key role in cancer metastasis. The presence of CTCs has been associated with worse prognosis in several major cancer types, including breast, prostate and colorectal cancer. There is considerable interest in CTC research and technologies for their potential use as cancer biomarkers that may enhance cancer diagnosis and prognosis, facilitate drug development, and improve the treatment of cancer patients. This review provides an update on recent progress in CTC isolation and molecular characterization technologies. Furthermore, the review covers significant advances and limitations in the clinical applications of CTC-based assays for cancer prognosis, response to anti-cancer therapies, and exploratory studies in biomarkers predictive of sensitivity and resistance to cancer therapies.

    更新日期:2019-11-01
  • Targeting notch signaling pathway in cancer: clinical development advances and challenges.
    Pharmacol. Therapeut. (IF 9.396) Pub Date : 2013-10-01
    Naoko Takebe,Dat Nguyen,Sherry X Yang

    Notch signaling plays an important role in development and cell fate determination, and it is deregulated in human hematologic malignancies and solid tumors. This review includes a brief introduction of the relevant pathophysiology of Notch signaling pathway and primarily focuses on the clinical development of promising agents that either obstruct Notch receptor cleavages such as γ-secretase inhibitors (GSIs) or interfere with the Notch ligand-receptor interaction by monoclonal antibodies (mAbs). Antitumor activity by GSIs and mAbs administered as single agent in early phases of clinical trials has been observed in advanced or metastatic thyroid cancer, non-small cell lung cancer, intracranial tumors, sarcoma or desmoid tumors, colorectal cancer with neuroendocrine features, melanoma and ovarian cancer. A number of mechanism-based adverse events particularly gastrointestinal toxicities emerged and mitigation strategies are developed after testing multiple GSIs and Notch targeting mAbs. We also discuss pharmacodynamic biomarkers in conjunction with methods of assessment of the molecular target inhibition validation. Biomarkers of efficacy or benefit may be of importance for a successful development of this class of drugs.

    更新日期:2019-11-01
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