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Sample records for effects potential targets

  1. Tea polyphenols, their biological effects and potential molecular targets.

    PubMed

    Chen, D; Milacic, V; Chen, M S; Wan, S B; Lam, W H; Huo, C; Landis-Piwowar, K R; Cui, Q C; Wali, A; Chan, T H; Dou, Q P

    2008-04-01

    Tea is the most popular beverage in the world, second only to water. Tea contains an infusion of the leaves from the Camellia sinensis plant rich in polyphenolic compounds known as catechins, the most abundant of which is (-)-EGCG. Although tea has been consumed for centuries, it has only recently been studied extensively as a health-promoting beverage that may act to prevent a number of chronic diseases and cancers. The results of several investigations indicate that green tea consumption may be of modest benefit in reducing the plasma concentration of cholesterol and preventing atherosclerosis. Additionally, the cancer-preventive effects of green tea are widely supported by results from epidemiological, cell culture, animal and clinical studies. In vitro cell culture studies show that tea polyphenols potently induce apoptotic cell death and cell cycle arrest in tumor cells but not in their normal cell counterparts. Green tea polyphenols were shown to affect several biological pathways, including growth factor-mediated pathway, the mitogen-activated protein (MAP) kinase-dependent pathway, and ubiquitin/proteasome degradation pathways. Various animal studies have revealed that treatment with green tea inhibits tumor incidence and multiplicity in different organ sites such as skin, lung, liver, stomach, mammary gland and colon. Recently, phase I and II clinical trials have been conducted to explore the anticancer effects of green tea in humans. A major challenge of cancer prevention is to integrate new molecular findings into clinical practice. Therefore, identification of more molecular targets and biomarkers for tea polyphenols is essential for improving the design of green tea trials and will greatly assist in a better understanding of the mechanisms underlying its anti-cancer activity.

  2. Sigma (σ) receptors as potential therapeutic targets to mitigate psychostimulant effects.

    PubMed

    Matsumoto, Rae R; Nguyen, Linda; Kaushal, Nidhi; Robson, Matthew J

    2014-01-01

    Many psychostimulants, including cocaine and methamphetamine, interact with sigma (σ) receptors at physiologically relevant concentrations. The potential therapeutic relevance of this interaction is underscored by the ability to selectively target σ receptors to mitigate many behavioral and physiological effects of psychostimulants in animal and cell-based model systems. This chapter begins with an overview of these enigmatic proteins. Provocative preclinical data showing that σ ligands modulate an array of cocaine and methamphetamine effects are summarized, along with emerging areas of research. Together, the literature suggests targeting of σ receptors as an innovative option for combating undesired actions of psychostimulants through both neuronal and glial mechanisms.

  3. Effect of surface capping on targeting potential of folate decorated poly (propylene imine) dendrimers.

    PubMed

    Birdhariya, Babulal; Kesharwani, Prashant; Jain, Narendra Kumar

    2015-01-01

    The objective of the present investigation was to assess and compare the effect of surface capping by different groups (-OH, -COOH and -NH2) on tumor targeting potential of folate conjugated poly (propylene imine) (PPI) (F-PPI) dendrimers using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The synthesized nanoconjugates (F-PPI, F-COOH-PPI, F-OH-PPI and F-CONH-PPI) were characterized by Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance ((1)H-NMR) and transmission electron microscopic (TEM) studies. The formulations were evaluated for drug entrapment, in vitro drug release and hemolytic toxicity, and cytotoxicity was evaluated on HeLa and SiHa cell line using MTT assay. In case of all surface capped formulation, Methotrexate (MTX) loading was found to increased; however MTX release rate was found to decrease as compared to unmodified formulation. Further, F-COOH-PPI displayed highest tumor targeting potential as compared to other formulations. This is the first study to explore the effect of surface capping on the targeting potential of folate-conjugated fifth generation (5.0 G) PPI dendrimer. In conclusion, the targeting potential of all the formulations (anticancer activity) for both HeLa and SiHa cells follows in the following order: F-COOH-PPI > F-OH-PPI > F-CONH-PPI > F-PPI.

  4. GM biofortified crops: potential effects on targeting the micronutrient intake gap in human populations.

    PubMed

    De Steur, Hans; Mehta, Saurabh; Gellynck, Xavier; Finkelstein, Julia L

    2017-04-01

    Genetic engineering has been successfully applied to increase micronutrient content in staple crops. Nutrition evidence is key to ensure scale-up and successful implementation. Unlike conventional plant breeding efforts, research on the efficacy or effectiveness of GM biofortified crops on nutritional status in human populations is lacking. This review reports on the potential role of GM biofortified crops in closing the micronutrient gap - increasing the dietary intake of micronutrients in human populations. To date, one clinical trial in the United States reported a high bio-conversion rate of β-carotene in Golden Rice, and potential effects of GM biofortified crop consumption on dietary intake and nutritional outcomes are promising. However, further research needs to confirm the ex ante assessments in target regions.

  5. Potential implications of the bystander effect on TCP and EUD when considering target volume dose heterogeneity.

    PubMed

    Balderson, Michael J; Kirkby, Charles

    2015-01-01

    In light of in vitro evidence suggesting that radiation-induced bystander effects may enhance non-local cell killing, there is potential for impact on radiotherapy treatment planning paradigms such as the goal of delivering a uniform dose throughout the clinical target volume (CTV). This work applies a bystander effect model to calculate equivalent uniform dose (EUD) and tumor control probability (TCP) for external beam prostate treatment and compares the results with a more common model where local response is dictated exclusively by local absorbed dose. The broad assumptions applied in the bystander effect model are intended to place an upper limit on the extent of the results in a clinical context. EUD and TCP of a prostate cancer target volume under conditions of increasing dose heterogeneity were calculated using two models: One incorporating bystander effects derived from previously published in vitro bystander data ( McMahon et al. 2012 , 2013a); and one using a common linear-quadratic (LQ) response that relies exclusively on local absorbed dose. Dose through the CTV was modelled as a normal distribution, where the degree of heterogeneity was then dictated by changing the standard deviation (SD). Also, a representative clinical dose distribution was examined as cold (low dose) sub-volumes were systematically introduced. The bystander model suggests a moderate degree of dose heterogeneity throughout a target volume will yield as good or better outcome compared to a uniform dose in terms of EUD and TCP. For a typical intermediate risk prostate prescription of 78 Gy over 39 fractions maxima in EUD and TCP as a function of increasing SD occurred at SD ∼ 5 Gy. The plots only dropped below the uniform dose values for SD ∼ 10 Gy, almost 13% of the prescribed dose. Small, but potentially significant differences in the outcome metrics between the models were identified in the clinically-derived dose distribution as cold sub-volumes were introduced. In terms of

  6. Non-Targeted Effects Induced by Ionizing Radiation: Mechanisms and Potential Impact on Radiation Induced Health Effects

    SciTech Connect

    Morgan, William F.; Sowa, Marianne B.

    2015-01-01

    Not-targeted effects represent a paradigm shift from the "DNA centric" view that ionizing radiation only elicits biological effects and subsequent health consequences as a result of an energy deposition event in the cell nucleus. While this is likely true at higher radiation doses (> 1Gy), at low doses (< 100mGy) non-targeted effects associated with radiation exposure might play a significant role. Here definitions of non-targeted effects are presented, the potential mechanisms for the communication of signals and signaling networks from irradiated cells/tissues are proposed, and the various effects of this intra- and intercellular signaling are described. We conclude with speculation on how these observations might lead to and impact long-term human health outcomes.

  7. Non-targeted effects induced by ionizing radiation: mechanisms and potential impact on radiation induced health effects.

    PubMed

    Morgan, William F; Sowa, Marianne B

    2015-01-01

    Not-targeted effects represent a paradigm shift from the "DNA centric" view that ionizing radiation only elicits biological effects and subsequent health consequences as a result of an energy deposition event in the cell nucleus. While this is likely true at higher radiation doses (>1 Gy), at low doses (<100 mGy) non-targeted effects associated with radiation exposure might play a significant role. Here definitions of non-targeted effects are presented, the potential mechanisms for the communication of signals and signaling networks from irradiated cells/tissues are proposed, and the various effects of this intra- and intercellular signaling are described. We conclude with speculation on how these observations might lead to and impact long-term human health outcomes.

  8. Photodynamic tumor eradication with a novel targetable photosensitizer: strong vascular effects and dependence on treatment repetition versus potentiation.

    PubMed

    Savellano, Mark D; Owusu-Brackett, Nicci; Son, Ji; Ganga, Tanay; Leung, Nadia L; Savellano, Dagmar H

    2013-01-01

    A novel pyropheophorbide-a (PPa) derivative, Ac-sPPp, was developed in our lab for targeted photodynamic therapy (PDT) and combination therapies. Its versatile peptide moiety, high water-solubility, amphiphilicity, and micellar aggregation allow efficient coupling to targeting moieties and convenient mixing with other therapeutics. Photosensitizer immunoconjugate (PIC) targeted PDT, using Ac-sPPp conjugated to therapeutic anti-epidermal growth factor receptor (EGFR) antibody cetuximab, and PDT + chemotherapy combination treatment, using Ac-sPPp mixed with stealth liposomal doxorubicin (Doxil), were investigated as promising strategies for potentiating PDT and improving target specificity. Passively targeted PDT with Ac-sPPp only or surfactant-solubilized PPa was also investigated for comparison. The A-431 human vulvar squamous cell carcinoma, xenografted in nude mice, was chosen as a tumor model because of its high EGFR expression and sensitivity to liposomal doxorubicin in vitro. Fluorescence imaging and PDT experiments showed that Ac-sPPp formulations circulated far longer and provided superior tumor contrast and superior tumor control compared to PPa. Strong PDT vascular effects were observed by laser Doppler imaging regardless of whether Ac-sPPp was passively or actively targeted. Passively targeted Ac-sPPp PDT gave equivalent or better tumor control than PIC-targeted PDT or PDT + Doxil combination therapy, and when treatments were repeated, it also yielded the highest cure rate.

  9. Neuroinflammation: a potential therapeutic target.

    PubMed

    Craft, Jeffrey M; Watterson, D Martin; Van Eldik, Linda J

    2005-10-01

    The increased appreciation of the importance of glial cell-propagated inflammation (termed 'neuroinflammation') in the progression of pathophysiology for diverse neurodegenerative diseases, has heightened interest in the rapid discovery of neuroinflammation-targeted therapeutics. Efforts include searches among existing drugs approved for other uses, as well as development of novel synthetic compounds that selectively downregulate neuroinflammatory responses. The use of existing drugs to target neuroinflammation has largely met with failure due to lack of efficacy or untoward side effects. However, the de novo development of new classes of therapeutics based on targeting selective aspects of glia activation pathways and glia-mediated pathophysiologies, versus targeting pathways of quantitative importance in non-CNS inflammatory responses, is yielding promising results in preclinical animal models. The authors briefly review selected clinical and preclinical data that reflect the prevailing approaches targeting neuroinflammation as a pathophysiological process contributing to onset or progression of neurodegenerative diseases. The authors conclude with opinions based on recent experimental proofs of concept using preclinical animal models of pathophysiology. The focus is on Alzheimer's disease, but the concepts are transferrable to other neurodegenerative disorders with an inflammatory component.

  10. Dual targeting of Angiopoetin-2 and VEGF potentiates effective vascular normalisation without inducing empty basement membrane sleeves in xenograft tumours

    PubMed Central

    Coutelle, O; Schiffmann, L M; Liwschitz, M; Brunold, M; Goede, V; Hallek, M; Kashkar, H; Hacker, U T

    2015-01-01

    Background: Effective vascular normalisation following vascular endothelial growth factor (VEGF) inhibition is associated with endothelial cell regression leaving empty basement membrane sleeves (BMS). These long-lived BMS permit the rapid regrowth of tumour vasculature upon treatment cessation and promote resistance to VEGF-targeting drugs. Previous attempts at removing BMS have failed. Angiopoietin-2 (Ang2) is a vascular destabilizing factor that antagonises normalisation. We hypothesised that Ang2 inhibition could permit vascular normalisation at significantly reduced doses of VEGF inhibition, avoiding excessive vessel regression and the formation of empty BMS. Methods: Mice xenografted with human colorectal cancer cells (LS174T) were treated with low (0.5 mg kg−1) or high (5 mg kg−1) doses of the VEGF-targeting antibody bevacizumab with or without an Ang2 blocking peptibody L1-10. Tumour growth, BMS formation and normalisation parameters were examined including vessel density, pericyte coverage, adherence junctions, leakiness, perfusion, hypoxia and proliferation. Results: Dual targeting of VEGF and Ang2 achieved effective normalisation at only one-tenth of the dose required with bevacizumab alone. Pericyte coverage, vascular integrity, adherence junctions and perfusion as prerequisites for improved access of chemotherapy were improved without inducing empty BMS that facilitate rapid vascular regrowth. Conclusions: Dual targeting of VEGF and Ang2 can potentiate the effectiveness of VEGF inhibitors and avoid the formation of empty BMS. PMID:25562438

  11. Sequential effects in continued visual search: Using fixation-related potentials to compare distractor processing before and after target detection

    PubMed Central

    Körner, Christof; Braunstein, Verena; Stangl, Matthias; Schlögl, Alois; Neuper, Christa; Ischebeck, Anja

    2014-01-01

    To search for a target in a complex environment is an everyday behavior that ends with finding the target. When we search for two identical targets, however, we must continue the search after finding the first target and memorize its location. We used fixation-related potentials to investigate the neural correlates of different stages of the search, that is, before and after finding the first target. Having found the first target influenced subsequent distractor processing. Compared to distractor fixations before the first target fixation, a negative shift was observed for three subsequent distractor fixations. These results suggest that processing a target in continued search modulates the brain's response, either transiently by reflecting temporary working memory processes or permanently by reflecting working memory retention. PMID:24512467

  12. Grape polyphenols inhibit Akt/mammalian target of rapamycin signaling and potentiate the effects of gefitinib in breast cancer.

    PubMed

    Castillo-Pichardo, Linette; Dharmawardhane, Suranganie F

    2012-01-01

    We recently reported that a combination of dietary grape polyphenols resveratrol, quercetin, and catechin (RQC), at low concentrations, was effective at inhibiting metastatic cancer progression. Herein, we investigate the molecular mechanisms of RQC in breast cancer and explore the potential of RQC as a potentiation agent for the epidermal growth factor receptor (EGFR) therapeutic gefitinib. Our in vitro experiments showed RQC induced apoptosis in gefitinib-resistant breast cancer cells via regulation of a myriad of proapoptotic proteins. Because the Akt/mammalian target of rapamycin (mTOR) signaling pathway is often elevated during development of anti-EGFR therapy resistance, the effect of RQC on the mTOR upstream effector Akt and the negative regulator AMP kinase (AMPK) was investigated. RQC was found to reduce Akt activity, induce the activation of AMPK, and inhibit mTOR signaling in breast cancer cells. Combined RQC and gefitinib decreased gefitinib resistant breast cancer cell viability to a greater extent than RQC or gefitinib alone. Moreover, RQC inhibited Akt and mTOR and activated AMPK even in the presence of gefitinib. Our in vivo experiments showed combined RQC and gefitinib was more effective than the individual treatments at inhibiting mammary tumor growth and metastasis in nude mice. Therefore, RQC treatment inhibits breast cancer progression and may potentiate anti-EGFR therapy by inhibition of Akt/mTOR signaling.

  13. Targeting Membrane Lipid a Potential Cancer Cure?

    PubMed

    Tan, Loh Teng-Hern; Chan, Kok-Gan; Pusparajah, Priyia; Lee, Wai-Leng; Chuah, Lay-Hong; Khan, Tahir Mehmood; Lee, Learn-Han; Goh, Bey-Hing

    2017-01-01

    Cancer mortality and morbidity is projected to increase significantly over the next few decades. Current chemotherapeutic strategies have significant limitations, and there is great interest in seeking novel therapies which are capable of specifically targeting cancer cells. Given that fundamental differences exist between the cellular membranes of healthy cells and tumor cells, novel therapies based on targeting membrane lipids in cancer cells is a promising approach that deserves attention in the field of anticancer drug development. Phosphatidylethanolamine (PE), a lipid membrane component which exists only in the inner leaflet of cell membrane under normal circumstances, has increased surface representation on the outer membrane of tumor cells with disrupted membrane asymmetry. PE thus represents a potential chemotherapeutic target as the higher exposure of PE on the membrane surface of cancer cells. This feature as well as a high degree of expression of PE on endothelial cells in tumor vasculature, makes PE an attractive molecular target for future cancer interventions. There have already been several small molecules and membrane-active peptides identified which bind specifically to the PE molecules on the cancer cell membrane, subsequently inducing membrane disruption leading to cell lysis. This approach opens up a new front in the battle against cancer, and is of particular interest as it may be a strategy that may be prove effective against tumors that respond poorly to current chemotherapeutic agents. We aim to highlight the evidence suggesting that PE is a strong candidate to be explored as a potential molecular target for membrane targeted novel anticancer therapy.

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

    PubMed

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

    2016-02-26

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

  15. Transient Receptor Potential (TRP) Channels as a Therapeutic Target for Intervention of Respiratory Effects and Lethality from Phosgene

    PubMed Central

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

    2015-01-01

    Phosgene (CG), a toxic inhalation and industrial hazard, causes bronchoconstriction, vasoconstriction and associated pathological effects that could be life threatening. Ion channels of the transient receptor potential (TRP) family have been identified to act as specific chemosensory molecules in the respiratory tract in the detection, control of adaptive responses and initiation of detrimental signaling cascades upon exposure to various toxic inhalation hazards (TIH); their activation due to TIH exposure may result in broncho- and vasoconstriction. We studied changes in the regulation of intracellular free Ca2+ concentration ([Ca2+]i) in cultures of human bronchial smooth muscle cells (BSMC) and human pulmonary microvascular endothelial cells (HPMEC) exposed to CG (16 ppm, 8 min), using an air/liquid interface exposure system. CG increased [Ca2+]i (p<0.05) in both cell types, The CG-induced [Ca2+]i was blocked (p<0.05) by two types of TRP channel blockers, SKF-96365, a general TRP channel blocker, and RR, a general TRPV (vanilloid type) blocker, in both BSMC and HPMEC. These effects correlate with the in vivo efficacies of these compounds to protect against lung injury and 24 hr lethality from whole body CG inhalation exposure in mice (8-10 ppm × 20 min). Thus the TRP channel mechanism appears to be a potential target for intervention in CG toxicity. PMID:26562769

  16. Potential Therapeutic Targets in Uterine Sarcomas

    PubMed Central

    Cuppens, Tine; Tuyaerts, Sandra; Amant, Frédéric

    2015-01-01

    Uterine sarcomas are rare tumors accounting for 3,4% of all uterine cancers. Even after radical hysterectomy, most patients relapse or present with distant metastases. The very limited clinical benefit of adjuvant cytotoxic treatments is reflected by high mortality rates, emphasizing the need for new treatment strategies. This review summarizes rising potential targets in four distinct subtypes of uterine sarcomas: leiomyosarcoma, low-grade and high-grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma. Based on clinical reports, promising approaches for uterine leiomyosarcoma patients include inhibition of VEGF and mTOR signaling, preferably in combination with other targeted or cytotoxic compounds. Currently, the only targeted therapy approved in leiomyosarcoma patients is pazopanib, a multitargeted inhibitor blocking VEGFR, PDGFR, FGFR, and c-KIT. Additionally, preclinical evidence suggests effect of the inhibition of histone deacetylases, tyrosine kinase receptors, and the mitotic checkpoint protein aurora kinase A. In low-grade endometrial stromal sarcomas, antihormonal therapies including aromatase inhibitors and progestins have proven activity. Other potential targets are PDGFR, VEGFR, and histone deacetylases. In high-grade ESS that carry the YWHAE/FAM22A/B fusion gene, the generated 14-3-3 oncoprotein is a putative target, next to c-KIT and the Wnt pathway. The observation of heterogeneity within uterine sarcoma subtypes warrants a personalized treatment approach. PMID:26576131

  17. Transient receptor potential vanilloid 4 (TRPV4) channel as a target of crotamiton and its bimodal effects.

    PubMed

    Kittaka, Hiroki; Yamanoi, Yu; Tominaga, Makoto

    2017-06-13

    The sensation of itching can be defined as "an unpleasant cutaneous sensation that provokes a desire to scratch." The perception of itching is not critical for the maintenance of life, but persistent itching can be extremely irritating and decreases the quality of life. Crotamiton (N-ethyl-o-crotonotoluidide) has been used as an anti-itch agent for humans for around 70 years. In spite of the long use of crotamiton, its mechanism of action remains unknown. We hypothesized that crotamiton might have effects on transient receptor potential (TRP) channels expressed in the peripheral nervous system and the skin. We first examined the effects of crotamiton on TRP channels by whole-cell patch-clamp recordings. We found that crotamiton strongly inhibited TRPV (vanilloid) 4 channels followed by large currents after crotamiton washout. In mice, crotamiton inhibited itch-related behaviors induced by a TRPV4-selective agonist (GSK1016790A). We biophysically investigated the large TRPV4 currents after crotamiton washout. Comparing single-channel open probabilities and current amplitudes of TRPV4, increases in both parameters were found to contribute to the large washout currents of TRPV4. Because the change in current amplitudes suggested pore dilation of TRPV4, we examined this possibility with cation replacement experiments and by measuring changes in reversal potentials. Greater cation influxes and changes in reversal potentials upon crotamiton washout were observed, suggesting that the TRPV4 pore dilated in its uninhibited state. From these results, we identified the molecular target of crotamiton as TRPV4 and demonstrated pore dilation of TRPV4 upon crotamiton washout.

  18. Neuroprotective effects of the catalytic subunit of telomerase: A potential therapeutic target in the central nervous system.

    PubMed

    González-Giraldo, Yeimy; Forero, Diego A; Echeverria, Valentina; Gonzalez, Janneth; Ávila-Rodriguez, Marco; Garcia-Segura, Luis Miguel; Barreto, George E

    2016-07-01

    Senescence plays an important role in neurodegenerative diseases and involves key molecular changes induced by several mechanisms such as oxidative stress, telomere shortening and DNA damage. Potential therapeutic strategies directed to counteract these molecular changes are of great interest for the prevention of the neurodegenerative process. Telomerase is a ribonucleoprotein composed of a catalytic subunit (TERT) and a RNA subunit (TERC). It is known that the telomerase is involved in the maintenance of telomere length and is a highly expressed protein in embryonic stages and decreases in adult cells. In the last decade, a growing number of studies have shown that TERT has neuroprotective effects in cellular and animal models after a brain injury. Significantly, differences in TERT expression between controls and patients with major depressive disorder have been observed. More recently, TERT has been associated with the decrease in reactive oxygen species and DNA protection in mitochondria of neurons. In this review, we highlight the role of TERT in some neurodegenerative disorders and discuss some studies focusing on this protein as a potential target for neuroprotective therapies. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Targeting Membrane Lipid a Potential Cancer Cure?

    PubMed Central

    Tan, Loh Teng-Hern; Chan, Kok-Gan; Pusparajah, Priyia; Lee, Wai-Leng; Chuah, Lay-Hong; Khan, Tahir Mehmood; Lee, Learn-Han; Goh, Bey-Hing

    2017-01-01

    Cancer mortality and morbidity is projected to increase significantly over the next few decades. Current chemotherapeutic strategies have significant limitations, and there is great interest in seeking novel therapies which are capable of specifically targeting cancer cells. Given that fundamental differences exist between the cellular membranes of healthy cells and tumor cells, novel therapies based on targeting membrane lipids in cancer cells is a promising approach that deserves attention in the field of anticancer drug development. Phosphatidylethanolamine (PE), a lipid membrane component which exists only in the inner leaflet of cell membrane under normal circumstances, has increased surface representation on the outer membrane of tumor cells with disrupted membrane asymmetry. PE thus represents a potential chemotherapeutic target as the higher exposure of PE on the membrane surface of cancer cells. This feature as well as a high degree of expression of PE on endothelial cells in tumor vasculature, makes PE an attractive molecular target for future cancer interventions. There have already been several small molecules and membrane-active peptides identified which bind specifically to the PE molecules on the cancer cell membrane, subsequently inducing membrane disruption leading to cell lysis. This approach opens up a new front in the battle against cancer, and is of particular interest as it may be a strategy that may be prove effective against tumors that respond poorly to current chemotherapeutic agents. We aim to highlight the evidence suggesting that PE is a strong candidate to be explored as a potential molecular target for membrane targeted novel anticancer therapy. PMID:28167913

  20. Targeting melanocortin receptors as potential novel therapeutics.

    PubMed

    Getting, Stephen J

    2006-07-01

    Adrenocorticotrophic hormone (ACTH(1-39)) and the melanocortins (alpha, beta and gamma-melanocyte-stimulating hormone [MSH]) are derived from a larger precursor molecule known as the pro-opiomelanocortin (POMC) protein. They exert their numerous biological effects by activating 7 transmembrane G-protein coupled receptors (GPCR), leading to adenylyl cyclase activation and subsequent cAMP accumulation within the target cell. To date, 5 melanocortin receptors (MCR) have been identified and termed MC1R to MC5R, they have been shown to have a wide and varied distribution throughout the body, being found in the central nervous system (CNS), periphery and immune cells. Melanocortins have a multitude of actions including: (i) modulating disease pathologies including arthritis, asthma, obesity; (ii) affecting functions, for example erectile dysfunction, skin tanning; and (iii) organ systems, for example cardiovascular system. Recently a mechanistic approach has been identified with alpha-MSH preventing NF-kappaB activation via the preservation and expression of IkappaBalphaprotein. This leads to a reduction of pro-inflammatory mediators including cytokines and inhibition of adhesion molecule expression, with subsequent reduction in leukocyte emigration. Development of selective ligands with an appropriate pharmacokinetic profile will enable a pharmacological evaluation of the potential beneficial effects of the melanocortins. In this review I have discussed the potential mechanistic action for the melanocortins and some of the disease pathologies shown to be modulated. This review proposes targeting the MCR with the ultimate aim of controlling many of the diseases that we face today.

  1. Tumour macrophages as potential targets of bisphosphonates

    PubMed Central

    2011-01-01

    Tumour cells communicate with the cells of their microenvironment via a series of molecular and cellular interactions to aid their progression to a malignant state and ultimately their metastatic spread. Of the cells in the microenvironment with a key role in cancer development, tumour associated macrophages (TAMs) are among the most notable. Tumour cells release a range of chemokines, cytokines and growth factors to attract macrophages, and these in turn release numerous factors (e.g. VEGF, MMP-9 and EGF) that are implicated in invasion-promoting processes such as tumour cell growth, flicking of the angiogenic switch and immunosuppression. TAM density has been shown to correlate with poor prognosis in breast cancer, suggesting that these cells may represent a potential therapeutic target. However, there are currently no agents that specifically target TAM's available for clinical use. Bisphosphonates (BPs), such as zoledronic acid, are anti-resorptive agents approved for treatment of skeletal complication associated with metastatic breast cancer and prostate cancer. These agents act on osteoclasts, key cells in the bone microenvironment, to inhibit bone resorption. Over the past 30 years this has led to a great reduction in skeletal-related events (SRE's) in patients with advanced cancer and improved the morbidity associated with cancer-induced bone disease. However, there is now a growing body of evidence, both from in vitro and in vivo models, showing that zoledronic acid can also target tumour cells to increase apoptotic cell death and decrease proliferation, migration and invasion, and that this effect is significantly enhanced in combination with chemotherapy agents. Whether macrophages in the peripheral tumour microenvironment are exposed to sufficient levels of bisphosphonate to be affected is currently unknown. Macrophages belong to the same cell lineage as osteoclasts, the major target of BPs, and are highly phagocytic cells shown to be sensitive to

  2. Potential targets for lung squamous cell carcinoma

    Cancer.gov

    Researchers have identified potential therapeutic targets in lung squamous cell carcinoma, the second most common form of lung cancer. The Cancer Genome Atlas (TCGA) Research Network study comprehensively characterized the lung squamous cell carcinoma gen

  3. Therapeutic Potential of Targeting the Ghrelin Pathway

    PubMed Central

    Colldén, Gustav; Tschöp, Matthias H.; Müller, Timo D.

    2017-01-01

    Ghrelin was discovered in 1999 as the endogenous ligand of the growth-hormone secretagogue receptor 1a (GHSR1a). Since then, ghrelin has been found to exert a plethora of physiological effects that go far beyond its initial characterization as a growth hormone (GH) secretagogue. Among the numerous well-established effects of ghrelin are the stimulation of appetite and lipid accumulation, the modulation of immunity and inflammation, the stimulation of gastric motility, the improvement of cardiac performance, the modulation of stress, anxiety, taste sensation and reward-seeking behavior, as well as the regulation of glucose metabolism and thermogenesis. Due to a variety of beneficial effects on systems’ metabolism, pharmacological targeting of the endogenous ghrelin system is widely considered a valuable approach to treat metabolic complications, such as chronic inflammation, gastroparesis or cancer-associated anorexia and cachexia. The aim of this review is to discuss and highlight the broad pharmacological potential of ghrelin pathway modulation for the treatment of anorexia, cachexia, sarcopenia, cardiopathy, neurodegenerative disorders, renal and pulmonary disease, gastrointestinal (GI) disorders, inflammatory disorders and metabolic syndrome. PMID:28398233

  4. TASK-3 as a Potential Antidepressant Target

    PubMed Central

    Gotter, Anthony L.; Santarelli, Vincent P.; Doran, Scott M.; Tannenbaum, Pamela L.; Kraus, Richard L.; Rosahl, Thomas W.; Meziane, Hamid; Montial, Marina; Reiss, Duane R.; Wessner, Keith; McCampbell, Alexander; Stevens, Joanne; Brunner, Joseph; Fox, Steven V.; Uebele, Victor N.; Bayliss, Douglas A.; Winrow, Christopher J.; Renger, John J.

    2011-01-01

    Modulation of TASK-3 (Kcnk9) potassium channels affect neurotransmitter release in thalamocortical centers and other sleep-related nuclei having the capacity to regulate arousal cycles and REM sleep changes associated with mood disorders and antidepressant action. Circumstantial evidence from this and previous studies suggest the potential for TASK-3 to be a novel antidepressant therapeutic target; TASK-3 knock-out mice display augmented circadian amplitude and exhibit sleep architecture characterized by suppressed REM activity. Detailed analysis of locomotor activity indicate that the amplitude of activity bout duration and bout number are augmented in TASK-3 mutants well beyond that seen wildtypes, findings substantiated by amplitude increases in body temperature and EEG recordings of sleep stage bouts. Polysomnographic analysis of TASK-3 mutants reveal increases in nocturnal active wake and suppressed REM sleep time while increased slow wave sleep typifies the inactive phase, findings that have implications for the cognitive impact of reduced TASK-3 activity. In direct measures of their resistance to despair behavior, TASK-3 knock-outs displayed significant decreases in immobility relative to wildtype controls in both tail suspension and forced swim tests. Treatment of wildtype animals with the antidepressant Fluoxetine markedly reduced REM sleep, while leaving active wake and slow wave sleep relatively intact. Remarkably, these effects were absent in TASK-3 mutants indicating that TASK-3 is either directly involved in the mechanism of this drug’s action, or participates in parallel pathways that achieve the same effect. Together, these results support the TASK-3 channel to act as a therapeutic target for antidepressant action. PMID:21885038

  5. Actin as a potential target for decavanadate.

    PubMed

    Ramos, Susana; Moura, José J G; Aureliano, Manuel

    2010-12-01

    ATP prevents G-actin cysteine oxidation and vanadyl formation specifically induced by decavanadate, suggesting that the oxometalate-protein interaction is affected by the nucleotide. The ATP exchange rate is increased by 2-fold due to the presence of decavanadate when compared with control actin (3.1×10(-3) s(-1)), and an apparent dissociation constant (k(dapp)) of 227.4±25.7 μM and 112.3±8.7 μM was obtained in absence or presence of 20 μM V(10), respectively. Moreover, concentrations as low as 50 μM of decameric vanadate species (V(10)) increases the relative G-actin intrinsic fluorescence intensity by approximately 80% whereas for a 10-fold concentration of monomeric vanadate (V(1)) no effects were observed. Upon decavanadate titration, it was observed a linear increase in G-actin hydrophobic surface (2.6-fold), while no changes were detected for V(1) (0-200 μM). Taken together, three major ideas arise: i) ATP prevents decavanadate-induced G-actin cysteine oxidation and vanadate reduction; ii) decavanadate promotes actin conformational changes resulting on its inactivation, iii) decavanadate has an effect on actin ATP binding site. Once it is demonstrated that actin is a new potential target for decavanadate, being the ATP binding site a suitable site for decavanadate binding, it is proposed that some of the biological effects of vanadate can be, at least in part, explained by decavanadate interactions with actin.

  6. Metalloproteinases: potential therapeutic targets for rheumatoid arthritis.

    PubMed

    Itoh, Yoshifumi

    2015-01-01

    In different inflammatory diseases, many metalloproteinases are over expressed and thought to promote progression of the disease. Understanding roles of these enzymes in disease progression as well as in normal homeostasis is crucial to identify target enzymes for the disease. Rheumatoid arthritis (RA) is one of the autoimmune inflammatory diseases in which around 1-2 % of the world populations are suffered from. Roles of metalloproteinases are well documented in RA, but so far none of them is proposed to be a target enzyme. However, there are at least three enzymes that can potentially be molecular targets to inhibit progression of RA. Understanding roles of these enzymes in more detail and developing highly selective inhibitors to these enzymes would be essential for novel antimetalloproteinase therapies in future.

  7. The Healthy Worker Survivor Effect: Target Parameters and Target Populations.

    PubMed

    Brown, Daniel M; Picciotto, Sally; Costello, Sadie; Neophytou, Andreas M; Izano, Monika A; Ferguson, Jacqueline M; Eisen, Ellen A

    2017-07-15

    We offer an in-depth discussion of the time-varying confounding and selection bias mechanisms that give rise to the healthy worker survivor effect (HWSE). In this update of an earlier review, we distinguish between the mechanisms collectively known as the HWSE and the statistical bias that can result. This discussion highlights the importance of identifying both the target parameter and the target population for any research question in occupational epidemiology. Target parameters can correspond to hypothetical workplace interventions; we explore whether these target parameters' true values reflect the etiologic effect of an exposure on an outcome or the potential impact of enforcing an exposure limit in a more realistic setting. If a cohort includes workers hired before the start of follow-up, HWSE mechanisms can limit the transportability of the estimates to other target populations. We summarize recent publications that applied g-methods to control for the HWSE, focusing on their target parameters, target populations, and hypothetical interventions.

  8. Achieving Plant CRISPR Targeting that Limits Off-Target Effects.

    PubMed

    Wolt, Jeffrey D; Wang, Kan; Sashital, Dipali; Lawrence-Dill, Carolyn J

    2016-11-01

    The CRISPR-Cas9 system (clustered regularly interspaced short palindromic repeats with associated Cas9 protein) has been used to generate targeted changes for direct modification of endogenous genes in an increasing number of plant species; but development of plant genome editing has not yet fully considered potential off-target mismatches that may lead to unintended changes within the genome. Assessing the specificity of CRISPR-Cas9 for increasing editing efficiency as well as the potential for unanticipated downstream effects from off-target mutations is an important regulatory consideration for agricultural applications. Increasing genome-editing specificity entails developing improved design methods that better predict the prevalence of off-target mutations as a function of genome composition and design of the engineered ribonucleoprotein (RNP). Early results from CRISPR-Cas9 genome editing in plant systems indicate that the incidence of off-target mutation frequencies is quite low; however, by analyzing CRISPR-edited plant lines and improving both computational tools and reagent design, it may be possible to further decrease unanticipated effects at potential mismatch sites within the genome. This will provide assurance that CRISPR-Cas9 reagents can be designed and targeted with a high degree of specificity. Improved and experimentally validated design tools for discriminating target and potential off-target positions that incorporate consideration of the designed nuclease fidelity and selectivity will help to increase confidence for regulatory decision making for genome-edited plants. Copyright © 2016 Crop Science Society of America.

  9. Accelerating yield potential in soybean: potential targets for biotechnological improvement.

    PubMed

    Ainsworth, Elizabeth A; Yendrek, Craig R; Skoneczka, Jeffrey A; Long, Stephen P

    2012-01-01

    Soybean (Glycine max Merr.) is the world's most widely grown legume and provides an important source of protein and oil. Global soybean production and yield per hectare increased steadily over the past century with improved agronomy and development of cultivars suited to a wide range of latitudes. In order to meet the needs of a growing world population without unsustainable expansion of the land area devoted to this crop, yield must increase at a faster rate than at present. Here, the historical basis for the yield gains realized in the past 90 years are examined together with potential metabolic targets for achieving further improvements in yield potential. These targets include improving photosynthetic efficiency, optimizing delivery and utilization of carbon, more efficient nitrogen fixation and altering flower initiation and abortion. Optimization of investment in photosynthetic enzymes, bypassing photorespiratory metabolism, engineering the electron transport chain and engineering a faster recovery from the photoprotected state are different strategies to improve photosynthesis in soybean. These potential improvements in photosynthetic carbon gain will need to be matched by increased carbon and nitrogen transport to developing soybean pods and seeds in order to maximize the benefit. Better understanding of control of carbon and nitrogen transport along with improved knowledge of the regulation of flower initiation and abortion will be needed to optimize sink capacity in soybean. Although few single targets are likely to deliver a quantum leap in yields, biotechnological advances in molecular breeding techniques that allow for alteration of the soybean genome and transcriptome promise significant yield gains. © 2011 Blackwell Publishing Ltd.

  10. Effects of aging and involuntary capture of attention on event-related potentials associated with the processing of and the response to a target stimulus

    PubMed Central

    Cid-Fernández, Susana; Lindín, Mónica; Díaz, Fernando

    2014-01-01

    The main aim of the present study was to assess whether aging modulates the effects of involuntary capture of attention by novel stimuli on performance, and on event-related potentials (ERPs) associated with target processing (N2b and P3b) and subsequent response processes (stimulus-locked Lateralized Readiness Potential -sLRP- and response-locked Lateralized Readiness Potential -rLRP-). An auditory-visual distraction-attention task was performed by 77 healthy participants, divided into three age groups (Young: 21–29, Middle-aged: 51–64, Old: 65–84 years old). Participants were asked to attend to visual stimuli and to ignore auditory stimuli. Aging was associated with slowed reaction times, target stimulus processing in working memory (WM, longer N2b and P3b latencies) and selection and preparation of the motor response (longer sLRP and earlier rLRP onset latencies). In the novel relative to the standard condition we observed, in the three age groups: (1) a distraction effect, reflected in a slowing of reaction times, of stimuli categorization in WM (longer P3b latency), and of motor response selection (longer sLRP onset latency); (2) a facilitation effect on response preparation (later rLRP onset latency), and (3) an increase in arousal (larger amplitudes of all ERPs evaluated, except for N2b amplitude in the Old group). A distraction effect on the stimulus evaluation processes (longer N2b latency) were also observed, but only in middle-aged and old participants, indicating that the attentional capture slows the stimulus evaluation in WM from early ages (from 50 years onwards, without differences between middle-age and older adults), but not in young adults. PMID:25294999

  11. Finding Potential Therapeutic Targets against Shigella flexneri through Proteome Exploration

    PubMed Central

    Hossain, Mohammad Uzzal; Khan, Md. Arif; Hashem, Abu; Islam, Md. Monirul; Morshed, Mohammad Neaz; Keya, Chaman Ara; Salimullah, Md.

    2016-01-01

    Background: Shigella flexneri is a gram negative bacteria that causes the infectious disease “shigellosis.” S. flexneri is responsible for developing diarrhea, fever, and stomach cramps in human. Antibiotics are mostly given to patients infected with shigella. Resistance to antibiotics can hinder its treatment significantly. Upon identification of essential therapeutic targets, vaccine and drug could be effective therapy for the treatment of shigellosis. Methods: The study was designed for the identification and qualitative characterization for potential drug targets from S. flexneri by using the subtractive proteome analysis. A set of computational tools were used to identify essential proteins those are required for the survival of S. flexneri. Total proteome (13,503 proteins) of S. flexneri was retrieved from NCBI and further analyzed by subtractive channel analysis. After identification of the metabolic proteins we have also performed its qualitative characterization to pave the way for the identification of promising drug targets. Results: Subtractive analysis revealed that a list of 53 targets of S. flexneri were human non-homologous essential metabolic proteins that might be used for potential drug targets. We have also found that 11 drug targets are involved in unique pathway. Most of these proteins are cytoplasmic, can be used as broad spectrum drug targets, can interact with other proteins and show the druggable properties. The functionality and drug binding site analysis suggest a promising effective way to design the new drugs against S. flexneri. Conclusion: Among the 53 therapeutic targets identified through this study, 13 were found highly potential as drug targets based on their physicochemical properties whilst only one was found as vaccine target against S. flexneri. The outcome might also be used as module as well as circuit design in systems biology. PMID:27920755

  12. Potential therapeutic effects of the simultaneous targeting of the Nrf2 and NF-κB pathways in diabetic neuropathy☆

    PubMed Central

    Ganesh Yerra, Veera; Negi, Geeta; Sharma, Shyam S; Kumar, Ashutosh

    2013-01-01

    The Nuclear factor-2 erythroid related factor-2 (Nrf2) is a redox regulated transcription factor involved in the regulation of antioxidant defence systems. It drives the production of endogenous antioxidant defences and detoxifying enzymes. Nuclear factor-kappa light chain enhancer of B cells (NF-κB) is a transcription factor, involved in proinflammatory cytokine production, in addition to its immunological function. Both Nrf2 and NF-κB regulation are co-ordinated in order to maintain redox homeostasis in healthy cells. However, during pathological conditions this regulation is perturbed offering an opportunity for therapeutic intervention. Diabetic neuropathy is a condition, in which change in expression pattern of Nrf2 and NF-κB has been reported. This review aims to focus on the role of the Nrf2 and NF-κB in diabetic neuropathy and summarizes the therapeutic outcomes of various pharmacological modulators targeted at the Nrf2–NF-κB axis in diabetic neuropathy. PMID:24024177

  13. Obesity: Current and potential pharmacotherapeutics and targets.

    PubMed

    Narayanaswami, Vidya; Dwoskin, Linda P

    2017-02-01

    Obesity is a global epidemic that contributes to a number of health complications including cardiovascular disease, type 2 diabetes, cancer and neuropsychiatric disorders. Pharmacotherapeutic strategies to treat obesity are urgently needed. Research over the past two decades has increased substantially our knowledge of central and peripheral mechanisms underlying homeostatic energy balance. Homeostatic mechanisms involve multiple components including neuronal circuits, some originating in hypothalamus and brain stem, as well as peripherally-derived satiety, hunger and adiposity signals that modulate neural activity and regulate eating behavior. Dysregulation of one or more of these homeostatic components results in obesity. Coincident with obesity, reward mechanisms that regulate hedonic aspects of food intake override the homeostatic regulation of eating. In addition to functional interactions between homeostatic and reward systems in the regulation of food intake, homeostatic signals have the ability to alter vulnerability to drug abuse. Regarding the treatment of obesity, pharmacological monotherapies primarily focus on a single protein target. FDA-approved monotherapy options include phentermine (Adipex-P®), orlistat (Xenical®), lorcaserin (Belviq®) and liraglutide (Saxenda®). However, monotherapies have limited efficacy, in part due to the recruitment of alternate and counter-regulatory pathways. Consequently, a multi-target approach may provide greater benefit. Recently, two combination products have been approved by the FDA to treat obesity, including phentermine/topiramate (Qsymia®) and naltrexone/bupropion (Contrave®). The current review provides an overview of homeostatic and reward mechanisms that regulate energy balance, potential therapeutic targets for obesity and current treatment options, including some candidate therapeutics in clinical development. Finally, challenges in anti-obesity drug development are discussed. Copyright © 2016 Elsevier

  14. Studies on the effect of window deformation on the scattering and energy profiles of the beam: Potential effects contributing to target mass

    SciTech Connect

    1994-12-31

    Recently, the authors installed a preformed 18.5 miL thick aluminum window, possessing a 5 mm hemispherical deformation, onto a 77 mL volume conical target, but with the deformation placed concave into the target. This was done because pressure and beam induced deformation of our flat aluminum windows would cause them to bow outward beyond the helium cooling axis, which eventually resulted in window failure. It was thought that placing a preformed window in a concave geometry would provide additional radial strength to minimize further deformation, and also optimum window cooling thus increasing window lifetime. The windows were fabricated from 6061 aluminum alloy. The alloy exists in a T{sub 6} state of hardness (the highest level), but can be converted to a T{sub 0} workable state through heating of the alloy for several hours at 500{degrees}C. Once in this state, the windows can be deformed over a mandrel with little or no stress added to the surface structure. The alloy automatically reverts back to its original state of hardness over a 48 hour period. In-direct observations made on [{sup 11}C]cocaine specific activity suggested that target mass contributions were somewhat reduced with the window placed in a concave configuration. This has not been verified directly through CO{sub 2} target mass measurements. Even so, this peaked interest in what effect window geometry might have on the scattering and energy profiles of the proton beam. These aspects could have significant effects on target surface contributions to mass.

  15. Potential of the microbial assay for risk assessment (MARA) for assessing ecotoxicological effects of herbicides to non-target organisms.

    PubMed

    Fai, Patricia Bi Asanga; Mbida, Mpoame; Demefack, Jean Marc; Yamssi, Cedric

    2015-11-01

    Many microbiotests that have been proposed for use in the risk assessment of environmental pollutants have the drawback of lacking relevant published data on various aspects of their test application possibilities and therefore do not receive the regulatory recognition which they may deserve. The MARA bioassay lacks published data for many relevant environmental pollutants, particularly pesticides and this may limit its use in regulatory framework. The present study has assessed the sensitivity of the MARA bioassay relative to other established bioassays (Daphnia magna and Oreochromis niloticus) to two widely used herbicide formulations: Roundup (having glyphosate as active ingredient) and Herbextra (with the active ingredient being 2,4-dichlorophenoxyacetic acid-2,4-D). Roundup was found to be more toxic than Herbextra in all three bioassays. The D. magna EC50 s obtained for Roundup and Herbextra were respectively 5.55 and 356.61 mg/l while the LC50 s for O. niloticus were 11.30 and 222,28 mg/l respectively. In the case of the MARA bioassay microbial toxic concentrations (MTCs) for individual species ranged from 6.85 to 468 mg/l with an overall mean MTC of 101.82 mg/l for glyphosate and from 74.67 to 13,333 mg/l for 2,4-D giving an overall mean MTC of 2855.88 mg/l. Although the overall MTCs from the MARA bioassay were much higher than the LC50 s and EC50 s from the fish and daphnia bioassays respectively, the most sensitive MARA organism for each of the herbicides had MTCs that were comparable to or lower than the corresponding endpoints from the other bioassays implying that the MARA assay is a potentially useful bioassay for risk assessment of pesticides.

  16. Effective neutron targets

    SciTech Connect

    Gao, H.

    1997-07-01

    Because of the lack of a free neutron target, deuterium targets have been used extensively in studying the neutron structure. The unique spin structure of the {sup 3}He ground state wave function and the recent developments in laser technologies made polarized {sup 3}He targets widely used in many experiments from neutron electromagnetic form factor studies to nucleon spin structure function measurements at all major electron accelerator facilities. In this talk, the current status of the polarized {sup 3}He targets will be reviewed. The author will focus on neutron electromagnetic form factor studies using polarized {sup 3}He targets. The polarized nucleon spin structure function measurements using polarized {sup 3}He targets will also be discussed.

  17. Colon-targeted delivery of piceatannol enhances anti-colitic effects of the natural product: potential molecular mechanisms for therapeutic enhancement.

    PubMed

    Yum, Soohwan; Jeong, Seongkeun; Lee, Sunyoung; Nam, Joon; Kim, Wooseong; Yoo, Jin-Wook; Kim, Min-Soo; Lee, Bok Luel; Jung, Yunjin

    2015-01-01

    Piceatannol (PCT), an anti-colitic natural product, undergoes extensive Phase II hepatic metabolism, resulting in very low bioavailability. We investigated whether colon-targeted delivery of PCT could enhance anti-colitic effects and how therapeutic enhancement occurred at the molecular level. Molecular effects of PCT were examined in human colon carcinoma cells and inflamed colons. The anti-colitic effects of PCT in a colon-targeted capsule (colon-targeted PCT) were compared with PCT in a gelatin capsule (conventional PCT) in a trinitrobenzene sulfonic acid-induced rat colitis model. Colon-targeted PCT elicited greatly enhanced recovery of the colonic inflammation. In HCT116 cells, PCT inhibited nuclear factor kappaB while activating anti-colitic transcription factors, nuclear factor-erythroid 2 (NF-E2) p45-related factor 2, and hypoxia-inducible factor-1. Colon-targeted PCT, but not conventional PCT, modulated production of the target gene products of the transcription factors in the inflamed colonic tissues. Rectal administration of PCT, which simulates the therapeutic action of colon-targeted PCT, also ameliorated rat colitis and reproduced the molecular effects in the inflamed colonic tissues. Colon-targeted delivery increased therapeutic efficacy of PCT against colitis, likely resulting from multitargeted effects exerted by colon-targeted PCT. The drug delivery technique may be useful for therapeutic optimization of anti-colitic lead compounds including natural products.

  18. Assessing the potential for unintended effects in genetically modified potatoes perturbed in metabolic and developmental processes. Targeted analysis of key nutrients and anti-nutrients.

    PubMed

    Shepherd, Louise V T; McNicol, James W; Razzo, Ruth; Taylor, Mark A; Davies, Howard V

    2006-08-01

    Targeted compositional analysis was carried out on transgenic potato tubers of either cultivar (cv.) Record or cv. Desirée to assess the potential for unintended effects caused by the genetic modification process. The range of transgenic lines analysed included those modified in primary carbohydrate metabolism, polyamine biosynthesis and glycoprotein processing. Controls included wildtype tubers, tubers produced from plants regenerated through tissue culture (including a callus phase) and tubers derived from transformation with the 'empty vector' i.e. no specific target gene included (with the exception of the kanamycin resistance gene as a selectable marker). Metabolite analysis included soluble carbohydrates, glycoalkaloids, vitamin C, total nitrogen and fatty acids. Trypsin inhibitor activity was also assayed. These cover the major compounds recommended by the OECD in their Consensus Document on Compositional Considerations for New Varieties of Potatoes: Key Food and Feed Nutrients, Anti-Nutrients and Toxicants (2002). Data was statistically analysed using analysis of variance (ANOVA) for individual compounds and, where applicable, principal component analysis (PCA). In general, targeted compositional analysis revealed no consistent differences between GM lines and respective controls. No construct specifically induced unintended effects. Statistically significant differences between wildtype controls and specific GM lines did occur but appeared to be random and not associated with any specific construct. Indeed such significant differences were also found between wildtypes and both tissue culture derived tubers and tubers derived from transformation with the empty vector. This raises the possibility that somaclonal variation (known to occur significantly in potato, depending on genotype) may be responsible for an unknown proportion of any differences observed between specific GM lines and the wildtype. The most obvious differences seen in GC-MS profiles were

  19. TRP Channels as Potential Drug Targets.

    PubMed

    Moran, Magdalene M

    2017-09-25

    The transient receptor potential (TRP) superfamily of channels comprises a diverse group of cation channels. Four TRP channel subunits coassemble to form functional homo- or heterotetramers that pass sodium, calcium, or both in the inward direction. Modulating TRP channel activity provides an important way to impact cellular function by regulating both membrane excitability and intracellular calcium levels. The import of these channels is underscored by the number of genetic diseases caused when they are mutated: Skeletal, skin, sensory, ocular, cardiac, and neuronal disturbances all arise from aberrant TRP function. Not surprisingly, there has been significant pharmaceutical interest in targeting these fascinating channels. Compounds that modulate TRP vanilloid 1 (TRPV1), TRPV3, TRPV4, TRP ankyrin 1 (TRPA1), and TRP melastatin 8 (TRPM8) have all entered clinical trials. The goal of this review is to familiarize the readers with the rationale behind the pursuit of these channels in drug discovery and the status of those efforts. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 58 is January 6, 2018. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

  20. Potential tumor-tropic effect of genetically engineered stem cells expressing suicide enzymes to selectively target invasive cancer in animal models.

    PubMed

    Kim, Seung U; Jeung, Eui-Bae; Kim, Yun-Bae; Cho, Myung-Haing; Choi, Kyung-Chul

    2011-04-01

    Stem cells have recently received a great deal of attention for their clinical and therapeutic potential to treat human disease and disorders. For instance, neural stem cells expressing a suicide gene which can concert prodrugs to their active metabolites may have great tropic and therapeutic potential for brain tumors, i.e., medulloblastoma and glioma. We are currently interested in therapeutic potential of these genetically engineered stem cells (GESTECs) to selectively target invasive tumors, i.e. ovarian, endometrial, breast, and lung cancer which can have a great impact on human and animal health. Thus, in this review we summarize the therapeutic potential of GESTEC, developed by us, and the putative mechanism(s) underlying their therapeutic and tropic potential in expressing suicide genes which can convert prodrugs to their active metabolites and in selectively targeting invasive tumors.

  1. Protein tyrosine phosphatases as potential therapeutic targets

    PubMed Central

    He, Rong-jun; Yu, Zhi-hong; Zhang, Ruo-yu; Zhang, Zhong-yin

    2014-01-01

    Protein tyrosine phosphorylation is a key regulatory process in virtually all aspects of cellular functions. Dysregulation of protein tyrosine phosphorylation is a major cause of human diseases, such as cancers, diabetes, autoimmune disorders, and neurological diseases. Indeed, protein tyrosine phosphorylation-mediated signaling events offer ample therapeutic targets, and drug discovery efforts to date have brought over two dozen kinase inhibitors to the clinic. Accordingly, protein tyrosine phosphatases (PTPs) are considered next-generation drug targets. For instance, PTP1B is a well-known targets of type 2 diabetes and obesity, and recent studies indicate that it is also a promising target for breast cancer. SHP2 is a bona-fide oncoprotein, mutations of which cause juvenile myelomonocytic leukemia, acute myeloid leukemia, and solid tumors. In addition, LYP is strongly associated with type 1 diabetes and many other autoimmune diseases. This review summarizes recent findings on several highly recognized PTP family drug targets, including PTP1B, Src homology phosphotyrosyl phosphatase 2(SHP2), lymphoid-specific tyrosine phosphatase (LYP), CD45, Fas associated phosphatase-1 (FAP-1), striatal enriched tyrosine phosphatases (STEP), mitogen-activated protein kinase/dual-specificity phosphatase 1 (MKP-1), phosphatases of regenerating liver-1 (PRL), low molecular weight PTPs (LMWPTP), and CDC25. Given that there are over 100 family members, we hope this review will serve as a road map for innovative drug discovery targeting PTPs. PMID:25220640

  2. Target cell extraction coupled with LC-MS/MS analysis for screening potential bioactive components in Ginkgo biloba extract with preventive effect against diabetic nephropathy.

    PubMed

    Qiu, Jing-ying; Chen, Xu; Zheng, Xiao-xiao; Jiang, Xiang-lan; Yang, Dong-zhi; Yu, Yan-yan; Du, Qian; Tang, Dao-quan; Yin, Xiao-xing

    2015-02-01

    A rapid and useful approach for screening potential bioactive components in Ginkgo biloba extract (GBE) with preventive effect against diabetic nephropathy (DN) was developed using mesangial cells extraction coupled with high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis. Mesangial cells were first divided into two groups according to their treatments with high glucose or high glucose plus GBE. After incubation for 4, 8, 12, 16, 24 and 48 h, the cells were harvested and extracted with 40% acetic acid in water before LC-MS/MS analysis. Then, 19 compounds and five metabolites were found to selectively combine with mesangial cells. Notably, compounds including quercetin and rutin were identified or tentatively characterized according to the results of retention time and MS spectra, which is highly consistent with our previous reports that quercetin and rutin are potent protective agents against glomerulosclerosis in DN. Therefore, all these results indicate that target cell extraction coupled with LC-MS/MS analysis can be successfully applied for predicting the bioactive components in GBE with preventive effect against DN. Copyright © 2014 John Wiley & Sons, Ltd.

  3. Second-Generation Sequencing Supply an Effective Way to Screen RNAi Targets in Large Scale for Potential Application in Pest Insect Control

    PubMed Central

    Li, Haichao; Miao, Xuexia

    2011-01-01

    The key of RNAi approach success for potential insect pest control is mainly dependent on careful target selection and a convenient delivery system. We adopted second-generation sequencing technology to screen RNAi targets. Illumina's RNA-seq and digital gene expression tag profile (DGE-tag) technologies were used to screen optimal RNAi targets from Ostrinia furnalalis. Total 14690 stage specific genes were obtained which can be considered as potential targets, and 47 were confirmed by qRT-PCR. Ten larval stage specific expression genes were selected for RNAi test. When 50 ng/µl dsRNAs of the genes DS10 and DS28 were directly sprayed on the newly hatched larvae which placed on the filter paper, the larval mortalities were around 40∼50%, while the dsRNAs of ten genes were sprayed on the larvae along with artificial diet, the mortalities reached 73% to 100% at 5 d after treatment. The qRT-PCR analysis verified the correlation between larval mortality and the down-regulation of the target gene expression. Topically applied fluorescent dsRNA confirmed that dsRNA did penetrate the body wall and circulate in the body cavity. It seems likely that the combination of DGE-tag with RNA-seq is a rapid, high-throughput, cost less and an easy way to select the candidate target genes for RNAi. More importantly, it demonstrated that dsRNAs are able to penetrate the integument and cause larval developmental stunt and/or death in a lepidopteron insect. This finding largely broadens the target selection for RNAi from just gut-specific genes to the targets in whole insects and may lead to new strategies for designing RNAi-based technology against insect damage. PMID:21494551

  4. Second-generation sequencing supply an effective way to screen RNAi targets in large scale for potential application in pest insect control.

    PubMed

    Wang, Yubing; Zhang, Hao; Li, Haichao; Miao, Xuexia

    2011-04-11

    The key of RNAi approach success for potential insect pest control is mainly dependent on careful target selection and a convenient delivery system. We adopted second-generation sequencing technology to screen RNAi targets. Illumina's RNA-seq and digital gene expression tag profile (DGE-tag) technologies were used to screen optimal RNAi targets from Ostrinia furnalalis. Total 14690 stage specific genes were obtained which can be considered as potential targets, and 47 were confirmed by qRT-PCR. Ten larval stage specific expression genes were selected for RNAi test. When 50 ng/µl dsRNAs of the genes DS10 and DS28 were directly sprayed on the newly hatched larvae which placed on the filter paper, the larval mortalities were around 40∼50%, while the dsRNAs of ten genes were sprayed on the larvae along with artificial diet, the mortalities reached 73% to 100% at 5 d after treatment. The qRT-PCR analysis verified the correlation between larval mortality and the down-regulation of the target gene expression. Topically applied fluorescent dsRNA confirmed that dsRNA did penetrate the body wall and circulate in the body cavity. It seems likely that the combination of DGE-tag with RNA-seq is a rapid, high-throughput, cost less and an easy way to select the candidate target genes for RNAi. More importantly, it demonstrated that dsRNAs are able to penetrate the integument and cause larval developmental stunt and/or death in a lepidopteron insect. This finding largely broadens the target selection for RNAi from just gut-specific genes to the targets in whole insects and may lead to new strategies for designing RNAi-based technology against insect damage.

  5. Magnetic albumin immuno-nanospheres as an efficient gene delivery system for a potential use in lung cancer: preparation, in vitro targeting and biological effect analysis.

    PubMed

    Hou, Xinxin; Zhang, Hao; Li, Hongbo; Zhang, Dongsheng

    2016-01-01

    Magnetic albumin immuno-nanospheres (MAINs), simultaneously loaded with super-paramagnetic iron oxide nanoparticles for targeting application and anticancer gene, plasmid-survivin/shRNA (pshRNA) and modified with anti-EGFR monoclonal antibody Cetuximab for targeting and treatment agents, were prepared for targeting lung cancer. Transmission electron microscopy images and transfection photographs, respectively, showed that magnetic nanoparticles and pshRNA were successfully encased in the albumin nanospheres. The release profiles in vitro indicated that nanospheres had an obvious effect of sustained release of pshRNA. The results of slide agglutination test and immunofluorescence analysis demonstrated that the immuno-nanospheres retained the immuno-reactivity of Cetuximab. The MAINs significantly increased adherence and uptake by GLC-82 lung cancer cells over-expressed epidermal growth factor receptor over a magnetic albumin nanospheres (MANs) control. The pshRNA-loaded MAINs formulation was more effective than equimolar doses of free Cetuximab, single magnetic targeting with pshRNA (pshRNA-loaded MANs) or single monoclonal antibody targeting with pshRNA (pshRNA-loaded AINs) in the treatment of GLC-82 lung cancer cells. Collectively, the study indicates that the novel pshRNA-loaded magnetic immuno-nanospheres represent a promising approach for magnetic and monoclonal antibody-dependent gene targeting in lung cancer therapy.

  6. Sphingolipid and Ceramide Homeostasis: Potential Therapeutic Targets

    PubMed Central

    Young, Simon A.; Mina, John G.; Denny, Paul W.; Smith, Terry K.

    2012-01-01

    Sphingolipids are ubiquitous in eukaryotic cells where they have been attributed a plethora of functions from the formation of structural domains to polarized cellular trafficking and signal transduction. Recent research has identified and characterised many of the key enzymes involved in sphingolipid metabolism and this has led to a heightened interest in the possibility of targeting these processes for therapies against cancers, Alzheimer's disease, and numerous important human pathogens. In this paper we outline the major pathways in eukaryotic sphingolipid metabolism and discuss these in relation to disease and therapy for both chronic and infectious conditions. PMID:22400113

  7. Wake potential of swift ion in amorphous carbon target

    NASA Astrophysics Data System (ADS)

    Al-Bahnam, Nabil janan; Ahmad, Khalid A.; Aboo Al-Numan, Abdullah Ibrahim

    2017-02-01

    The wake potential and wake phenomena for swift proton in an amorphous carbon target were studied by utilising various dielectric function formalisms, including the Drude dielectric function, the Drude-Lorentz dielectric function and quantum dielectric function. The Drude model results exhibited a damped oscillatory behaviour in the longitudinal direction behind the projectile; the pattern of these oscillations decreases exponentially in the transverse direction. In addition, the wake potential extends slightly ahead of the projectile which also depends on the proton coordinate and velocity. The effect of electron binding on the wake potential, characterised by the ratio ωp2 / ω02 = 10 to 0.1, has been studied alongside the Drude-Lorentz dielectric function and quantum dielectric function formalisms; the results evidently show that the wake potential dip depth decreases with more oscillations when the electron density ratio ωp2 / ω02 decreases from 10 to 0.1. One of the primary objectives of the present work is to construct a reasonably realistic procedure for simulating the response of target to swift ions by combining an expression for the induced wake potential along with several important dielectric function models; the aim of this research is to reduce computational complexity without sacrificing accuracy. This is regarded as being an efficient strategy in that it creates suitable computer simulation procedures which are relevant to actual solids. After comparing this method with other models, the main differences and similarities have been noted while the end results have proved encouraging.

  8. Molecular Mechanisms of Diabetic Retinopathy: Potential Therapeutic Targets

    PubMed Central

    Coucha, Maha; Elshaer, Sally L.; Eldahshan, Wael S.; Mysona, Barbara A.; El-Remessy, Azza B.

    2015-01-01

    Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults in United States. Research indicates an association between oxidative stress and the development of diabetes complications. However, clinical trials with general antioxidants have failed to prove effective in diabetic patients. Mounting evidence from experimental studies that continue to elucidate the damaging effects of oxidative stress and inflammation in both vascular and neural retina suggest its critical role in the pathogenesis of DR. This review will outline the current management of DR as well as present potential experimental therapeutic interventions, focusing on molecules that link oxidative stress to inflammation to provide potential therapeutic targets for treatment or prevention of DR. Understanding the biochemical changes and the molecular events under diabetic conditions could provide new effective therapeutic tools to combat the disease. PMID:25949069

  9. ING Proteins as Potential Anticancer Drug Targets

    PubMed Central

    Unoki, M.; Kumamoto, K.; Harris, C.C.

    2009-01-01

    Recent emerging evidence suggests that ING family proteins play roles in carcinogenesis both as oncogenes and tumor suppressor genes depending on the family members and on cell status. Previous results from non-physiologic overexpression experiments showed that all five family members induce apoptosis or cell cycle arrest, thus it had been thought until very recently that all of the family members function as tumor suppressor genes. Therefore restoration of ING family proteins in cancer cells has been proposed as a treatment for cancers. However, ING2 knockdown experiments showed unexpected results: ING2 knockdown led to senescence in normal human fibroblast cells and suppressed cancer cell growth. ING2 is also overexpressed in colorectal cancer, and promotes cancer cell invasion through an MMP13 dependent pathway. Additionally, it was reported that ING2 has two isoforms, ING2a and ING2b. Although expression of ING2a predominates compared with ING2b, both isoforms confer resistance against cell cycle arrest or apoptosis to cancer cells, thus knockdown of both isoforms is critical to remove this resistance. Taken together, these results suggest that ING2 can function as an oncogene in some specific types of cancer cells, indicating restoration of this gene in cancer cells could cause cancer progression. Because knockdown of ING2 suppresses cancer cell invasion and induces apoptosis or cell cycle arrest, ING2 may be an anticancer drug target. In this brief review, we discuss possible clinical applications of ING2 with the latest knowledge of molecular targeted therapies. PMID:19442116

  10. Hydrogen Peroxide: A Potential Wound Therapeutic Target.

    PubMed

    Zhu, Guanya; Wang, Qi; Lu, Shuliang; Niu, Yiwen

    2017-04-05

    Hydrogen peroxide (H2O2) is a topical antiseptic used in wound cleaning which kills pathogens through oxidation burst and local oxygen production. Hydrogen peroxide had been reported to be a reactive biochemical molecule synthesized by various cells which influences biological behavior through multiple mechanisms: alterations of membrane potential, generation of new molecules and changing intracellular redox balance which results in activation or inactivation of different signaling transduction pathways. Contrary to the traditional viewpoint that H2O2 probably impairs tissue through its high oxidative property, however, a proper level of H2O2 is considered as an important requirement for normal wound healing. Although the present clinical use of H2O2 is still limited to the elimination of microbial contamination and sometimes hemostasis, better understanding towards the sterilization ability and cell behavior regulatory function of H2O2 within wound will enhance the potential to exogenously augment and manipulate healing.

  11. Characterization of a Conjugate between Rose Bengal and Chitosan for Targeted Antibiofilm and Tissue Stabilization Effects as a Potential Treatment of Infected Dentin

    PubMed Central

    Shrestha, Annie; Hamblin, Michael R.

    2012-01-01

    Bacterial biofilms and dentin structural changes are some of the major challenges in the management of infected dentin tissue. This study characterized a photosensitizer-conjugated chitosan with enhanced photodynamic efficacy against dental biofilms, as well as the ability to reinforce the postinfected dentin matrix in order to improve its mechanical and chemical stability. Rose Bengal-conjugated chitosan (CSRB) was synthesized using a chemical cross-linking method and characterized for photophysical, photobiological, and cytotoxicity properties. Its potential as an antibacterial and matrix-reinforcing agent on dentin collagen was also evaluated. Enterococcus faecalis as planktonic and in vitro biofilms was treated with CSRB and photodynamically activated with 5 to 60 J/cm2 green light. Dentin collagen was used for the CSRB cross-linking experiments and evaluated for chemical changes, resistance to enzymatic degradation, and mechanical properties. CSRB was a photosensitizer with efficient singlet oxygen yield. In vitro photoactivation gave higher fibroblast cell survival than did RB alone. CSRB showed significant antibiofilm photoinactivation (P < 0.01). The CSRB-cross-linked dentin collagen showed higher resistance to collagenase degradation and superior mechanical properties (P < 0.05). In summary, the photoactivated CSRB particles synthesized in this study may be a synergistic multifunctional treatment approach with lower cytotoxicity and effective antibiofilm activity as well as the ability to reinforce the dentin collagen to enhance resistance to degradation and improve mechanical properties. This may be a targeted treatment strategy to deal with infected dentin hard tissues in a clinical scenario, where both disinfection and structural integrity need to be addressed concomitantly. PMID:22777042

  12. Suitability of two root-mining weevils for the biological control of scentless chamomile, Tripleurospermum perforatum, with special regard to potential non-target effects.

    PubMed

    Hinz, H L; Müller-Schärer, H

    2000-12-01

    The biology and host range of the two root-mining weevils Diplapion confluens Kirby and Coryssomerus capucinus (Beck), two potential agents for the biological control of scentless chamomile Tripleurospermum perforatum (Mérat) Laínz, were studied in the field in southern Germany and eastern Austria, and in a common garden and under laboratory conditions in Delémont, Switzerland from 1993 to 1999. Both weevils were univoltine, and females started to lay eggs in early spring. Diplapion confluens had three and C. capucinus five instars. Larvae of both species were found in the field from mid-April until the end of July; later instars preferentially fed in the vascular cylinder of the shoot base, root crown or root. Although larvae of both species occupy the same temporal and spatial niche within their host plants, they occurred at all investigated field sites together, and showed a similar distribution within sites. No negative or positive interspecific association was detected. Host-specificity tests including no-choice, single-choice, and multiple-choice tests under confined conditions, as well as tests under field conditions with natural and augmented insect densities revealed that both herbivores were specific to plant species in the tribe Anthemideae. However, their development to mature larva or adult on several cultivated plants, as well as on one plant species native to North America, rendered them unsuitable for field release in North America. It was concluded that to investigate non-target effects reliably, host-specificity tests with biological control agents should be carried out under a variety of conditions, particularly with augmented insect densities, as are expected to occur naturally after release.

  13. Androgen receptor in human health: a potential therapeutic target.

    PubMed

    Siddique, Hifzur Rahman; Nanda, Sanjeev; Parray, Aijaz; Saleem, Mohammad

    2012-12-01

    Androgen is a key for the activation of Androgen Receptor (AR) in most of the disease conditions, however androgen-independent activation of AR is also found in aggressive type human malignancies. An intense search for the inhibitors of AR is underway to cure AR-dependent diseases. In addition to targeting various components of AR signaling pathway, compounds which directly target AR are under preclinical and clinical investigation. Various In vitro and preclinical animal studies suggest that different natural compounds have potential to act against AR. Some natural compounds have been found to be pharmacologically effective against AR irrespective of varying routs of administration viz; oral, intra-peritoneal and intravenous. This mini-review summarizes the studies conducted with different natural agents in determining their pharmacological utility against AR signaling.

  14. Targeting PARP-1 allosteric regulation offers therapeutic potential against cancer

    PubMed Central

    Steffen, Jamin D.; Tholey, Renee M.; Langelier, Marie-France; Planck, Jamie L.; Schiewer, Matthew J.; Lal, Shruti; Bildzukewicz, Nikolai A.; Yeo, Charles J.; Knudsen, Karen E.; Brody, Jonathan R.; Pascal, John M.

    2014-01-01

    PARP-1 is a nuclear protein that has important roles in maintenance of genomic integrity. During genotoxic stress, PARP-1 recruits to sites of DNA damage where PARP-1 domain architecture initiates catalytic activation and subsequent poly(ADP-ribose)-dependent DNA repair. PARP-1 inhibition is a promising new way to selectively target cancers harboring DNA repair deficiencies. However, current inhibitors target other PARPs raising important questions concerning long-term off-target effects. Here we propose a new strategy that targets PARP-1 allosteric regulation as a selective way of inhibiting PARP-1. We found that disruption of PARP-1 domain-domain contacts through mutagenesis held no cellular consequences on recruitment to DNA damage or a model system of transcriptional regulation, but prevented DNA-damage dependent catalytic activation. Further, PARP-1 mutant overexpression in a pancreatic cancer cell line (MIA PaCa-2) increased sensitivity to platinum-based anti-cancer agents. These results not only highlight the potential of a synergistic drug combination of allosteric PARP inhibitors with DNA damaging agents in genomically unstable cancer cells (regardless of homologous recombination status), but also signify important applications of selective PARP-1 inhibition. Lastly, the development of a high-throughput (HT) PARP-1 assay is described as a tool to promote discovery of novel PARP-1 selective inhibitors. PMID:24189460

  15. Targeting PARP-1 allosteric regulation offers therapeutic potential against cancer.

    PubMed

    Steffen, Jamin D; Tholey, Renee M; Langelier, Marie-France; Planck, Jamie L; Schiewer, Matthew J; Lal, Shruti; Bildzukewicz, Nikolai A; Yeo, Charles J; Knudsen, Karen E; Brody, Jonathan R; Pascal, John M

    2014-01-01

    PARP-1 is a nuclear protein that has important roles in maintenance of genomic integrity. During genotoxic stress, PARP-1 recruits to sites of DNA damage where PARP-1 domain architecture initiates catalytic activation and subsequent poly(ADP-ribose)-dependent DNA repair. PARP-1 inhibition is a promising new way to selectively target cancers harboring DNA repair deficiencies. However, current inhibitors target other PARPs, raising important questions about long-term off-target effects. Here, we propose a new strategy that targets PARP-1 allosteric regulation as a selective way of inhibiting PARP-1. We found that disruption of PARP-1 domain-domain contacts through mutagenesis held no cellular consequences on recruitment to DNA damage or a model system of transcriptional regulation, but prevented DNA-damage-dependent catalytic activation. Furthermore, PARP-1 mutant overexpression in a pancreatic cancer cell line (MIA PaCa-2) increased sensitivity to platinum-based anticancer agents. These results not only highlight the potential of a synergistic drug combination of allosteric PARP inhibitors with DNA-damaging agents in genomically unstable cancer cells (regardless of homologous recombination status), but also signify important applications of selective PARP-1 inhibition. Finally, the development of a high-throughput PARP-1 assay is described as a tool to promote discovery of novel PARP-1 selective inhibitors.

  16. TLRs, future potential therapeutic targets for RA.

    PubMed

    Elshabrawy, Hatem A; Essani, Abdul E; Szekanecz, Zoltán; Fox, David A; Shahrara, Shiva

    2017-02-01

    Toll like receptors (TLR)s have a central role in regulating innate immunity and in the last decade studies have begun to reveal their significance in potentiating autoimmune diseases such as rheumatoid arthritis (RA). Earlier investigations have highlighted the importance of TLR2 and TLR4 function in RA pathogenesis. In this review, we discuss the newer data that indicate roles for TLR5 and TLR7 in RA and its preclinical models. We evaluate the pathogenicity of TLRs in RA myeloid cells, synovial tissue fibroblasts, T cells, osteoclast progenitor cells and endothelial cells. These observations establish that ligation of TLRs can transform RA myeloid cells into M1 macrophages and that the inflammatory factors secreted from M1 and RA synovial tissue fibroblasts participate in TH-17 cell development. From the investigations conducted in RA preclinical models, we conclude that TLR-mediated inflammation can result in osteoclastic bone erosion by interconnecting the myeloid and TH-17 cell response to joint vascularization. In light of emerging unique aspects of TLR function, we summarize the novel approaches that are being tested to impair TLR activation in RA patients. Copyright © 2016 Elsevier B.V. All rights reserved.

  17. Neutrophils: potential therapeutic targets in tularemia?

    PubMed Central

    Allen, Lee-Ann H.

    2013-01-01

    The central role of neutrophils in innate immunity and host defense has long been recognized, and the ability of these cells to efficiently engulf and kill invading bacteria has been extensively studied, as has the role of neutrophil apoptosis in resolution of the inflammatory response. In the past few years additional immunoregulatory properties of neutrophils were discovered, and it is now clear that these cells play a much greater role in control of the immune response than was previously appreciated. In this regard, it is noteworthy that Francisella tularensis is one of relatively few pathogens that can successfully parasitize neutrophils as well as macrophages, DC and epithelial cells. Herein we will review the mechanisms used by F. tularensis to evade elimination by neutrophils. We will also reprise effects of this pathogen on neutrophil migration and lifespan as compared with other infectious and inflammatory disease states. In addition, we will discuss the evidence which suggests that neutrophils contribute to disease progression rather than effective defense during tularemia, and consider whether manipulation of neutrophil migration or turnover may be suitable adjunctive therapeutic strategies. PMID:24409419

  18. Schistosoma mansoni Sirtuins: Characterization and Potential as Chemotherapeutic Targets

    PubMed Central

    Lancelot, Julien; Caby, Stéphanie; Dubois-Abdesselem, Florence; Vanderstraete, Mathieu; Trolet, Jacques; Oliveira, Guilherme; Bracher, Franz; Jung, Manfred; Pierce, Raymond J.

    2013-01-01

    Background The chemotherapy of schistosomiasis currently depends on the use of a single drug, praziquantel. In order to develop novel chemotherapeutic agents we are investigating enzymes involved in the epigenetic modification of chromatin. Sirtuins are NAD+ dependent lysine deacetylases that are involved in a wide variety of cellular processes including histone deacetylation, and have been demonstrated to be therapeutic targets in various pathologies, including cancer. Methodology, Principal Findings In order to determine whether Schistosoma mansoni sirtuins are potential therapeutic targets we first identified and characterized their protein sequences. Five sirtuins (SmSirt) are encoded in the S. mansoni genome and phylogenetic analysis showed that they are orthologues of mammalian Sirt1, Sirt2, Sirt5, Sirt6 and Sirt7. Both SmSirt1 and SmSirt7 have large insertion in the catalytic domain compared to their mammalian orthologues. SmSirt5 is the only mitochondrial sirtuin encoded in the parasite genome (orthologues of Sirt3 and Sirt4 are absent) and transcripts corresponding to at least five splicing isoforms were identified. All five sirtuins are expressed throughout the parasite life-cycle, but with distinct patterns of expression. Sirtuin inhibitors were used to treat both schistosomula and adult worms maintained in culture. Three inhibitors in particular, Sirtinol, Salermide and MS3 induced apoptosis and death of schistosomula, the separation of adult worm pairs, and a reduction in egg laying. Moreover, Salermide treatment led to a marked disruption of the morphology of ovaries and testes. Transcriptional knockdown of SmSirt1 by RNA interference in adult worms led to morphological changes in the ovaries characterized by a marked increase in mature oocytes, reiterating the effects of sirtuin inhibitors and suggesting that SmSirt1 is their principal target. Conclusion, Significance Our data demonstrate the potential of schistosome sirtuins as therapeutic targets

  19. Macrophages associated with tumors as potential targets and therapeutic intermediates

    PubMed Central

    Vinogradov, Serguei; Warren, Galya; Wei, Xin

    2014-01-01

    Tumor-associated macrophages (TAMs) form approximately 50% of tumor mass. TAMs were shown to promote tumor growth by suppressing immunocompetent cells, inducing neovascularization and supporting cancer stem cells. TAMs retain mobility in tumor mass, which can potentially be employed for better intratumoral biodistribution of nanocarriers and effective tumor growth inhibition. Due to the importance of TAMs, they are increasingly becoming principal targets of novel therapeutic approaches. In this review, we compare features of macrophages and TAMs that are essential for TAM-directed therapies, and illustrate the advantages of nanomedicine that are related to the preferential capture of nanocarriers by Mφ in the process of drug delivery. We discuss recent efforts in reprogramming or inhibiting tumor-protecting properties of TAMs, and potential strategies to increase efficacy of conventional chemotherapy by combining with macrophage-associated delivery of nanodrugs. PMID:24827844

  20. Macrophages associated with tumors as potential targets and therapeutic intermediates.

    PubMed

    Vinogradov, Serguei; Warren, Galya; Wei, Xin

    2014-04-01

    Tumor-associated macrophages (TAMs) form approximately 50% of tumor mass. TAMs were shown to promote tumor growth by suppressing immunocompetent cells, inducing neovascularization and supporting cancer stem cells. TAMs retain mobility in tumor mass, which can potentially be employed for better intratumoral biodistribution of nanocarriers and effective tumor growth inhibition. Due to the importance of TAMs, they are increasingly becoming principal targets of novel therapeutic approaches. In this review, we compare features of macrophages and TAMs that are essential for TAM-directed therapies, and illustrate the advantages of nanomedicine that are related to the preferential capture of nanocarriers by Mϕ in the process of drug delivery. We discuss recent efforts in reprogramming or inhibiting tumor-protecting properties of TAMs, and potential strategies to increase efficacy of conventional chemotherapy by combining with macrophage-associated delivery of nanodrugs.

  1. Potential targets for intervention in radiation-induced heart disease.

    PubMed

    Boerma, M; Hauer-Jensen, M

    2010-11-01

    Radiotherapy of thoracic and chest wall tumors, if all or part of the heart was included in the radiation field, can lead to radiation-induced heart disease (RIHD), a late and potentially severe side effect. RIHD presents clinically several years after irradiation and manifestations include accelerated atherosclerosis, pericardial and myocardial fibrosis, conduction abnormalities, and injury to cardiac valves. The pathogenesis of RIHD is largely unknown, and a treatment is not available. Hence, ongoing pre-clinical studies aim to elucidate molecular and cellular mechanisms of RIHD. Here, an overview of recent pre-clinical studies is given, and based on the results of these studies, potential targets for intervention in RIHD are discussed.

  2. The effects of foreknowledge and task-set shifting as mirrored in cue- and target-locked event-related potentials.

    PubMed

    Finke, Mareike; Escera, Carles; Barceló, Francisco

    2012-01-01

    The present study examined the use of foreknowledge in a task-cueing protocol while manipulating sensory updating and executive control in both, informatively and non-informatively pre-cued trials. Foreknowledge, sensory updating (cue switch effects) and task-switching were orthogonally manipulated in order to address the question of whether, and to which extent, the sensory processing of cue changes can partly or totally explain the final task switch costs. Participants responded faster when they could prepare for the upcoming task and if no task-set updating was necessary. Sensory cue switches influenced cue-locked ERPs only when they contained conceptual information about the upcoming task: frontal P2 amplitudes were modulated by task-relevant cue changes, mid-parietal P3 amplitudes by the anticipatory updating of stimulus-response mappings, and P3 peak latencies were modulated by task switching. Task preparation was advantageous for efficient stimulus-response re-mapping at target-onset as mirrored in target N2 amplitudes. However, N2 peak latencies indicate that this process is faster for all repeat trials. The results provide evidence to support a very fast detection of task-relevance in sensory (cue) changes and argue against the view of task repetition benefits as secondary to purely perceptual repetition priming. Advanced preparation may have a stronger influence on behavioral performance and target-locked brain activity than the local effect of repeating or switching the task-set in the current trial.

  3. Cardiac calmodulin kinase: a potential target for drug design.

    PubMed

    Bányász, T; Szentandrássy, N; Tóth, A; Nánási, P P; Magyar, J; Chen-Izu, Y

    2011-01-01

    Therapeutic strategy for cardiac arrhythmias has undergone a remarkable change during the last decades. Currently implantable cardioverter defibrillator therapy is considered to be the most effective therapeutic method to treat malignant arrhythmias. Some even argue that there is no room for antiarrhythmic drug therapy in the age of implantable cardioverter defibrillators. However, in clinical practice, antiarrhythmic drug therapies are frequently needed, because implantable cardioverter defibrillators are not effective in certain types of arrhythmias (i.e. premature ventricular beats or atrial fibrillation). Furthermore, given the staggering cost of device therapy, it is economically imperative to develop alternative effective treatments. Cardiac ion channels are the target of a number of current treatment strategies, but therapies based on ion channel blockers only resulted in moderate success. Furthermore, these drugs are associated with an increased risk of proarrhythmia, systemic toxicity, and increased defibrillation threshold. In many cases, certain ion channel blockers were found to increase mortality. Other drug classes such as ßblockers, angiotensin-converting enzyme inhibitors, aldosterone antagonists, and statins appear to have proven efficacy for reducing cardiac mortality. These facts forced researchers to shift the focus of their research to molecular targets that act upstream of ion channels. One of these potential targets is calcium/calmodulin-dependent kinase II (CaMKII). Several lines of evidence converge to suggest that CaMKII inhibition may provide an effective treatment strategy for heart diseases. (1) Recent studies have elucidated that CaMKII plays a key role in modulating cardiac function and regulating hypertrophy development. (2) CaMKII activity has been found elevated in the failing hearts from human patients and animal models. (3) Inhibition of CaMKII activity has been shown to mitigate hypertrophy, prevent functional remodeling and

  4. Cardiac Calmodulin Kinase: A Potential Target for Drug Design

    PubMed Central

    Bányász, T.; Szentandrássy, N.; Tóth, A.; Nánási, P.P.; Magyar, J.; Chen-Izu, Y.

    2014-01-01

    Therapeutic strategy for cardiac arrhythmias has undergone a remarkable change during the last decades. Currently implantable cardioverter defibrillator therapy is considered to be the most effective therapeutic method to treat malignant arrhythmias. Some even argue that there is no room for antiarrhythmic drug therapy in the age of implantable cardioverter defibrillators. However, in clinical practice, antiarrhythmic drug therapies are frequently needed, because implantable cardioverter defibrillators are not effective in certain types of arrhythmias (i.e. premature ventricular beats or atrial fibrillation). Furthermore, given the staggering cost of device therapy, it is economically imperative to develop alternative effective treatments. Cardiac ion channels are the target of a number of current treatment strategies, but therapies based on ion channel blockers only resulted in moderate success. Furthermore, these drugs are associated with an increased risk of proarrhythmia, systemic toxicity, and increased defibrillation threshold. In many cases, certain ion channel blockers were found to increase mortality. Other drug classes such as β-blockers, angiotensin-converting enzyme inhibitors, aldosterone antagonists, and statins appear to have proven efficacy for reducing cardiac mortality. These facts forced researchers to shift the focus of their research to molecular targets that act upstream of ion channels. One of these potential targets is calcium/calmodulin-dependent kinase II (CaMKII). Several lines of evidence converge to suggest that CaMKII inhibition may provide an effective treatment strategy for heart diseases. (1) Recent studies have elucidated that CaMKII plays a key role in modulating cardiac function and regulating hypertrophy development. (2) CaMKII activity has been found elevated in the failing hearts from human patients and animal models. (3) Inhibition of CaMKII activity has been shown to mitigate hypertrophy, prevent functional remodeling and

  5. TCGA bladder cancer study reveals potential drug targets

    Cancer.gov

    Investigators with TCGA have identified new potential therapeutic targets for a major form of bladder cancer, including important genes and pathways that are disrupted in the disease. They also discovered that, at the molecular level, some subtypes of bla

  6. TCGA Bladder Cancer Study Reveals Potential Drug Targets - TCGA

    Cancer.gov

    Investigators with the TCGA Research Network have identified new potential therapeutic targets for a major form of bladder cancer, including important genes and pathways that are disrupted in the disease.

  7. Structure-Based Development of Small Molecule PFKFB3 Inhibitors: A Framework for Potential Cancer Therapeutic Agents Targeting the Warburg Effect

    SciTech Connect

    Seo, Minsuh; Kim, Jeong-Do; Neau, David; Sehgal, Inder; Lee, Yong-Hwan

    2012-02-10

    Cancer cells adopt glycolysis as the major source of metabolic energy production for fast cell growth. The HIF-1-induced PFKFB3 plays a key role in this adaptation by elevating the concentration of Fru-2,6-BP, the most potent glycolysis stimulator. As this metabolic conversion has been suggested to be a hallmark of cancer, PFKFB3 has emerged as a novel target for cancer chemotherapy. Here, we report that a small molecular inhibitor, N4A, was identified as an initial lead compound for PFKFB3 inhibitor with therapeutic potential. In an attempt to improve its potency, we determined the crystal structure of the PFKFB3 {sm_bullet} N4A complex to 2.4 {angstrom} resolution and, exploiting the resulting molecular information, attained the more potent YN1. When tested on cultured cancer cells, both N4A and YN1 inhibited PFKFB3, suppressing the Fru-2,6-BP level, which in turn suppressed glycolysis and, ultimately, led to cell death. This study validates PFKFB3 as a target for new cancer therapies and provides a framework for future development efforts.

  8. Using Click Chemistry to Identify Potential Drug Targets in Plasmodium

    DTIC Science & Technology

    2016-06-01

    AWARD NUMBER: W81XWH-13-1-0429 TITLE: Using "Click Chemistry " to Identify Potential Drug Targets in Plasmodium PRINCIPAL INVESTIGATOR...29Mar2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-13-1-0429 Using click chemistry to identify potential drug targets in Plasmodium 5b...Al-Tsp derivatives begins. Two classes of Tsp derivatives (Al-Tsp) are appropriate for click chemistry (Fig. 1). Class I derivatives carry a

  9. Deep brain stimulation in Huntington's disease: assessment of potential targets.

    PubMed

    Sharma, Mayur; Deogaonkar, Milind

    2015-05-01

    Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder that has very few effective therapeutic interventions. Since the disease has a defined neural circuitry abnormality, neuromodulation could be an option. Case reports, original research, and animal model studies were selected from the databases of Medline and PubMed. All related studies published up to July 2014 were included in this review. The following search terms were used: "Deep brain stimulation," "DBS," "thalamotomy," "pallidal stimulation," and "Huntington's Disease," "HD," "chorea," or "hyperkinetic movement disorders." This review examines potential nodes in the HD circuitry that could be modulated using deep brain stimulation (DBS) therapy. With rapid evolution of imaging and ability to reach difficult targets in the brain with refined DBS technology, some phenotypes of HD could potentially be treated with DBS in the near future. Further clinical studies are warranted to validate the efficacy of neuromodulation and to determine the most optimal target for HD. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. MicroRNAs and Potential Targets in Osteosarcoma: Review

    PubMed Central

    Sampson, Valerie B.; Yoo, Soonmoon; Kumar, Asmita; Vetter, Nancy S.; Kolb, E. Anders

    2015-01-01

    Osteosarcoma is the most common bone cancer in children and young adults. Surgery and multi-agent chemotherapy are the standard treatment regimens for this disease. New therapies are being investigated to improve overall survival in patients. Molecular targets that actively modulate cell processes, such as cell-cycle control, cell proliferation, metabolism, and apoptosis, have been studied, but it remains a challenge to develop novel, effective-targeted therapies to treat this heterogeneous and complex disease. MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in regulating cell processes including growth, development, and disease. miRNAs function as oncogenes or tumor suppressors to regulate gene and protein expression. Several studies have demonstrated the involvement of miRNAs in the pathogenesis of osteosarcoma with the potential for development in disease diagnostics and therapeutics. In this review, we discuss the current knowledge on the role of miRNAs and their target genes and evaluate their potential use as therapeutic agents in osteosarcoma. We also summarize the efficacy of inhibition of oncogenic miRNAs or expression of tumor suppressor miRNAs in preclinical models of osteosarcoma. Recent progress on systemic delivery as well as current applications for miRNAs as therapeutic agents has seen the advancement of miR-34a in clinical trials for adult patients with non-resectable primary liver cancer or metastatic cancer with liver involvement. We suggest a global approach to the understanding of the pathogenesis of osteosarcoma may identify candidate miRNAs as promising biomarkers for this rare disease. PMID:26380245

  11. Alveolar bone loss: mechanisms, potential therapeutic targets, and interventions.

    PubMed

    Intini, G; Katsuragi, Y; Kirkwood, K L; Yang, S

    2014-05-01

    This article reviews recent research into mechanisms underlying bone resorption and highlights avenues of investigation that may generate new therapies to combat alveolar bone loss in periodontitis. Several proteins, signaling pathways, stem cells, and dietary supplements are discussed as they relate to periodontal bone loss and regeneration. RGS12 is a crucial protein that mediates osteoclastogenesis and bone destruction, and a potential therapeutic target. RGS12 likely regulates osteoclast differentiation through regulating calcium influx to control the calcium oscillation-NFATc1 pathway. A working model for RGS10 and RGS12 in the regulation of Ca(2+) oscillations during osteoclast differentiation is proposed. Initiation of inflammation depends on host cell-microbe interactions, including the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Oral p38 inhibitors reduced lipopolysaccharide (LPS)-induced bone destruction in a rat periodontitis model but showed unsatisfactory safety profiles. The p38 substrate MK2 is a more specific therapeutic target with potentially superior tolerability. Furthermore, MKP-1 shows anti-inflammatory activity, reducing inflammatory cytokine biosynthesis and bone resorption. Multipotent skeletal stem cell (SSC) populations exist within the bone marrow and periosteum of long bones. These bone-marrow-derived SSCs and periosteum-derived SSCs have shown therapeutic potential in several applications, including bone and periodontal regeneration. The existence of craniofacial bone-specific SSCs is suggested based on existing studies. The effects of calcium, vitamin D, and soy isoflavone supplementation on alveolar and skeletal bone loss in post-menopausal women were investigated. Supplementation resulted in stabilization of forearm bone mass density and a reduced rate of alveolar bone loss over 1 yr, compared with placebo. Periodontal attachment levels were also well-maintained and alveolar bone loss suppressed during 24 wk of

  12. TRPV1 Channel: A Potential Drug Target for Treating Epilepsy

    PubMed Central

    Nazıroğlu, Mustafa

    2015-01-01

    Epilepsy has 2-3% incidence worldwide. However, present antiepileptic drugs provide only partial control of seizures. Calcium ion accumulation in hippocampal neurons has long been known as a major contributor to the etiology of epilepsy. TRPV1 is a calcium-permeable channel and mediator of epilepsy in the hippocampus. TRPV1 is expressed in epileptic brain areas such as CA1 area and dentate gyrus of the hippocampus. Here the author reviews the patent literature on novel molecules targeting TRPV1 that are currently being investigated in the laboratory and are candidates for future clinical evaluation in the management of epilepsy. A limited number of recent reports have implicated TRPV1 in the induction or treatment of epilepsy suggesting that this may be new area for potential drugs targeting this debilitating disease. Thus activation of TRPV1 by oxidative stress, resiniferatoxin, cannabinoid receptor (CB1) activators (i.e. anandamide) or capsaicin induced epileptic effects, and these effects could be reduced by appropriate inhibitors, including capsazepine (CPZ), 5'-iodoresiniferatoxin (IRTX), resolvins, and CB1 antagonists. It has been also reported that CPZ and IRTX reduced spontaneous excitatory synaptic transmission through modulation of glutaminergic systems and desensitization of TRPV1 channels in the hippocampus of rats. Immunocytochemical studies indicated that TRPV1 channel expression increased in the hippocampus of mice and patients with temporal lobe epilepsy Taken together, findings in the current literature support a role for calcium ion accumulation through TRPV1 channels in the etiology of epileptic seizures, indicating that inhibition of TRPV1 in the hippocampus may possibly be a novel target for prevention of epileptic seizures. PMID:26411767

  13. FAK and paxillin, two potential targets in pancreatic cancer

    PubMed Central

    Kanteti, Rajani; Batra, Surinder K.; Lennon, Frances E.; Salgia, Ravi

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer in large part due to late diagnosis and a lack of effective screening tests. In spite of recent progress in imaging, surgery and new therapeutic options for pancreatic cancer, the overall five-year survival still remains unacceptably low. Numerous studies have shown that focal adhesion kinase (FAK) is activated in many cancers including PDAC and promotes cancer progression and metastasis. Paxillin, an intracellular adaptor protein that plays a key role in cytoskeletal organization, connects integrins to FAK and plays a key role in assembly and disassembly of focal adhesions. Here, we have reviewed evidence in support of FAK as a potential therapeutic target and summarized related combinatorial therapies. PMID:26980710

  14. Combretastatin A-4 and Derivatives: Potential Fungicides Targeting Fungal Tubulin.

    PubMed

    Ma, Zhong-lin; Yan, Xiao-jing; Zhao, Lei; Zhou, Jiu-jiu; Pang, Wan; Kai, Zhen-peng; Wu, Fan-hong

    2016-02-03

    Combretastatin A-4, first isolated from the African willow tree Combretum caffrum, is a tubulin polymerization inhibitor in medicine. It was first postulated as a potential fungicide targeting fungal tubulin for plant disease control in this study. Combretastatin A-4 and its derivatives were synthesized and tested against Rhizoctonia solani and Pyricularia oryzae. Several compounds have EC50 values similar to or better than that of isoprothiolane, which is widely used for rice disease control. Structure-activity relationship study indicated the the cis configuration and hydroxyl group in combretastatin A-4 are crucial to the antifungal effect. Molecular modeling indicated the binding sites of combretastatin A-4 and carbendazim on fungal tubulin are totally different. The bioactivity of combretastatin A-4 and its derivatives against carbendazim-resistant strains was demonstrated in this study. The results provide a new approach for fungicide discovery and fungicide resistance management.

  15. Alzheimer's associated inflammation, potential drug targets and future therapies.

    PubMed

    Stuchbury, G; Münch, G

    2005-03-01

    Alzheimer's disease is the most common cause of dementia in the elderly population. The most widely used treatment for Alzheimer's disease at present is acetylcholinesterase inhibitors, which aim to prolong cognitive function through increased synaptic activity, without providing neuroprotection. This treatment is only symptomatic and provides modest outcomes for patients. The recent elucidation of the inflammatory pathways involved in Alzheimer's disease however, has opened doors for better treatment and prevention by identification of areas of therapeutic intervention that target the cause of the disease rather than the symptoms. This review describes the inflammatory pathways that are thought to be present in Alzheimer's disease and some of the new therapies that have shown promise, via alteration or inhibition of these pathways. Some of the therapies included in this review, which have already demonstrated beneficial effects in the treatment of Alzheimer's disease, or have the potential to do so, are nonsteroidal anti-inflammatory drugs, statins, RAGE antagonists and antioxidants.

  16. Cytokines: Roles in atherosclerosis disease progression and potential therapeutic targets

    PubMed Central

    Moss, Joe W. E.; Ramji, Dipak P.

    2017-01-01

    Atherosclerosis, the primary cause of cardiovascular disease (CVD), is a chronic inflammatory disorder in the walls of medium and large arteries. CVD is currently responsible for about one in three global deaths and this is expected to rise in the future due to an increase in the prevalence of obesity and diabetes. Current therapies for atherosclerosis mainly modulate lipid homeostasis and whilst successful at reducing the risk of a CVD-related death, they are associated with considerable residual risk and various side effects. There is therefore a need for alternative therapies aimed at regulating inflammation in order to reduce atherogenesis. This review will highlight the key role cytokines play during disease progression as well as potential therapeutic strategies to target them. PMID:27357616

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

    PubMed Central

    Aso, Ester; Ferrer, Isidro

    2016-01-01

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

  18. Extracellular Bacterial Proteases in Chronic Wounds: A Potential Therapeutic Target?

    PubMed

    Suleman, Louise

    2016-10-01

    Significance: Bacterial biofilms are considered to be responsible for over 80% of persistent infections, including chronic lung infections, osteomyelitis, periodontitis, endocarditis, and chronic wounds. Over 60% of chronic wounds are colonized with bacteria that reside within a biofilm. The exaggerated proteolytic environment of chronic wounds, more specifically elevated matrix metalloproteinases, is thought to be one of the possible reasons as to why chronic wounds fail to heal. However, the role of bacterial proteases within chronic wounds is not fully understood. Recent Advances: Recent research has shown that bacterial proteases can enable colonization and facilitate bacterial immune evasion. The inhibition of bacterial proteases such as Pseudomonas aeruginosa elastase B (LasB) has resulted in the disruption of the bacterial biofilm in vitro. P. aeruginosa is thought to be a key pathogen in chronic wound infection, and therefore, the disruption of these biofilms, potentially through the targeting of P. aeruginosa bacterial proteases, is an attractive therapeutic endeavor. Critical Issues: Disrupting biofilm formation through the inhibition of bacterial proteases may lead to the dissemination of bacteria from the biofilm, allowing planktonic cells to colonize new sites within the wound. Future Directions: Despite a plethora of evidence supporting the role of bacterial proteases as virulence factors in infection, there remains a distinct lack of research into the effect of bacterial proteases in chronic wounds. To assess the viability of targeting bacterial proteases, future research should aim to understand the role of these proteases in a variety of chronic wound subtypes.

  19. Glycine transporter-1: a new potential therapeutic target for schizophrenia.

    PubMed

    Hashimoto, Kenji

    2011-01-01

    The hypofunction hypothesis of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors in the pathophysiology of schizophrenia suggests that increasing NMDA receptor function via pharmacological manipulation could provide a new therapeutic strategy for schizophrenia. The glycine modulatory site on NMDA receptor complex is the one of the most attractive therapeutic targets for schizophrenia. One means of enhancing NMDA receptor neurotransmission is to increase the availability of the obligatory co-agonist glycine at modulatory site on the NMDA receptors through the inhibition of glycine transporter-1 (GlyT-1) on glial cells. Some clinical studies have demonstrated that the GlyT-1 inhibitor sarcosine (N-methylglycine) shows antipsychotic activity in patients with schizophrenia. Currently, a number of pharmaceutical companies have been developing novel and selective GlyT-1 inhibitors for the treatment of schizophrenia. A recent double blind phase II study demonstrated that the novel GlyT-1 inhibitor RG1678 has a robust and clinically meaningful effect in patients with schizophrenia. In this article, the author reviews the recent findings on the GlyT-1 as a potential therapeutic target of schizophrenia.

  20. Phosphoglycerate dehydrogenase: potential therapeutic target and putative metabolic oncogene.

    PubMed

    Zogg, Cheryl K

    2014-01-01

    Exemplified by cancer cells' preference for glycolysis, for example, the Warburg effect, altered metabolism in tumorigenesis has emerged as an important aspect of cancer in the past 10-20 years. Whether due to changes in regulatory tumor suppressors/oncogenes or by acting as metabolic oncogenes themselves, enzymes involved in the complex network of metabolic pathways are being studied to understand their role and assess their utility as therapeutic targets. Conversion of glycolytic intermediate 3-phosphoglycerate into phosphohydroxypyruvate by the enzyme phosphoglycerate dehydrogenase (PHGDH)-a rate-limiting step in the conversion of 3-phosphoglycerate to serine-represents one such mechanism. Forgotten since classic animal studies in the 1980s, the role of PHGDH as a potential therapeutic target and putative metabolic oncogene has recently reemerged following publication of two prominent papers near-simultaneously in 2011. Since that time, numerous studies and a host of metabolic explanations have been put forward in an attempt to understand the results observed. In this paper, I review the historic progression of our understanding of the role of PHGDH in cancer from the early work by Snell through its reemergence and rise to prominence, culminating in an assessment of subsequent work and what it means for the future of PHGDH.

  1. Causes of CNS inflammation and potential targets for anticonvulsants.

    PubMed

    Falip, Mercé; Salas-Puig, Xavier; Cara, Carlos

    2013-08-01

    Inflammation is one of the most important endogenous defence mechanisms in an organism. It has been suggested that inflammation plays an important role in the pathophysiology of a number of human epilepsies and convulsive disorders, and there is clinical and experimental evidence to suggest that inflammatory processes within the CNS may either contribute to or be a consequence of epileptogenesis. This review discusses evidence from human studies on the role of inflammation in epilepsy and highlights potential new targets in the inflammatory cascade for antiepileptic drugs. A number of mechanisms have been shown to be involved in CNS inflammatory reactions. These include an inflammatory response at the level of the blood-brain barrier (BBB), immune-mediated damage to the CNS, stress-induced release of inflammatory mediators and direct neuronal dysfunction or damage as a result of inflammatory reactions. Mediators of inflammation in the CNS include interleukin (IL)-1β, tumour necrosis factor-α, nuclear factor-κB and toll-like receptor-4 (TLR4). IL-1β, BBB and high-mobility group box-1-TLR4 signalling appear to be the most promising targets for anticonvulsant agents directed at inflammation. Such agents may provide effective therapy for drug-resistant epilepsies in the future.

  2. Pathophysiology of hemophilic arthropathy and potential targets for therapy.

    PubMed

    Pulles, Astrid E; Mastbergen, Simon C; Schutgens, Roger E G; Lafeber, Floris P J G; van Vulpen, Lize F D

    2017-01-01

    Hemophilia is a congenital clotting factor deficiency characterized by spontaneous and trauma-related bleeding. Spontaneous bleeding shows a predilection for joints, and repeated hemarthroses lead to a disabling condition called hemophilic arthropathy. Treatment of this condition consists of preventing joint bleeding on the one hand and orthopedic surgery as a last resort on the other. Up till now, there is no disease modifying therapy available to fill the gap between these extremes. This review provides an overview of the pathogenesis of hemophilic arthropathy in order to identify potential targets for therapy. Joint bleeding induces synovial inflammation, cartilage degeneration and bone damage. These processes interact with each other and result in a vicious circle. Hemarthrosis promotes synovial hypertrophy and neoangiogenesis, increasing the susceptibility to mechanical damage and subsequent bleeding. The inflamed synovium affects the cartilage, while cartilage is also directly affected by blood via the release of cytokines and metalloproteinases, and via hydroxyl radical formation inducing chondrocyte apoptosis. Apart from the inflammatory pathways, iron plays a pivotal role in this process, as does the fibrinolytic system. Considering its pathogenesis, potential targets for disease modifying therapy in hemophilic arthropathy are iron, inflammation, vascular remodeling, hyperfibrinolysis, bone remodeling and cartilage regeneration. So far, iron chelators, anti-inflammatory therapy, anti-fibrinolytics and bone remodeling agents have demonstrated beneficial effects, predominantly in a preclinical setting. There is still a long way to go before these interventions will translate into clinical practice. The most important challenges are: establishing a universal outcome measure to predict efficacy in humans, and determination of the optimal route and timing to administer disease modifying therapy.

  3. Dietary exposure of juvenile female mice to polyhalogenated seafood contaminants (HBCD, BDE-47, PCB-153, TCDD): comparative assessment of effects in potential target tissues.

    PubMed

    Maranghi, F; Tassinari, R; Moracci, G; Altieri, I; Rasinger, J D; Carroll, T S; Hogstrand, C; Lundebye, A-K; Mantovani, A

    2013-06-01

    Fish represents source of nutrients and major dietary vehicle of lipophilic persistent contaminants. The study compared the effects of two legacy and two emerging fish pollutants (Hexabromocyclododecane HBCD; 2,2',4,4'-Tetrabromodiphenyl ether BDE-47; 2,2',4,4',5,5'-Hexachlorobiphenyl PCB-153; 2,3,7,8-Tetrachlorodibenzo-p-doxin TCDD) in juvenile female mice exposed through a salmon based rodent diet for 28 days (dietary doses: HBCD 199 mg/kg bw/day; BDE-47 450 μg/kg bw/day; PCB-153 195 μg/kg bw/day; TCDD 90 ng/kg bw/day). Dose levels were comparable to previously reported developmental Lowest Observed Adverse Effect Levels. None of the treatments elicited signs of overt toxicity, but HBCD increased relative liver weight. All compounds caused changes in liver, thymus and thyroid; spleen was affected by BDE-47 and PCB-153; no effects were seen in uterus and adrenals. Strongest effects in thyroid follicles were elicited by PCB-153, in thymus and liver by BDE-47. HBCD and BDE-47 induced liver fatty changes, but appeared to be less potent in the other tissues. HBCD, BDE-47 and TCDD increased serum testosterone levels and the testosterone/estradiol ratio, suggesting a potential involvement of pathways related to sex steroid biosynthesis and/or metabolism. The results support the role of toxicological studies on juvenile rodents in the hazard characterization of chemicals, due to endocrine and/or immune effects.

  4. Transient Receptor Potential Channels as Targets for Phytochemicals

    PubMed Central

    2015-01-01

    To date, 28 mammalian transient receptor potential (TRP) channels have been cloned and characterized. They are grouped into six subfamilies on the basis of their amino acid sequence homology: TRP Ankyrin (TRPA), TRP Canonical (TRPC), TRP Melastatin (TRPM), TRP Mucolipin (TRPML), TRP Polycystin (TRPP), and TRP Vanilloid (TRPV). Most of the TRP channels are nonselective cation channels expressed on the cell membrane and exhibit variable permeability ratios for Ca2+ versus Na+. They mediate sensory functions (such as vision, nociception, taste transduction, temperature sensation, and pheromone signaling) and homeostatic functions (such as divalent cation flux, hormone release, and osmoregulation). Significant progress has been made in our understanding of the specific roles of these TRP channels and their activation mechanisms. In this Review, the emphasis will be on the activation of TRP channels by phytochemicals that are claimed to exert health benefits. Recent findings complement the anecdotal evidence that some of these phytochemicals have specific receptors and the activation of which is responsible for the physiological effects. Now, the targets for these phytochemicals are being unveiled; a specific hypothesis can be proposed and tested experimentally to infer a scientific validity of the claims of the health benefits. The broader and pressing issues that have to be addressed are related to the quantities of the active ingredients in a given preparation, their bioavailability, metabolism, adverse effects, excretion, and systemic versus local effects. PMID:24926802

  5. Innate inflammatory responses in stroke: mechanisms and potential therapeutic targets

    PubMed Central

    Kim, Jong Youl; Kawabori, Masahito; Yenari, Midori A.

    2014-01-01

    Stroke is a frequent cause of long-term disability and death worldwide. Ischemic stroke is more commonly encountered compared to hemorrhagic stroke, and leads to tissue death by ischemia due to occlusion of a cerebral artery. Inflammation is known to result as a result of ischemic injury, long thought to be involved in initiating the recovery and repair process. However, work over the past few decades indicates that aspects of this inflammatory response may in fact be detrimental to stroke outcome. Acutely, inflammation appears to have a detrimental effect, and anti-inflammatory treatments have been been studied as a potential therapeutic target. Chronically, reports suggest that post-ischemic inflammation is also essential for the tissue repairing and remodeling. The majority of the work in this area has centered around innate immune mechanisms, which will be the focus of this review. This review describes the different key players in neuroinflammation and their possible detrimental and protective effects in stroke. A better understanding of the roles of the different immune cells and their temporal profile of damage versus repair will help to clarify more effective modulation of inflammation post stroke. Introduction Stroke refers to conditions caused by occlusion and/or rupture of blood vessels in the brain, and is a leading cause of death and disability in the industrialized world. PMID:24372209

  6. CD6 as a potential target for treating multiple sclerosis.

    PubMed

    Li, Yan; Singer, Nora G; Whitbred, Joy; Bowen, Michael A; Fox, David A; Lin, Feng

    2017-03-07

    CD6 was established as a marker of T cells more than three decades ago, and recent studies have identified CD6 as a risk gene for multiple sclerosis (MS), a disease in which autoreactive T cells are integrally involved. Nevertheless, the precise role of CD6 in regulating T-cell responses is controversial and its significance in the pathogenesis of various diseases remains elusive, partly due to the lack of animals engineered to alter expression of the CD6 gene. In this report, we found that CD6 KO mice showed decreased pathogenic T-cell responses, reduced spinal cord T-cell infiltration, and attenuated disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. CD6-deficient T cells exhibited augmented activation, but also significantly reduced survival and proliferation after activation, leading to overall decreased Th1 and Th17 polarization. Activated CD6-deficient T cells also showed impaired infiltration through brain microvascular endothelial cell monolayers. Furthermore, by developing CD6 humanized mice, we identified a mouse anti-human CD6 monoclonal antibody that is highly effective in treating established EAE without depleting T cells. These results suggest that (i) CD6 is a negative regulator of T-cell activation, (ii) at the same time, CD6 is a positive regulator of activated T-cell survival/proliferation and infiltration; and (iii) CD6 is a potential new target for treating MS and potentially other T-cell-driven autoimmune conditions.

  7. Therapeutic potential of stem cells expressing suicide genes that selectively target human breast cancer cells: Evidence that they exert tumoricidal effects via tumor tropism

    PubMed Central

    YI, BO-RIM; CHOI, KELVIN J.; KIM, SEUNG U.; CHOI, KYUNG-CHUL

    2012-01-01

    Breast cancer is the most prevalent cancer in women worldwide and is classified into ductal and lobular carcinoma. Breast cancer as well as lobular carcinoma is associated with various risk factors such as gender, age, female hormone exposure, ethnicity, family history and genetic risk factor-associated genes. Genes associated with a high risk of developing breast cancer include BRCA1, BRCA2, p53, PTEN, CHEK2 and ATM. Surgery, chemotherapy, radiotherapy and hormone therapy are used to treat breast cancer but these therapies, except for surgery, have many side-effects such as alopecia, anesthesia, diarrhea and arthralgia. Gene-directed enzyme/prodrug therapy (GEPT) or suicide gene therapy, may improve the therapeutic efficacy of conventional cancer radiotherapy and chemotherapy without side-effects. GEPT most often involves the use of a viral vector to deliver a gene not found in mammalian cells and that produces enzymes which can convert a relatively non-toxic prodrug into a toxic agent. Examples of these systems include cytosine deaminase/5-fluorocytosine (CD/5-FC), carboxyl esterase/irinotecan (CE/CPT-11), and thymidine kinase/ganciclovir (TK/GCV). Recently, therapies based on genetically engineered stem cells (GESTECs) using a GEPT system have received a great deal of attention for their clinical and therapeutic potential to treat breast cancer. In this review, we discuss the potential of GESTECs via tumor tropism effects and therapeutic efficacy against several different types of cancer cells. GESTECs represent a useful tool for treating breast cancer without inducing injuries associated with conventional therapeutic modalities. PMID:22736197

  8. Potential anti-cancer activity of 7-O-pentyl quercetin: Efficient, membrane-targeted kinase inhibition and pro-oxidant effect.

    PubMed

    Sassi, Nicola; Mattarei, Andrea; Espina, Virginia; Liotta, Lance; Zoratti, Mario; Paradisi, Cristina; Biasutto, Lucia

    2017-10-01

    Quercetin is a redox-active plant-derived flavonoid with potential anticancer effects, stemming largely from its interaction with a number of proteins, and in particular from inhibition of pro-life kinases. To improve efficacy, we reasoned that a local increase in concentration of the compound at the level of cell membranes would result in a more efficient interaction with membrane-associated signaling kinases. We report here the synthesis of all five isomeric quercetin derivatives in which an n-pentyl group was linked via an ether bond to each hydroxyl of the flavonoid kernel. This strategy proved effective in directing quercetin to cellular membranes, and revealed a remarkable dependence of the derivatives' bioactivity on the specific site of functionalization. The isomer bearing the pentyl group in position 7, Q-7P, turned out to be the most effective and promising derivative, selectively inducing apoptosis in tumoral and fast-growing cells, while sparing slow-growing, non-tumoral ones. Cytotoxicity for tumoral cells was strongly enhanced compared to quercetin itself. Q-7P induced massive ROS production, which however accounted only partially for cell death. Alterations in the levels of various signaling phospho-proteins were observed in a proteomics screen. An important contribution seems to come from inhibition of the PI3K/Akt pathway. This work opens new perspectives in developing membrane-associating, polyphenol-based anticancer agents. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Molecular sonography with targeted microbubbles: current investigations and potential applications.

    PubMed

    Hwang, Misun; Lyshchik, Andrej; Fleischer, Arthur C

    2010-06-01

    Sonography using targeted microbubbles affords a variety of diagnostic and potentially therapeutic clinical applications. It provides a whole new world of functional information at the cellular and molecular level. This information can then be used to diagnose and possibly prevent diseases at early stages as well as devise therapeutic strategies at the molecular level. It is also useful in monitoring tumor response to therapy and devising treatment timing and plans based on the molecular state of an individual's health. Moreover, targeted microbubble-enhanced sonography has several advantages over other imaging modalities, including widespread availability, low cost, fast acquisition times, and lack of radiation risk. These traits are likely to advance it as one of the imaging methods of choice in future clinical trials examining the impact of molecular imaging on treatment outcome. This review describes the fundamental concepts of targeted microbubble-enhanced sonography as well as its potential clinical applications.

  10. AT2 Receptors: Potential Therapeutic Targets for Hypertension.

    PubMed

    Carey, Robert M

    2017-04-01

    The renin-angiotensin system (RAS) is arguably the most important and best studied hormonal system in the control of blood pressure (BP) and the pathogenesis of hypertension. The RAS features its main effector angiotensin II (Ang II) acting via its 2 major receptors, angiotensin type-1(AT1R) and type-2 (AT2R). In general, AT2Rs oppose the detrimental actions of Ang II via AT1Rs. AT2R activation induces vasodilation and natriuresis, but its effects to lower BP in hypertension have not been as clear as anticipated. Recent studies, however, have demonstrated that acute and chronic AT2R stimulation can induce natriuresis and lower BP in the Ang II infusion model of experimental hypertension. AT2R activation induces receptor recruitment from intracellular sites to the apical plasma membranes of renal proximal tubule cells via a bradykinin, nitric oxide, and cyclic guanosine 3',5' monophosphate signaling pathway that results in internalization and inactivation of sodium (Na+) transporters Na+-H+ exchanger-3 and Na+/K+ATPase. These responses do not require the presence of concurrent AT1R blockade and are effective both in the prevention and reversal of hypertension. This review will address the role of AT2Rs in the control of BP and Na+ excretion and the case for these receptors as potential therapeutic targets for hypertension in humans. © American Journal of Hypertension, Ltd 2016. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease?

    PubMed

    Harrison, Ian F; Dexter, David T

    2013-10-01

    Parkinson's disease (PD) is the most common movement disorder affecting more than 4million people worldwide. The primary motor symptoms of the disease are due to degeneration of dopaminergic nigrostriatal neurons. Dopamine replacement therapies have therefore revolutionised disease management by partially controlling these symptoms. However these drugs can produce debilitating side effects when used long term and do not protect degenerating neurons against death. Recent evidence has highlighted a pathological imbalance in PD between the acetylation and deacetylation of the histone proteins around which deoxyribonucleic acid (DNA) is coiled, in favour of excessive histone deacetylation. This mechanism of adding/removing acetyl groups to histone lysine residues is one of many epigenetic regulatory processes which control the expression of genes, many of which will be essential for neuronal survival. Hence, such epigenetic modifications may have a pathogenic role in PD. It has therefore been hypothesised that if this pathological imbalance can be corrected with the use of histone deacetylase inhibiting agents then neurodegeneration observed in PD can be ameliorated. This article will review the current literature with regard to epigenetic changes in PD and the use of histone deacetylase inhibitors (HDACIs) in PD: examining the evidence of the neuroprotective effects of numerous HDACIs in cellular and animal models of Parkinsonian cell death. Ultimately answering the question: does epigenetic targeting of histone deacetylases hold therapeutic potential in PD?

  12. Evaluation of a targeted nanobubble ultrasound contrast agent for potential tumor imaging

    NASA Astrophysics Data System (ADS)

    Li, Chunfang; Shen, Chunxu; Liu, Haijuan; Wu, Kaizhi; Zhou, Qibing; Ding, Mingyue

    2015-03-01

    Targeted nanobubbles have been reported to improve the contrast effect of ultrasound imaging due to the enhanced permeation and retention effects at tumor vascular leaks. In this work, the contrast enhancement abilities and the tumor targeting potential of a self-made VEGFR2-targeted nanobubble ultrasound contrast agent was evaluated in-vitro and in-vivo. Size distribution and zeta potential were assessed. Then the contrast-enhanced ultrasound imaging of the VEGFR2 targeted nanobubbles were evaluated with a custom-made experimental apparatus and in normal Wistar rats. Finally, the in-vivo tumor-targeting ability was evaluated on nude mice with subcutaneous tumor. The results showed that the target nanobubbles had uniform distribution with the average diameter of 208.1 nm, polydispersity index (PDI) of 0.411, and zeta potential of -13.21 mV. Significant contrast enhancement was observed in both in-vitro and in-vivo ultrasound imaging, demonstrating that the self-made target nanobubbles can enhance the contrast effect of ultrasound imaging efficiently. Targeted tumor imaging showed less promising result, due to the fact that the targeted nanobubbles arriving and permeating through tumor vessels were not many enough to produce significant enhancement. Future work will focus on exploring new imaging algorithm which is sensitive to targeted nanobubbles, so as to correctly detect the contrast agent, particularly at a low bubble concentration.

  13. Preclinical evaluation of potential therapeutic targets in dedifferentiated liposarcoma

    PubMed Central

    Hanes, Robert; Grad, Iwona; Lorenz, Susanne; Stratford, Eva W.; Munthe, Else; Reddy, Chilamakuri Chandra Sekhar; Meza-Zepeda, Leonardo A.; Myklebost, Ola

    2016-01-01

    Sarcomas are rare cancers with limited treatment options. Patients are generally treated by chemotherapy and/or radiotherapy in combination with surgery, and would benefit from new personalized approaches. In this study we demonstrate the potential of combining personal genomic characterization of patient tumors to identify targetable mutations with in vitro testing of specific drugs in patient-derived cell lines. We have analyzed three metastases from a patient with high-grade metastatic dedifferentiated liposarcoma (DDLPS) by exome and transcriptome sequencing as well as DNA copy number analysis. Genomic aberrations of several potentially targetable genes, including amplification of KITLG and FRS2, in addition to amplification of CDK4 and MDM2, characteristic of this disease, were identified. We evaluated the efficacy of drugs targeting these aberrations or the corresponding signaling pathways in a cell line derived from the patient. Interestingly, the pan-FGFR inhibitor NVP-BGJ398, which targets FGFR upstream of FRS2, strongly inhibited cell proliferation in vitro and induced an accumulation of cells into the G0 phase of the cell cycle. This study indicates that FGFR inhibitors have therapeutic potential in the treatment of DDLPS with amplified FRS2. PMID:27409346

  14. The late positive potential predicts subsequent interference with target processing.

    PubMed

    Weinberg, Anna; Hajcak, Greg

    2011-10-01

    The current study investigated the association between neural engagement with task-irrelevant images and subsequent interference with target processing using the Emotional Interrupt paradigm [Mitchell, D., Richell, R., Leonard, A., & Blair, R. Emotion at the expense of cognition: Psychopathic individuals outperform controls on an operant response task. Journal of Abnormal Psychology, 115, 559, 2006]. Consistent with previous studies, PCA-derived factors corresponding to the early posterior negativity, P300, and late positive potential (LPP) were enhanced for emotional (i.e., both unpleasant and pleasant) compared with neutral distracters, and the P300 elicited by targets was smaller following emotional compared with neutral pictures. In addition, RTs were increased to targets that followed emotional pictures. Within-subject analyses demonstrated that slow trials were characterized by a smaller P300 and were preceded by pictures with a larger LPP. Additionally, between-subject analyses indicate that individuals with a larger LPP also demonstrated slower RTs to targets and reduced target-elicited P300s. All results were specific to the LPP and were not observed for either the early posterior negativity or the P300 elicited by task-irrelevant pictures. By relating the LPP to subsequent behavioral and ERP interference in both within- and between-subject analyses, the current study provides direct support for the notion that LPP indexes attentional engagement with visual stimuli that is uniquely associated with subsequent interference in terms of both RT slowing and P300 reduction to targets.

  15. Targets Need Their Own Personal Space: Effects of Clutter on Multiple-Target Search Accuracy.

    PubMed

    Adamo, Stephen H; Cain, Matthew S; Mitroff, Stephen R

    2015-01-01

    Visual search is an essential task for many lifesaving professions; airport security personnel search baggage X-ray images for dangerous items and radiologists examine radiographs for tumors. Accuracy is critical for such searches; however, there are potentially negative influences that can affect performance; for example, the displays can be cluttered and can contain multiple targets. Previous research has demonstrated that clutter can hurt search performance and a second target is less likely to be detected in a multiple-target search after a first target has been found, which raises a concern-how does clutter affect multiple-target search performance? The current study explored clutter in a multiple-target search paradigm, where there could be one or two targets present, and targets appeared in varying levels of clutter. There was a significant interaction between clutter and target number: Increasing levels of clutter did not affect single-target detection but did reduce detection of a second target. Multiple-target search accuracy is known to be sensitive to contextual influences, and the current results reveal a specific effect wherein clutter disproportionally affected multiple-target search accuracy. These results suggest that the detection and processing of a first target might enhance the masking effects of clutter around a second target.

  16. MPS1 kinase as a potential therapeutic target in medulloblastoma

    PubMed Central

    Alimova, Irina; Ng, June; Harris, Peter; Birks, Diane; Donson, Andrew; Taylor, Michael D.; Foreman, Nicholas K.; Venkataraman, Sujatha; Vibhakar, Rajeev

    2016-01-01

    Medulloblastoma is the most common type of malignant brain tumor that affects children. Although recent advances in chemotherapy and radiation have improved outcomes, high-risk patients perform poorly with significant morbidity. Gene expression profiling has revealed that monopolar spindle 1 (MPS1) (TTK1) is highly expressed in medulloblastoma patient samples compared to that noted in normal cerebellum. MPS1 is a key regulator of the spindle assembly checkpoint (SAC), a mitotic mechanism specifically required for proper chromosomal alignment and segregation. The SAC can be activated in aneuploid cancer cells and MPS1 is overexpressed in many types of cancers. A previous study has demonstrated the effectiveness of inhibiting MPS1 with small-molecule inhibitors, but the role of MPS1 in medulloblastoma is unknown. In the present study, we demonstrated that MPS1 inhibition by shRNA or with a small-molecule drug, NMS-P715, resulted in decreased cell growth, inhibition of clonogenic potential and induction of apoptosis in cells belonging to both the Shh and group 3 medulloblastoma genomic signature. These findings highlight MPS1 as a rational therapeutic target for medulloblastoma. PMID:27633003

  17. TRAF6 Activation in Multiple Myeloma: A Potential Therapeutic Target

    PubMed Central

    Liu, Hong; Tamashiro, Samantha; Baritaki, Stavroula; Penichet, Manuel; Yu, Youhua; Chen, Haiming; Berenson, James; Bonavida, Benjamin

    2013-01-01

    Multiple myeloma (MM) is an incurable B-lymphocyte malignancy. New therapeutic options have become available during the past several years; however nearly all patients acquire resistance to currently available therapeutic agents. Mechanisms contributing to the pathogenesis and chemoresistance of MM include genetic abnormalities, chromosomal translocations, gene mutations, the interaction between MM cells and the bone marrow microenvironment, and defects in the apoptotic signaling pathways. Survival signaling pathways associated with the pathogenesis of MM and bone marrow stromal cells play crucial roles in promoting growth, survival, adhesion, immortalization, angiogenesis, and drug resistance. The receptor activator of nuclear factor-kappa B/receptor activator of nuclear factor-kappa B ligand/tumor necrosis factor receptor-associated factor (RANK/RANKL-TRAF6) signal pathway mediates osteolytic bone lesions through the activation of the NF-κB and Janus kinase/signal transducer and activator of transcription (JNK) pathways in osteoclast precursor cells and thus contributes to the main clinical manifestations of bone disease. TRAF6 has also been identified as a ligase for Akt ubiquitination and membrane recruitment and its phosphorylation on growth factor stimulation. The inhibition of TRAF6 by silencing RNA or by decoy peptides decreases MM tumor cell proliferation and increases apoptosis as well as bone resorption. Some proteasome inhibitors and benzoxadiazole derivatives showed inhibitory effects on the activity and function of TRAF6. Overall, we propose that TRAF6 may be considered as a potential therapeutic target for the treatment of MM. PMID:22440007

  18. Therapeutic potential of targeting acinar cell reprogramming in pancreatic cancer.

    PubMed

    Wong, Chi-Hin; Li, You-Jia; Chen, Yang-Chao

    2016-08-21

    Pancreatic ductal adenocarcinoma (PDAC) is a common pancreatic cancer and the fourth leading cause of cancer death in the United States. Treating this life-threatening disease remains challenging due to the lack of effective prognosis, diagnosis and therapy. Apart from pancreatic duct cells, acinar cells may also be the origin of PDAC. During pancreatitis or combined with activating KRas(G12D) mutation, acinar cells lose their cellular identity and undergo a transdifferentiation process called acinar-to-ductal-metaplasia (ADM), forming duct cells which may then transform into pancreatic intraepithelial neoplasia (PanIN) and eventually PDAC. During ADM, the activation of mitogen-activated protein kinases, Wnt, Notch and phosphatidylinositide 3-kinases/Akt signaling inhibits the transcription of acinar-specific genes, including Mist and amylase, but promotes the expression of ductal genes, such as cytokeratin-19. Inhibition of this transdifferentiation process hinders the development of PanIN and PDAC. In addition, the transdifferentiated cells regain acinar identity, indicating ADM may be a reversible process. This provides a new therapeutic direction in treating PDAC through cancer reprogramming. Many studies have already demonstrated the success of switching PanIN/PDAC back to normal cells through the use of PD325901, the expression of E47, and the knockdown of Dickkopf-3. In this review, we discuss the signaling pathways involved in ADM and the therapeutic potential of targeting reprogramming in order to treat PDAC.

  19. Cell migration in paediatric glioma; characterisation and potential therapeutic targeting

    PubMed Central

    Cockle, J V; Picton, S; Levesley, J; Ilett, E; Carcaboso, A M; Short, S; Steel, L P; Melcher, A; Lawler, S E; Brüning-Richardson, A

    2015-01-01

    Background: Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are highly aggressive brain tumours. Their invasive phenotype contributes to their limited therapeutic response, and novel treatments that block brain tumour invasion are needed. Methods: Here, we examine the migratory characteristics and treatment effect of small molecule glycogen synthase kinase-3 inhibitors, lithium chloride (LiCl) and the indirubin derivative 6-bromoindirubin-oxime (BIO), previously shown to inhibit the migration of adult glioma cells, on two pHGG cell lines (SF188 and KNS42) and one patient-derived DIPG line (HSJD-DIPG-007) using 2D (transwell membrane, immunofluorescence, live cell imaging) and 3D (migration on nanofibre plates and spheroid invasion in collagen) assays. Results: All lines were migratory, but there were differences in morphology and migration rates. Both LiCl and BIO reduced migration and instigated cytoskeletal rearrangement of stress fibres and focal adhesions when viewed by immunofluorescence. In the presence of drugs, loss of polarity and differences in cellular movement were observed by live cell imaging. Conclusions: Ours is the first study to demonstrate that it is possible to pharmacologically target migration of paediatric glioma in vitro using LiCl and BIO, and we conclude that these agents and their derivatives warrant further preclinical investigation as potential anti-migratory therapeutics for these devastating tumours. PMID:25628092

  20. Optimizing Interacting Potentials to Form Targeted Materials Structures

    SciTech Connect

    Torquato, Salvatore

    2015-09-28

    Conventional applications of the principles of statistical mechanics (the "forward" problems), start with particle interaction potentials, and proceed to deduce local structure and macroscopic properties. Other applications (that may be classified as "inverse" problems), begin with targeted configurational information, such as low-order correlation functions that characterize local particle order, and attempt to back out full-system configurations and/or interaction potentials. To supplement these successful experimental and numerical "forward" approaches, we have focused on inverse approaches that make use of analytical and computational tools to optimize interactions for targeted self-assembly of nanosystems. The most original aspect of our work is its inherently inverse approach: instead of predicting structures that result from given interaction potentials among particles, we determine the optimal potential that most robustly stabilizes a given target structure subject to certain constraints. Our inverse approach could revolutionize the manner in which materials are designed and fabricated. There are a number of very tangible properties (e.g. zero thermal expansion behavior), elastic constants, optical properties for photonic applications, and transport properties.

  1. IDMap: facilitating the detection of potential leads with therapeutic targets.

    PubMed

    Ha, Soyang; Seo, Young-Ju; Kwon, Min-Seok; Chang, Byung-Ha; Han, Cheol-Kyu; Yoon, Jeong-Hyeok

    2008-06-01

    Pharmaceutical industry has been striving to reduce the costs of drug development and increase productivity. Among the many different attempts, drug repositioning (retargeting existing drugs) comes into the spotlight because of its financial efficiency. We introduce IDMap which predicts novel relationships between targets and chemicals and thus is capable of repositioning the marketed drugs by using text mining and chemical structure information. Also capable of mapping commercial chemicals to possible drug targets and vice versa, IDMap creates convenient environments for identifying the potential lead and its targets, especially in the field of drug repositioning. IDMap executable and its user manual including color images are freely available to non-commercial users at http://www.equispharm.com/idmap

  2. Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: A beneficial off-target effect?⋆☆

    PubMed Central

    Birrell, Mark A.; Bonvini, Sara J.; Dubuis, Eric; Maher, Sarah A.; Wortley, Michael A.; Grace, Megan S.; Raemdonck, Kristof; Adcock, John J.; Belvisi, Maria G.

    2014-01-01

    Background Recent studies have suggested that the long-acting muscarinic receptor antagonist tiotropium, a drug widely prescribed for its bronchodilator activity in patients with chronic obstructive pulmonary disease and asthma, improves symptoms and attenuates cough in preclinical and clinical tussive agent challenge studies. The mechanism by which tiotropium modifies tussive responses is not clear, but an inhibition of vagal tone and a consequent reduction in mucus production from submucosal glands and bronchodilation have been proposed. Objective The aim of this study was to investigate whether tiotropium can directly modulate airway sensory nerve activity and thereby the cough reflex. Methods We used a conscious cough model in guinea pigs, isolated vagal sensory nerve and isolated airway neuron tissue– and cell-based assays, and in vivo single-fiber recording electrophysiologic techniques. Results Inhaled tiotropium blocked cough and single C-fiber firing in the guinea pig to the transient receptor potential (TRP) V1 agonist capsaicin, a clinically relevant tussive stimulant. Tiotropium and ipratropium, a structurally similar muscarinic antagonist, inhibited capsaicin responses in isolated guinea pig vagal tissue, but glycopyrrolate and atropine did not. Tiotropium failed to modulate other TRP channel–mediated responses. Complementary data were generated in airway-specific primary ganglion neurons, demonstrating that tiotropium inhibited capsaicin-induced, but not TRPA1-induced, calcium movement and voltage changes. Conclusion For the first time, we have shown that tiotropium inhibits neuronal TRPV1-mediated effects through a mechanism unrelated to its anticholinergic activity. We speculate that some of the clinical benefit associated with taking tiotropium (eg, in symptom control) could be explained through this proposed mechanism of action. PMID:24506933

  3. Potential chemotherapeutic targets in the purine metabolism of parasites.

    PubMed

    el Kouni, Mahmoud H

    2003-09-01

    Parasites are responsible for a wide variety of infectious diseases in human as well as in domestic and wild animals, causing an enormous health and economical blight. Current containment strategies are not entirely successful and parasitic infections are on the rise. In the absence of availability of antiparasitic vaccines, chemotherapy remains the mainstay for the treatment of most parasitic diseases. However, there is an urgent need for new drugs to prevent or combat some major parasitic infections because of lack of a single effective approach for controlling the parasites (e.g., trypanosomiasis) or because some serious parasitic infections developed resistance to presently available drugs (e.g., malaria). The rational design of a drug is usually based on biochemical and physiological differences between pathogens and host. Some of the most striking differences between parasites and their mammalian host are found in purine metabolism. Purine nucleotides can be synthesized by the de novo and/or the so-called "salvage" pathways. Unlike their mammalian host, most parasites studied lack the pathways for de novo purine biosynthesis and rely on the salvage pathways to meet their purine demands. Moreover, because of the great phylogenic separation between the host and the parasite, there are in some cases sufficient distinctions between corresponding enzymes of the purine salvage from the host and the parasite that can be exploited to design specific inhibitors or "subversive substrates" for the parasitic enzymes. Furthermore, the specificities of purine transport, the first step in purine salvage, diverge significantly between parasites and their mammalian host. This review highlights the unique transporters and enzymes responsible for the salvage of purines in parasites that could constitute excellent potential targets for the design of safe and effective antiparasitic drugs.

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  6. Target and Non-Target Processing during Oddball and Cyberball: A Comparative Event-Related Potential Study

    PubMed Central

    Weschke, Sarah; Niedeggen, Michael

    2016-01-01

    The phenomenon of social exclusion can be investigated by using a virtual ball-tossing game called Cyberball. In neuroimaging studies, structures have been identified which are activated during social exclusion. But to date the underlying mechanisms are not fully disclosed. In previous electrophysiological studies it was shown that the P3 complex is sensitive to exclusion manipulations in the Cyberball paradigm and that there is a correlation between P3 amplitude and self-reported social pain. Since this posterior event-related potential (ERP) was widely investigated using the oddball paradigm, we directly compared the ERP effects elicited by the target (Cyberball: “ball possession”) and non-target (Cyberball: “ball possession of a co-player) events in both paradigms. Analyses mainly focused on the effect of altered stimulus probabilities of the target and non-target events between two consecutive blocks of the tasks. In the first block, the probability of the target and non-target event was 33% (Cyberball: inclusion), in the second block target probability was reduced to 17%, and accordingly, non-target probability was increased to 66% (Cyberball: exclusion). Our results indicate that ERP amplitude differences between inclusion and exclusion are comparable to ERP amplitude effects in a visual oddball task. We therefore suggest that ERP effects–especially in the P3 range–in the Oddball and Cyberball paradigm rely on similar mechanisms, namely the probability of target and non-target events. Since the simulation of social exclusion (Cyberball) did not trigger a unique ERP response, the idea of an exclusion-specific neural alarm system is not supported. The limitations of an ERP-based approach will be discussed. PMID:27100787

  7. Selecting Potential Targetable Biomarkers for Imaging Purposes in Colorectal Cancer Using TArget Selection Criteria (TASC): A Novel Target Identification Tool.

    PubMed

    van Oosten, Marleen; Crane, Lucia Ma; Bart, Joost; van Leeuwen, Fijs W; van Dam, Gooitzen M

    2011-04-01

    Peritoneal carcinomatosis (PC) of colorectal origin is associated with a poor prognosis. However, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is available for a selected group of PC patients, which significantly increases overall survival rates up to 30%. As a consequence, there is substantial room for improvement. Tumor targeting is expected to improve the treatment efficacy of colorectal cancer (CRC) further through 1) more sensitive preoperative tumor detection, thus reducing overtreatment; 2) better intraoperative detection and surgical elimination of residual disease using tumor-specific intraoperative imaging; and 3) tumor-specific targeted therapeutics. This review focuses, in particular, on the development of tumor-targeted imaging agents. A large number of biomarkers are known to be upregulated in CRC. However, to date, no validated criteria have been described for the selection of the most promising biomarkers for tumor targeting. Such a scoring system might improve the selection of the correct biomarker for imaging purposes. In this review, we present the TArget Selection Criteria (TASC) scoring system for selection of potential biomarkers for tumor-targeted imaging. By applying TASC to biomarkers for CRC, we identified seven biomarkers (carcinoembryonic antigen, CXC chemokine receptor 4, epidermal growth factor receptor, epithelial cell adhesion molecule, matrix metalloproteinases, mucin 1, and vascular endothelial growth factor A) that seem most suitable for tumor-targeted imaging applications in colorectal cancer. Further cross-validation studies in CRC and other tumor types are necessary to establish its definitive value.

  8. Identifying Targets from Filtering Effects

    DTIC Science & Technology

    2012-10-24

    Introduction Considering a radar (or sonar) target as more than a simple point scatterer brings up the possibility of identifying the target based on the...2000. [8] M. Vespe, C. J. Baker, and H. D. Griffiths , "Automatic target regognition using multi-diversity radar," Radar, Sonar \\& Navigation, IET, vol...A. Taflove and S. C. Hagness, Computational Electrodynamics : The Finite Difference Time Domain Method. Norwood, MA: Artech House, 2005.

  9. Castration-resistant prostate cancer: potential targets and therapies.

    PubMed

    Parray, Aijaz; Siddique, Hifzur R; Nanda, Sanjeev; Konety, Badrinath R; Saleem, Mohammad

    2012-01-01

    The treatment landscape for patients with castration-resistant prostate cancer (CRPC) is undergoing significant changes with the advent of new therapies and multidisciplinary efforts by scientists and clinicians. As activation of multiple molecular pathways in the neoplastic prostate makes it impossible for single-target drugs to be completely effective in treating CRPC, this has led to combination therapy strategy, where several molecules involved in tumor growth and disease progression are targeted by a therapeutic regimen. In the present review, we provide an update on the molecular pathways that play an important role in the pathogenesis of CRPC and discuss the current wave of new treatments to combat this lethal disease.

  10. Potential Targets for Antifungal Drug Discovery Based on Growth and Virulence in Candida albicans.

    PubMed

    Li, Xiuyun; Hou, Yinglong; Yue, Longtao; Liu, Shuyuan; Du, Juan; Sun, Shujuan

    2015-10-01

    Fungal infections, especially infections caused by Candida albicans, remain a challenging problem in clinical settings. Despite the development of more-effective antifungal drugs, their application is limited for various reasons. Thus, alternative treatments with drugs aimed at novel targets in C. albicans are needed. Knowledge of growth and virulence in fungal cells is essential not only to understand their pathogenic mechanisms but also to identify potential antifungal targets. This article reviews the current knowledge of the mechanisms of growth and virulence in C. albicans and examines potential targets for the development of new antifungal drugs.

  11. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.

    PubMed

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com .

  12. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models

    NASA Astrophysics Data System (ADS)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.

  13. Targeting to the hair follicles: current status and potential.

    PubMed

    Wosicka, Hanna; Cal, Krzysztof

    2010-02-01

    The pilosebaceous unit is a complex structure that undergoes a specific growth cycle and comprises a few important drug targeting sites. For example, drugs can be targeted to the bulge region with stem cells or to the sebaceous glands. Interest in pilosebaceous units is directed towards their utilization as reservoirs for localized therapy and also as a transport pathway for systemic drug delivery. Improved investigative methods, such as differential stripping, are being developed in order to determine follicular penetration. This article reviews relevant aspects of effective follicle-targeting formulations and delivery systems as well as the activity status of hair follicles, and variations in follicle size and distribution throughout various body regions. Each of these factors strongly affects follicular permeation. We provide examples of improved penetration of particle-based formulations and of a size-dependent manner of follicular penetration. Contradictions are also discussed, indicating the need for detailed future investigations.

  14. Acylation in trypanosomatids: an essential process and potential drug target

    PubMed Central

    Goldston, Amanda M.; Sharma, Aabha I.; Paul, Kimberly S.; Engman, David M.

    2014-01-01

    Fatty acylation—the addition of fatty acid moieties such as myristate and palmitate to proteins—is essential for the survival, growth, and infectivity of the trypanosomatids: Trypanosoma brucei, Trypanosoma cruzi, and Leishmania. Myristoylation and palmitoylation are critical for parasite growth, targeting and localization, and the intrinsic function of some proteins. The trypanosomatids possess a single N-myristoyltransferase (NMT) and multiple palmitoyl acyltransferases, and these enzymes and their cellular targets are only now being characterized. Global inhibition of either process leads to cell death in trypanosomatids, and genetic ablation of NMT compromises virulence. Moreover, NMT inhibitors effectively cure T. brucei infection in rodents. Thus, protein acylation represents an attractive target for the development of trypanocidal drugs. PMID:24954795

  15. Phosphorylation events during viral infections provide potential therapeutic targets

    PubMed Central

    Keating, Julie A.; Striker, Rob

    2012-01-01

    SUMMARY For many medically relevant viruses, there is now considerable evidence that both viral and cellular kinases play important roles in viral infection. Ultimately, these kinases, and the cellular signaling pathways that they exploit, may serve as therapeutic targets for treating patients. Currently, small molecule inhibitors of kinases are under investigation as therapy for herpes viral infections. Additionally, a number of cellular or host-directed tyrosine kinase inhibitors that have been previously FDA-approved for cancer treatment are under study in animal models and clinical trials, as they have shown promise for the treatment of various viral infections as well. This review will highlight the wide range of viral proteins phosphorylated by viral and cellular kinases, and the potential for variability of kinase recognition sites within viral substrates to impact phosphorylation and kinase prediction. Research studying kinase-targeting prophylactic and therapeutic treatments for a number of viral infections will also be discussed. PMID:22113983

  16. Genetic determinants and potential therapeutic targets for pancreatic adenocarcinoma

    PubMed Central

    Reznik, Robert; Hendifar, Andrew E.; Tuli, Richard

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in both men and women in the United States, carrying a 5-year survival rate of approximately 5%, which is the poorest prognosis of any solid tumor type. Given the dismal prognosis associated with PDAC, a more thorough understanding of risk factors and genetic predisposition has important implications not only for cancer prevention, but also for screening techniques and the development of personalized therapies. While screening of the general population is not recommended or practicable with current diagnostic methods, studies are ongoing to evaluate its usefulness in people with at least 5- to 10-fold increased risk of PDAC. In order to help identify high-risk populations who would be most likely to benefit from early detection screening tests for pancreatic cancer, discovery of additional pancreatic cancer susceptibility genes is crucial. Thus, specific gene-based, gene-product, and marker-based testing for the early detection of pancreatic cancer are currently being developed, with the potential for these to be useful as potential therapeutic targets as well. The goal of this review is to provide an overview of the genetic basis for PDAC with a focus on germline and familial determinants. A discussion of potential therapeutic targets and future directions in screening and treatment is also provided. PMID:24624093

  17. Targeting nuclear transporters in cancer: Diagnostic, prognostic and therapeutic potential.

    PubMed

    Stelma, Tamara; Chi, Alicia; van der Watt, Pauline J; Verrico, Annalisa; Lavia, Patrizia; Leaner, Virna D

    2016-04-01

    The Karyopherin superfamily is a major class of soluble transport receptors consisting of both import and export proteins. The trafficking of proteins involved in transcription, cell signalling and cell cycle regulation among other functions across the nuclear membrane is essential for normal cellular functioning. However, in cancer cells, the altered expression or localization of nuclear transporters as well as the disruption of endogenous nuclear transport inhibitors are some ways in which the Karyopherin proteins are dysregulated. The value of nuclear transporters in the diagnosis, prognosis and treatment of cancer is currently being elucidated with recent studies highlighting their potential as biomarkers and therapeutic targets.

  18. CARD9 as a potential target in cardiovascular disease

    PubMed Central

    Peterson, Matthew R; Haller, Samantha E; Ren, Jun; Nair, Sreejayan; He, Guanglong

    2016-01-01

    Systemic inflammation and localized macrophage infiltration have been implicated in cardiovascular pathologies, including coronary artery disease, carotid atherosclerosis, heart failure, obesity-associated heart dysfunction, and cardiac fibrosis. Inflammation induces macrophage infiltration and activation and release of cytokines and chemokines, causing tissue dysfunction by instigating a positive feedback loop that further propagates inflammation. Cytosolic adaptor caspase recruitment domain family, member 9 (CARD9) is a protein expressed primarily by dendritic cells, neutrophils, and macrophages, in which it mediates cytokine secretion. The purpose of this review is to highlight the role of CARD9 as a potential target in inflammation-related cardiovascular pathologies. PMID:27920495

  19. Candidate genes and potential targets for therapeutics in Wilms' tumour.

    PubMed

    Blackmore, Christopher; Coppes, Max J; Narendran, Aru

    2010-09-01

    Wilms' tumour (WT) is the most common malignant renal tumour of childhood. During the past two decades or so, molecular studies carried out on biopsy specimens and tumour-derived cell lines have identified a multitude of chromosomal and epigenetic alterations in WT. In addition, a significant amount of evidence has been gathered to identify the genes and signalling pathways that play a defining role in its genesis, growth, survival and treatment responsiveness. As such, these molecules and mechanisms constitute potential targets for novel therapeutic strategies for refractory WT. In this report we aim to review some of the many candidate genes and intersecting pathways that underlie the complexities of WT biology.

  20. Statins as Targeted "Magical Pills" for the Conservative Treatment of Endometriosis: May Potential Adverse Effects on Female Fertility Represent the "Dark Side of the Same Coin"? A Systematic Review of Literature.

    PubMed

    Vitagliano, Amerigo; Noventa, Marco; Quaranta, Michela; Gizzo, Salvatore

    2016-04-01

    The aim of the study was to analyze all the available evidence from both in vitro and in vivo studies regarding the efficacy of statin therapy in the treatment of endometriosis, evaluating the potential efficacy, side effects, and contraindications of their administration in humans. We focused on defining the potential benefits that the administration of statins may have on patients affected by endometriosis and the possible adverse effects of such a therapy on ovarian function and fertility profile. According to our article selection criteria, we included in the review in vitro and in vivo studies performed on human or animal models. The systematic review of literature identified 24 eligible articles, 12 of which reported evidence regarding the effects of statins on endometrial/endometriotic cells and 12 regarding their effects on ovarian function and fertility. All articles seem to emphasize the utility of statin administration in the treatment of endometriosis due to their anti-proliferative/proapoptotic effects, their ability to reduce cell viability and migration, and the inhibition of angiogenesis and anti-inflammatory activities. Regarding the potential adverse effects on gonadal activities, steroidogenesis and fertility function, no conclusive data were collected in human models (excluding women affected by polycystic ovary syndrome in which significant decline of androgen levels was reported after statin treatment), while contrasting results were reported by studies conducted in in vitro and in vivo in animal models. Despite evidence supporting statins as the potential therapeutic agent for a targeted conservative treatment of endometriosis, the uncertainties regarding their impact on gonadal function may not define them as an appropriate therapy for all young fertile women.

  1. The in vitro and vivo effects of nuclear and cytosolic parafibromin expression on the aggressive phenotypes of colorectal cancer cells: a search of potential gene therapy target.

    PubMed

    Zheng, Hua-Chuan; Liu, Jia-Jie; Li, Jing; Wu, Ji-Cheng; Yang, Lei; Zhao, Gui-Feng; Zhao, Xin; Jiang, Hua-Mao; Huang, Ke-Qiang; Li, Zhi-Jie

    2017-02-16

    Down-regulated parafibromin is positively linked to the pathogenesis of parathyroid, lung, breast, ovarian, gastric and colorectal cancers. Here, we found that wild-type (WT) parafibromin overexpression suppressed proliferation, tumor growth, induced cell cycle arrest and apoptosis in colorectal cancer cells (p<0.05), but it was the converse for mutant-type (MT, mutation in nucleus localization sequence) parafibromin (p<0.05). Both WT and MT transfectants inhibited migration and invasion, and caused better differentiation (p<0.05) of cancer cells. WT parafibromin transfectants showed the overexpression of Cyclin B1, Cyclin D1, Cyclin E, p38, p53, and AIF in HCT-15 and HCT-116 cells, while MT parafibromin only up-regulated p38 expression. There was lower mRNA expression of bcl-2 in parafibromin transfectants than the control and mock, while higher expression of c-myc, Cyclin D1, mTOR, and Raptor. According to transcriptomic analysis, WT parafibromin suppressed PI3K-Akt and FoxO signaling pathways, while MT one promoted PI3K-Akt pathway, focal adhesion, and regulation of actin cytoskeleton. Parafibromin was less expressed in colorectal cancer than paired mucosa (p<0.05), and inversely correlated with its differentiation at both mRNA and protein levels (p<0.05). These findings indicated that WT parafibromin might reverse the aggressive phenotypes of colorectal cancer cells and be employed as a target for gene therapy. Down-regulated parafibromin expression might be closely linked to colorectal carcinogenesis and cancer differentiation.

  2. Modular Nanotransporters for Targeted Intracellular Delivery of Drugs: Folate Receptors as Potential Targets

    PubMed Central

    Slastnikova, Tatiana A.; Rosenkranz, Andrey A.; Zalutsky, Michael R.; Sobolev, Alexander S.

    2015-01-01

    The review is devoted to a subcellular drug delivery system, modular nanotransporters (MNT) that can penetrate into target cells and deliver a therapeutic into their subcellular compartments, particularly into the nucleus. The therapeutics which need such type of delivery belong to two groups: (i) those that exert their effect only when delivered into a certain cell compartment (like DNA delivered into the nucleus); and (ii) those drugs that are capable of exerting their effect in different parts of the cells, however there can be found a cell compartment that is the most sensitive to their effect. A particular interest attract such cytotoxic agents as Auger electron emitters which are known to be ineffective outside the cell nucleus, whereas they possess high cytotoxicity in the vicinity of nuclear DNA through the induction of non-reparable double-strand DNA breaks. The review discusses main approaches permitting to choose internalizable receptors permitting both recognition of target cells and penetration into them. Special interest attract folate receptors which become accessible to blood circulating therapeutics after malignant transformation or on activated macrophages which makes them an attractive target for both several oncological and inflammatory diseases, like atherosclerosis. In vitro and in vivo experiments demonstrated that MNT is a promising platform for targeted delivery of different therapeutics into the nuclei of target cells. PMID:25312738

  3. The trajectory of the target probability effect.

    PubMed

    Hon, Nicholas; Yap, Melvin J; Jabar, Syaheed B

    2013-05-01

    The effect of target probability on detection times is well-established: Even when detection accuracy is high, lower probability targets are detected more slowly than higher probability ones. Although this target probability effect on detection times has been well-studied, one aspect of it has remained largely unexamined: How the effect develops over the span of an experiment. Here, we investigated this issue with two detection experiments that assessed different target probability ratios. Conventional block segment analysis and linear mixed-effects modeling converged on two key findings. First, we found that the magnitude of the target probability effect increases as one progresses through a block of trials. Second, we found, by examining the trajectories of the low- and high-probability targets, that this increase in effect magnitude was driven by the low-probability targets. Specifically, we found that low-probability targets were detected more slowly as a block of trials progressed. Performance to high-probability targets, on the other hand, was largely invariant across the block. The latter finding is of particular interest because it cannot be reconciled with accounts that propose that the target probability effect is driven by the high-probability targets.

  4. Antiapoptotic Bcl-2 protein as a potential target for cancer therapy: A mini review.

    PubMed

    Jagani, Hitesh; Kasinathan, Narayanan; Meka, Sreenivasa Reddy; Josyula, Venkata Rao

    2016-08-01

    Bcl-2, an antiapoptotic protein, is considered as a potential target in cancer treatment since its oncogenic potential has been proven and is well documented. Antisense technology and RNA interference (RNAi) have been used to reduce the expression of the Bcl-2 gene in many types of cancer cells and are effective as adjuvant therapy along with the chemotherapeutic agents. The lack of appropriate delivery systems is considered to be the main hurdle associated with the RNAi. In this review, we discuss the antiapoptotic Bcl-2 protein, its oncogenic potential, and various approaches utilized to target Bcl-2 including suitable delivery systems employed for successful delivery of siRNA.

  5. Metabolic isoenzyme shifts in cancer as potential novel therapeutic targets.

    PubMed

    Ononye, S N; Shi, W; Wali, V B; Aktas, B; Jiang, T; Hatzis, C; Pusztai, L

    2014-12-01

    The functional redundancy of metabolic enzyme expression may present a new strategy for developing targeted therapies in cancer. To satisfy the increased metabolic demand required during neoplastic transformations and proliferation, cancer cells may rely on additional isoforms of a metabolic enzyme to satisfy the increased demand for metabolic precursors, which could subsequently render cancer cells more vulnerable to isoform-specific inhibitors. In this review, we provide a survey of common isoenzyme shifts that have been reported to be important in cancer metabolism and link those to metabolic pathways that currently have drugs in various stages of development. This phenomenon suggests a potentially new therapeutic strategy for the treatment of cancer by identifying shifts in the expression of metabolic isoenzymes between cancer and normal cells. We also delineate other putative metabolic isoenzymes that could be targets for novel targeted therapies for cancer. Changes in isoenzyme expression that occur during neoplastic transformations or in response to environmental pressure in cancer cells may result in isoenzyme diversity that may subsequently render cancer cells more vulnerable to isoform-specific inhibitors due to reliance on a single isoform to perform a vital enzymatic function.

  6. Melatonin Suppresses the Growth of Ovarian Cancer Cell Lines (OVCAR-429 and PA-1) and Potentiates the Effect of G1 Arrest by Targeting CDKs

    PubMed Central

    Shen, Ching-Ju; Chang, Chi-Chang; Chen, Yi-Tz; Lai, Chung-Sheng; Hsu, Yi-Chiang

    2016-01-01

    Melatonin is found in animals as well as plants. In animals, it is a hormone that anticipates the daily onset of darkness and regulates physiological functions, such as sleep timing, blood pressure, and reproduction. Melatonin has also been found to have anti-tumor properties. Malignant cancers are the most common cause of death, and the mortality rate of ovarian tumor is the highest among gynecological diseases. This study investigated the anti-tumor effects of melatonin on the ovarian cancer lines, OVCAR-429 and PA-1. We observed the accumulation of melatonin-treated cells in the G1 phase due to the down-regulation of CDK 2 and 4. Our results suggest that in addition to the known effects on prevention, melatonin may also provide anti-tumor activity in established ovarian cancer. PMID:26840297

  7. Potential Vaccine Targets against Rabbit Coccidiosis by Immunoproteomic Analysis

    PubMed Central

    Song, Hongyan; Dong, Ronglian; Qiu, Baofeng; Jing, Jin; Zhu, Shunxing; Liu, Chun; Jiang, Yingmei; Wu, Liucheng; Wang, Shengcun; Miao, Jin; Shao, Yixiang

    2017-01-01

    The aim of this study was to identify antigens for a vaccine or drug target to control rabbit coccidiosis. A combination of 2-dimensional electrophoresis, immunoblotting, and mass spectrometric analysis were used to identify novel antigens from the sporozoites of Eimeria stiedae. Protein spots were recognized by the sera of New Zealand rabbits infected artificially with E. stiedae. The proteins were characterized by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF/TOF-MS) analysis in combination with bioinformatics. Approximately 868 protein spots were detected by silver-staining, and a total of 41 immunoreactive protein spots were recognized by anti-E. stiedae sera. Finally, 23 protein spots were successfully identified. The proteins such as heat shock protein 70 and aspartyl protease may have potential as immunodiagnostic or vaccine antigens. The immunoreactive proteins were found to possess a wide range of biological functions. This study is the first to report the proteins recognized by sera of infected rabbits with E. stiedae, which might be helpful in identifying potential targets for vaccine development to control rabbit coccidiosis. PMID:28285502

  8. Potential Vaccine Targets against Rabbit Coccidiosis by Immunoproteomic Analysis.

    PubMed

    Song, Hongyan; Dong, Ronglian; Qiu, Baofeng; Jing, Jin; Zhu, Shunxing; Liu, Chun; Jiang, Yingmei; Wu, Liucheng; Wang, Shengcun; Miao, Jin; Shao, Yixiang

    2017-02-01

    The aim of this study was to identify antigens for a vaccine or drug target to control rabbit coccidiosis. A combination of 2-dimensional electrophoresis, immunoblotting, and mass spectrometric analysis were used to identify novel antigens from the sporozoites of Eimeria stiedae. Protein spots were recognized by the sera of New Zealand rabbits infected artificially with E. stiedae. The proteins were characterized by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF/TOF-MS) analysis in combination with bioinformatics. Approximately 868 protein spots were detected by silver-staining, and a total of 41 immunoreactive protein spots were recognized by anti-E. stiedae sera. Finally, 23 protein spots were successfully identified. The proteins such as heat shock protein 70 and aspartyl protease may have potential as immunodiagnostic or vaccine antigens. The immunoreactive proteins were found to possess a wide range of biological functions. This study is the first to report the proteins recognized by sera of infected rabbits with E. stiedae, which might be helpful in identifying potential targets for vaccine development to control rabbit coccidiosis.

  9. Two-component signal transduction as potential drug targets in pathogenic bacteria.

    PubMed

    Gotoh, Yasuhiro; Eguchi, Yoko; Watanabe, Takafumi; Okamoto, Sho; Doi, Akihiro; Utsumi, Ryutaro

    2010-04-01

    Gene clusters contributing to processes such as cell growth and pathogenicity are often controlled by two-component signal transduction systems (TCSs). Specific inhibitors against TCS systems work differently from conventional antibiotics, and developing them into new drugs that are effective against various drug-resistant bacteria may be possible. Furthermore, inhibitors of TCSs that control virulence factors may reduce virulence without killing the pathogenic bacteria. Previous TCS inhibitors targeting the kinase domain of the histidine kinase sensor suffered from poor selectivity. Recent TCS inhibitors, however, target the sensory domains of the sensors blocking the quorum sensing system, or target the essential response regulator. These new targets are introduced, together with several specific TCSs that have the potential to serve as effective drug targets. Copyright 2010 Elsevier Ltd. All rights reserved.

  10. Castration-resistant prostate cancer: potential targets and therapies

    PubMed Central

    Parray, Aijaz; Siddique, Hifzur R; Nanda, Sanjeev; Konety, Badrinath R; Saleem, Mohammad

    2012-01-01

    The treatment landscape for patients with castration-resistant prostate cancer (CRPC) is undergoing significant changes with the advent of new therapies and multidisciplinary efforts by scientists and clinicians. As activation of multiple molecular pathways in the neoplastic prostate makes it impossible for single-target drugs to be completely effective in treating CRPC, this has led to combination therapy strategy, where several molecules involved in tumor growth and disease progression are targeted by a therapeutic regimen. In the present review, we provide an update on the molecular pathways that play an important role in the pathogenesis of CRPC and discuss the current wave of new treatments to combat this lethal disease. PMID:22956858

  11. Increasing the potential for malaria elimination by targeting zoophilic vectors

    PubMed Central

    Waite, Jessica L.; Swain, Sunita; Lynch, Penelope A.; Sharma, S. K.; Haque, Mohammed Asrarul; Montgomery, Jacqui; Thomas, Matthew B.

    2017-01-01

    Countries in the Asia Pacific region aim to eliminate malaria by 2030. A cornerstone of malaria elimination is the effective management of Anopheles mosquito vectors. Current control tools such as insecticide treated nets or indoor residual sprays target mosquitoes in human dwellings. We find in a high transmission region in India, malaria vector populations show a high propensity to feed on livestock (cattle) and rest in outdoor structures such as cattle shelters. We also find evidence for a shift in vector species complex towards increased zoophilic behavior in recent years. Using a malaria transmission model we demonstrate that in such regions dominated by zoophilic vectors, existing vector control tactics will be insufficient to achieve elimination, even if maximized. However, by increasing mortality in the zoophilic cycle, the elimination threshold can be reached. Current national vector control policy in India restricts use of residual insecticide sprays to domestic dwellings. Our study suggests substantial benefits of extending the approach to treatment of cattle sheds, or deploying other tactics that target zoophilic behavior. Optimizing use of existing tools will be essential to achieving the ambitious 2030 elimination target. PMID:28091570

  12. Biological targets for therapeutic interventions in COPD: clinical potential

    PubMed Central

    Pelaia, Girolamo; Vatrella, Alessandro; Gallelli, Luca; Renda, Teresa; Caputi, Mario; Maselli, Rosario; Marsico, Serafino A

    2006-01-01

    COPD is a widespread inflammatory respiratory disorder characterized by a progressive, poorly reversible airflow limitation. Currently available therapies are mostly based on those used to treat asthma. However, such compounds are not able to effectively reduce the gradual functional deterioration, as well as the ongoing airway and lung inflammation occurring in COPD patients. Therefore, there is an urgent need to improve the efficacy of the existing drug classes and to develop new treatments, targeting the main cellular and molecular mechanisms underlying disease pathogenesis. These therapeutic strategies will be highlighted in the present review. PMID:18046869

  13. Therapeutic potential of HMGB1-targeting agents in sepsis

    PubMed Central

    Wang, Haichao; Zhu, Shu; Zhou, Rongrong; Li, Wei; Sama, Andrew E.

    2008-01-01

    Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. The inflammatory response is partly mediated by innate immune cells (such as macrophages, monocytes and neutrophils), which not only ingest and eliminate invading pathogens but also initiate an inflammatory response upon recognition of pathogen-associated molecular patterns (PAMPs). The prevailing theories of sepsis as a dysregulated inflammatory response, as manifested by excessive release of inflammatory mediators such as tumour necrosis factor and high-mobility group box 1 protein (HMGB1), are supported by extensive studies employing animal models of sepsis. Here we review emerging evidence that support extracellular HMGB1 as a late mediator of experimental sepsis, and discuss the therapeutic potential of several HMGB1-targeting agents (including neutralising antibodies and steroid-like tanshinones) in experimental sepsis. PMID:18980707

  14. Mitochondrial metals as a potential therapeutic target in neurodegeneration

    PubMed Central

    Grubman, A; White, A R; Liddell, J R

    2014-01-01

    Transition metals are critical for enzyme function and protein folding, but in excess can mediate neurotoxic oxidative processes. As mitochondria are particularly vulnerable to oxidative damage due to radicals generated during ATP production, mitochondrial biometal homeostasis must therefore be tightly controlled to safely harness the redox potential of metal enzyme cofactors. Dysregulation of metal functions is evident in numerous neurological disorders including Alzheimer's disease, stroke, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and Friedrich's ataxia. This review describes the mitochondrial metal defects in these disorders and highlights novel metal-based therapeutic approaches that target mitochondrial metal homeostasis in neurological disorders. Linked Articles This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8 PMID:24206195

  15. Hepatic macrophages in liver fibrosis: pathogenesis and potential therapeutic targets

    PubMed Central

    Li, Hai; You, Hong; Fan, Xu; Jia, Jidong

    2016-01-01

    Hepatic macrophages account for the largest non-parenchymal cell population in the liver. Recent studies have found that hepatic macrophages have different functions in different stages of experimental liver fibrosis. Some studies found that there are different types of hepatic macrophages in the liver, although others have suggested that hepatic macrophages could switch to different phenotypes in different environments. Many studies demonstrated that while hepatic macrophages promoted fibrosis through the recruitment of proinflammatory immune cells, and the secretion of proinflammatory cytokines and chemokines in the early stages, these also promoted the resolution of hepatic fibrosis through the secretion of matrix metalloproteinases in the late stages. This article will review the current role played by hepatic macrophages in liver fibrosis and the potential therapeutic targets that modulate hepatic macrophages. PMID:27252881

  16. Cognitive 'Omics': Pattern-Based Validation of Potential Drug Targets.

    PubMed

    Gyertyán, István

    2017-02-01

    Despite the abundance of cognitive enhancer mechanisms identified in basic research, drugs approved for cognitive disorders are scarce and of limited efficacy. Although the so-called 'gold-standard' animal assays are well suited to the study of fundamental learning processes, they fail to predict clinical efficacy against complex and robust cognitive defects. Preclinical validation of potential drug targets requires new approaches with higher translational value. Here I propose a rodent cognitive test system that encompasses several learning paradigms each modeling a certain human cognitive domain. Cognitive deficits are brought about by several impairing methods and a particular mechanism of action is tested on each defective cognitive function. The outcome is a cognitive efficacy pattern that should then be matched to the cognitive deficit patterns of the clinical disorders. The best fit will highlight the clinical indication with the greatest chance for success.

  17. The prokaryotic FAD synthetase family: a potential drug target.

    PubMed

    Serrano, Ana; Ferreira, Patricia; Martínez-Júlvez, Marta; Medina, Milagros

    2013-01-01

    Disruption of cellular production of the flavin cofactors, flavin adenine mononucleotide (FMN) and flavin adenine dinucleotide(FAD) will prevent the assembly of a large number of flavoproteins and flavoenzymes involved in key metabolic processes in all types of organisms. The enzymes responsible for FMN and FAD production in prokaryotes and eukaryotes exhibit various structural characteristics to catalyze the same chemistry, a fact that converts the prokaryotic FAD synthetase (FADS) in a potential drug target for the development of inhibitors endowed with anti-pathogenic activity. The first step before searching for selective inhibitors of FADS is to understand the structural and functional mechanisms for the riboflavin kinase and FMN adenylyltransferase activities of the prokaryotic enzyme, and particularly to identify their differential functional characteristics with regard to the enzymes performing similar functions in other organisms, particularly humans. In this paper, an overview of the current knowledge of the structure-function relationships in prokaryotic FADS has been presented, as well as of the state of the art in the use of these enzymes as drug targets.

  18. Cardiorenal syndrome: pathophysiology and potential targets for clinical management.

    PubMed

    Hatamizadeh, Parta; Fonarow, Gregg C; Budoff, Matthew J; Darabian, Sirous; Kovesdy, Csaba P; Kalantar-Zadeh, Kamyar

    2013-02-01

    Combined dysfunction of the heart and the kidneys, which can be associated with haemodynamic impairment, is classically referred to as cardiorenal syndrome (CRS). Cardiac pump failure with resulting volume retention by the kidneys, once thought to be the major pathophysiologic mechanism of CRS, is now considered to be only a part of a much more complicated phenomenon. Multiple body systems may contribute to the development of this pathologic constellation in an interconnected network of events. These events include heart failure (systolic or diastolic), atherosclerosis and endothelial cell dysfunction, uraemia and kidney failure, neurohormonal dysregulation, anaemia and iron disorders, mineral metabolic derangements including fibroblast growth factor 23, phosphorus and vitamin D disorders, and inflammatory pathways that may lead to malnutrition-inflammation-cachexia complex and protein-energy wasting. Hence, a pathophysiologically and clinically relevant classification of CRS based on the above components would be prudent. With the existing medical knowledge, it is almost impossible to identify where the process has started in any given patient. Rather, the events involved are closely interrelated, so that once the process starts at a particular point, other pathways of the network are potentially activated. Current therapies for CRS as well as ongoing studies are mostly focused on haemodynamic adjustments. The timely targeting of different components of this complex network, which may eventually lead to haemodynamic and vascular compromise and cause refractoriness to conventional treatments, seems necessary. Future studies should focus on interventions targeting these components.

  19. Dihydrofolate reductase: A potential drug target in trypanosomes and leishmania

    NASA Astrophysics Data System (ADS)

    Zuccotto, Fabio; Martin, Andrew C. R.; Laskowski, Roman A.; Thornton, Janet M.; Gilbert, Ian H.

    1998-05-01

    Dihydrofolate reductase has successfully been used as a drug target in the area of anti-cancer, anti-bacterial and anti-malarial chemotherapy. Little has been done to evaluate it as a drug target for treatment of the trypanosomiases and leishmaniasis. A crystal structure of Leishmania major dihydrofolate reductase has been published. In this paper, we describe the modelling of Trypanosoma cruzi and Trypanosoma brucei dihydrofolate reductases based on this crystal structure. These structures and models have been used in the comparison of protozoan, bacterial and human enzymes in order to highlight the different features that can be used in the design of selective anti-protozoan agents. Comparison has been made between residues present in the active site, the accessibility of these residues, charge distribution in the active site, and the shape and size of the active sites. Whilst there is a high degree of similarity between protozoan, human and bacterial dihydrofolate reductase active sites, there are differences that provide potential for selective drug design. In particular, we have identified a set of residues which may be important for selective drug design and identified a larger binding pocket in the protozoan than the human and bacterial enzymes.

  20. Potential drug targets for calcific aortic valve disease

    PubMed Central

    Hutcheson, Joshua D.; Aikawa, Elena; Merryman, W. David

    2014-01-01

    Calcific aortic valve disease (CAVD) is a major contributor to cardiovascular morbidity and mortality and, given its association with age, the prevalence of CAVD is expected to continue to rise as global life expectancy increases. No drug strategies currently exist to prevent or treat CAVD. Given that valve replacement is the only available clinical option, patients often cope with a deteriorating quality of life until diminished valve function demands intervention. The recognition that CAVD results from active cellular mechanisms suggests that the underlying pathways might be targeted to treat the condition. However, no such therapeutic strategy has been successfully developed to date. One hope was that drugs already used to treat vascular complications might also improve CAVD outcomes, but the mechanisms of CAVD progression and the desired therapeutic outcomes are often different from those of vascular diseases. We, therefore, discuss the benchmarks that must be met by a CAVD treatment approach, and highlight advances in the understanding of CAVD mechanisms to identify potential novel therapeutic targets. PMID:24445487

  1. Aldehyde dehydrogenases in cancer stem cells: potential as therapeutic targets

    PubMed Central

    Clark, David W.

    2016-01-01

    Resistance to current chemotherapeutic or radiation-based cancer treatment strategies is a serious concern. Cancer stem cells (CSCs) are typically able to evade treatment and establish a recurrent tumor or metastasis, and it is these that lead to the majority of cancer deaths. Therefore, a major current goal is to develop treatment strategies that eliminate the resistant CSCs as well as the bulk tumor cells in order to achieve complete disease clearance. Aldehyde dehydrogenases (ALDHs) are important for maintenance and differentiation of stem cells as well as normal development. There is expanding evidence that ALDH expression increases in response to therapy and promotes chemoresistance and survival mechanisms in CSCs. This perspective will discuss a paper by Cojoc and colleagues recently published in Cancer Research, that indicates ALDHs play a key role in resistance to radiation therapy and tumor recurrence in prostate cancer. The authors suggest that ALDHs are a potential therapeutic target for treatment prostate cancer patients to limit radiation resistance and disease recurrence. The findings are consistent with work from other cancers showing ALDHs are major contributors of CSC signaling and resistance to anti-cancer treatments. This perspective will address representative work concerning the validity of ALDH and the associated retinoic acid signaling pathway as chemotherapeutic targets for prostate as well as other cancers. PMID:28149880

  2. PD-1 as a potential target in cancer therapy.

    PubMed

    McDermott, David F; Atkins, Michael B

    2013-10-01

    Recently, an improved understanding of the molecular mechanisms governing the host response to tumors has led to the identification of checkpoint signaling pathways involved in limiting the anticancer immune response. One of the most critical checkpoint pathways responsible for mediating tumor-induced immune suppression is the programmed death-1 (PD-1) pathway, normally involved in promoting tolerance and preventing tissue damage in settings of chronic inflammation. Many human solid tumors express PD ligand 1 (PD-L1), and this is often associated with a worse prognosis. Tumor-infiltrating lymphocytes from patients with cancer typically express PD-1 and have impaired antitumor functionality. Proof-of-concept has come from several preclinical studies in which blockade of PD-1 or PD-L1 enhanced T-cell function and tumor cell lysis. Three monoclonal antibodies against PD-1, and one against PD-L1, have reported phase 1 data. All four agents have shown encouraging preliminary activity, and those that have been evaluated in larger patient populations appear to have encouraging safety profiles. Additional data are eagerly awaited. This review summarizes emerging clinical data and potential of PD-1 pathway-targeted antibodies in development. If subsequent investigations confirm the initial results, it is conceivable that agents blocking the PD-1/PD-L1 pathway will prove valuable additions to the growing armamentarium of targeted immunotherapeutic agents.

  3. Analyzing the Effectiveness of Targeted Instruction

    ERIC Educational Resources Information Center

    Hibbs, Eric Michael

    2010-01-01

    This action research study examines targeted instruction and its effect on academic referrals to elementary intervention and referral service committees. The West Harvard School District was not effectively utilizing targeted instruction, and there was a distinct lack of a differentiated vision throughout the district. This lack of differentiation…

  4. The natural flavonoid pinocembrin: molecular targets and potential therapeutic applications

    PubMed Central

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

    2015-01-01

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

  5. Sigma receptors as potential therapeutic targets for neuroprotection.

    PubMed

    Nguyen, Linda; Kaushal, Nidhi; Robson, Matthew J; Matsumoto, Rae R

    2014-11-15

    Sigma receptors comprise a unique family of proteins that have been implicated in the pathophysiology and treatment of many central nervous system disorders, consistent with their high level of expression in the brain and spinal cord. Mounting evidence indicate that targeting sigma receptors may be particularly beneficial in a number of neurodegenerative conditions including Alzheimer׳s disease, Parkinson׳s disease, stroke, methamphetamine neurotoxicity, Huntington׳s disease, amyotrophic lateral sclerosis, and retinal degeneration. In this perspective, a brief overview is given on sigma receptors, followed by a focus on common mechanisms of neurodegeneration that appear amenable to modulation by sigma receptor ligands to convey neuroprotective effects and/or restorative functions. Within each of the major mechanisms discussed herein, the neuroprotective effects of sigma ligands are summarized, and when known, the specific sigma receptor subtype(s) involved are identified. Together, the literature suggests sigma receptors may provide a novel target for combatting neurodegenerative diseases through both neuronal and glial mechanisms. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. DEPDC5 as a potential therapeutic target for epilepsy.

    PubMed

    Myers, Kenneth A; Scheffer, Ingrid E

    2017-06-01

    Dishevelled, Egl-10 and Pleckstrin (DEP) domain-containing protein 5 (DEPDC5) is a protein subunit of the GTPase-activating proteins towards Rags 1 (GATOR1) complex. GATOR1 is a recently identified modulator of mechanistic target of rapamycin (mTOR) activity. mTOR is a key regulator of cell proliferation and metabolism; disruption of the mTOR pathway is implicated in focal epilepsy, both acquired and genetic. Tuberous sclerosis is the prototypic mTOR genetic syndrome with epilepsy, however GATOR1 gene mutations have recently been shown to cause lesional and non-lesional focal epilepsy. Areas covered: This review summarizes the mTOR pathway, including regulators and downstream effectors, emphasizing recent developments in the understanding of the complex role of the GATOR1 complex. We review the epilepsy types associated with mTOR overactivity, including tuberous sclerosis, polyhydramnios megalencephaly symptomatic epilepsy, cortical dysplasia, non-lesional focal epilepsy and post-traumatic epilepsy. Currently available mTOR inhibitors are discussed, primarily rapamycin analogs and ATP competitive mTOR inhibitors. Expert opinion: DEPDC5 is an attractive therapeutic target in focal epilepsy, as effects of DEPDC5 agonists would likely be anti-epileptogenic and more selective than currently available mTOR inhibitors. Therapeutic effects might be synergistic with certain existing dietary therapies, including the ketogenic diet.

  7. Adiponectin isoforms: a potential therapeutic target in rheumatoid arthritis?

    PubMed

    Frommer, Klaus W; Schäffler, Andreas; Büchler, Christa; Steinmeyer, Jürgen; Rickert, Markus; Rehart, Stefan; Brentano, Fabia; Gay, Steffen; Müller-Ladner, Ulf; Neumann, Elena

    2012-10-01

    Several clinical studies have suggested the adipocytokine adiponectin is involved in the progression of rheumatoid arthritis (RA). From this point of view, adiponectin might present a new therapeutic target. However, as adiponectin also exerts beneficial effects in the human organism, a strategy that would allow its detrimental effects to be abolished while maintaining the positive effects would be highly favourable. To elucidate such a strategy, the authors analysed whether the different adiponectin isoforms induce diverging effects, especially with regard to rheumatoid arthritis synovial fibroblasts (RASF), a central cell type in RA pathogenesis capable of invading into and destroying cartilage. Affymetrix microarrays were used to screen for changes in gene expression of RASF. Messenger RNA levels were quantified by real-time PCR, protein levels by immunoassay. The migration of RASF and primary human lymphocytes was analysed using a two-chamber migration assay. In RASF, the individual adiponectin isoforms induced numerous genes/proteins relevant in RA pathogenesis to clearly different extents. In general, the most potent isoforms were the high molecular weight/middle molecular weight isoforms and the globular isoform, while the least potent isoform was the adiponectin trimer. The chemokines secreted by RASF upon adiponectin stimulation resulted in an increased migration of RASF and lymphocytes. The results clearly suggest a pro-inflammatory and joint-destructive role of all adiponectin isoforms in RA pathophysiology, indicating that in chronic inflammatory joint diseases the detrimental effects outweigh the beneficial effects of adiponectin.

  8. Heat Shock Protein 70s as Potential Molecular Targets for Colon Cancer Therapeutics.

    PubMed

    Black, Jennifer D; Rezvani, Khosrow

    2016-01-01

    Targeted drugs modulate selective pathways activated or repressed only in cancer cells, resulting in a higher response to chemotherapy with less severe side effects. The use of a selected member of the heat shock protein 70 family (HSP70) as an effective therapeutic target in the treatment of colorectal cancer (CRC) will be the focus of this review. We generated two main questions for this study: 1) What are the current and potential future molecular therapies in CRC? 2) Can selective members of the HSP70 family advance drug design and drug discovery for treatment of CRC patients? We discuss related articles based on their significance and translational contributions to the existing literature. The first part of this review discusses molecularly targeted agents that are currently used successfully in the clinic for the treatment of patients with CRC and highlights several novel targeted agents that are being investigated in ongoing trials. The second part of this review focuses on the unique tumorigenic functions of heat shock proteins, particularly mortalin-2, an essential heat shock protein for mitochondrial biogenesis in normal cells and a dominant oncoprotein in colon cancer cells. Basic and clinical studies have justified mortalin-2 as a potential molecular target, and its inhibition could dramatically improve patients' responses to standard chemotherapies. Further understanding of the contributions of HSP70 family members to CRC at the molecular level, combined with translation of new concepts into effective targeted therapies, are anticipated to improve clinical outcomes and increase the therapeutic synergy with combination treatment with cytotoxic agents.

  9. Microbiome and Potential Targets for Chemoprevention of Esophageal Adenocarcinoma

    PubMed Central

    Neto, Antonio Galvao; Whitaker, April; Pei, Zhiheng

    2015-01-01

    Esophageal cancer is one of the deadliest cancers, with a dismal prognosis. It is increasingly recognized that esophageal cancer is a heterogeneous disease. It can be subdivided into two distinct groups: squamous cell carcinoma and adenocarcinoma, based on histological appearance. In the Western world, the incidence of squamous cell carcinoma was considerably higher than esophageal adenocarcinoma (EA) until the 1990s when, due to a dramatic increase, the incidence of EA surpassed that of squamous cell carcinoma. EA typically follows a well-established stepwise evolution from chronic inflammation due to reflux esophagitis (RE) that progresses to metaplasia (Barrett’s esophagus- BE) to dysplasia, which often culminates in EA. The pathophysiology of EA is complex and involves diverse factors, including gastroesophageal reflux, gastric acid secretion, dysfunction of the antireflux barrier, gastric emptying disturbances, and abnormalities in esophageal defense mechanisms. The current understanding of the etiology of EA is mainly derived from epidemiological studies of risk factors such as cigarette smoking, obesity, gastroesophageal reflux disorders (GERD), and low fruit and vegetable consumption. Numerous studies have been done but the factors that drive the dynamic increase in the incidence of EA remain elusive. The advent of widespread antibiotic use occurred in the 1950s, preceding the surge of EA. Based on this temporal sequence, it has been hypothesized that antibiotics alter the microbiome to which the esophagus is exposed in patients who have GERD and that chronic exposure to this abnormal microbiome (i.e., changes in species diversity or abundance) accounts for the increase in EA. If changes in the proposed factors alter the stepwise progression (RE-BE-dysplasia- EA), they may represent potential targets for chemoprevention. New discoveries will help improve our understanding of the biology and pathogenesis of these cancers, and aid in finding novel

  10. Brown fat tissue - a potential target to combat obesity.

    PubMed

    Ginter, E; Simko, V

    2012-01-01

    From the global population perspective, the epidemic of "globesity" (more than one billion adults being overweight) represents one of the largest public health problems (1). Traditional reasoning related to the dysbalance between caloric intake and energy expenditure does not provide a satisfying explanation for a complexfailure to combat obesity. The brown adipose tisue (BAT) has a unique chemical structure and a specific metabolic role. A potential preventive co-factor is thermogenesis. BAT has the ability to dissipate energy byproducing heat, rather than storing energy as triglycerides. The cells of the white adipose tissue (WAT) contain one large globule of triglycerides which displaces the cell nucleus and other cell organelles excentrically, to the cell periphery. BAT contains numerous smaller droplets of triglycerides, much higher number of mitochondria and a specific uncoupling protein 1 or thermogenin. This specialized protein uncouples ATP production from mitochondrial respiration and converts energy into heat. Using sophisticated diagnostic techniques (e.g. imaging combination of positron-emisson tomography and computed tomography), scientists confirmed the importance of BAT not only in the newborn but also in adults who were found to possess considerable body stores of BAT.The highest proportion of BAT has been detected in lean individuals. As the body mass increases, BAT proportionately drops. Data both from animal and human studies suggest that BAT and mitochondrial uncoupling can be targeted for interventions to prevent and treat obesity. Melatonin and arginine have been proposed as possible interventional tools. The scientific world eagerly awaits further advanced studies to document possible metabolic and pharmacologic interventions, using BAT as a primary target to prevent and manage obesity (Fig. 5, Ref. 41).

  11. Microbiome and potential targets for chemoprevention of esophageal adenocarcinoma.

    PubMed

    Neto, Antonio Galvao; Whitaker, April; Pei, Zhiheng

    2016-02-01

    Esophageal cancer is one of the deadliest cancers, with a dismal prognosis. It is increasingly recognized that esophageal cancer is a heterogeneous disease. It can be subdivided into two distinct groups: squamous cell carcinoma and adenocarcinoma, based on histological appearance. In the Western world, the incidence of squamous cell carcinoma was considerably higher than esophageal adenocarcinoma (EA) until the 1990s when, due to a dramatic increase, the incidence of EA surpassed that of squamous cell carcinoma. EA typically follows a well-established stepwise evolution from chronic inflammation due to reflux esophagitis (RE) that progresses to metaplasia (Barrett's esophagus [BE]) to dysplasia, which often culminates in EA. The pathophysiology of EA is complex and involves diverse factors, including gastroesophageal reflux, gastric acid secretion, dysfunction of the antireflux barrier, gastric emptying disturbances, and abnormalities in esophageal defense mechanisms. The current understanding of the etiology of EA is mainly derived from epidemiological studies of risk factors such as cigarette smoking, obesity, gastroesophageal reflux disorders (GERD), and low fruit and vegetable consumption. Numerous studies have been done, but the factors that drive the dynamic increase in the incidence of EA remain elusive. The advent of widespread antibiotic use occurred in the 1950s, preceding the surge of EA. Based on this temporal sequence, it has been hypothesized that antibiotics alter the microbiome to which the esophagus is exposed in patients who have GERD and that chronic exposure to this abnormal microbiome (ie, changes in species diversity or abundance) accounts for the increase in EA. If changes in the proposed factors alter the stepwise progression (RE-BE-dysplasia-EA), they may represent potential targets for chemoprevention. New discoveries will help improve our understanding of the biology and pathogenesis of these cancers, and aid in finding novel therapeutic

  12. [Alternative splicing: a novel pharmacological target with wide therapeutic potential].

    PubMed

    Jeanteur, Philippe; Tazi, Jamal

    2005-05-01

    Alternative splicing is a process by which a single stretch of genomic DNA yields several mRNAs encoding different proteins. Once believed to be a marginal phenomenon, alternative splicing now appears to be widespread among higher organisms and to be behind a large repertoire of human diseases. It involves a flexible mechanism for selecting splice sites, based on regulatory sequences recognized by cognate trans-acting protein factors (stimulatory SR proteins, or their antagonists). This RNA-protein interaction provides two types of targets for therapeutic manipulation. Masking regulatory RNA sequences with an antisense strategy is the most obvious, and encouraging results are beginning to accrue. Our lab is currently developing an entirely new approach in which activating proteins are targeted by small chemical molecules. A large screening program has been conducted with the chemical library from the Curie Institute. Several molecules (all indole derivatives) were found to counter the stimulatory effects of individual activating proteins, and have been selected for further development.

  13. Targeting glutamate homeostasis for potential treatment of nicotine dependence

    PubMed Central

    Alasmari, Fawaz; Al-Rejaie, Salim S.; AlSharari, Shakir D.; Sari, Youssef

    2015-01-01

    Several studies demonstrated that impairment in glutamatergic neurotransmission is linked to drug dependence and drug-seeking behavior. Increased extracellular glutamate concentration in mesocorticolimbic regions has been observed in animals developing nicotine dependence. Changes in glutamate release might be associated with stimulatory effect of nicotinic acetylcholine receptors (nAChRs) via nicotine exposure. We and others have shown increased extracellular glutamate concentration, which was associated with downregulation of the major glutamate transporter, glutamate transporter 1 (GLT-1), in brain reward regions of animals exposed to drug abuse, including nicotine and ethanol. Importantly, studies from our laboratory and others showed that upregulation of GLT-1 expression in the mesocorticolimbic brain regions may have potential therapeutic effects in drug dependence. In this review article, we discussed the effect of antagonizing presynaptic nAChRs in glutamate release, the upregulatory effect in GLT-1 expression and the role of glutamate receptors antagonists in the treatment of nicotine dependence. PMID:26589642

  14. Nutraceuticals: Potential for Chondroprotection and Molecular Targeting of Osteoarthritis

    PubMed Central

    Leong, Daniel J.; Choudhury, Marwa; Hirsh, David M.; Hardin, John A.; Cobelli, Neil J.; Sun, Hui B.

    2013-01-01

    Osteoarthritis (OA) is a degenerative joint disease and a leading cause of adult disability. There is no cure for OA, and no effective treatments which arrest or slow its progression. Current pharmacologic treatments such as analgesics may improve pain relief but do not alter OA disease progression. Prolonged consumption of these drugs can result in severe adverse effects. Given the nature of OA, life-long treatment will likely be required to arrest or slow its progression. Consequently, there is an urgent need for OA disease-modifying therapies which also improve symptoms and are safe for clinical use over long periods of time. Nutraceuticals—food or food products that provide medical or health benefits, including the prevention and/or treatment of a disease—offer not only favorable safety profiles, but may exert disease- and symptom-modification effects in OA. Forty-seven percent of OA patients use alternative medications, including nutraceuticals. This review will overview the efficacy and mechanism of action of commonly used nutraceuticals, discuss recent experimental and clinical data on the effects of select nutraceuticals, such as phytoflavonoids, polyphenols, and bioflavonoids on OA, and highlight their known molecular actions and limitations of their current use. We will conclude with a proposed novel nutraceutical-based molecular targeting strategy for chondroprotection and OA treatment. PMID:24284399

  15. Targeting CBLB as a Potential Therapeutic Approach for Disseminated Candidiasis

    PubMed Central

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

    2016-01-01

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

  16. Hydrogen Sulfide as a Potential Therapeutic Target in Fibrosis

    PubMed Central

    Zhang, Shufang; Pan, Chuli; Zhou, Feifei; Yuan, Zhi; Wang, Huiying; Cui, Wei; Zhang, Gensheng

    2015-01-01

    Hydrogen sulfide (H2S), produced endogenously by the activation of two major H2S-generating enzymes (cystathionine β-synthase and cystathionine γ-lyase), plays important regulatory roles in different physiologic and pathologic conditions. The abnormal metabolism of H2S is associated with fibrosis pathogenesis, causing damage in structure and function of different organs. A number of in vivo and in vitro studies have shown that both endogenous H2S level and the expressions of H2S-generating enzymes in plasma and tissues are significantly downregulated during fibrosis. Supplement with exogenous H2S mitigates the severity of fibrosis in various experimental animal models. The protective role of H2S in the development of fibrosis is primarily attributed to its antioxidation, antiapoptosis, anti-inflammation, proangiogenesis, and inhibition of fibroblasts activities. Future studies might focus on the potential to intervene fibrosis by targeting the pathway of endogenous H2S-producing enzymes and H2S itself. PMID:26078809

  17. Nrf2: a potential therapeutic target for diabetic neuropathy.

    PubMed

    Kumar, Anil; Mittal, Ruchika

    2017-08-01

    Different aspects involved in pathophysiology of diabetic neuropathy are related to inflammatory and apoptotic pathways. This article summarizes evidence that Nrf2 acts as a bridging link in various inflammatory and apoptotic pathways impacting progression of diabetic neuropathy. Nrf2 is involved in expression of various antioxidant proteins (such as detoxifying enzymes) via antioxidant response element (ARE) binding site. Under normal conditions, Nrf2 is inactive and remains in the cytosol. Hyperglycemia is a strong stimulus for oxidative stress and inflammation that downregulates the activity of Nrf2 through various neuroinflammatory pathways. Acute hyperglycemia increases the expression of Nrf2, but persistent hyperglycemia decreases its expression. This downregulation of Nrf2 causes various microvascular changes, which result in diabetic neuropathy. The key contribution of Nrf2 in progression of diabetic neuropathy has been summarized in the article. Despite involvement of Nrf2 in progression of diabetic neuropathy, targeting Nrf2 activators as a therapeutic potential will provide important new insights into the ways that influence treatment of diabetic neuropathy.

  18. Pyruvate Kinase M2: A Potential Target for Regulating Inflammation

    PubMed Central

    Alves-Filho, Jose C.; Pålsson-McDermott, Eva M.

    2016-01-01

    Pyruvate kinase (PK) is the enzyme responsible for catalyzing the last step of glycolysis. Of the four PK isoforms expressed in mammalian cells, PKM2 has generated the most interest due to its impact on changes in cellular metabolism observed in cancer as well as in activated immune cells. As our understanding of dysregulated metabolism in cancer develops, and in light of the growing field of immunometabolism, intense efforts are in place to define the mechanism by which PKM2 regulates the metabolic profile of cancer as well as of immune cells. The enzymatic activity of PKM2 is heavily regulated by endogenous allosteric effectors as well as by intracellular signaling pathways, affecting both the enzymatic activity of PKM2 as a PK and the regulation of the recently described non-canonical nuclear functions of PKM2. We here review the current literature on PKM2 and its regulation, and discuss the potential for this protein as a therapeutic target in inflammatory disorders. PMID:27148264

  19. TRPV1: A Potential Drug Target for Treating Various Diseases

    PubMed Central

    Brito, Rafael; Sheth, Sandeep; Mukherjea, Debashree; Rybak, Leonard P.; Ramkumar, Vickram

    2014-01-01

    Transient receptor potential vanilloid 1 (TRPV1) is an ion channel present on sensory neurons which is activated by heat, protons, capsaicin and a variety of endogenous lipids termed endovanilloids. As such, TRPV1 serves as a multimodal sensor of noxious stimuli which could trigger counteractive measures to avoid pain and injury. Activation of TRPV1 has been linked to chronic inflammatory pain conditions and peripheral neuropathy, as observed in diabetes. Expression of TRPV1 is also observed in non-neuronal sites such as the epithelium of bladder and lungs and in hair cells of the cochlea. At these sites, activation of TRPV1 has been implicated in the pathophysiology of diseases such as cystitis, asthma and hearing loss. Therefore, drugs which could modulate TRPV1 channel activity could be useful for the treatment of conditions ranging from chronic pain to hearing loss. This review describes the roles of TRPV1 in the normal physiology and pathophysiology of selected organs of the body and highlights how drugs targeting this channel could be important clinically. PMID:24861977

  20. Ion Channels in Obesity: Pathophysiology and Potential Therapeutic Targets

    PubMed Central

    Vasconcelos, Luiz H. C.; Souza, Iara L. L.; Pinheiro, Lílian S.; Silva, Bagnólia A.

    2016-01-01

    Obesity is a multifactorial disease related to metabolic disorders and associated with genetic determinants. Currently, ion channels activity has been linked to many of these disorders, in addition to the central regulation of food intake, energetic balance, hormone release and response, as well as the adipocyte cell proliferation. Therefore, the objective of this work is to review the current knowledge about the influence of ion channels in obesity development. This review used different sources of literature (Google Scholar, PubMed, Scopus, and Web of Science) to assess the role of ion channels in the pathophysiology of obesity. Ion channels present diverse key functions, such as the maintenance of physiological homeostasis and cell proliferation. Cell biology and pharmacological experimental evidences demonstrate that proliferating cells exhibit ion channel expression, conductance, and electrical properties different from the resting cells. Thereby, a large variety of ion channels has been identified in the pathogenesis of obesity such as potassium, sodium, calcium and chloride channels, nicotinic acetylcholine receptor and transient receptor potential channels. The fundamental involvement of these channels on the generation of obesity leads to the progress in the knowledge about the mechanisms responsible for the obesity pathophysiology, consequently emerging as new targets for pharmacological modulation. PMID:27065858

  1. Myocardial fibroblast-matrix interactions and potential therapeutic targets.

    PubMed

    Goldsmith, Edie C; Bradshaw, Amy D; Zile, Michael R; Spinale, Francis G

    2014-05-01

    The cardiac extracellular matrix (ECM) is a dynamic structure, adapting to physiological and pathological stresses placed on the myocardium. Deposition and organization of the matrix fall under the purview of cardiac fibroblasts. While often overlooked compared to myocytes, fibroblasts play a critical role in maintaining ECM homeostasis under normal conditions and in response to pathological stimuli assume an activated, myofibroblast phenotype associated with excessive collagen accumulation contributing to impaired cardiac function. Complete appreciation of fibroblast function is hampered by the lack of fibroblast-specific reagents and the heterogeneity of fibroblast precursors. This is further complicated by our ability to dissect the role of myofibroblasts versus fibroblasts in myocardial in remodeling. This review highlights critical points in the regulation of collagen deposition by fibroblasts, the current panel of molecular tools used to identify fibroblasts and the role of fibroblast-matrix interactions in fibroblast function and differentiation into the myofibroblast phenotype. The clinical potential of exploiting differences between fibroblasts and myofibroblasts and using them to target specific fibroblast populations is also discussed. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium." Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. [Epigenetic mechanisms and alcohol use disorders: a potential therapeutic target].

    PubMed

    Legastelois, Rémi; Jeanblanc, Jérôme; Vilpoux, Catherine; Bourguet, Erika; Naassila, Mickael

    2017-01-01

    both the motivation to consume ethanol (25% decrease), relapse (by about 50%) and postponed reacquisition after abstinence. Both literature and several of our studies strongly support the potential therapeutic interest of targeting epigenetic mechanisms in excessive alcohol drinking and strengthen theinterest of focusing on specific isoforms of histone deacetylases. © Société de Biologie, 2017.

  3. Pharmacoinformatics elucidation of potential drug targets against migraine to target ion channel protein KCNK18

    PubMed Central

    Sehgal, Sheikh Arslan; Hassan, Mubashir; Rashid, Sajid

    2014-01-01

    Migraine, a complex debilitating neurological disorder is strongly associated with potassium channel subfamily K member 18 (KCNK18). Research has emphasized that high levels of KCNK18 may be responsible for improper functioning of neurotransmitters, resulting in neurological disorders like migraine. In the present study, a hybrid approach of molecular docking and virtual screening were followed by pharmacophore identification and structure modeling. Screening was performed using a two-dimensional similarity search against recommended migraine drugs, keeping in view the physicochemical properties of drugs. LigandScout tool was used for exploring pharmacophore properties and designing novel molecules. Here, we report the screening of four novel compounds that have showed maximum binding affinity against KCNK18, obtained through the ZINC database, and Drug and Drug-Like libraries. Docking studies revealed that Asp-46, Ile-324, Ile-44, Gly-118, Leu-338, Val-113, and Phe-41 are critical residues for receptor–ligand interaction. A virtual screening approach coupled with docking energies and druglikeness rules illustrated that ergotamine and PB-414901692 are potential inhibitor compounds for targeting KCNK18. We propose that selected compounds may be more potent than the previously listed drug analogs based on the binding energy values. Further analysis of these inhibitors through site-directed mutagenesis could be helpful for exploring the details of ligand-binding pockets. Overall, the findings of this study may be helpful for designing novel therapeutic targets to cure migraine. PMID:24899801

  4. Integrative exploration of genomic profiles for triple negative breast cancer identifies potential drug targets

    PubMed Central

    Wang, Xiaosheng; Guda, Chittibabu

    2016-01-01

    different types of genomic data to molecularly characterize TNBC and identify potential targets for TNBC therapy. The integrative analysis of genomic profiles for TNBC could assist in identifying potential new therapeutic targets and predicting the effectiveness of a targeted treatment strategy for TNBC therapy. PMID:27472710

  5. Potential surgical targets for deep brain stimulation in treatment-resistant depression.

    PubMed

    Hauptman, Jason S; DeSalles, Antonio A F; Espinoza, Randall; Sedrak, Mark; Ishida, Warren

    2008-01-01

    The goal of this study was to evaluate the definition of treatment-resistant depression (TRD), review the literature regarding deep brain stimulation (DBS) for TRD, and identify potential anatomical and functional targets for future widespread clinical application. A comprehensive literature review was performed to determine the current status of DBS for TRD, with an emphasis on the scientific support for various implantation sites. The definition of TRD is presented, as is its management scheme. The rationale behind using DBS for depression is reviewed. Five potential targets have been identified in the literature: ventral striatum/nucleus accumbens, subgenual cingulate cortex (area 25), inferior thalamic peduncle, rostral cingulate cortex (area 24a), and lateral habenula. Deep brain stimulation electrodes thus far have been implanted and activated in only the first 3 of these structures in humans. These targets have proven to be safe and effective, albeit in a small number of cases. Surgical intervention for TRD in the form of DBS is emerging as a viable treatment alternative to existing modalities. Although the studies reported thus far have small sample sizes, the results appear to be promising. Various surgical targets, such as the subgenual cingulate cortex, inferior thalamic peduncle, and nucleus accumbens, have been shown to be safe and to lead to beneficial effects with various stimulation parameters. Further studies with larger patient groups are required to adequately assess the safety and efficacy of these targets, as well as the optimal stimulation parameters and long-term effects.

  6. Off-target effects of engineered nucleases.

    PubMed

    Yee, Jiing-Kuan

    2016-09-01

    Recent advances in gene editing with engineered nucleases have transformed our ability to manipulate the genome from diverse organisms for applications ranging from biomedical research to disease treatment. A major complication with these engineered nucleases is the binding of the nuclease to unintended genomic sites that share sequence homology with the on-target site. Cleavage of these off-target sites followed by DNA repair using normal cellular DNA repair mechanisms can cause gene mutation or gross chromosome rearrangement. Identification of nuclease-generated off-target sites is a daunting task due to the size and complexity of the mammalian genome. Five unbiased, genome-wide strategies have been developed to detect the off-target cleavage. Some of these strategies reach the sensitivity near the detection limit of directed deep sequencing and have sufficient precision and resolution to objectively assessing the off-target effect of any engineered nuclease. Significant progress has also been made recently to boost the nuclease targeting specificity by protein engineering to modify the structure of the nuclease and alter the interaction with its genomic target. In several studied cases, the off-target effect generated by the modified nuclease is completely eliminated. These modified nucleases significantly improve the overall fidelity of gene editing. These developments will enable gene editing tools to be applied more broadly and safely in basic research and disease treatment. © 2016 Federation of European Biochemical Societies.

  7. Reverse screening approach to identify potential anti-cancer targets of dipyridamole

    PubMed Central

    Ge, Shu-Min; Zhan, Dong-Ling; Zhang, Shu-Hua; Song, Li-Qiang; Han, Wei-Wei

    2016-01-01

    Dipyridamole (DIP) inhibits thrombus formation when given chronically, and causes vasodilation over a short time. To date, DIP can increase the anticancer drugs (5-fluorouracil, methotrexate, piperidine, vincristine) concentration in cancer cells and hence enhance the efficacy of treatment cancer. The inhibition of DIP may result in increased 5-fluorouracil efficacy and diminish the drug side effects. But the actual molecular targets remain unknown. In this study, reverse protein-ligands docking, and quantum mechanics were used to search for the potential molecular targets of DIP. The quantum mechanics calculation was performed by using Gaussian 03 program package. Reverse pharmacophore mapping was used to search for potential molecular target candidates for a given small molecule. The docking study was used for exploring the potential anti-cancer targets of dipyridamole. The two predicted binders with the statistically significant prediction are dihydropyrimidine dehydrogenase (DPD) (PDB Id: 1GTE) and human spindle checkpoint kinase Bub1 (PDB Id: 3E7E). Structure analysis suggests that electrostatic interaction and hydrogen bonding play an important role in their binding process. The strong functional linkage of DIP and 5FU supports our prediction. In conclusion, these results generate a tractable set of anticancer proteins. The exploration of polypharmacology will provide us new opportunities in treating systematic diseases, such as the cancers. The results would generate a tractable set of anticancer target proteins for future experimental validations. PMID:28077994

  8. Discoidin Domain Receptors: Potential Actors and Targets in Cancer.

    PubMed

    Rammal, Hassan; Saby, Charles; Magnien, Kevin; Van-Gulick, Laurence; Garnotel, Roselyne; Buache, Emilie; El Btaouri, Hassan; Jeannesson, Pierre; Morjani, Hamid

    2016-01-01

    The extracellular matrix critically controls cancer cell behavior by inducing several signaling pathways through cell membrane receptors. Besides conferring structural properties to tissues around the tumor, the extracellular matrix is able to regulate cell proliferation, survival, migration, and invasion. Among these receptors, the integrins family constitutes a major class of receptors that mediate cell interactions with extracellular matrix components. Twenty years ago, a new class of extracellular matrix receptors has been discovered. These tyrosine kinase receptors are the two discoidin domain receptors DDR1 and DDR2. DDR1 was first identified in the Dictyostelium discoideum and was shown to mediate cell aggregation. DDR2 shares highly conserved sequences with DDR1. Both receptors are activated upon binding to collagen, one of the most abundant proteins in extracellular matrix. While DDR2 can only be activated by fibrillar collagen, particularly types I and III, DDR1 is mostly activated by type I and IV collagens. In contrast with classical growth factor tyrosine kinase receptors which display a rapid and transient activation, DDR1 and DDR2 are unique in that they exhibit delayed and sustained receptor phosphorylation upon binding to collagen. Recent studies have reported differential expression and mutations of DDR1 and DDR2 in several cancer types and indicate clearly that these receptors have to be taken into account as new players in the different aspects of tumor progression, from non-malignant to highly malignant and invasive stages. This review will discuss the current knowledge on the role of DDR1 and DDR2 in malignant transformation, cell proliferation, epithelial to mesenchymal transition, migratory, and invasive processes, and finally the modulation of the response to chemotherapy. These new insights suggest that DDR1 and DDR2 are new potential targets in cancer therapy.

  9. CD70: A Potential Target in Breast Cancer?

    PubMed Central

    Petrau, Camille; Cornic, Marie; Bertrand, Philippe; Maingonnat, Catherine; Marchand, Vinciane; Picquenot, Jean-Michel; Jardin, Fabrice; Clatot, Florian

    2014-01-01

    CD70 is a co-stimulatory molecule involved in the immune response and also in cancer development and progression. Recent studies show that high CD70 expression in cancer cells may inhibit the anti-tumor response. Furthermore, CD70 expression has been reported as a predictive marker of resistance to chemotherapy in ovarian cancers. Some in vitro studies have shown that CD70 expression is epigenetically down-regulated through hypermethylation of its promoter during tumoral progression. This study evaluated the level of CD70 expression in surgical samples of breast invasive tumors and determined its correlation with CD70 promoter methylation. Twenty “luminal A” and 20 “basal-like” frozen samples from early breast tumors were retrospectively selected. CD70 expression was evaluated by quantitative real-time PCR. Total DNA was bisulfite-treated, and methylation levels of 5 consecutive CG sites present in the proximal region (-464, -421) of the promoter were assessed by pyrosequencing analysis. Statistical analyses were performed using the Mann-Whitney test. The median relative CD70 expression level was 0.37 and was significantly higher in the basal-like group (0.78 [0.24-31.7]) compared to the luminal A group (0.25 [0.03-1.83], p=0.0001). The median methylation level was 61%, with no significant difference between the basal-like (63%) and luminal A (58%) groups. No correlation was found between CD70 expression and CD70 methylation level. In this study, higher CD70 expression was observed in the basal-like group, but this expression was not related to promoter methylation. The higher expression in the poor-prognosis subgroup of patients makes CD70 a potential target for emerging anti-CD70 therapies. PMID:25368676

  10. Discoidin Domain Receptors: Potential Actors and Targets in Cancer

    PubMed Central

    Rammal, Hassan; Saby, Charles; Magnien, Kevin; Van-Gulick, Laurence; Garnotel, Roselyne; Buache, Emilie; El Btaouri, Hassan; Jeannesson, Pierre; Morjani, Hamid

    2016-01-01

    The extracellular matrix critically controls cancer cell behavior by inducing several signaling pathways through cell membrane receptors. Besides conferring structural properties to tissues around the tumor, the extracellular matrix is able to regulate cell proliferation, survival, migration, and invasion. Among these receptors, the integrins family constitutes a major class of receptors that mediate cell interactions with extracellular matrix components. Twenty years ago, a new class of extracellular matrix receptors has been discovered. These tyrosine kinase receptors are the two discoidin domain receptors DDR1 and DDR2. DDR1 was first identified in the Dictyostelium discoideum and was shown to mediate cell aggregation. DDR2 shares highly conserved sequences with DDR1. Both receptors are activated upon binding to collagen, one of the most abundant proteins in extracellular matrix. While DDR2 can only be activated by fibrillar collagen, particularly types I and III, DDR1 is mostly activated by type I and IV collagens. In contrast with classical growth factor tyrosine kinase receptors which display a rapid and transient activation, DDR1 and DDR2 are unique in that they exhibit delayed and sustained receptor phosphorylation upon binding to collagen. Recent studies have reported differential expression and mutations of DDR1 and DDR2 in several cancer types and indicate clearly that these receptors have to be taken into account as new players in the different aspects of tumor progression, from non-malignant to highly malignant and invasive stages. This review will discuss the current knowledge on the role of DDR1 and DDR2 in malignant transformation, cell proliferation, epithelial to mesenchymal transition, migratory, and invasive processes, and finally the modulation of the response to chemotherapy. These new insights suggest that DDR1 and DDR2 are new potential targets in cancer therapy. PMID:27014069

  11. Cancer stem cell metabolism: a potential target for cancer therapy.

    PubMed

    Deshmukh, Abhijeet; Deshpande, Kedar; Arfuso, Frank; Newsholme, Philip; Dharmarajan, Arun

    2016-11-08

    Cancer Stem cells (CSCs) are a unipotent cell population present within the tumour cell mass. CSCs are known to be highly chemo-resistant, and in recent years, they have gained intense interest as key tumour initiating cells that may also play an integral role in tumour recurrence following chemotherapy. Cancer cells have the ability to alter their metabolism in order to fulfil bio-energetic and biosynthetic requirements. They are largely dependent on aerobic glycolysis for their energy production and also are associated with increased fatty acid synthesis and increased rates of glutamine utilisation. Emerging evidence has shown that therapeutic resistance to cancer treatment may arise due to dysregulation in glucose metabolism, fatty acid synthesis, and glutaminolysis. To propagate their lethal effects and maintain survival, tumour cells alter their metabolic requirements to ensure optimal nutrient use for their survival, evasion from host immune attack, and proliferation. It is now evident that cancer cells metabolise glutamine to grow rapidly because it provides the metabolic stimulus for required energy and precursors for synthesis of proteins, lipids, and nucleic acids. It can also regulate the activities of some of the signalling pathways that control the proliferation of cancer cells.This review describes the key metabolic pathways required by CSCs to maintain a survival advantage and highlights how a combined approach of targeting cellular metabolism in conjunction with the use of chemotherapeutic drugs may provide a promising strategy to overcome therapeutic resistance and therefore aid in cancer therapy.

  12. Erythropoietin Pathway: A Potential Target for the Treatment of Depression

    PubMed Central

    Ma, Chongyang; Cheng, Fafeng; Wang, Xueqian; Zhai, Changming; Yue, Wenchao; Lian, Yajun; Wang, Qingguo

    2016-01-01

    During the past decade, accumulating evidence from both clinical and experimental studies has indicated that erythropoietin may have antidepressant effects. In addition to the kidney and liver, many organs have been identified as secretory tissues for erythropoietin, including the brain. Its receptor is expressed in cerebral and spinal cord neurons, the hypothalamus, hippocampus, neocortex, dorsal root ganglia, nerve axons, and Schwann cells. These findings may highlight new functions for erythropoietin, which was originally considered to play a crucial role in the progress of erythroid differentiation. Erythropoietin and its receptor signaling through JAK2 activate multiple downstream signaling pathways including STAT5, PI3K/Akt, NF-κB, and MAPK. These factors may play an important role in inflammation and neuroprogression in the nervous system. This is particularly true for the hippocampus, which is possibly related to learning, memory, neurocognitive deficits and mood alterations. Thus, the influence of erythropoietin on the downstream pathways known to be involved in the treatment of depression makes the erythropoietin-related pathway an attractive target for the development of new therapeutic approaches. Focusing on erythropoietin may help us understand the pathogenic mechanisms of depression and the molecular basis of its treatment. PMID:27164096

  13. The potential for targeting extracellular LOX proteins in human malignancy.

    PubMed

    Mayorca-Guiliani, Alejandro; Erler, Janine T

    2013-11-25

    The extracellular matrix (ECM) is the physical scaffold where cells are organized into tissues and organs. The ECM may be modified during cancer to allow and promote proliferation, invasion, and metastasis. The family of lysyl oxidase (LOX) enzymes cross-links collagens and elastin and, therefore, is a central player in ECM deposition and maturation. Extensive research has revealed how the LOX proteins participate in every stage of cancer progression, and two family members, LOX and LOX-like 2, have been linked to metastasis, the final stage of cancer responsible for over 90% of cancer patient deaths. However, LOX biosynthesis results in by-product with antiproliferative properties in certain cancers, and LOX enzymes may have different effects depending on the molecular network in which they are active. Therefore, the design of therapies targeting the LOX family needs to be guided by the molecular makeup of the individual disease and will probably require other agents to act on both the LOX enzymes and their associated network.

  14. The potential for targeting extracellular LOX proteins in human malignancy

    PubMed Central

    Mayorca-Guiliani, Alejandro; Erler, Janine T

    2013-01-01

    The extracellular matrix (ECM) is the physical scaffold where cells are organized into tissues and organs. The ECM may be modified during cancer to allow and promote proliferation, invasion, and metastasis. The family of lysyl oxidase (LOX) enzymes cross-links collagens and elastin and, therefore, is a central player in ECM deposition and maturation. Extensive research has revealed how the LOX proteins participate in every stage of cancer progression, and two family members, LOX and LOX-like 2, have been linked to metastasis, the final stage of cancer responsible for over 90% of cancer patient deaths. However, LOX biosynthesis results in by-product with antiproliferative properties in certain cancers, and LOX enzymes may have different effects depending on the molecular network in which they are active. Therefore, the design of therapies targeting the LOX family needs to be guided by the molecular makeup of the individual disease and will probably require other agents to act on both the LOX enzymes and their associated network. PMID:24348049

  15. Targeting ILK and {beta}4 integrin abrogates the invasive potential of ovarian cancer

    SciTech Connect

    Choi, Yoon Pyo; Kim, Baek Gil; Gao, Ming-Qing; Kang, Suki; Cho, Nam Hoon

    2012-10-26

    Highlights: Black-Right-Pointing-Pointer The potential of targeting ILK and integrins for highly aggressive ovarian cancer. Black-Right-Pointing-Pointer Unanticipated synergistic effect for the combination of ILK/{beta}4 integrin. Black-Right-Pointing-Pointer Combination of ILK/{beta}4 integrin effectively inhibited the PI3K/Akt/Rac1 cascade. Black-Right-Pointing-Pointer Targeting of {beta}4 integrin/ILK had potent inhibitory effects in ovarian cancer. -- Abstract: Integrins and integrin-linked kinase (ILK) are essential to cancerous invasion because they mediate physical interactions with the extracellular matrix, and regulate oncogenic signaling pathways. The purpose of our study is to determine whether deletion of {beta}1 and {beta}4 integrin and ILK, alone or in combination, has antitumoral effects in ovarian cancer. Expression of {beta}1 and {beta}4 integrin and ILK was analyzed by immunohistochemistry in 196 ovarian cancer tissue samples. We assessed the effects of depleting these molecules with shRNAs in ovarian cancer cells by Western blot, conventional RT-PCR, cell proliferation, migration, invasion, and in vitro Rac1 activity assays, and in vivo xenograft formation assays. Overexpression of {beta}4 integrin and ILK in human ovarian cancer specimens was found to correlate with tumor aggressiveness. Depletion of these targets efficiently suppresses ovarian cancer cell proliferation, migration, and invasion in vitro and xenograft tumor formation in vivo. We also demonstrated that single depletion of ILK or combination depletion of {beta}4 integrin/ILK inhibits phosphorylation of downstream signaling targets, p-Ser 473 Akt and p-Thr202/Tyr204 Erk1/2, and activation of Rac1, as well as reduce expression of MMP-2 and MMP-9 and increase expression of caspase-3 in vitro. In conclusion, targeting {beta}4 integrin combined with ILK can instigate the latent tumorigenic potential and abrogate the invasive potential in ovarian cancer.

  16. Cancer targeting potential of folate targeted nanocarrier under comparative influence of tretinoin and dexamethasone.

    PubMed

    Dhakad, Raghvendra Singh; Tekade, Rakesh Kumar; Jain, Narendra Kumar

    2013-08-01

    The objective of this investigation was aimed to explore the cancer targeting potential of folate conjugated dendrimer (polypropylene imine, PPI) under strategic influence of folate receptor up-regulators (all trans Retinoic acid, ATRA and Dexamethasone, DEXA). The folate conjugated dendrimer nanoconjugate (FPPI) was synthesized and characterized by FTIR, and (1)H-NMR spectroscopy. The cell line studies investigations were performed on MCF-7 cells. ATRA and DEXA caused 2.17 and 1.65 folds selective up-regulation of folate receptor respectively, when compared with untreated control, after 48 h of pretreatment. ATRA caused 50.47±2.11% more up regulation of folate receptor, than DEXA treated cell. Both up regulators showed a lag phase of 12 h in up-regulating the folate receptors. After 48 h, the IC50 values of naked docetaxel (DTX) and DTX loaded dendrimer (PPI-DTX) were found to be 678.93±11.99 nM and 663.51±15.23 nM, respectively, while DTX loaded folate-anchored dendrimer (FPPI-DTX) showed a selectively lowered IC50 value of 468.56±20.86 nM. FPPI-DTX further showed a significant reduction in IC50 value in ATRA and DEXA pretreated cells, wherein IC50 values of 184.21 nM and 290.40±14.05 nM, respectively were observed. The study also concludes ATRA to be a superior receptor up-regulator as well as promoter of folate based targeting compared to DEXA.

  17. Mito-methyl coumarin, a novel mitochondria-targeted drug with great antitumor potential was synthesized.

    PubMed

    Wang, Huanan; Xu, Wenqing

    2017-07-15

    Due to higher transmembrane potential of tumor cells, enhanced accumulation of cationic drugs in tumor mitochondria has been attributed to a higher (more negative inside) mitochondrial transmembrane potential compared with normal cells, emerging researchers are focus on developing mitochondria-targeted antitumor drugs. Coumarins showed great potential on antitumor, but mitochondria-targeted coumarin derivatives have not been reported. In the present study, we synthesized mitochondria-targeted-methyl coumarin (mito-methyl coumarin) through coupling 6-methyl coumarin to TPP. We confirmed that mito-methyl coumarin inhibited HeLa cells proliferation selectively, induced ROS generation, reduced mitochondrial membrane potential, promoted mitochondria Ca(2+) accumulation, decreased mitochondria mass and induced HeLa cells apoptosis, but methyl coumarin did not. These results demonstrate that we succeed in synthesizing a novel mitochondria-targeted drug, mito-methyl coumarin, which is effective in inhibiting HeLa cells proliferation and inducing HeLa cells apoptosis through promoting ROS generation and mitochondria Ca(2+) accumulation. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Target weight achievement and ultrafiltration rate thresholds: potential patient implications.

    PubMed

    Flythe, Jennifer E; Assimon, Magdalene M; Overman, Robert A

    2017-06-02

    Higher ultrafiltration (UF) rates and extracellular hypo- and hypervolemia are associated with adverse outcomes among maintenance hemodialysis patients. The Centers for Medicare and Medicaid Services recently considered UF rate and target weight achievement measures for ESRD Quality Incentive Program inclusion. The dual measures were intended to promote balance between too aggressive and too conservative fluid removal. The National Quality Forum endorsed the UF rate measure but not the target weight measure. We examined the proposed target weight measure and quantified weight gains if UF rate thresholds were applied without treatment time (TT) extension or interdialytic weight gain (IDWG) reduction. Data were taken from the 2012 database of a large dialysis organization. Analyses considered 152,196 United States hemodialysis patients. We described monthly patient and dialysis facility target weight achievement patterns and examined differences in patient characteristics across target weight achievement status and differences in facilities across target weight measure scores. We computed the cumulative, theoretical 1-month fluid-related weight gain that would occur if UF rates were capped at 13 mL/h/kg without concurrent TT extension or IDWG reduction. Target weight achievement patterns were stable over the year. Patients who did not achieve target weight (post-dialysis weight ≥ 1 kg above or below target weight) tended to be younger, black and dialyze via catheter, and had shorter dialysis vintage, greater body weight, higher UF rate and more missed treatments compared with patients who achieved target weight. Facilities had, on average, 27.1 ± 9.7% of patients with average post-dialysis weight ≥ 1 kg above or below the prescribed target weight. In adjusted analyses, facilities located in the midwest and south and facilities with higher proportions of black and Hispanic patients and higher proportions of patients with shorter TTs were more likely to

  19. Assessing potential peptide targeting ligands by quantification of cellular adhesion of model nanoparticles under flow conditions.

    PubMed

    Broda, Ellen; Mickler, Frauke Martina; Lächelt, Ulrich; Morys, Stephan; Wagner, Ernst; Bräuchle, Christoph

    2015-09-10

    Sophisticated drug delivery systems are coated with targeting ligands to improve the specific adhesion to surface receptors on diseased cells. In our study, we developed a method with which we assessed the potential of peptide ligands to specifically bind to receptor overexpressing target cells. Therefore, a microfluidic setup was used where the cellular adhesion of nanoparticles with ligand and of control nanoparticles was observed in parallel under the same experimental conditions. The effect of the ligand on cellular binding was quantified by counting the number of adhered nanoparticles with ligand and differently labeled control nanoparticles on single cells after incubation under flow conditions. To provide easy-to-synthesize, stable and reproducible nanoparticles which mimic the surface characteristics of drug delivery systems and meet the requirements for quantitative analysis, latex beads based on amine-modified polystyrene were used as model nanoparticles. Two short peptides were tested to serve as targeting ligand on the beads by increasing the specific binding to HuH7 cells. The c-Met binding peptide cMBP2 was used for hepatocyte growth factor receptor (c-Met) targeting and the peptide B6 for transferrin receptor (TfR) targeting. The impact of the targeting peptide on binding was investigated by comparing the beads with ligand to different internal control beads: 1) without ligand and tailored surface charge (electrostatic control) and 2) with scrambled peptide and similar surface charge, but a different amino acid sequence (specificity control). Our results demonstrate that the method is very useful to select suitable targeting ligands for specific nanoparticle binding to receptor overexpressing tumor cells. We show that the cMBP2 ligand specifically enhances nanoparticle adhesion to target cells, whereas the B6 peptide mediates binding to tumor cells mainly by nonspecific interactions. All together, we suggest that cMBP2 is a suitable choice for

  20. MOLECULAR ALTERATIONS IN GLIOBLASTOMA: POTENTIAL TARGETS FOR IMMUNOTHERAPY

    PubMed Central

    Haque, Azizul; Banik, Naren L.; Ray, Swapan K.

    2015-01-01

    Glioblastoma is the most common and deadly brain tumor, possibly arising from genetic and epigenetic alterations in normal astroglial cells. Multiple cytogenetic, chromosomal, and genetic alterations have been identified in glioblastoma, with distinct expression of antigens (Ags) and biomarkers that may alter therapeutic potential of this aggressive cancer. Current therapy consists of surgical resection, followed by radiation therapy and chemotherapy. In spite of these treatments, the prognosis for glioblastoma patients is poor. Although recent studies have focused on the development of novel immunotherapeutics against glioblastoma, little is known about glioblastoma specific immune responses. A better understanding of the molecular interactions among glioblastoma tumors, host immune cells, and the tumor microenvironment may give rise to novel integrated approaches for the simultaneous control of tumor escape pathways and the activation of antitumor immune responses. This review provides a detailed overview concerning genetic alterations in glioblastoma, their effects on Ag and biomarker expression and the future design of chemoimmunotherapeutics against glioblastoma. PMID:21199773

  1. Siglec-15 is a potential therapeutic target for postmenopausal osteoporosis.

    PubMed

    Kameda, Yusuke; Takahata, Masahiko; Mikuni, Shintaro; Shimizu, Tomohiro; Hamano, Hiroki; Angata, Takashi; Hatakeyama, Shigetsugu; Kinjo, Masataka; Iwasaki, Norimasa

    2015-02-01

    organization of osteoclasts in both RANKL and TNF-α induced osteoclastogenesis. The present findings indicate that Siglec-15 is involved in estrogen deficiency-induced differentiation of osteoclasts and is thus a potential therapeutic target for postmenopausal osteoporosis.

  2. Using Click Chemistry to Identify Potential Drug Targets in Plasmodium

    DTIC Science & Technology

    2015-04-01

    mammalian cycle. Inhibiting this step can block malaria at an early step. However, few anti-malar ials target l iver infection by sporozo ites. Our...step of the Plasmodium mammalian cycle. Inhibiting this step can block malaria at an early step. However, few anti-malarials target liver infection...intrahepatic development 2. Keywords Plasmodium, sporozoites, liver infection, kinase, drugs, malaria 3. Accomplishments • What were the major

  3. Medicinal Plants: A Potential Source of Compounds for Targeting Cell Division

    PubMed Central

    Zulkipli, Ihsan N; David, Sheba R; Rajabalaya, Rajan; Idris, Adi

    2015-01-01

    Modern medicinal plant drug discovery has provided pharmacologically active compounds targeted against a multitude of conditions and diseases, such as infection, inflammation, and cancer. To date, natural products from medicinal plants remain a solid niche as a source from which cancer therapies can be derived. Among other properties, one favorable characteristic of an anticancer drug is its ability to block the uncontrollable process of cell division, as cancer cells are notorious for their abnormal cell division. There are numerous other documented works on the potential anticancer activity of drugs derived from medicinal plants, and their effects on cell division are an attractive and growing therapeutic target. Despite this, there remains a vast number of unidentified natural products that are potentially promising sources for medical applications. This mini review aims to revise the current knowledge of the effects of natural plant products on cell division. PMID:26106261

  4. SOX12: a novel potential target for acute myeloid leukaemia.

    PubMed

    Wan, Haixia; Cai, Jiayi; Chen, Fangyuan; Zhu, Jianyi; Zhong, Jihua; Zhong, Hua

    2017-02-01

    The role of SRY-related high-mobility-group box (SOX) 12 in leukaemia progression and haematopoiesis remains elusive. This study aimed to examine the expression and function of SOX12 in acute myeloid leukaemia (AML) using human myeloid leukaemia samples and the acute myeloid cell line THP1. Mononuclear cells were isolated from the bone marrow of AML patients and healthy donors. SOX12 expression in haematopoietic cells was evaluated by reverse transcription polymerase chain reaction (RT-PCR). SOX12 short hairpin RNAs (shRNAs) were transduced into THP1 cells, and gene knockdown was confirmed by quantitative RT-PCR and Western blot analysis. SOX12 was preferentially expressed in CD34(+) cells in AML patients. The THP1 cells transduced with SOX12 shRNAs exhibited significantly reduced SOX12 expression and cell proliferation. SOX12 knockdown had no effect on apoptosis, but it induced cell cycle arrest at G1 phase and reduced the number of colonies. The transduced THP1 and primary AML cells were reconstituted in non-obese diabetic-severe combined immunodeficient (NOD/SCID) mice, and their numbers were significantly reduced 6-12 weeks after transplantation. The mRNA and protein levels of β-catenin were significantly diminished following SOX12 knockdown, accompanied by a decrease in TCF/Wnt activity. SOX12 may be involved in leukaemia progression by regulating the expression of β-catenin and then interfering with TCF/Wnt pathway, which may be a target for AML. © 2016 John Wiley & Sons Ltd.

  5. Gaussian effective potential: Quantum mechanics

    NASA Astrophysics Data System (ADS)

    Stevenson, P. M.

    1984-10-01

    We advertise the virtues of the Gaussian effective potential (GEP) as a guide to the behavior of quantum field theories. Much superior to the usual one-loop effective potential, the GEP is a natural extension of intuitive notions familiar from quantum mechanics. A variety of quantum-mechanical examples are studied here, with an eye to field-theoretic analogies. Quantum restoration of symmetry, dynamical mass generation, and "quantum-mechanical resuscitation" are among the phenomena discussed. We suggest how the GEP could become the basis of a systematic approximation procedure. A companion paper will deal with scalar field theory.

  6. Carborane-layered double hydroxide nanohybrids for potential targeted- and magnetically targeted-BNCT applications.

    PubMed

    Ay, Ahmet Nedim; Akar, Hande; Zaulet, Adnana; Viňas, Clara; Teixidor, Francesc; Zumreoglu-Karan, Birgul

    2017-03-07

    Carborane-intercalated layered double hydroxide nanohybrids (CB-LDH) and a magnesium ferrite (MF) supported-CB-LDH core-shell nanocomposite (CB-LDH@MF) are reported. The preparation of nanohybrids were carried out by exchanging the interlayer nitrate groups of Mg-Al-NO3-LDH with monothiol-o-carborane (SCB), 1-methyl-2-carboxyl-o-carborane (MeCB), 1-phenyl-2-carboxyl-o-carborane (PhCB) and 1,12-dicarboxyl-p-carborane (COOHCB) molecules. A magnetic core-shell nanocomposite was further prepared by supporting the COOHCB-LDH nanohybrid on MF nanoparticles. The obtained materials were characterized by means of several physical and chemical methods. Chemical compositions were determined by elemental analysis, ICP measurements and SEM-EDX data. Structural characterization was performed with powder-XRD, FTIR and magnetization measurements. Morphological analyses were conducted with electron microscopy imaging (SEM and TEM). Thermal stabilities were investigated by TGA/DTA. Carborane release from LDH layers was tested by tracing the amount of boron species transferred to the solution phase with ICP-MS measurements. The results verified that the prepared nanohybrids have the potential to be used in Boron Neutron Capture Therapy (BNCT) and magnetically targeted-BNCT applications.

  7. The Woman's Heart: Insights into New Potential Targeted Therapy.

    PubMed

    Gianfrilli, Daniele; Pofi, Ricardo; Feola, Tiziana; Lenzi, Andrea; Giannetta, Elisa

    2017-01-01

    Cardiovascular disease is an increasingly common cause of death in women. There is as yet no consensus on the analysis of cardiovascular risk factors with regard to the specific, personalised treatment of pre- and post-menopausal women. Clinically significant cardioprotective and antiremodelling effects have been observed in animal and human studies exploring chronic inhibition of phosphodiesterase type 5 (PDE5). The relationship between the heart, estrogens and PDE5 inhibitors (PDE5is) remains unclear. Experimental data suggest potential beneficial effects on cardiac geometry, function, endothelial function and microvascular coronary flow in women. It was recently postulated that the efficacy of PDE5is is estrogen-dependent in female heart disease. A registered randomised, placebo-controlled study, RECOGITO (NCT01803828), aimed at identifying the genderspecific efficacy of long-term PDE5 inhibition in diabetic cardiomyopathy, is currently recruiting patients. Estrogen receptor modulation could be a new promising approach to heart protection via PDE5is. PDE5is could be indicated as a gender-oriented strategy in modulated cardiac dysfunction and remodelling and in cardiac risk factors for selected cardiovascular diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. Targeted PRINTRTM nanoparticles for effective cancer therapy

    NASA Astrophysics Data System (ADS)

    McGowan, Kelly Marie

    Conventional therapeutics for the treatment of cancer are often faced with challenges such as systemic biodistribution within the body, drug degradation in vivo, low bioavailability at the site of disease, and off-target toxicity. As such, particulate drug delivery systems have been developed with the aim of minimizing these limitations of current therapies. Through the PRINTRTM (Particle Replication in Non-wetting Templates) technology, hydrogel nanoparticles, prepared from biocompatible poly(ethylene glycol) and acid-sensitive silyl ether crosslinkers, were functionalized and conjugated with targeting ligands for the folate receptor (FR), HER2 receptor, and transferrin receptor (TfR). By conjugating specific ligands to nanoparticles to impart specificity, highly selective targeting and internalization (>80%) of nanoparticles were demonstrated in various cancer cell lines. The extent of cellular uptake of targeted nanoparticles was dependent on the surface characteristics of the nanoparticles, particle concentration, and kinetics. Because a negative surface charge reduces nonspecific cellular uptake, attaching monoclonal antibodies to the surface of negatively charged PRINT nanoparticles facilitated specific binding of the antibodies to cellular surface receptors that subsequently triggered receptor-mediated endocytosis. Additionally, the multivalent nature of nanoparticles influenced cellular uptake. Specifically, nanoparticles with a higher valence internalized more rapidly and efficiently than those with a lower valence. Nanoparticles that selectively target and accumulate within diseased cells have the potential of minimizing drug degradation under physiological conditions, enhancing bioavailability at the tumor, improving the efficacy of the drug, and reducing toxicity from systemic biodistribution. Drug delivery through targeted nanoparticles was achieved by loading nanoparticles with silyl ether-modified gemcitabine prodrugs. Covalently reacting the prodrug

  9. The Validation of Nematode-Specific Acetylcholine-Gated Chloride Channels as Potential Anthelmintic Drug Targets

    PubMed Central

    Wever, Claudia M.; Farrington, Danielle; Dent, Joseph A.

    2015-01-01

    New compounds are needed to treat parasitic nematode infections in humans, livestock and plants. Small molecule anthelmintics are the primary means of nematode parasite control in animals; however, widespread resistance to the currently available drug classes means control will be impossible without the introduction of new compounds. Adverse environmental effects associated with nematocides used to control plant parasitic species are also motivating the search for safer, more effective compounds. Discovery of new anthelmintic drugs in particular has been a serious challenge due to the difficulty of obtaining and culturing target parasites for high-throughput screens and the lack of functional genomic techniques to validate potential drug targets in these pathogens. We present here a novel strategy for target validation that employs the free-living nematode Caenorhabditis elegans to demonstrate the value of new ligand-gated ion channels as targets for anthelmintic discovery. Many successful anthelmintics, including ivermectin, levamisole and monepantel, are agonists of pentameric ligand-gated ion channels, suggesting that the unexploited pentameric ion channels encoded in parasite genomes may be suitable drug targets. We validated five members of the nematode-specific family of acetylcholine-gated chloride channels as targets of agonists with anthelmintic properties by ectopically expressing an ivermectin-gated chloride channel, AVR-15, in tissues that endogenously express the acetylcholine-gated chloride channels and using the effects of ivermectin to predict the effects of an acetylcholine-gated chloride channel agonist. In principle, our strategy can be applied to validate any ion channel as a putative anti-parasitic drug target. PMID:26393923

  10. The target effect: visual memory for unnamed search targets.

    PubMed

    Thomas, Mark D; Williams, Carrick C

    2014-01-01

    Search targets are typically remembered much better than other objects even when they are viewed for less time. However, targets have two advantages that other objects in search displays do not have: They are identified categorically before the search, and finding them represents the goal of the search task. The current research investigated the contributions of both of these types of information to the long-term visual memory representations of search targets. Participants completed either a predefined search or a unique-object search in which targets were not defined with specific categorical labels before searching. Subsequent memory results indicated that search target memory was better than distractor memory even following ambiguously defined searches and when the distractors were viewed significantly longer. Superior target memory appears to result from a qualitatively different representation from those of distractor objects, indicating that decision processes influence visual memory.

  11. Bacterial targets as potential indicators of diesel fuel toxicity in subantarctic soils.

    PubMed

    van Dorst, Josie; Siciliano, Steven D; Winsley, Tristrom; Snape, Ian; Ferrari, Belinda C

    2014-07-01

    Appropriate remediation targets or universal guidelines for polar regions do not currently exist, and a comprehensive understanding of the effects of diesel fuel on the natural microbial populations in polar and subpolar soils is lacking. Our aim was to investigate the response of the bacterial community to diesel fuel and to evaluate if these responses have the potential to be used as indicators of soil toxicity thresholds. We set up short- and long-exposure tests across a soil organic carbon gradient. Utilizing broad and targeted community indices, as well as functional genes involved in the nitrogen cycle, we investigated the bacterial community structure and its potential functioning in response to special Antarctic blend (SAB) diesel fuel. We found the primary effect of diesel fuel toxicity was a reduction in species richness, evenness, and phylogenetic diversity, with the resulting community heavily dominated by a few species, principally Pseudomonas. The decline in richness and phylogenetic diversity was linked to disruption of the nitrogen cycle, with species and functional genes involved in nitrification significantly reduced. Of the 11 targets we evaluated, we found the bacterial amoA gene indicative of potential ammonium oxidation, the most suitable indicator of toxicity. Dose-response modeling for this target generated an average effective concentration responsible for 20% change (EC20) of 155 mg kg(-1), which is consistent with previous Macquarie Island ecotoxicology assays. Unlike traditional single-species tolerance testing, bacterial targets allowed us to simultaneously evaluate more than 1,700 species from 39 phyla, inclusive of rare, sensitive, and functionally relevant portions of the community.

  12. Bacterial Targets as Potential Indicators of Diesel Fuel Toxicity in Subantarctic Soils

    PubMed Central

    van Dorst, Josie; Siciliano, Steven D.; Winsley, Tristrom; Snape, Ian

    2014-01-01

    Appropriate remediation targets or universal guidelines for polar regions do not currently exist, and a comprehensive understanding of the effects of diesel fuel on the natural microbial populations in polar and subpolar soils is lacking. Our aim was to investigate the response of the bacterial community to diesel fuel and to evaluate if these responses have the potential to be used as indicators of soil toxicity thresholds. We set up short- and long-exposure tests across a soil organic carbon gradient. Utilizing broad and targeted community indices, as well as functional genes involved in the nitrogen cycle, we investigated the bacterial community structure and its potential functioning in response to special Antarctic blend (SAB) diesel fuel. We found the primary effect of diesel fuel toxicity was a reduction in species richness, evenness, and phylogenetic diversity, with the resulting community heavily dominated by a few species, principally Pseudomonas. The decline in richness and phylogenetic diversity was linked to disruption of the nitrogen cycle, with species and functional genes involved in nitrification significantly reduced. Of the 11 targets we evaluated, we found the bacterial amoA gene indicative of potential ammonium oxidation, the most suitable indicator of toxicity. Dose-response modeling for this target generated an average effective concentration responsible for 20% change (EC20) of 155 mg kg−1, which is consistent with previous Macquarie Island ecotoxicology assays. Unlike traditional single-species tolerance testing, bacterial targets allowed us to simultaneously evaluate more than 1,700 species from 39 phyla, inclusive of rare, sensitive, and functionally relevant portions of the community. PMID:24771028

  13. Cancer stem cells: a potential target for cancer therapy.

    PubMed

    Qiu, Hong; Fang, Xiaoguang; Luo, Qi; Ouyang, Gaoliang

    2015-09-01

    Current evidence indicates that a subpopulation of cancer cells, named cancer stem cells (CSCs) or tumor-initiating cells, are responsible for the initiation, growth, metastasis, therapy resistance and recurrence of cancers. CSCs share core regulatory pathways with normal stem cells; however, CSCs rely on distinct reprogrammed pathways to maintain stemness and to contribute to the progression of cancers. The specific targeting of CSCs, together with conventional chemotherapy or radiotherapy, may achieve stable remission or cure cancer. Therefore, the identification of CSCs and a better understanding of the complex characteristics of CSCs will provide invaluable diagnostic, therapeutic and prognostic targets for clinical application. In this review, we will introduce the dysregulated properties of CSCs in cancers and discuss the possible challenges in targeting CSCs for cancer treatment.

  14. Harnessing the potential of epigenetic therapy to target solid tumors

    PubMed Central

    Ahuja, Nita; Easwaran, Hariharan; Baylin, Stephen B.

    2014-01-01

    Epigenetic therapies may play a prominent role in the future management of solid tumors. This possibility is based on the clinical efficacy of existing drugs in treating defined hematopoietic neoplasms, paired with promising new data from preclinical and clinical studies that examined these agents in solid tumors. We suggest that current drugs may represent a targeted therapeutic approach for reprogramming solid tumor cells, a strategy that must be pursued in concert with the explosion in knowledge about the molecular underpinnings of normal and cancer epigenomes. We hypothesize that understanding targeted proteins in the context of their enzymatic and scaffolding functions and in terms of their interactions in complexes with proteins that are targets of new drugs under development defines the future of epigenetic therapies for cancer. PMID:24382390

  15. Animal lectins: potential antitumor therapeutic targets in apoptosis.

    PubMed

    Liu, Zhe; Zhang, Qian; Peng, Hao; Zhang, Wen-zhi

    2012-10-01

    Lectins, a group of carbohydrate-binding proteins ubiquitously distributed into plants and animals, are well-known to have astonishing numerous links to human cancers. In this review, we present a brief outline of the representative animal lectins such as galectins, C-type lectins, and annexins by targeting programmed cell death (or apoptosis) pathways, and also summarize these representative lectins as possible anti-cancer drug targets. Taken together, these inspiring findings would provide a comprehensive perspective for further elucidating the multifaceted roles of animal lectins in apoptosis pathways of cancer, which, in turn, may ultimately help us to exploit lectins for their therapeutic purposes in future drug discovery.

  16. A whole genome bioinformatic approach to determine potential latent phase specific targets in Mycobacterium tuberculosis.

    PubMed

    Defelipe, Lucas A; Do Porto, Dario Fernández; Pereira Ramos, Pablo Ivan; Nicolás, Marisa Fabiana; Sosa, Ezequiel; Radusky, Leandro; Lanzarotti, Esteban; Turjanski, Adrián G; Marti, Marcelo A

    2016-03-01

    Current Tuberculosis treatment is long and expensive, faces the increasing burden of MDR/XDR strains and lack of effective treatment against latent form, resulting in an urgent need of new anti-TB drugs. Key to TB biology is its capacity to fight the host's RNOS mediated attack. RNOS are known to display a concentration dependent mycobactericidal activity, which leads to the following hypothesis "if we know which proteins are targeted by RNOS and kill TB, we we might be able to inhibit them with drugs resulting in a synergistic bactericidal effect". Based on this idea, we performed an Mtb metabolic network whole proteome analysis of potential RNOS sensitive and relevant targets which includes target druggability and essentiality criteria. Our results, available at http://tuberq.proteinq.com.ar yield new potential TB targets, like I3PS, while also providing and updated view of previous proposals becoming an important tool for researchers looking for new ways of killing TB. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Omen: identifying potential spear-phishing targets before the email is sent.

    SciTech Connect

    Wendt, Jeremy Daniel.

    2013-07-01

    We present the results of a two year project focused on a common social engineering attack method called "spear phishing". In a spear phishing attack, the user receives an email with information specifically focused on the user. This email contains either a malware-laced attachment or a link to download the malware that has been disguised as a useful program. Spear phishing attacks have been one of the most effective avenues for attackers to gain initial entry into a target network. This project focused on a proactive approach to spear phishing. To create an effective, user-specific spear phishing email, the attacker must research the intended recipient. We believe that much of the information used by the attacker is provided by the target organization's own external website. Thus when researching potential targets, the attacker leaves signs of his research in the webserver's logs. We created tools and visualizations to improve cybersecurity analysts' abilities to quickly understand a visitor's visit patterns and interests. Given these suspicious visitors and log-parsing tools, analysts can more quickly identify truly suspicious visitors, search for potential spear-phishing targeted users, and improve security around those users before the spear phishing email is sent.

  18. Deregulated MicroRNAs in Biliary Tract Cancer: Functional Targets and Potential Biomarkers

    PubMed Central

    Beyreis, Marlena; Wagner, Andrej; Pichler, Martin; Neureiter, Daniel

    2016-01-01

    Biliary tract cancer (BTC) is still a fatal disease with very poor prognosis. The lack of reliable biomarkers for early diagnosis and of effective therapeutic targets is a major demanding problem in diagnosis and management of BTC. Due to the clinically silent and asymptomatic characteristics of the tumor, most patients are diagnosed at an already advanced stage allowing only for a palliative therapeutic approach. MicroRNAs are small noncoding RNAs well known to regulate various cellular functions and pathologic events including the formation and progression of cancer. Over the last years, several studies have shed light on the role of microRNAs in BTC, making them potentially attractive therapeutic targets and candidates as biomarkers. In this review, we will focus on the role of oncogenic and tumor suppressor microRNAs and their direct targets in BTC. Furthermore, we summarize and discuss data that evaluate the diagnostic power of deregulated microRNAs as possible future biomarkers for BTC. PMID:27957497

  19. Sirtuins as potential drug targets for metablic diseases

    USDA-ARS?s Scientific Manuscript database

    Recent studies of the sirtuin family of proteins, which possess NAD+/-dependent deacetylase and ADP ribosyltransferase activities, indicate that they regulate many biological functions, such as longevity and metabolism. These findings also suggest that sirtuins might serve as valuable drug targets f...

  20. Potential therapeutic targets in energy metabolism pathways of breast cancer.

    PubMed

    Islam, Rowshan Ara; Hossain, Sazzad; Chowdhury, Ezharul Hoque

    2017-03-30

    Mutations in proto-oncogenes and tumor suppressor genes make cancer cells proliferate indefinitely. As they possess almost all mechanisms for cell proliferation and survival like healthy cells, it is difficult to specifically target cancer cells in the body. Current treatments in most of the cases are harmful to healthy cells as well. Thus, it would be of great prudence to target specific characters of cancer cells. Since cancer cells avidly use glucose and glutamine to survive and proliferate by upregulating the relevant enzymes and their specific isoforms having important regulatory roles, it has been of great interest recently to target the energy-related metabolic pathways as part of the therapeutic interventions. This paper summarizes the roles of energy metabolism and their cross-talks with other important signaling pathways in regulating proliferation, invasion and metastasis in breast cancer. As breast cancer is a highly heterogeneous disease, a clear understanding of the variations of energy metabolism in different molecular subtypes would help in treating each type with a very customized, safer and efficient treatment regimen, by targeting specific glucose metabolism and related pathways with gene silencing nucleic acid sequences or small molecule drugs, or the combination of both.

  1. PLK-1 Targeted Inhibitors and Their Potential against Tumorigenesis

    PubMed Central

    Kumar, Shiv; Kim, Jaebong

    2015-01-01

    Mitotic kinases are the key components of the cell cycle machinery and play vital roles in cell cycle progression. PLK-1 (Polo-like kinase-1) is a crucial mitotic protein kinase that plays an essential role in both the onset of G2/M transition and cytokinesis. The overexpression of PLK-1 is strongly correlated with a wide spectrum of human cancers and poor prognosis. The (si)RNA-mediated depletion of PLK-1 arrests tumor growth and triggers apoptosis in cancer cells without affecting normal cells. Therefore, PLK-1 has been selected as an attractive anticancer therapeutic drug target. Some small molecules have been discovered to target the catalytic and noncatalytic domains of PLK-1. These domains regulate the catalytic activation and subcellular localization of PLK-1. However, while PLK-1 inhibitors block tumor growth, they have been shown to cause severe adverse complications, such as toxicity, neutropenia, and bone marrow suppression during clinical trials, due to a lack of selectivity and specificity within the human kinome. To minimize these toxicities, inhibitors should be tested against all protein kinases in vivo and in vitro to enhance selectivity and specificity against targets. Here, we discuss the potency and selectivity of PLK-1-targeted inhibitors and their molecular interactions with PLK-1 domains. PMID:26557691

  2. Interaction of a potential vacuolar targeting receptor with amino- and carboxyl-terminal targeting determinants.

    PubMed

    Kirsch, T; Saalbach, G; Raikhel, N V; Beevers, L

    1996-06-01

    A protein of 80 kD from developing pea (Pisum sativum) cotyledons has previously been shown to exhibit characteristics of a vacuolar targeting receptor by means of its affinity for the amino-terminal vacuolar targeting sequence of proaleurain from barley (Hordeum vulgare). In this report we show that the same protein also binds to the amino-terminal targeting peptide of prosporamin from sweet potato (Ipomoea batatas) and to the carboxyl-terminal targeting determinant of pro-2S albumin from Brazil nut (Bertholletia excelsa). The receptor protein does not bind to the carboxyl-terminal propeptide (representing the targeting sequence) of barley lectin. The binding of the 80-kD protein to the sporamin determinant involves a motif (NPIR) that has been shown to be crucial for vacuolar targeting in vivo. The binding to the carboxyl-terminal targeting determinant of pro-2S albumin appears to involve the carboxyl-terminal propeptide and the adjacent five amino acids of the mature protein. The 80-kD protein does not bind to peptide sequences that have been shown to be incompetent in directing vacuolar targeting.

  3. Histamine H3 receptor as a potential target for cognitive symptoms in neuropsychiatric diseases.

    PubMed

    Sadek, Bassem; Saad, Ali; Sadeq, Adel; Jalal, Fakhreya; Stark, Holger

    2016-10-01

    The potential contributions of the brain histaminergic system in neurodegenerative diseases, and the possiblity of histamine-targeting treatments is attracting considerable interests. The histamine H3 receptor (H3R) is expressed mainly in the central nervous system, and is, consequently, an attractive pharmacological target. Although recently described clinical trials have been disappointing in attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCH), numerous H3R antagonists, including pitolisant, demonstrate potential in the treatment of narcolepsy, excessive daytime sleepiness associated with cognitive impairment, epilepsy, and Alzheimer's disease (AD). This review focuses on the recent preclinical as well as clinical results that support the relevance of H3R antagonists for the treatment of cognitive symptoms in neuropsychiatric diseases, namely AD, epilepsy and SCH. The review summarizes the role of histaminergic neurotransmission with focus on these brain disorders, as well as the effects of numerous H3R antagonists on animal models and humans.

  4. Targeting heterochromatin formation to transposable elements in Drosophila: potential roles of the piRNA system.

    PubMed

    Sentmanat, M; Wang, S H; Elgin, S C R

    2013-06-01

    Successful heterochromatin formation is critical for genome stability in eukaryotes, both to maintain structures needed for mitosis and meiosis and to silence potentially harmful transposable elements. Conversely, inappropriate heterochromatin assembly can lead to inappropriate silencing and other deleterious effects. Hence targeting heterochromatin assembly to appropriate regions of the genome is of utmost importance. Here we focus on heterochromatin assembly in Drosophila melanogaster, the model organism in which variegation, or cell-to-cell variable gene expression resulting from heterochromatin formation, was first described. In particular, we review the potential role of transposable elements as genetic determinants of the chromatin state and examine how small RNA pathways may participate in the process of targeted heterochromatin formation.

  5. Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges

    PubMed Central

    Hoshida, Yujin; Fuchs, Bryan C.; Tanabe, Kenneth K.

    2013-01-01

    Chronic fibrotic liver diseases such as viral hepatitis eventually develop liver cirrhosis, which causes occurrence of hepatocellular carcinoma (HCC). Given the limited therapeutic efficacy in advanced HCC, prevention of HCC development could be an effective strategy for improving patient prognosis. However, there is still no established therapy to meet the goal. Studies have elucidated a wide variety of molecular mechanisms and signaling pathways involved in HCC development. Genetically-engineered or chemically-treated experimental models of cirrhosis and HCC have been developed and shown their potential value in investigating molecular therapeutic targets and diagnostic biomarkers for HCC prevention. In this review, we overview potential targets of prevention and currently available experimental models, and discuss strategies to translate the findings into clinical practice. PMID:22873223

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

    PubMed Central

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

    2015-01-01

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

  7. Caveat of RNAi in plants: the off-target effect.

    PubMed

    Senthil-Kumar, Muthappa; Mysore, Kirankumar S

    2011-01-01

    RNA interference (RNAi), mediated by short interfering RNAs (siRNAs), is one of the widely used functional genomics method for suppressing the gene expression in plants. Initially, gene silencing by RNAi mechanism was believed to be specific requiring sequence homology between siRNA and target mRNA. However, several recent reports have showed that non-specific effects often referred as off-target gene silencing can occur during RNAi. This unintended gene silencing can lead to false conclusions in RNAi experiments that are aimed to study the functional role of a particular target gene in plants. This especially is a major problem in large-scale RNAi-based screens aiming for gene discovery. Hence, understanding the off-target effects is crucial for minimizing such effects to better conclude gene function analyzed by RNAi. We discuss here potential problems of off-target gene silencing and focus on possibilities that favor this effect during post-transcriptional gene silencing. Suggestions to overcome the off-target effects during RNAi studies are also presented. We believe that information available in present-day plant science literature about specificity of siRNA actions is inadequate. In-depth systematic studies to understand their molecular basis are necessary to enable improved design of more specific RNAi vectors. In the meantime, gene function and phenotype results from present-day RNAi studies need to be interpreted with caution.

  8. Lepidopteran HMG-CoA reductase is a potential selective target for pest control

    PubMed Central

    Li, Yuan-mei; Huang, Juan; Tobe, Stephen S.

    2017-01-01

    As a consequence of the negative impacts on the environment of some insecticides, discovery of eco-friendly insecticides and target has received global attention in recent years. Sequence alignment and structural comparison of the rate-limiting enzyme HMG-CoA reductase (HMGR) revealed differences between lepidopteran pests and other organisms, which suggested insect HMGR could be a selective insecticide target candidate. Inhibition of JH biosynthesis in vitro confirmed that HMGR inhibitors showed a potent lethal effect on the lepidopteran pest Manduca sexta, whereas there was little effect on JH biosynthesis in Apis mellifera and Diploptera punctata. The pest control application of these inhibitors demonstrated that they can be insecticide candidates with potent ovicidal activity, larvicidal activity and insect growth regulatory effects. The present study has validated that Lepidopteran HMGR can be a potent selective insecticide target, and the HMGR inhibitors (especially type II statins) could be selective insecticide candidates and lead compounds. Furthermore, we demonstrated that sequence alignment, homology modeling and structural comparison may be useful for determining potential enzymes or receptors which can be eco-friendly pesticide  targets. PMID:28133568

  9. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity.

    PubMed

    Beltran, Himisha; Yelensky, Roman; Frampton, Garrett M; Park, Kyung; Downing, Sean R; MacDonald, Theresa Y; Jarosz, Mirna; Lipson, Doron; Tagawa, Scott T; Nanus, David M; Stephens, Philip J; Mosquera, Juan Miguel; Cronin, Maureen T; Rubin, Mark A

    2013-05-01

    gene (BRCA2) loss (12%) and ataxia telangiectasia mutated gene (ATM) mutations (8%); these alterations are potentially targetable with poly(adenosine diphosphate-ribose)polymerase inhibitors. A novel and actionable rearrangement involving the v-raf murine sarcoma viral oncogene homolog B1 gene (BRAF) was also detected. This first-in-principle study demonstrates the feasibility of performing in-depth DNA analyses using FFPE tissue and brings new insight toward understanding the genomic landscape within advanced PCa. Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  10. Lactoferrin bioconjugated solid lipid nanoparticles: a new drug delivery system for potential brain targeting.

    PubMed

    Singh, Indu; Swami, Rajan; Pooja, Deep; Jeengar, Manish Kumar; Khan, Wahid; Sistla, Ramakrishna

    2016-01-01

    Delivery of drugs to brain is a subtle task in the therapy of many severe neurological disorders. Solid lipid nanoparticles (SLN) easily diffuse the blood-brain barrier (BBB) due to their lipophilic nature. Furthermore, ligand conjugation on SLN surface enhances the targeting efficiency. Lactoferin (Lf) conjugated SLN system is first time attempted for effective brain targeting in this study. Preparation of Lf-modified docetaxel (DTX)-loaded SLN for proficient delivery of DTX to brain. DTX-loaded SLN were prepared using emulsification and solvent evaporation method and conjugation of Lf on SLN surface (C-SLN) was attained through carbodiimide chemistry. These lipidic nanoparticles were evaluated by DLS, AFM, FTIR, XRD techniques and in vitro release studies. Colloidal stability study was performed in biologically simulated environment (normal saline and serum). These lipidic nanoparticles were further evaluated for its targeting mechanism for uptake in brain tumour cells and brain via receptor saturation studies and distribution studies in brain, respectively. Particle size of lipidic nanoparticles was found to be optimum. Surface morphology (zeta potential, AFM) and surface chemistry (FTIR) confirmed conjugation of Lf on SLN surface. Cytotoxicity studies revealed augmented apoptotic activity of C-SLN than SLN and DTX. Enhanced cytotoxicity was demonstrated by receptor saturation and uptake studies. Brain concentration of DTX was elevated significantly with C-SLN than marketed formulation. It is evident from the cytotoxicity, uptake that SLN has potential to deliver drug to brain than marketed formulation but conjugating Lf on SLN surface (C-SLN) further increased the targeting potential for brain tumour. Moreover, brain distribution studies corroborated the use of C-SLN as a viable vehicle to target drug to brain. Hence, C-SLN was demonstrated to be a promising DTX delivery system to brain as it possessed remarkable biocompatibility, stability and efficacy than

  11. S100-alarmins: potential therapeutic targets for arthritis.

    PubMed

    Austermann, Judith; Zenker, Stefanie; Roth, Johannes

    2017-07-01

    In arthritis, inflammatory processes are triggered by numerous factors that are released from joint tissues, promoting joint destruction and pathological progression. During inflammation, a novel family of pro-inflammatory molecules called alarmins is released, amplifying inflammation and joint damage. Areas covered: With regard to the role of the alarmins S100A8 and S100A9 in the pathogenesis of arthritis, recent advances and the future prospects in terms of therapeutic implications are considered. Expert opinion: There is still an urgent need for novel treatment strategies addressing the local mechanisms of joint inflammation and tissue destruction, offering promising therapeutic alternatives. S100A8 and S100A9, which are the most up-regulated alarmins during arthritis, are endogenous triggers of inflammation, defining these proteins as promising targets for local suppression of arthritis. In murine models, the blockade of S100A8/S100A9 ameliorates inflammatory processes, including arthritis, and there are several lines of evidence that S100-alarmins may already be targeted in therapeutic approaches in man.

  12. Brain: The Potential Diagnostic and Therapeutic Target for Glaucoma.

    PubMed

    Faiq, Muneeb A; Dada, Rima; Kumar, Ashutosh; Saluja, Daman; Dada, Tanuj

    2016-01-01

    Glaucoma is a form of multifactorial ocular neurodegeneration with immensely complex etiology, pathogenesis and pathology. Though the mainstream therapeutic management of glaucoma is lowering of intraocular pressure, there is, as of now, no cure for the disease. New evidences ardently suggest brain involvement in all aspects of this malady. This consequently advocates the opinion that brain should be the spotlight of glaucoma research and may form the impending and promising target for glaucoma diagnosis and treatment. The present analysis endeavors at understanding glaucoma vis-à-vis brain structural and/or functional derangement and central nervous system (CNS) degeneration. Commencing with the premise of developing some understanding about the brain-nature of ocular structures; we discuss the nature of the cellular and molecular moieties involved in glaucoma and Alzheimer's disease. Substantial deal of literature implies that glaucoma may well be a disease of the brain, nevertheless, manifesting as progressive loss of vision. If that is the case, then targeting brain will be far more imperative in glaucoma therapeutics than any other remedial regimen currently being endorsed.

  13. How Actuated Particles Effectively Capture Biomolecular Targets

    PubMed Central

    2017-01-01

    Because of their high surface-to-volume ratio and adaptable surface functionalization, particles are widely used in bioanalytical methods to capture molecular targets. In this article, a comprehensive study is reported of the effectiveness of protein capture by actuated magnetic particles. Association rate constants are quantified in experiments as well as in Brownian dynamics simulations for different particle actuation configurations. The data reveal how the association rate depends on the particle velocity, particle density, and particle assembly characteristics. Interestingly, single particles appear to exhibit target depletion zones near their surface, caused by the high density of capture molecules. The depletion effects are even more limiting in cases with high particle densities. The depletion effects are overcome and protein capture rates are enhanced by applying dynamic particle actuation, resulting in an increase in the association rate constants by up to 2 orders of magnitude. PMID:28192952

  14. Assessing Potential Impact of Bt Eggplants on Non-Target Arthropods in the Philippines.

    PubMed

    Navasero, Mario V; Candano, Randolph N; Hautea, Desiree M; Hautea, Randy A; Shotkoski, Frank A; Shelton, Anthony M

    2016-01-01

    Studies on potential adverse effects of genetically engineered crops are part of an environmental risk assessment that is required prior to the commercial release of these crops. Of particular concern are non-target organisms (NTOs) that provide important ecosystem services. Here, we report on studies conducted in the Philippines over three cropping seasons with Bt eggplants expressing Cry1Ac for control of the eggplant fruit and shoot borer (EFSB), Leucinodes orbonalis, to examine potential effects on field abundance, community composition, structure and biodiversity of NTO's, particularly non-target arthropod (NTA) communities. We document that many arthropod taxa are associated with Bt eggplants and their non-Bt comparators and that the number of taxa and their densities varied within season and across trials. However, we found few significant differences in seasonal mean densities of arthropod taxa between Bt and non-Bt eggplants. As expected, a lower abundance of lepidopteran pests was detected in Bt eggplants. Higher abundance of a few non-target herbivores was detected in non-Bt eggplants as were a few non-target beneficials that might control them. Principal Response Curve (PRC) analyses showed no statistically significant impact of Bt eggplants on overall arthropod communities through time in any season. Furthermore, we found no significant adverse impacts of Bt eggplants on species abundance, diversity and community dynamics, particularly for beneficial NTAs. These results support our previous studies documenting that Bt eggplants can effectively and selectively control the main pest of eggplant in Asia, the EFSB. The present study adds that it can do so without adverse effects on NTAs. Thus, Bt eggplants can be a foundational component for controlling EFSB in an Integrated Pest Management (IPM) program and dramatically reduce dependence on conventional insecticides.

  15. Assessing Potential Impact of Bt Eggplants on Non-Target Arthropods in the Philippines

    PubMed Central

    Navasero, Mario V.; Candano, Randolph N.; Hautea, Desiree M.; Hautea, Randy A.; Shotkoski, Frank A.; Shelton, Anthony M.

    2016-01-01

    Studies on potential adverse effects of genetically engineered crops are part of an environmental risk assessment that is required prior to the commercial release of these crops. Of particular concern are non-target organisms (NTOs) that provide important ecosystem services. Here, we report on studies conducted in the Philippines over three cropping seasons with Bt eggplants expressing Cry1Ac for control of the eggplant fruit and shoot borer (EFSB), Leucinodes orbonalis, to examine potential effects on field abundance, community composition, structure and biodiversity of NTO’s, particularly non-target arthropod (NTA) communities. We document that many arthropod taxa are associated with Bt eggplants and their non-Bt comparators and that the number of taxa and their densities varied within season and across trials. However, we found few significant differences in seasonal mean densities of arthropod taxa between Bt and non-Bt eggplants. As expected, a lower abundance of lepidopteran pests was detected in Bt eggplants. Higher abundance of a few non-target herbivores was detected in non-Bt eggplants as were a few non-target beneficials that might control them. Principal Response Curve (PRC) analyses showed no statistically significant impact of Bt eggplants on overall arthropod communities through time in any season. Furthermore, we found no significant adverse impacts of Bt eggplants on species abundance, diversity and community dynamics, particularly for beneficial NTAs. These results support our previous studies documenting that Bt eggplants can effectively and selectively control the main pest of eggplant in Asia, the EFSB. The present study adds that it can do so without adverse effects on NTAs. Thus, Bt eggplants can be a foundational component for controlling EFSB in an Integrated Pest Management (IPM) program and dramatically reduce dependence on conventional insecticides. PMID:27798662

  16. Doxorubicin-loaded micelle targeting MUC1: a potential therapeutics for triple negative breast cancer treatment.

    PubMed

    Khondee, Supang; Chittasupho, Chuda; Tima, Singkome; Anuchapreeda, Songyot

    2017-07-12

    Triple negative breast cancer (TNBC) is an aggressive disease associated with poor prognosis and lack of validated targeted therapy. Thus chemotherapy is a main adjuvant treatment for TNBC patients, but it associates with severe toxicities. For a better treatment outcome, we developed an alternative therapeutic, doxorubicin (DOX)-loaded micelles targeting human mucin1 protein (MUC1) that is less toxic, more effective and targeted to TNBC. From many candidate peptides, QNDRHPR-GGGSK (QND) and HSQLPQV-GGGSK (HSQ), were identified computationally, synthesized and purified using solid phase peptide synthesis and semi-preparative HPLC. The peptides showed significant high binding to MUC1 expressing cells using a fluorescent microscope. The peptides were then conjugated on pegylated octadecyl lithocholate copolymer. DOX-encapsulated micelles were formed through self-assembly. MUC1-targeted micelles were characterized using dynamic light scattering (DLS) and Transmission Electron Microscopy (TEM). Drug entrapment efficiency was examined using a microplate reader. Cytotoxicity and binding and uptake were also investigated. Two types of DOX-loaded micelles with different targeting peptides, QND or HSQ, were developed. DOX-loaded micelles were spherical in shape with average particle size around 300-320 nm. Drug entrapment efficiency of untargeted and targeted DOX micelles was about 71-93%. Targeted QND-DOX and HSQ-DOX micelles exhibited significantly higher cytotoxicity compared to free DOX and untargeted DOX micelles on BT549-Luc cells. In addition, significantly greater binding and uptake were observed for QND-DOX and HSQ-DOX micelles on BT549-Luc and T47D cells. Taken together, these results suggested that QND-DOX and HSQ-DOX micelles have a potential application in the treatment of TNBC-expressing MUC1. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Is EGR1 a potential target for prostate cancer therapy?

    PubMed Central

    Gitenay, Delphine; Baron, Véronique T

    2009-01-01

    Prostate cancer is a major cause of cancer-related death in American men, for which finding new therapeutic strategies remains a challenge. Early growth response-1 (EGR1) is a transcription factor involved in cell proliferation and in the regulation of apoptosis. Although it has long been considered a tumor suppressor, a wealth of new evidence shows that EGR1 promotes the progression of prostate cancer. This review addresses the paradoxes of EGR1 function. While EGR1 mediates apoptosis in response to stress and DNA damage by regulating a tumor suppressor network, it also promotes the proliferation of prostate cancer cells by a mechanism that is not fully understood. Thus, EGR1 might be targeted for prostate cancer therapy either by ectopic expression in combination with radiotherapy or chemotherapy, or by direct inhibition for systemic treatment. Possible strategies to antagonize EGR1 function in a therapeutic setting are discussed. PMID:19792968

  18. Dual-targeting anti-angiogenic cyclic peptides as potential drug leads for cancer therapy

    PubMed Central

    Chan, Lai Yue; Craik, David J.; Daly, Norelle L.

    2016-01-01

    Peptide analogues derived from bioactive hormones such as somatostatin or certain growth factors have great potential as angiogenesis inhibitors for cancer applications. In an attempt to combat emerging drug resistance many FDA-approved anti-angiogenesis therapies are co-administered with cytotoxic drugs as a combination therapy to target multiple signaling pathways of cancers. However, cancer therapies often encounter limiting factors such as high toxicities and side effects. Here, we combined two anti-angiogenic epitopes that act on different pathways of angiogenesis into a single non-toxic cyclic peptide framework, namely MCoTI-II (Momordica cochinchinensis trypsin inhibitor-II), and subsequently assessed the anti-angiogenic activity of the novel compound. We hypothesized that the combination of these two epitopes would elicit a synergistic effect by targeting different angiogenesis pathways and result in improved potency, compared to that of a single epitope. This novel approach has resulted in the development of a potent, non-toxic, stable and cyclic analogue with nanomolar potency inhibition in in vitro endothelial cell migration and in vivo chorioallantoic membrane angiogenesis assays. This is the first report to use the MCoTI-II framework to develop a 2-in-1 anti-angiogenic peptide, which has the potential to be used as a form of combination therapy for targeting a wide range of cancers. PMID:27734947

  19. Dual-targeting anti-angiogenic cyclic peptides as potential drug leads for cancer therapy.

    PubMed

    Chan, Lai Yue; Craik, David J; Daly, Norelle L

    2016-10-13

    Peptide analogues derived from bioactive hormones such as somatostatin or certain growth factors have great potential as angiogenesis inhibitors for cancer applications. In an attempt to combat emerging drug resistance many FDA-approved anti-angiogenesis therapies are co-administered with cytotoxic drugs as a combination therapy to target multiple signaling pathways of cancers. However, cancer therapies often encounter limiting factors such as high toxicities and side effects. Here, we combined two anti-angiogenic epitopes that act on different pathways of angiogenesis into a single non-toxic cyclic peptide framework, namely MCoTI-II (Momordica cochinchinensis trypsin inhibitor-II), and subsequently assessed the anti-angiogenic activity of the novel compound. We hypothesized that the combination of these two epitopes would elicit a synergistic effect by targeting different angiogenesis pathways and result in improved potency, compared to that of a single epitope. This novel approach has resulted in the development of a potent, non-toxic, stable and cyclic analogue with nanomolar potency inhibition in in vitro endothelial cell migration and in vivo chorioallantoic membrane angiogenesis assays. This is the first report to use the MCoTI-II framework to develop a 2-in-1 anti-angiogenic peptide, which has the potential to be used as a form of combination therapy for targeting a wide range of cancers.

  20. The JAK2/STAT5 signaling pathway as a potential therapeutic target in canine mastocytoma.

    PubMed

    Keller, Alexandra; Wingelhofer, Bettina; Peter, Barbara; Bauer, Karin; Berger, Daniela; Gamperl, Susanne; Reifinger, Martin; Cerny-Reiterer, Sabine; Moriggl, Richard; Willmann, Michael; Valent, Peter; Hadzijusufovic, Emir

    2017-04-11

    Mastocytoma are frequently diagnosed cutaneous neoplasms in dogs. In non-resectable mastocytoma patients, novel targeted drugs are often applied. The transcription factor STAT5 has been implicated in the survival of human neoplastic mast cells (MC). Our study evaluated the JAK2/STAT5 pathway as a novel target in canine mastocytoma. We employed inhibitors of JAK2 (R763, TG101348, AZD1480, ruxolitinib) and STAT5 (pimozide, piceatannol) and evaluated their effects on 2 mastocytoma cell lines, C2 and NI-1. Activated JAK2 and STAT5 were detected in both cell lines. The drugs applied were found to inhibit proliferation and survival in these cells with the following rank-order of potency: R763 > TG101348 > AZD1480 > pimozide > ruxolitinib > piceatannol. Moreover, synergistic anti-neoplastic effects were obtained by combining pimozide with KIT-targeting drugs (toceranib, masitinib, nilotinib, midostaurin) in NI-1 cells. The JAK2/STAT5 pathway is a novel potential target of therapy in canine mastocytoma. © 2017 John Wiley & Sons Ltd.

  1. Target Fishing by Cross-Docking to Explain Polypharmacological Effects.

    PubMed

    Patel, Hitesh; Lucas, Xavier; Bendik, Igor; Günther, Stefan; Merfort, Irmgard

    2015-07-01

    Drugs may have polypharmacological phenomena, that is, in addition to the desired target, they may also bind to many undesired or unknown physiological targets. As a result, they often exert side effects. In some cases, off-target interactions may lead to drug repositioning or to explaining a drug's mode of action. Herein we present an in silico approach for target fishing by cross-docking as a method to identify new drug-protein interactions. As an example and proof of concept, this method predicted the peroxisome proliferator-activated receptor (PPAR)-γ as a target of ethacrynic acid, which may explain the hyperglycemic effect brought on by this molecule. The antagonistic effect of ethacrynic acid on PPAR-γ was validated in a transient transactivation assay using human HEK293 cells. The cross-docking approach also predicted the potential mechanisms of many other drug side effects and discloses new drug repositioning opportunities. These putative interactions are described herein, and can be readily used to discover therapeutically relevant drug effects.

  2. Combined expressional analysis, bioinformatics and targeted proteomics identify new potential therapeutic targets in glioblastoma stem cells.

    PubMed

    Stangeland, Biljana; Mughal, Awais A; Grieg, Zanina; Sandberg, Cecilie Jonsgar; Joel, Mrinal; Nygård, Ståle; Meling, Torstein; Murrell, Wayne; Vik Mo, Einar O; Langmoen, Iver A

    2015-09-22

    Glioblastoma (GBM) is both the most common and the most lethal primary brain tumor. It is thought that GBM stem cells (GSCs) are critically important in resistance to therapy. Therefore, there is a strong rationale to target these cells in order to develop new molecular therapies.To identify molecular targets in GSCs, we compared gene expression in GSCs to that in neural stem cells (NSCs) from the adult human brain, using microarrays. Bioinformatic filtering identified 20 genes (PBK/TOPK, CENPA, KIF15, DEPDC1, CDC6, DLG7/DLGAP5/HURP, KIF18A, EZH2, HMMR/RHAMM/CD168, NOL4, MPP6, MDM1, RAPGEF4, RHBDD1, FNDC3B, FILIP1L, MCC, ATXN7L4/ATXN7L1, P2RY5/LPAR6 and FAM118A) that were consistently expressed in GSC cultures and consistently not expressed in NSC cultures. The expression of these genes was confirmed in clinical samples (TCGA and REMBRANDT). The first nine genes were highly co-expressed in all GBM subtypes and were part of the same protein-protein interaction network. Furthermore, their combined up-regulation correlated negatively with patient survival in the mesenchymal GBM subtype. Using targeted proteomics and the COGNOSCENTE database we linked these genes to GBM signalling pathways.Nine genes: PBK, CENPA, KIF15, DEPDC1, CDC6, DLG7, KIF18A, EZH2 and HMMR should be further explored as targets for treatment of GBM.

  3. Effects-Based Targeting: Another Empty Promise?

    DTIC Science & Technology

    2001-12-01

    while there is still ample time to correct them. If we wait until we actually need these capabilities, it will be too late. As Bertolt Brecht sagely...current combat practices. Readers may observe that this study concentrates on large-scale con- ventional conflict in which American airpower played a...effort.20 Given these discussions, it is evident that effects played a key role in tar- get identification; however, selecting targets was one thing

  4. Targeted treatment for chronic lymphocytic leukemia: clinical potential of obinutuzumab

    PubMed Central

    Smolej, Lukáš

    2015-01-01

    Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL) in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS) in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL. Obinutuzumab (GA101) is the newest monoclonal antibody approved for the treatment of CLL. This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies. Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients. These results led to approval of obinuzutumab for the treatment of CLL. Numerous clinical trials combining obinutuzumab with other cytotoxic drugs and novel small molecules are currently under way. This review focuses on the role of obinutuzumab in the treatment of CLL. PMID:25691812

  5. Potential targeted therapy for liver fluke associated cholangiocarcinoma.

    PubMed

    Vaeteewoottacharn, Kulthida; Seubwai, Wunchana; Bhudhisawasdi, Vajarabhongsa; Okada, Seiji; Wongkham, Sopit

    2014-06-01

    Biliary tree cancer or cholangiocarcinoma (CCA) is an unusual subtype of liver cancer with exceptionally poor prognosis. Lack of specific symptoms and availability of early diagnostic markers account for late diagnosis of CCA. Surgical treatment is a gold standard choice but few patients are candidates and local recurrence after surgery is high. Benefit of systemic chemotherapy is limited; hence, better treatment options are required. The differences in etiology, anatomical positions and pathology make it difficult to generalize all CCA subtypes for a single treatment regimen. Herein, we review the uniqueness of molecular profiling identified by multiple approaches, for example, serial analysis of gene expression, exome sequencing, transcriptomics/proteomics profiles, protein kinase profile, etc., that provide the opportunity for treatment of liver fluke-associated CCA. Anti-inflammatory, immunomodulator/immunosuppressor, epidermal growth factor receptor or platelet-derived growth factor receptor inhibitors, multi-targeted tyrosine kinase inhibitor, IL6 antagonist, nuclear factor-κB inhibitor, histone modulator, proteasome inhibitor as well as specific inhibitors suggested from various study approaches, such as MetAP2 inhibitor, 1,25(OH)2 D3 and cyclosporine A are suggested in this review for the treatments of this specific CCA subtype. This might provide an alternative treatment option for CCA patients; however, clinical trials in this specific CCA group are required. © 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.

  6. Theranostic Potential Of Targeted Nanoparticles For Brain Cancer.

    PubMed

    Bhatt, Ajita; Gurnany, Ekta; Modi, Anuj; Gulbake, Arvind; Jain, Aviral

    2017-09-26

    Cancer is one of the most important causes of morbidity and mortality all across the world. On an average, every year approximately 238,000 new cases of brain and other central nervous system tumors are diagnosed around the world. Amongst all, tumors of brain account for nearly 85% to 90% of all primary central nervous system (CNS) tumors. Regardless of tremendous scientific efforts to develop newer diagnostic techniques and latest therapy, the management of brain cancer is still challenge in neuro-oncology. Inadequate concentration of chemotherapeutics at site of tumor restricts the complete destruction of malignant cells due to the presence of blood brain barrier. Besides, there is a necessity for improvement in tumor imaging for better characterization and visualization of tumor cells for surgical procedure. Nanoparticles offer the advantages upon many of these concerns i.e., diagnosis, capability to target therapeutic agents to the tumor sites and the ability of getting across the blood-brain barrier. Thus utilization of nanoparticles may lead to breakthrough in brain cancer management. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Polyamine catabolism in carcinogenesis: potential targets for chemotherapy and chemoprevention

    PubMed Central

    Battaglia, Valentina; Shields, Christina DeStefano; Murray-Stewart, Tracy; Casero, Robert A.

    2013-01-01

    Polyamines, including spermine, spermidine, and the precursor diamine, putrescine, are naturally occurring polycationic alkylamines that are required for eukaryotic cell growth, differentiation, and survival. This absolute requirement for polyamines and the need to maintain intracellular levels within specific ranges requires a highly regulated metabolic pathway primed for rapid changes in response to cellular growth signals, environmental changes, and stress. Although the polyamine metabolic pathway is strictly regulated in normal cells, dysregulation of polyamine metabolism is a frequent event in cancer. Recent studies suggest that the polyamine catabolic pathway may be involved in the etiology of some epithelial cancers. The catabolism of spermine to spermidine utilizes either the one-step enzymatic reaction of spermine oxidase (SMO) or the two-step process of spermidine/spermine N1-acetyltransferase (SSAT) coupled with the peroxisomal enzyme N1-acetylpolyamine oxidase (APAO). Both catabolic pathways produce hydrogen peroxide (H2O2) and a reactive aldehyde that are capable of damaging DNA and other critical cellular components. The catabolic pathway also depletes the intracellular concentrations of spermidine and spermine, which are free radical scavengers. Consequently, the polyamine catabolic pathway in general and specifically SMO and SSAT provide exciting new targets for chemoprevention and/or chemotherapy. PMID:23771789

  8. Novel Class of Potential Therapeutics that Target Ricin Retrograde Translocation

    PubMed Central

    Redmann, Veronika; Gardner, Thomas; Lau, Zerlina; Morohashi, Keita; Felsenfeld, Dan; Tortorella, Domenico

    2013-01-01

    Ricin toxin, an A-B toxin from Ricinus communis, induces cell death through the inhibition of protein synthesis. The toxin binds to the cell surface via its B chain (RTB) followed by its retrograde trafficking through intracellular compartments to the ER where the A chain (RTA) is transported across the membrane and into the cytosol. Ricin A chain is transported across the ER membrane utilizing cellular proteins involved in the disposal of aberrant ER proteins by a process referred to as retrograde translocation. Given the current lack of therapeutics against ricin intoxication, we developed a high-content screen using an enzymatically attenuated RTA chimera engineered with a carboxy-terminal enhanced green fluorescent protein (RTAE177Qegfp) to identify compounds that target RTA retrograde translocation. Stabilizing RTAE177Qegfp through the inclusion of proteasome inhibitor produced fluorescent peri-nuclear granules. Quantitative analysis of the fluorescent granules provided the basis to discover compounds from a small chemical library (2080 compounds) with known bioactive properties. Strikingly, the screen found compounds that stabilized RTA molecules within the cell and several compounds limited the ability of wild type RTA to suppress protein synthesis. Collectively, a robust high-content screen was developed to discover novel compounds that stabilize intracellular ricin and limit ricin intoxication. PMID:24366208

  9. Mycobacterium tuberculosis chorismate mutase: A potential target for TB.

    PubMed

    Khanapur, Manjulatha; Alvala, Mallika; Prabhakar, Maddela; Shiva Kumar, K; Edwin, R K; Sri Saranya, P S V K; Patel, Raj Kumar; Bulusu, Gopalakrishnan; Misra, P; Pal, Manojit

    2017-03-15

    Mycobacterium tuberculosis chorismate mutase (MtbCM) catalyzes the rearrangement of chorismate to prephenate in the shikimate biosynthetic pathway to form the essential amino acids, phenylalanine and tyrosine. Two genes encoding chorismate mutase have been identified in Mtb. The secretory form,∗MtbCM (encoded by Rv1885c) is assumed to play a key role in pathogenesis of tuberculosis. Also, the inhibition of MtbCM may hinder the supply of nutrients to the organism. Indeed, the existence of chorismate mutase (CM) in bacteria, fungi and higher plants but not in human and low sequence homology among known CM makes it an interesting target for the discovery of anti-tubercular agents. The present article mainly focuses on the recent developments in the structure, function and inhibition of MtbCM. The understanding of various aspects of MtbCM as presented in the current article may facilitate the design and subsequent chemical synthesis of new inhibitors against ∗MtbCM, that could lead to the discovery and development of novel and potent anti-tubercular agents in future.

  10. Natural antisense and noncoding RNA transcripts as potential drug targets.

    PubMed

    Wahlestedt, Claes

    2006-06-01

    Information on the complexity of mammalian RNA transcription has increased greatly in the past few years. Notably, thousands of sense transcripts (conventional protein-coding genes) have antisense transcript partners, most of which are noncoding. Interestingly, a number of antisense transcripts regulate the expression of their sense partners, either in a discordant (antisense knockdown results in sense-transcript elevation) or concordant (antisense knockdown results in concomitant sense-transcript reduction) manner. Two new pharmacological strategies based on the knockdown of antisense RNA transcripts by siRNA (or another RNA targeting principle) are proposed in this review. In the case of discordant regulation, knockdown of antisense transcript elevates the expression of the conventional (sense) gene, thereby conceivably mimicking agonist-activator action. In the case of concordant regulation, knockdown of antisense transcript, or concomitant knockdown of antisense and sense transcripts, results in an additive or even synergistic reduction of the conventional gene expression. Although both strategies have been demonstrated to be valid in cell culture, it remains to be seen whether they provide advantages in other contexts.

  11. CD30 is a potential therapeutic target in malignant mesothelioma

    PubMed Central

    Dabir, Snehal; Kresak, Adam; Yang, Michael; Fu, Pingfu; Wildey, Gary; Dowlati, Afshin

    2015-01-01

    CD30 is a cytokine receptor belonging to the tumor necrosis factor superfamily (TNFRSF8) that acts as a regulator of apoptosis. The presence of CD30 antigen is important in the diagnosis of Hodgkin’s disease and anaplastic large cell lymphoma. There have been sporadic reports of CD30 expression in non-lymphoid tumors, including malignant mesothelioma. Given the remarkable success of brentuximab vedotin, an antibody-drug conjugate directed against CD30 antigen, in lymphoid malignancies, we undertook a study to examine the incidence of CD30 in mesothelioma and to investigate the ability to target CD30 antigen in mesothelioma. Mesothelioma tumor specimens (N = 83) were examined for CD30 expression by immunohistochemistry. Positive CD30 expression was noted in 13 mesothelioma specimens, primarily those of epithelial histology. There was no significant correlation of CD30 positivity with either tumor grade, stage or survival. Examination of four mesothelioma cell lines (H28, H2052, H2452, and 211H) for CD30 expression by both FACS analysis and confocal microscopy showed that CD30 antigen localized to the cell membrane. Brentuximab vedotin treatment of cultured mesothelioma cells produced a dose-dependent decrease in cell growth and viability at clinically relevant concentrations. Our studies validate the presence of CD30 antigen in a subgroup of epithelial-type mesothelioma tumors and indicate that selected mesothelioma patients may derive benefit from brentuximab vedotin treatment. PMID:25589494

  12. Approaches for targeted proteomics and its potential applications in neuroscience.

    PubMed

    Sethi, Sumit; Chourasia, Dipti; Parhar, Ishwar S

    2015-09-01

    An extensive guide on practicable and significant quantitative proteomic approaches in neuroscience research is important not only because of the existing overwhelming limitations but also for gaining valuable understanding into brain function and deciphering proteomics from the workbench to the bedside. Early methodologies to understand the functioning of biological systems are now improving with high-throughput technologies, which allow analysis of various samples concurrently, or of thousand of analytes in a particular sample. Quantitative proteomic approaches include both gel-based and non-gel-based methods that can be further divided into different labelling approaches. This review will emphasize the role of existing technologies, their advantages and disadvantages, as well as their applications in neuroscience. This review will also discuss advanced approaches for targeted proteomics using isotope-coded affinity tag (ICAT) coupled with laser capture microdissection (LCM) followed by liquid chromatography tandem mass spectrometric (LC-MS/MS) analysis. This technology can further be extended to single cell proteomics in other areas of biological sciences and can be combined with other 'omics' approaches to reveal the mechanism of a cellular alterations. This approach may lead to further investigation in basic biology, disease analysis and surveillance, as well as drug discovery. Although numerous challenges still exist, we are confident that this approach will increase the understanding of pathological mechanisms involved in neuroendocrinology, neuropsychiatric and neurodegenerative disorders by delivering protein biomarker signatures for brain dysfunction.

  13. Stat3 as a potential therapeutic target for rheumatoid arthritis.

    PubMed

    Oike, Takatsugu; Sato, Yuiko; Kobayashi, Tami; Miyamoto, Kana; Nakamura, Satoshi; Kaneko, Yosuke; Kobayashi, Shu; Harato, Kengo; Saya, Hideyuki; Matsumoto, Morio; Nakamura, Masaya; Niki, Yasuo; Miyamoto, Takeshi

    2017-09-08

    Rheumatoid arthritis (RA) is a multi-factorial disease characterized by chronic inflammation and destruction of multiple joints. To date, various biologic treatments for RA such as anti-tumor necrosis factor alpha antibodies have been developed; however, mechanisms underlying RA development remain unclear and targeted therapy for this condition has not been established. Here, we provide evidence that signal transducer and activator of transcription 3 (Stat3) promotes inflammation and joint erosion in a mouse model of arthritis. Stat3 global KO mice show early embryonic lethality; thus, we generated viable Stat3 conditional knockout adult mice and found that they were significantly resistant to collagen-induced arthritis (CIA), the most common RA model, compared with controls. We then used an in vitro culture system to screen ninety-six existing drugs to select Stat3 inhibitors and selected five candidate inhibitors. Among them, three significantly inhibited development of arthritis and joint erosion in CIA wild-type mice. These findings suggest that Stat3 inhibitors may serve as promising drugs for RA therapy.

  14. AAC as a Potential Target Gene to Control Verticillium dahliae

    PubMed Central

    Su, Xiaofeng; Rehman, Latifur; Guo, Huiming; Li, Xiaokang; Zhang, Rui; Cheng, Hongmei

    2017-01-01

    Verticillium dahliae invades the roots of host plants and causes vascular wilt, which seriously diminishes the yield of cotton and other important crops. The protein AAC (ADP, ATP carrier) is responsible for transferring ATP from the mitochondria into the cytoplasm. When V. dahliae protoplasts were transformed with short interfering RNAs (siRNAs) targeting the VdAAC gene, fungal growth and sporulation were significantly inhibited. To further confirm a role for VdAAC in fungal development, we generated knockout mutants (ΔVdACC). Compared with wild-type V. dahliae (Vd wt), ΔVdAAC was impaired in germination and virulence; these impairments were rescued in the complementary strains (ΔVdAAC-C). Moreover, when an RNAi construct of VdAAC under the control of the 35S promoter was used to transform Nicotiana benthamiana, the expression of VdAAC was downregulated in the transgenic seedlings, and they had elevated resistance against V. dahliae. The results of this study suggest that VdAAC contributes to fungal development, virulence and is a promising candidate gene to control V. dahliae. In addition, RNAi is a highly efficient way to silence fungal genes and provides a novel strategy to improve disease resistance in plants. PMID:28075391

  15. Polyamine catabolism in carcinogenesis: potential targets for chemotherapy and chemoprevention.

    PubMed

    Battaglia, Valentina; DeStefano Shields, Christina; Murray-Stewart, Tracy; Casero, Robert A

    2014-03-01

    Polyamines, including spermine, spermidine, and the precursor diamine, putrescine, are naturally occurring polycationic alkylamines that are required for eukaryotic cell growth, differentiation, and survival. This absolute requirement for polyamines and the need to maintain intracellular levels within specific ranges require a highly regulated metabolic pathway primed for rapid changes in response to cellular growth signals, environmental changes, and stress. Although the polyamine metabolic pathway is strictly regulated in normal cells, dysregulation of polyamine metabolism is a frequent event in cancer. Recent studies suggest that the polyamine catabolic pathway may be involved in the etiology of some epithelial cancers. The catabolism of spermine to spermidine utilizes either the one-step enzymatic reaction of spermine oxidase (SMO) or the two-step process of spermidine/spermine N (1)-acetyltransferase (SSAT) coupled with the peroxisomal enzyme N (1)-acetylpolyamine oxidase. Both catabolic pathways produce hydrogen peroxide and a reactive aldehyde that are capable of damaging DNA and other critical cellular components. The catabolic pathway also depletes the intracellular concentrations of spermidine and spermine, which are free radical scavengers. Consequently, the polyamine catabolic pathway in general and specifically SMO and SSAT provide exciting new targets for chemoprevention and/or chemotherapy.

  16. Gene expression profiling in bladder cancer identifies potential therapeutic targets

    PubMed Central

    Hussain, Syed A.; Palmer, Daniel H.; Syn, Wing-Kin; Sacco, Joseph J.; Greensmith, Richard M.D.; Elmetwali, Taha; Aachi, Vijay; Lloyd, Bryony H.; Jithesh, Puthen V.; Arrand, John; Barton, Darren; Ansari, Jawaher; Sibson, D. Ross; James, Nicholas D.

    2017-01-01

    Despite advances in management, bladder cancer remains a major cause of cancer related complications. Characterisation of gene expression patterns in bladder cancer allows the identification of pathways involved in its pathogenesis, and may stimulate the development of novel therapies targeting these pathways. Between 2004 and 2005, cystoscopic bladder biopsies were obtained from 19 patients and 11 controls. These were subjected to whole transcript-based microarray analysis. Unsupervised hierarchical clustering was used to identify samples with similar expression profiles. Hypergeometric analysis was used to identify canonical pathways and curated networks having statistically significant enrichment of differentially expressed genes. Osteopontin (OPN) expression was validated by immunohistochemistry. Hierarchical clustering defined signatures, which differentiated between cancer and healthy tissue, muscle-invasive or non-muscle invasive cancer and healthy tissue, grade 1 and grade 3. Pathways associated with cell cycle and proliferation were markedly upregulated in muscle-invasive and grade 3 cancers. Genes associated with the classical complement pathway were downregulated in non-muscle invasive cancer. Osteopontin was markedly overexpressed in invasive cancer compared to healthy tissue. The present study contributes to a growing body of work on gene expression signatures in bladder cancer. The data support an important role for osteopontin in bladder cancer, and identify several pathways worthy of further investigation. PMID:28259975

  17. Targeted treatment for chronic lymphocytic leukemia: clinical potential of obinutuzumab.

    PubMed

    Smolej, Lukáš

    2015-01-01

    Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL) in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS) in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL. Obinutuzumab (GA101) is the newest monoclonal antibody approved for the treatment of CLL. This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies. Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients. These results led to approval of obinuzutumab for the treatment of CLL. Numerous clinical trials combining obinutuzumab with other cytotoxic drugs and novel small molecules are currently under way. This review focuses on the role of obinutuzumab in the treatment of CLL.

  18. Novel class of potential therapeutics that target ricin retrograde translocation.

    PubMed

    Redmann, Veronika; Gardner, Thomas; Lau, Zerlina; Morohashi, Keita; Felsenfeld, Dan; Tortorella, Domenico

    2013-12-23

    Ricin toxin, an A-B toxin from Ricinus communis, induces cell death through the inhibition of protein synthesis. The toxin binds to the cell surface via its B chain (RTB) followed by its retrograde trafficking through intracellular compartments to the ER where the A chain (RTA) is transported across the membrane and into the cytosol. Ricin A chain is transported across the ER membrane utilizing cellular proteins involved in the disposal of aberrant ER proteins by a process referred to as retrograde translocation. Given the current lack of therapeutics against ricin intoxication, we developed a high-content screen using an enzymatically attenuated RTA chimera engineered with a carboxy-terminal enhanced green fluorescent protein (RTA(E177Q)egfp) to identify compounds that target RTA retrograde translocation. Stabilizing RTA(E177Q)egfp through the inclusion of proteasome inhibitor produced fluorescent peri-nuclear granules. Quantitative analysis of the fluorescent granules provided the basis to discover compounds from a small chemical library (2080 compounds) with known bioactive properties. Strikingly, the screen found compounds that stabilized RTA molecules within the cell and several compounds limited the ability of wild type RTA to suppress protein synthesis. Collectively, a robust high-content screen was developed to discover novel compounds that stabilize intracellular ricin and limit ricin intoxication.

  19. Introduction to the special issue: GIS-based mineral potential targeting

    NASA Astrophysics Data System (ADS)

    Yousefi, Mahyar; Nykänen, Vesa

    2017-04-01

    Mineral potential targeting using geographical information system is an efficient technique to delimit a study area for further exploration of mineral deposits. This introduction presents an overview of the mineral potential modeling methods and future perspectives of research in the fields of target generation and summarizes the papers that have been incorporated into this Special Issue of the Journal of African Earth Sciences.

  20. Potential targets in the search for extraterrestrial life.

    NASA Technical Reports Server (NTRS)

    Klein, H. P.

    1972-01-01

    Discussion of the potential for increasing understanding of the origins of terrestrial life by examination of other planets. If living organisms should be found on another planet, they could only have been transported from an inhabited planet or originated independently. The fundamental chemical and structural attributes of terrestrial organisms are so remarkably uniform that any living forms outside the terrestrial blueprint would almost certainly be regarded as alien organisms. It has been shown experimentally by various investigators that life can exist in an extremely wide range of temperatures and pressures. The presence of an atmosphere appears to be necessary.

  1. Galectin-3 as a Potential Target to Prevent Cancer Metastasis

    PubMed Central

    Ahmed, Hafiz; AlSadek, Dina M. M.

    2015-01-01

    Interactions between two cells or between cell and extracellular matrix mediated by protein–carbohydrate interactions play pivotal roles in modulating various biological processes such as growth regulation, immune function, cancer metastasis, and apoptosis. Galectin-3, a member of the β-galactoside-binding lectin family, is involved in fibrosis as well as cancer progression and metastasis, but the detailed mechanisms of its functions remain elusive. This review discusses its structure, carbohydrate-binding properties, and involvement in various aspects of tumorigenesis and some potential carbohydrate ligands that are currently investigated to block galectin-3 activity. PMID:26640395

  2. Potential targets in the search for extraterrestrial life.

    NASA Technical Reports Server (NTRS)

    Klein, H. P.

    1972-01-01

    Discussion of the potential for increasing understanding of the origins of terrestrial life by examination of other planets. If living organisms should be found on another planet, they could only have been transported from an inhabited planet or originated independently. The fundamental chemical and structural attributes of terrestrial organisms are so remarkably uniform that any living forms outside the terrestrial blueprint would almost certainly be regarded as alien organisms. It has been shown experimentally by various investigators that life can exist in an extremely wide range of temperatures and pressures. The presence of an atmosphere appears to be necessary.

  3. AMPK as a Potential Anticancer Target – Friend or Foe?

    PubMed Central

    Chuang, Hsiao-Ching; Chou, Chih-Chien; Kulp, Samuel K.; Chen, Ching-Shih

    2014-01-01

    Adenosine monophosphate-activated protein kinase (AMPK) is a key player in maintaining energy homeostasis in response to metabolic stress. Beyond diabetes and metabolic syndrome, there is a growing interest in the therapeutic exploitation of the AMPK pathway in cancer treatment in light of its unique ability to regulate cancer cell proliferation through the reprogramming of cell metabolism. Although many studies support the tumor-suppressive role of AMPK, emerging evidence suggests that the metabolic checkpoint function of AMPK might be overridden by stress or oncogenic signals so that tumor cells use AMPK activation as a survival strategy to gain growth advantage. These findings underscore the complexity in the cellular function of AMPK in maintaining energy homeostasis under physiological versus pathological conditions. Thus, this review aims to provide an overview of recent findings on the functional interplay of AMPK with different cell metabolic and signaling effectors, particularly histone deacetylases, in mediating downstream tumor suppressive or promoting mechanisms in different cell systems. Although AMPK activation inhibits tumor growth by targeting multiple signaling pathways relevant to tumorigenesis, under certain cellular contexts or certain stages of tumor development, AMPK might act as a protective response to metabolic stresses, such as nutrient deprivation, low oxygen, and low pH, or as a downstream effectors of oncogenic proteins, including androgen receptor, hypoxia-inducible factor-1α, c-Src, and MYC. Thus, investigations to define at which stage(s) of tumorigenesis and cancer progression or for which genetic aberrations AMPK inhibition might represent a more relevant strategy than AMPK activation for cancer treatment are clearly warranted. PMID:23859619

  4. IMP dehydrogenase from Pneumocystis carinii as a potential drug target.

    PubMed Central

    O'Gara, M J; Lee, C H; Weinberg, G A; Nott, J M; Queener, S F

    1997-01-01

    Mycophenolic acid, a specific inhibitor of IMP dehydrogenase (IMPDH; EC 1.1.1.205), is a potent inhibitor of Pneumocystis carinii growth in culture, suggesting that IMPDH may be a sensitive target for chemotherapy in this organism. The IMPDH gene was cloned as a first step to characterizing the enzyme and developing selective inhibitors. A 1.3-kb fragment containing a portion of the P. carinii IMPDH gene was amplified by PCR with two degenerate oligonucleotides based on conserved sequences in IMPDH from humans and four different microorganisms. Northern hybridization analysis showed the P. carinii IMPDH mRNA to be approximately 1.6 kb. The entire cDNA encoding P. carinii IMPDH was isolated and cloned. The deduced amino acid sequence of P. carinii IMPDH shared homology with bacterial (31 to 38%), protozoal (48 to 59%), mammalian (60 to 62%), and fungal (62%) IMPDH enzymes. The IMPDH cDNA was expressed by using a T7 expression system in an IMPDH-deficient strain of Escherichia coli (strain S phi 1101). E. coli S phi 1101 cells containing the P. carinii IMPDH gene were able to grow on medium lacking guanine, implying that the protein expressed in vivo was functional. Extracts of these E. coli cells contained IMPDH activity that had an apparent Km for IMP of 21.7 +/- 0.3 microM and an apparent Km for NAD of 314 +/- 84 microM (mean +/- standard error of the mean; n = 3), and the activity was inhibited by mycophenolic acid (50% inhibitory concentration, 24 microM; n = 2). PMID:8980752

  5. Cancer Stem Cells: Potential Target for Bioactive Food Components

    PubMed Central

    Kim, Young S.; Farrar, William; Colburn, Nancy H.; Milner, John A.

    2015-01-01

    Cancer stem cells often have phenotypic and functional characteristics similar to normal stem cells including the properties of self-renewal and differentiation. Recent findings suggest that uncontrolled self-renewal may explain cancer relapses and may represent a critical target for cancer prevention. It is conceivable that the loss of regulatory molecules resulting from inappropriate consumption of specific foods and their constituents may foster the aberrant self-renewal of cancer stem cells. In fact, increasing evidence points to the network delivering signals for self-renewal from extracellular compartments to the nucleus including changes in stem cell environments, inducible expression of microRNAs, hyperplastic nuclear chromatin structures, and the on/off of differentiation process as possible sites of action for bioactive food components. Diverse dietary constituents such as vitamins A and D, genistein, (−)-epigallocatechin-3-gallate (EGCG), sulforaphane, curcumin, piperine, theanine, and choline have been shown to modify self-renewal properties of cancer stem cells. The ability of these bioactive food components to influence the balance between proliferative and quiescent cells by regulating critical feedback molecules in the network including dickkopf 1 (DKK-1), secreted frizzled-related protein 2 (sFRP2), B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1), and cyclin-dependent kinase 6 (CDK6) may account for their biological response. Overall, the response to food components does not appear to be tissue or organ specific, suggesting there may be common cellular mechanisms. Unquestionably, additional studies are needed to clarify the physiological role of these dietary components in preventing the resistance of tumor cells to traditional drugs and cancer recurrence. PMID:22704055

  6. Cherry juice targets antioxidant potential and pain relief.

    PubMed

    Kuehl, Kerry S

    2012-01-01

    Strenuous physical activity increases the risk of musculoskeletal injury and can induce muscle damage resulting in acute inflammation and decreased performance. The human body's natural response to injury results in inflammation-induced pain, swelling, and erythema. Among sports medicine physicians and athletic trainers, the mainstays of urgent treatment of soft tissue injury are rest, ice, compression, and elevation (RICE). In order to reduce pain and inflammation, anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (NSAIDs) act on the multiple inflammatory pathways, which, although often very effective, can have undesirable side effects such as gastric ulceration and, infrequently, myocardial infarction and stroke. For centuries, natural anti-inflammatory compounds have been used to mediate the inflammatory process and often with fewer side effects. Tart cherries appear to possess similar effectiveness in treating the inflammatory reaction seen in both acute and chronic pain syndromes encountered among athletes and non-athletes with chronic inflammatory disease. This article reviews the antioxidant and anti-inflammatory effects of tart cherries on prevention, treatment, and recovery of soft tissue injury and pain.

  7. Potential Therapeutic Strategies for Alzheimer's Disease Targeting or Beyond β-Amyloid: Insights from Clinical Trials

    PubMed Central

    Jia, Qiutian; Qing, Hong

    2014-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder with two hallmarks: β-amyloid plagues and neurofibrillary tangles. It is one of the most alarming illnesses to elderly people. No effective drugs and therapies have been developed, while mechanism-based explorations of therapeutic approaches have been intensively investigated. Outcomes of clinical trials suggested several pitfalls in the choice of biomarkers, development of drug candidates, and interaction of drug-targeted molecules; however, they also aroused concerns on the potential deficiency in our understanding of pathogenesis of AD, and ultimately stimulated the advent of novel drug targets tests. The anticipated increase of AD patients in next few decades makes development of better therapy an urgent issue. Here we attempt to summarize and compare putative therapeutic strategies that have completed clinical trials or are currently being tested from various perspectives to provide insights for treatments of Alzheimer's disease. PMID:25136630

  8. Intracellular signaling as a potential target for antiplatelet therapy.

    PubMed

    Andre, Patrick

    2012-01-01

    Three classes of inhibitors of platelet aggregation have demonstrated substantial clinical benfits. Aspirin acts by irreversibly inhibiting COX-1 and therefore blocking the synthesis of proaggregatory thromboxane A (2) (TxA(2)). The indirect acting (ticlopidine, clopidogrel, prasugrel) and the direct acting (ticagrelor) antagonists of P2Y(12) block the thrombus stabilizing activity of ADP. Parenteral GP IIb-IIIa inhibitors directly block platelet-platelet interactions. Despite well-established benefits, all antiplatelet agents have important limitations: increased bleeding and gastrointestinal toxicities (aspirin), high incidence of thrombotic thrombocytopenic purpura (ticlopidine), potentially nonresponders (clopidogrel), severe bleeding (prasugrel, GP IIb-IIIa antagonists) and "complicated" relationships with aspirin ticagrelor). In this chapter, we present the genetic and pharmacological evidence that supports the development and expectations associated with novel antiplatelet strategies directed at intrasignaling pathways.

  9. DTMiner: identification of potential disease targets through biomedical literature mining

    PubMed Central

    Xu, Dong; Zhang, Meizhuo; Xie, Yanping; Wang, Fan; Chen, Ming; Zhu, Kenny Q.; Wei, Jia

    2016-01-01

    Motivation: Biomedical researchers often search through massive catalogues of literature to look for potential relationships between genes and diseases. Given the rapid growth of biomedical literature, automatic relation extraction, a crucial technology in biomedical literature mining, has shown great potential to support research of gene-related diseases. Existing work in this field has produced datasets that are limited both in scale and accuracy. Results: In this study, we propose a reliable and efficient framework that takes large biomedical literature repositories as inputs, identifies credible relationships between diseases and genes, and presents possible genes related to a given disease and possible diseases related to a given gene. The framework incorporates name entity recognition (NER), which identifies occurrences of genes and diseases in texts, association detection whereby we extract and evaluate features from gene–disease pairs, and ranking algorithms that estimate how closely the pairs are related. The F1-score of the NER phase is 0.87, which is higher than existing studies. The association detection phase takes drastically less time than previous work while maintaining a comparable F1-score of 0.86. The end-to-end result achieves a 0.259 F1-score for the top 50 genes associated with a disease, which performs better than previous work. In addition, we released a web service for public use of the dataset. Availability and Implementation: The implementation of the proposed algorithms is publicly available at http://gdr-web.rwebox.com/public_html/index.php?page=download.php. The web service is available at http://gdr-web.rwebox.com/public_html/index.php. Contact: jenny.wei@astrazeneca.com or kzhu@cs.sjtu.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27506226

  10. DTMiner: identification of potential disease targets through biomedical literature mining.

    PubMed

    Xu, Dong; Zhang, Meizhuo; Xie, Yanping; Wang, Fan; Chen, Ming; Zhu, Kenny Q; Wei, Jia

    2016-12-01

    Biomedical researchers often search through massive catalogues of literature to look for potential relationships between genes and diseases. Given the rapid growth of biomedical literature, automatic relation extraction, a crucial technology in biomedical literature mining, has shown great potential to support research of gene-related diseases. Existing work in this field has produced datasets that are limited both in scale and accuracy. In this study, we propose a reliable and efficient framework that takes large biomedical literature repositories as inputs, identifies credible relationships between diseases and genes, and presents possible genes related to a given disease and possible diseases related to a given gene. The framework incorporates name entity recognition (NER), which identifies occurrences of genes and diseases in texts, association detection whereby we extract and evaluate features from gene-disease pairs, and ranking algorithms that estimate how closely the pairs are related. The F1-score of the NER phase is 0.87, which is higher than existing studies. The association detection phase takes drastically less time than previous work while maintaining a comparable F1-score of 0.86. The end-to-end result achieves a 0.259 F1-score for the top 50 genes associated with a disease, which performs better than previous work. In addition, we released a web service for public use of the dataset. The implementation of the proposed algorithms is publicly available at http://gdr-web.rwebox.com/public_html/index.php?page=download.php The web service is available at http://gdr-web.rwebox.com/public_html/index.php CONTACT: jenny.wei@astrazeneca.com or kzhu@cs.sjtu.edu.cn Supplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

  11. Detecting drug targets with minimum side effects in metabolic networks.

    PubMed

    Li, Z; Wang, R-S; Zhang, X-S; Chen, L

    2009-11-01

    High-throughput techniques produce massive data on a genome-wide scale which facilitate pharmaceutical research. Drug target discovery is a crucial step in the drug discovery process and also plays a vital role in therapeutics. In this study, the problem of detecting drug targets was addressed, which finds a set of enzymes whose inhibition stops the production of a given set of target compounds and meanwhile minimally eliminates non-target compounds in the context of metabolic networks. The model aims to make the side effects of drugs as small as possible and thus has practical significance of potential pharmaceutical applications. Specifically, by exploiting special features of metabolic systems, a novel approach was proposed to exactly formulate this drug target detection problem as an integer linear programming model, which ensures that optimal solutions can be found efficiently without any heuristic manipulations. To verify the effectiveness of our approach, computational experiments on both Escherichia coli and Homo sapiens metabolic pathways were conducted. The results show that our approach can identify the optimal drug targets in an exact and efficient manner. In particular, it can be applied to large-scale networks including the whole metabolic networks from most organisms.

  12. The Network of Epithelial-mesenchymal transition: potential new targets for tumor resistance

    PubMed Central

    Nantajit, Danupon; Lin, Dong; Li, Jian Jian

    2014-01-01

    Purpose In multiple cell metazoans, the ability of polarized epithelial cells to convert to motile mesenchymal cells in order to relocate to another location is governed by a unique process termed epithelial-mesenchymal transition (EMT). While being an essential process of cellular plasticity for normal tissue and organ developments, EMT is found to be involved in an array of malignant phenotypes of tumor cells including proliferation and invasion, angiogenesis, stemness of cancer cells and resistance to chemo-radiotherapy. Although EMT is being extensively studied and demonstrated to play a key role in tumor metastasis and in sustaining tumor hallmarks, there is a lack of clear picture of the overall EMT signaling network, wavering the potential clinical trials targeting EMT. Methods In this review, we highlight the potential key therapeutic targets of EMT linked with tumor aggressiveness, hypoxia, angiogenesis and cancer stem cells, emphasizing on an emerging EMT-associated NF-κB/HER2/STAT3 pathway in radioresistance of breast cancer stem cells. Results Further definition of cancer stem cell repopulation due to EMT-controlled tumor microenvironment will help to understand how tumors exploit the EMT mechanisms for their survival and expansion advantages. Conclusions The knowledge of EMT will offer more effective targets in clinical trials to treat therapy-resistant metastatic lesions. PMID:25270087

  13. Hedgehog signaling pathway is a potential therapeutic target for gallbladder cancer

    PubMed Central

    Matsushita, Shojiro; Onishi, Hideya; Nakano, Kenji; Nagamatsu, Iori; Imaizumi, Akira; Hattori, Masami; Oda, Yoshinao; Tanaka, Masao; Katano, Mitsuo

    2014-01-01

    Gallbladder cancer (GBC) is a particularly deadly type of cancer with a 5-year survival rate of only 10%. New effective therapeutic strategies are greatly needed. Recently, we have shown that Hedgehog (Hh) signaling is reactivated in various types of cancer and is a potential therapeutic target. However, little is known about the biological significance of Hh signaling in human GBC. In this study, we determined whether Hh signaling could be a therapeutic target in GBC. The Hh transcription factor Gli1 was detected in the nucleus of GBC cells but not in the nucleus of normal gallbladder cells. The expression levels of Sonic Hh (Shh) and Smoothened (Smo) in human GBC specimens (n = 37) were higher than those in normal gallbladder tissue. The addition of exogenous Shh ligand augmented the anchor-dependent and anchor-independent proliferation and invasiveness of GBC cells in vitro. In contrast, inhibiting the effector Smo decreased the anchor-dependent and anchor-independent proliferation. Furthermore, the suppression of Smo decreased GBC cell invasiveness through the inhibition of MMP-2 and MMP-9 expression and inhibited the epithelial–mesenchymal transition. In a xenograft model, tumor volume in Smo siRNA-transfected GBC cells was significantly lower than in control tumors. These results suggest that Hh signaling is elevated in GBC and may be involved in the acquisition of malignant phenotypes, and that Hh signaling may be a potential therapeutic target for GBC. PMID:24438533

  14. MiRNAs: potential diagnostic and therapeutic targets for cerebral ischaemia.

    PubMed

    Zhu, Ruixia; Liu, Xu; Zhu, Ying; He, Zhiyi

    2016-01-01

    MiRNAs are short single-stranded non-coding RNAs that cause degradation or repression of target mRNAs by base pairing with their 3'-untranslated regions. Recent studies have shown that miRNAs play an important role in the occurrence and development of cerebral ischaemia, as well as exerting regulatory effects. Additionally, circulating miRNAs in peripheral blood, which are dysregulated following cerebral ischaemia, have recently been identified as useful biomarkers in diagnosis and prognosis of cerebral ischaemia. Single-nucleotide polymorphisms (SNPs) located in miRNA genes or target sites are likely to cause complex functional consequences by affecting miRNA biogenesis or target selection. Research on miRNA-SNPs is rapidly growing, and recent studies have identified a significant relationship between miRNAs and ischemic disease. We also address the latest advances in miRNA-based therapeutic approaches for ischemic disease. In conclusion, our review summarizes current research regarding miRNAs and cerebral ischaemia, focusing on the regulatory role of miRNAs in cerebral ischaemia, as well as the potential of miRNAs as biomarkers and therapeutic targets in cerebral ischaemia.

  15. Lethal ovitrap deployment for Aedes aegypti control: potential implications for non-target organisms.

    PubMed

    Long, Sharron A; Jacups, Susan P; Ritchie, Scott A

    2015-06-01

    In Australia, dengue control combines source reduction with lethal ovitraps to reduce Aedes aegypti populations during outbreaks. Lethal ovitraps are considered a sustainable and environmentally friendly method of controlling container-inhabiting mosquitoes, however, to-date, this claim has not been quantified. This study assesses the potential impact of lethal ovitraps on non-target organisms when used to control Ae. aegypti in tropical Australia. For retention of specimens, we substituted standard sticky ovitraps for lethal ovitraps. We collected 988 Ae. aegypti and 44,132 non-target specimens over 13 months from 16 sites. Although Ae. aegypti comprised only 2.2% of the total collection, they were were the eighth most dominant taxa collected, on the 93(rd) percentile. Of the non-target organisms, Collembola were the dominant taxa, 44.2%, with 36.8% and 10.5% Diptera and Hymenoptera, respectively. Of the Dipterans, 61% were family Phoridae. Lethal ovitraps were visited by 90 insect or invertebrate families in total. Ovitraps are attractive to Collembola, Phoridae, Sciaridae, Formicidae, and Culicidae, with minimal attraction by Apidae and other commonly monitored non-target organisms. For container-inhabiting mosquitoes, LOs are cost effective operationally, requiring minimal staff resources for placement and retrieval.

  16. Potential biological targets for bioassay development in drug discovery of Sturge-Weber syndrome.

    PubMed

    Mohammadipanah, Fatemeh; Salimi, Fatemeh

    2017-09-21

    Sturge-Weber Syndrome (SWS) is a neurocutaneous disease with clinical manifestations including ocular (glaucoma), cutaneous (port-wine birthmark), neurologic (seizures), and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis. By analysis of the interrelated molecular targets of SWS, some in vitro bioassay systems can be allotted for drug screening against its progression. Development of such platforms of bioassay can bring along the implementation of high-throughput screening of natural or synthetic compounds in drug discovery programs. Regarding the fact that study of molecular targets and their integration in biological assay design can facilitate the process of effective drug discovery; some potential biological targets and their respective biological assay for SWS drug discovery are propounded in this review. For this purpose, some biological targets for SWS drug discovery such as acetylcholinesterase, alkaline phosphatase, GABAergic receptors, Hypoxia-Inducible Factor (HIF)-1α and 2α are suggested. © 2017 John Wiley & Sons A/S.

  17. Therapeutic Potential of Targeting the Oncogenic SHP2 Phosphatase

    PubMed Central

    2015-01-01

    The Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase associated with various kinds of leukemia and solid tumors. Thus, there is substantial interest in developing SHP2 inhibitors as potential anticancer and antileukemia agents. Using a structure-guided and fragment-based library approach, we identified a novel hydroxyindole carboxylic acid-based SHP2 inhibitor 11a-1, with an IC50 value of 200 nM and greater than 5-fold selectivity against 20 mammalian PTPs. Structural and modeling studies reveal that the hydroxyindole carboxylic acid anchors the inhibitor to the SHP2 active site, while interactions of the oxalamide linker and the phenylthiophene tail with residues in the β5–β6 loop contribute to 11a-1’s binding potency and selectivity. Evidence suggests that 11a-1 specifically attenuates the SHP2-dependent signaling inside the cell. Moreover, 11a-1 blocks growth factor mediated Erk1/2 and Akt activation and exhibits excellent antiproliferative activity in lung cancer and breast cancer as well as leukemia cell lines. PMID:25003231

  18. Targeting Cancer Metabolism - Revisiting the Warburg Effects

    PubMed Central

    Tran, Quangdon; Lee, Hyunji; Park, Jisoo; Kim, Seon-Hwan; Park, Jongsun

    2016-01-01

    After more than half of century since the Warburg effect was described, this atypical metabolism has been standing true for almost every type of cancer, exhibiting higher glycolysis and lactate metabolism and defective mitochondrial ATP production. This phenomenon had attracted many scientists to the problem of elucidating the mechanism of, and reason for, this effect. Several models based on oncogenic studies have been proposed, such as the accumulation of mitochondrial gene mutations, the switch from oxidative phosphorylation respiration to glycolysis, the enhancement of lactate metabolism, and the alteration of glycolytic genes. Whether the Warburg phenomenon is the consequence of genetic dysregulation in cancer or the cause of cancer remains unknown. Moreover, the exact reasons and physiological values of this peculiar metabolism in cancer remain unclear. Although there are some pharmacological compounds, such as 2-deoxy-D-glucose, dichloroacetic acid, and 3-bromopyruvate, therapeutic strategies, including diet, have been developed based on targeting the Warburg effect. In this review, we will revisit the Warburg effect to determine how much scientists currently understand about this phenomenon and how we can treat the cancer based on targeting metabolism. PMID:27437085

  19. Molecular targets of diabetic vascular complications and potential new drugs.

    PubMed

    Da Ros, Roberto; Assaloni, Roberta; Ceriello, Antonio

    2005-06-01

    In diabetes, oxidative stress plays a key role in the pathogenesis of vascular complications, and an early step of such damage is considered to be the development of an endothelial dysfunction. Hyperglycemia directly promotes an endothelial dysfunction inducing process of overproduction of superoxide and consequently peroxynitrite, that damages DNA and activates the nuclear enzyme poly(ADP-ribose) polymerase. This process, depleting NAD+, slowing glycolsis, ATP formation and electron transport, results in acute endothelial dysfunction in diabetic blood vessels and contributes to the development of diabetic complications. These new findings may explain why classical antioxidants, like vitamin E, that work scavenging already formed toxic oxidation products, have failed to show beneficial effects on diabetic complications, and suggest new and attractive "causal" antioxidant therapy. New, low molecular mass compounds that act as SOD or catalase mimetics or L-propionyl-carnitine and lipoic acid, that work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such strategy, and preliminary studies support this hypothesis. This "causal" therapy would also be associated with other promising tools such as LY 333531, PJ34 and FP15, which block protein kinase beta isoform, poly(ADP-ribose) polymerase and peroxynitrite, respectively. It is now evident that, statins, ACE inhibitors, AT-1 blockers, calcium channel blockers and thiazolidinediones have a strong intracellular antioxidant activity, and it has been suggested that many of their beneficial ancillary effects are due to this property. This preventive activity against oxidative stress generation can justify a large utilization and association of this compounds for preventing complications in diabetic patients where antioxidant defences have been shown to be defective.

  20. Enhanced Delivery of Gold Nanoparticles with Therapeutic Potential for Targeting Human Brain Tumors

    NASA Astrophysics Data System (ADS)

    Etame, Arnold B.

    The blood brain barrier (BBB) remains a major challenge to the advancement and application of systemic anti-cancer therapeutics into the central nervous system. The structural and physiological delivery constraints of the BBB significantly limit the effectiveness of conventional chemotherapy, thereby making systemic administration a non-viable option for the vast majority of chemotherapy agents. Furthermore, the lack of specificity of conventional systemic chemotherapy when applied towards malignant brain tumors remains a major shortcoming. Hence novel therapeutic strategies that focus both on targeted and enhanced delivery across the BBB are warranted. In recent years nanoparticles (NPs) have emerged as attractive vehicles for efficient delivery of targeted anti-cancer therapeutics. In particular, gold nanoparticles (AuNPs) have gained prominence in several targeting applications involving systemic cancers. Their enhanced permeation and retention within permissive tumor microvasculature provide a selective advantage for targeting. Malignant brain tumors also exhibit transport-permissive microvasculature secondary to blood brain barrier disruption. Hence AuNPs may have potential relevance for brain tumor targeting. However, the permeation of AuNPs across the BBB has not been well characterized, and hence is a potential limitation for successful application of AuNP-based therapeutics within the central nervous system (CNS). In this dissertation, we designed and characterized AuNPs and assessed the role of polyethylene glycol (PEG) on the physical and biological properties of AuNPs. We established a size-dependent permeation profile with respect to core size as well as PEG length when AuNPs were assessed through a transport-permissive in-vitro BBB. This study was the first of its kind to systematically examine the influence of design on permeation of AuNPs through transport-permissive BBB. Given the significant delivery limitations through the non

  1. Potential cellular targets and antibacterial efficacy of atmospheric pressure non-thermal plasma.

    PubMed

    Alkawareek, Mahmoud Y; Gorman, Sean P; Graham, William G; Gilmore, Brendan F

    2014-02-01

    Atmospheric pressure non-thermal plasma (APNTP) has been gaining increasing interest as a new alternative antibacterial approach. Although this approach has demonstrated promising antibacterial activity, its exact mechanism of action remains unclear. Mechanistic elucidation of the antimicrobial activity will facilitate development and rational optimisation of this approach for potential medical applications. In this study, the antibacterial efficacy of an in-house-built APNTP jet was evaluated alongside an investigation of the interactions between APNTP and major cellular components in order to identify the potential cellular targets involved in plasma-mediated bacterial destruction mechanisms. The investigated plasma jet exhibited excellent, rapid antibacterial activity against a selected panel of clinically significant bacterial species including Bacillus cereus, meticillin-resistant Staphylococcus aureus (MRSA), Escherichia coli and Pseudomonas aeruginosa, all of which were completely inactivated within 2 min of plasma exposure. Plasma-mediated damaging effects were observed, to varying degrees, on all of the investigated cellular components including DNA, a model protein enzyme, and lipid membrane integrity and permeability. The antibacterial efficacy of APNTP appears to involve a multiple-target mechanism, which potentially reduces the likelihood of emergence of microbial resistance towards this promising antimicrobial approach. However, cellular membrane damage and resulting permeability perturbation was found to be the most likely rate-determining step in this mechanism.

  2. The therapeutic potential of targeting ABC transporters to combat multi-drug resistance.

    PubMed

    Bugde, Piyush; Biswas, Riya; Merien, Fabrice; Lu, Jun; Liu, Dong-Xu; Chen, Mingwei; Zhou, Shufeng; Li, Yan

    2017-05-01

    Most disseminated cancers remain fatal despite the availability of a variety of conventional and novel treatments including surgery, chemotherapy, radiotherapy, immunotherapy, and biologically targeted therapy. A major factor responsible for the failure of chemotherapy in the treatment of cancer is the development of multidrug resistance (MDR). The overexpression of various ABC transporters in cancer cells can efficiently remove the anticancer drug from the cell, thus causing the drug to lose its effect. Areas covered: In this review, we summarised the ongoing research related to the mechanism, function, and regulation of ABC transporters. We integrated our current knowledge at different levels from molecular biology to clinical trials. We also discussed potential therapeutic strategies of targeting ABC transporters to reverse MDR in cancer cells. Expert opinion: Involvement of various ABC transporters to cancer MDR lays the foundation for developing tailored therapies that can overcome MDR. An ideal MDR reversal agent should have broad-spectrum ABC-transporter inhibitory activity, be potent, have good pharmacokinetics, have no trans-stimulation effects, and have low or no toxicity. Alternatively, nanotechnology-based drug delivery systems containing both the cytotoxic drug and reversing agent may represent a useful approach to reversing MDR with minimal off-target toxicity.

  3. Neuregulin-1 signalling and antipsychotic treatment: potential therapeutic targets in a schizophrenia candidate signalling pathway.

    PubMed

    Deng, Chao; Pan, Bo; Engel, Martin; Huang, Xu-Feng

    2013-03-01

    Identifying the signalling pathways underlying the pathophysiology of schizophrenia is an essential step in the rational development of new antipsychotic drugs for this devastating disease. Evidence from genetic, transgenic and post-mortem studies have strongly supported neuregulin-1 (NRG1)-ErbB4 signalling as a schizophrenia susceptibility pathway. NRG1-ErbB4 signalling plays crucial roles in regulating neurodevelopment and neurotransmission, with implications for the pathophysiology of schizophrenia. Post-mortem studies have demonstrated altered NRG1-ErbB4 signalling in the brain of schizophrenia patients. Antipsychotic drugs have different effects on NRG1-ErbB4 signalling depending on treatment duration. Abnormal behaviours relevant to certain features of schizophrenia are displayed in NRG1/ErbB4 knockout mice or those with NRG1/ErbB4 over-expression, some of these abnormalities can be improved by antipsychotic treatment. NRG1-ErbB4 signalling has extensive interactions with the GABAergic, glutamatergic and dopaminergic neurotransmission systems that are involved in the pathophysiology of schizophrenia. These interactions provide a number of targets for the development of new antipsychotic drugs. Furthermore, the key interaction points between NRG1-ErbB4 signalling and other schizophrenia susceptibility genes may also potentially provide specific targets for new antipsychotic drugs. In general, identification of these targets in NRG1-ErbB4 signalling and interacting pathways will provide unique opportunities for the development of new generation antipsychotics with specific efficacy and fewer side effects.

  4. The siRNA Non-seed Region and Its Target Sequences Are Auxiliary Determinants of Off-Target Effects

    PubMed Central

    Kamola, Piotr J.; Nakano, Yuko; Takahashi, Tomoko; Wilson, Paul A.; Ui-Tei, Kumiko

    2015-01-01

    RNA interference (RNAi) is a powerful tool for post-transcriptional gene silencing. However, the siRNA guide strand may bind unintended off-target transcripts via partial sequence complementarity by a mechanism closely mirroring micro RNA (miRNA) silencing. To better understand these off-target effects, we investigated the correlation between sequence features within various subsections of siRNA guide strands, and its corresponding target sequences, with off-target activities. Our results confirm previous reports that strength of base-pairing in the siRNA seed region is the primary factor determining the efficiency of off-target silencing. However, the degree of downregulation of off-target transcripts with shared seed sequence is not necessarily similar, suggesting that there are additional auxiliary factors that influence the silencing potential. Here, we demonstrate that both the melting temperature (Tm) in a subsection of siRNA non-seed region, and the GC contents of its corresponding target sequences, are negatively correlated with the efficiency of off-target effect. Analysis of experimentally validated miRNA targets demonstrated a similar trend, indicating a putative conserved mechanistic feature of seed region-dependent targeting mechanism. These observations may prove useful as parameters for off-target prediction algorithms and improve siRNA ‘specificity’ design rules. PMID:26657993

  5. Potential adverse effects of phytoestrogens.

    PubMed

    Whitten, P L; Lewis, C; Russell, E; Naftolin, F

    1995-03-01

    Evaluation of the potential benefits and risks offered by naturally occurring plant estrogens requires investigation of their potency and sites of action when consumed at natural dietary concentrations. Our investigations have examined the effects of a range of natural dietary concentrations of the most potent plant isoflavonoid, coumestrol, using a rat model and a variety of estrogen-dependent tissues and endpoints. Treatments of immature females demonstrated agonistic action in the reproductive tract, brain, and pituitary at natural dietary concentrations. Experiments designed to test for estrogen antagonism demonstrated that coumestrol did not conform to the picture of a classic antiestrogen. However, coumestrol did suppress estrous cycles in adult females. Developmental actions were examined by neonatal exposure of pups through milk of rat dams fed a coumestrol, control, or commercial soy-based diet during the critical period of the first 10 postnatal days or throughout the 21 days of lactation. The 10-day treatment did not significantly alter adult estrous cyclicity, but the 21-day treatment produced in a persistent estrus state in coumestrol-treated females by 132 days of age. In contrast, the 10-day coumestrol treatments produced significant deficits in the sexual behavior of male offspring. These findings illustrate the broad range of actions of these natural estrogens and the variability in potency across endpoints. This variability argues for the importance of fully characterizing each phytoestrogen in terms of its sites of action, balance of agonistic and antagonistic properties, natural potency, and short-term and long-term effects.

  6. Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets.

    PubMed

    Jangra, Ashok; Sriram, Chandra Shaker; Pandey, Suryanarayan; Choubey, Priyansha; Rajput, Prabha; Saroha, Babita; Bezbaruah, Babul Kumar; Lahkar, Mangala

    2016-10-01

    Acute and chronic alcohol exposure evidently influences epigenetic changes, both transiently and permanently, and these changes in turn influence a variety of cells and organ systems throughout the body. Many of the alcohol-induced epigenetic modifications can contribute to cellular adaptations that ultimately lead to behavioral tolerance and alcohol dependence. The persistence of behavioral changes demonstrates that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. The research activities over the past years have demonstrated a crucial role of epigenetic mechanisms in causing long lasting and transient changes in the expression of several genes in diverse tissues, including brain. This has stimulated recent research work that is aimed at characterizing the influence of epigenetic regulatory events in mediating the long lasting and transient effects of alcohol abuse on the brain in humans and animal models of alcohol addiction. In this study, we update our current understanding of the impact of alcohol exposure on epigenetic mechanisms in the brain and refurbish the knowledge of epigenetics in the direction of new drugs development.

  7. Epigenetic Modifications, Alcoholic Brain and Potential Drug Targets

    PubMed Central

    Jangra, Ashok; Sriram, Chandra Shaker; Pandey, Suryanarayan; Choubey, Priyansha; Rajput, Prabha; Saroha, Babita; Bezbaruah, Babul Kumar; Lahkar, Mangala

    2016-01-01

    Acute and chronic alcohol exposure evidently influences epigenetic changes, both transiently and permanently, and these changes in turn influence a variety of cells and organ systems throughout the body. Many of the alcohol-induced epigenetic modifications can contribute to cellular adaptations that ultimately lead to behavioral tolerance and alcohol dependence. The persistence of behavioral changes demonstrates that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. The research activities over the past years have demonstrated a crucial role of epigenetic mechanisms in causing long lasting and transient changes in the expression of several genes in diverse tissues, including brain. This has stimulated recent research work that is aimed at characterizing the influence of epigenetic regulatory events in mediating the long lasting and transient effects of alcohol abuse on the brain in humans and animal models of alcohol addiction. In this study, we update our current understanding of the impact of alcohol exposure on epigenetic mechanisms in the brain and refurbish the knowledge of epigenetics in the direction of new drugs development. PMID:27780992

  8. Interventional value of total flavonoids from Rhizoma Drynariae on Cathepsin K, a potential target of osteoporosis.

    PubMed

    Shi, Xiao-Lin; Liu, Kang; Wu, Lian-Guo

    2011-07-01

    Osteoporosis, the sixth most common disease in the world, is bringing increasingly serious harm to people's health. Cathepsin K, which plays an important role in bone resorption, is a potential target in the treatment of osteoporosis. Total flavonoids, the active ingredients in Rhizoma Drynariae, have shown obvious, therapeutic effect on osteoporosis. In previous studies, it was presumed that the mechanism for the therapeutic effect was through inhibiting the expression of Cathepsin K. However, there are still no detailed reports on some key issues such as the specific inhibitory results of total flavonoids on Cathepsin K and the pathway of inhibition and so on. Based on previous studies on total flavonoids from Rhizoma Drynariae, the pathway for the effect of, total flavonoids inhibiting Cathepsin K and their interventional value on Cathepsin K were analyzed in this paper, so as to explore the interventional feasibility and value of total flavonoids in Rhizoma Drynariae on Cathepsin K.

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

    PubMed Central

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

    2015-01-01

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

  10. Sigma-1 receptors: potential targets for the treatment of substance abuse.

    PubMed

    Robson, Matthew J; Noorbakhsh, Bahar; Seminerio, Michael J; Matsumoto, Rae R

    2012-01-01

    Drug abuse is currently a large economic and societal burden in countries around the globe. Many drugs of abuse currently lack adequate therapies aimed at treating both the addiction and negative complications often associated with their use. Sigma-1 receptors were discovered over 30 years ago and have recently become targets for the development of pharmacotherapies aimed at treating substance abuse and addiction. In vivo preclinical studies have revealed that sigma receptor ligands are able to ameliorate select behavioral effects of many drugs of abuse including cocaine, methamphetamine, ethanol and nicotine. In addition, recent studies have begun to elucidate the mechanisms by which sigma-1 receptors modulate the effects of these drugs on neurotransmission, gene regulation and neuroplasticity. Overall, these recent findings suggest that compounds targeting sigma-1 receptors may represent a potential new class of therapeutics aimed at treating drug abuse. Future studies involving clinical populations will be critical for validating the therapeutic potential of sigma-1 receptor ligands for the treatment of substance abuse.

  11. Diacylglycerol Kinases as Emerging Potential Drug Targets for a Variety of Diseases: An Update

    PubMed Central

    Sakane, Fumio; Mizuno, Satoru; Komenoi, Suguru

    2016-01-01

    Ten mammalian diacylglycerol kinase (DGK) isozymes (α–κ) have been identified to date. Our previous review noted that several DGK isozymes can serve as potential drug targets for cancer, epilepsy, autoimmunity, cardiac hypertrophy, hypertension and type II diabetes (Sakane et al., 2008). Since then, recent genome-wide association studies have implied several new possible relationships between DGK isozymes and diseases. For example, DGKθ and DGKκ have been suggested to be associated with susceptibility to Parkinson's disease and hypospadias, respectively. In addition, the DGKη gene has been repeatedly identified as a bipolar disorder (BPD) susceptibility gene. Intriguingly, we found that DGKη-knockout mice showed lithium (BPD remedy)-sensitive mania-like behaviors, suggesting that DGKη is one of key enzymes of the etiology of BPD. Because DGKs are potential drug targets for a wide variety of diseases, the development of DGK isozyme-specific inhibitors/activators has been eagerly awaited. Recently, we have identified DGKα-selective inhibitors. Because DGKα has both pro-tumoral and anti-immunogenic properties, the DGKα-selective inhibitors would simultaneously have anti-tumoral and pro-immunogenic (anti-tumor immunogenic) effects. Although the ten DGK isozymes are highly similar to each other, our current results have encouraged us to identify and develop specific inhibitors/activators against every DGK isozyme that can be effective regulators and drugs against a wide variety of physiological events and diseases. PMID:27583247

  12. Transient receptor potential canonical 4 and 5 proteins as targets in cancer therapeutics.

    PubMed

    Gaunt, Hannah J; Vasudev, Naveen S; Beech, David J

    2016-10-01

    Novel approaches towards cancer therapy are urgently needed. One approach might be to target ion channels mediating Ca(2+) entry because of the critical roles played by Ca(2+) in many cell types, including cancer cells. There are several types of these ion channels, but here we address those formed by assembly of transient receptor potential canonical (TRPC) proteins, particularly those which involve two closely related members of the family: TRPC4 and TRPC5. We focus on these proteins because recent studies point to roles in important aspects of cancer: drug resistance, transmission of drug resistance through extracellular vesicles, tumour vascularisation, and evoked cancer cell death by the TRPC4/5 channel activator (-)-englerin A. We conclude that further research is both justified and necessary before these proteins can be considered as strong targets for anti-cancer cell drug discovery programmes. It is nevertheless already apparent that inhibitors of the channels would be unlikely to cause significant adverse effects, but, rather, have other effects which may be beneficial in the context of cancer and chemotherapy, potentially including suppression of innate fear, visceral pain and pathological cardiac remodelling.

  13. The effect of intermediate clothing targets on shotgun ballistics.

    PubMed

    Cail, Kenneth; Klatt, Edward

    2013-12-01

    The ballistic properties of shotgun shells are complex because of multiple projectiles fired simultaneously that interact and spread out to affect their energy relayed to a human target. Intermediate targets such as clothing can affect penetration into tissues. We studied the effect of common clothing fabrics as intermediate targets on penetration of shotgun shell pellets, using ordnance gelatin to simulate soft tissue and thin cowhide to simulate skin. A standard 12-gauge shotgun with modified choke was used with no. 8 shot ammunition. We found that protection afforded by fabrics to reduce penetration of shotgun pellets into tissues was greater at increasing distance from the muzzle beyond 40 yd (36.6 m). The thicker denim and cotton fabrics provided slightly greater protection than polyester. This study demonstrates that clothing modifies the potential wound patterns to victims of shotgun injuries.

  14. Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight.

    PubMed

    Regad, Leslie; Chéron, Jean-Baptiste; Triki, Dhoha; Senac, Caroline; Flatters, Delphine; Camproux, Anne-Claude

    2017-01-01

    Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http://www.mti.univ-paris-diderot.fr/recherche/plateformes/logiciels.

  15. Exploring the potential of a structural alphabet-based tool for mining multiple target conformations and target flexibility insight

    PubMed Central

    Chéron, Jean-Baptiste; Triki, Dhoha; Senac, Caroline; Flatters, Delphine; Camproux, Anne-Claude

    2017-01-01

    Protein flexibility is often implied in binding with different partners and is essential for protein function. The growing number of macromolecular structures in the Protein Data Bank entries and their redundancy has become a major source of structural knowledge of the protein universe. The analysis of structural variability through available redundant structures of a target, called multiple target conformations (MTC), obtained using experimental or modeling methods and under different biological conditions or different sources is one way to explore protein flexibility. This analysis is essential to improve the understanding of various mechanisms associated with protein target function and flexibility. In this study, we explored structural variability of three biological targets by analyzing different MTC sets associated with these targets. To facilitate the study of these MTC sets, we have developed an efficient tool, SA-conf, dedicated to capturing and linking the amino acid and local structure variability and analyzing the target structural variability space. The advantage of SA-conf is that it could be applied to divers sets composed of MTCs available in the PDB obtained using NMR and crystallography or homology models. This tool could also be applied to analyze MTC sets obtained by dynamics approaches. Our results showed that SA-conf tool is effective to quantify the structural variability of a MTC set and to localize the structural variable positions and regions of the target. By selecting adapted MTC subsets and comparing their variability detected by SA-conf, we highlighted different sources of target flexibility such as induced by binding partner, by mutation and intrinsic flexibility. Our results support the interest to mine available structures associated with a target using to offer valuable insight into target flexibility and interaction mechanisms. The SA-conf executable script, with a set of pre-compiled binaries are available at http

  16. Bioconjugates: harnessing potential for effective therapeutics.

    PubMed

    Khare, Piush; Jain, Aviral; Gulbake, Arvind; Soni, Vandana; Jain, Nitin K; Jain, Sanjay K

    2009-01-01

    The accomplishment of selective delivery can be brought through efficient drug targeting in which the attack of drug moiety is visualized only by the diseased organ and not by the organs of the whole body. This, in turn, consequently minimizes the unwanted effects or side effects caused by the drug action on the other organs. Bioconjugation is a fascinating technique that explores new vistas of drug delivery, and at the same time opens new possibilities for safe and effective therapy. This review is dedicated to and describes the science of bioconjugation and its potential in the drug delivery field, including different bioconjugates and their use in various therapeutic strategies. These have been classified as polymer based, macromolecule based, carrier based, and novel bioconjugates. This review describes the utility of bioconjugates in major diseases like cancer and others, and discusses experiments and research on the same. Bioconjugates have immense potential and extend a promising future in the drug delivery field. The review can act as a quick reference for those actively engaged in drug delivery and drug research to help overcome the hurdles of therapeutics.

  17. Eph receptor A10 has a potential as a target for a prostate cancer therapy

    SciTech Connect

    Nagano, Kazuya; Yamashita, Takuya; Inoue, Masaki; Higashisaka, Kazuma; Yoshioka, Yasuo; Abe, Yasuhiro; Kamada, Haruhiko; and others

    2014-07-18

    Highlights: • EphA10 mRNA is overexpressed in breast, prostate and colon cancer cell lines. • EphA10 is overexpressed in clinical prostate tumors at mRNA and protein levels. • Anti-EphA10 antibodies were cytotoxic on EphA10-positive prostate cancer cells. - Abstract: We recently identified Eph receptor A10 (EphA10) as a novel breast cancer-specific protein. Moreover, we also showed that an in-house developed anti-EphA10 monoclonal antibody (mAb) significantly inhibited proliferation of breast cancer cells, suggesting EphA10 as a promising target for breast cancer therapy. However, the only other known report for EphA10 was its expression in the testis at the mRNA level. Therefore, the potency of EphA10 as a drug target against cancers other than the breast is not known. The expression of EphA10 in a wide variety of cancer cells was studied and the potential of EphA10 as a drug target was evaluated. Screening of EphA10 mRNA expression showed that EphA10 was overexpressed in breast cancer cell lines as well as in prostate and colon cancer cell lines. Thus, we focused on prostate cancers in which EphA10 expression was equivalent to that in breast cancers. As a result, EphA10 expression was clearly shown in clinical prostate tumor tissues as well as in cell lines at the mRNA and protein levels. In order to evaluate the potential of EphA10 as a drug target, we analyzed complement-dependent cytotoxicity effects of anti-EphA10 mAb and found that significant cytotoxicity was mediated by the expression of EphA10. Therefore, the idea was conceived that the overexpression of EphA10 in prostate cancers might have a potential as a target for prostate cancer therapy, and formed the basis for the studies reported here.

  18. Aminopyridines potentiate synaptic and neuromuscular transmission by targeting the voltage-activated calcium channel beta subunit.

    PubMed

    Wu, Zi-Zhen; Li, De-Pei; Chen, Shao-Rui; Pan, Hui-Lin

    2009-12-25

    Aminopyridines such as 4-aminopyridine (4-AP) are widely used as voltage-activated K(+) (Kv) channel blockers and can improve neuromuscular function in patients with spinal cord injury, myasthenia gravis, or multiple sclerosis. Here, we present novel evidence that 4-AP and several of its analogs directly stimulate high voltage-activated Ca(2+) channels (HVACCs) in acutely dissociated neurons. 4-AP, 4-(aminomethyl)pyridine, 4-(methylamino)pyridine, and 4-di(methylamino)pyridine profoundly increased HVACC, but not T-type, currents in dissociated neurons from the rat dorsal root ganglion, superior cervical ganglion, and hippocampus. The widely used Kv channel blockers, including tetraethylammonium, alpha-dendrotoxin, phrixotoxin-2, and BDS-I, did not mimic or alter the effect of 4-AP on HVACCs. In HEK293 cells expressing various combinations of N-type (Cav2.2) channel subunits, 4-AP potentiated Ca(2+) currents primarily through the intracellular beta(3) subunit. In contrast, 4-AP had no effect on Cav3.2 channels expressed in HEK293 cells. Furthermore, blocking Kv channels did not mimic or change the potentiating effects of 4-AP on neurotransmitter release from sensory and motor nerve terminals. Thus, our findings challenge the conventional view that 4-AP facilitates synaptic and neuromuscular transmission by blocking Kv channels. Aminopyridines can directly target presynaptic HVACCs to potentiate neurotransmitter release independent of Kv channels.

  19. Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics.

    PubMed

    McKinnon, Brett D; Kocbek, Vida; Nirgianakis, Kostantinos; Bersinger, Nick A; Mueller, Michael D

    2016-04-01

    clinical trials. The current generation of kinase inhibitors carry a potential for adverse side effects. Kinase signalling pathways represent viable targets for endometriosis treatment. At present, however, further improvements in clinical efficacy and the profile of adverse effects are required before these compounds can be useful for long-term endometriosis treatment. A better understanding of the molecular activity of these kinases, including the specific extracellular compounds that lead to their activation in endometriotic cells specifically should facilitate their improvement and could potentially lead to new, non-hormonal treatments of endometriosis. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Potential Molecular Targets for Narrow-Spectrum Agents to Combat Mycoplasma pneumoniae Infection and Disease.

    PubMed

    Balish, Mitchell F; Distelhorst, Steven L

    2016-01-01

    As Mycoplasma pneumoniae macrolide resistance grows and spreads worldwide, it is becoming more important to develop new drugs to prevent infection or limit disease. Because other mycoplasma species have acquired resistance to other classes of antibiotics, it is reasonable to presume that M. pneumoniae can do the same, so switching to commonly used antibiotics like fluoroquinolones will not result in forms of therapy with long-term utility. Moreover, broad-spectrum antibiotics can have serious consequences for the patient, as these drugs may have severe impacts on the natural microbiota of the individual, compromising the health of the patient either short-term or long-term. Therefore, developing narrow-spectrum antibiotics that effectively target only M. pneumoniae and no more than a small portion of the microbiota is likely to yield impactful, positive results that can be used perhaps indefinitely to combat M. pneumoniae. Development of these agents requires a deep understanding of the basic biology of M. pneumoniae, in many areas deeper than what is currently known. In this review, we discuss potential targets for new, narrow-spectrum agents and both the positive and negative aspects of selecting these targets, which include toxic molecules, metabolic pathways, and attachment and motility. By gathering this information together, we anticipate that it will be easier for researchers to evaluate topics of priority for study of M. pneumoniae.

  1. Drug design with Cdc7 kinase: a potential novel cancer therapy target

    PubMed Central

    Sawa, Masaaki; Masai, Hisao

    2008-01-01

    Identification of novel molecular targets is critical in development of new and efficient cancer therapies. Kinases are one of the most common drug targets with a potential for cancer therapy. Cell cycle progression is regulated by a number of kinases, some of which are being developed to treat cancer. Cdc7 is a serine-threonine kinase originally discovered in budding yeast, which has been shown to be necessary to initiate the S phase. Inhibition of Cdc7 in cancer cells retards the progression of the S phase, accumulates DNA damage, and induces p53-independent cell death, but the same treatment in normal cells does not significantly affect of less than viability. Low-molecular-weight compounds that inhibit Cdc7 kinase with an IC50 10 nM have been identified, and shown to be effective in the inhibition of tumor growth in animal models. Thus Cdc7 kinase can be recognized as a novel molecular target for cancer therapy. PMID:19920912

  2. Therapeutic potential of the metabolic modulator phenformin in targeting the stem cell compartment in melanoma

    PubMed Central

    Albini, Adriana; Longo, Caterina; Argenziano, Giuseppe; Grisendi, Giulia; Dominici, Massimo; Ciarrocchi, Alessia; Dallaglio, Katiuscia

    2017-01-01

    Melanoma is the most dangerous and treatment-resistant skin cancer. Tumor resistance and recurrence are due to the persistence in the patient of aggressive cells with stem cell features, the cancer stem cells (CSC). Recent evidences have shown that CSC display a distinct metabolic profile as compared to tumor bulk population: a promising anti-tumor strategy is therefore to target specific metabolic pathways driving CSC behavior. Biguanides (metformin and phenformin) are anti-diabetic drugs able to perturb cellular metabolism and displaying anti-cancer activity. However, their ability to target the CSC compartment in melanoma is not known. Here we show that phenformin, but not metformin, strongly reduces melanoma cell viability, growth and invasion in both 2D and 3D (spheroids) models. While phenformin decreases melanoma CSC markers expression and the levels of the pro-survival factor MITF, MITF overexpression fails to prevent phenformin effects. Phenformin significantly reduces cell viability in melanoma by targeting both CSC (ALDHhigh) and non-CSC cells and by significantly reducing the number of viable cells in ALDHhigh and ALDHlow-derived spheroids. Consistently, phenformin reduces melanoma cell viability and growth independently from SOX2 levels. Our results show that phenformin is able to affect both CSC and non-CSC melanoma cell viability and growth and suggests its potential use as anti-cancer therapy in melanoma. PMID:28036292

  3. Magnetic micelles as a potential platform for dual targeted drug delivery in cancer therapy.

    PubMed

    Huang, Chi; Tang, Zhaomin; Zhou, Yangbo; Zhou, Xiaofeng; Jin, Yong; Li, Dan; Yang, Ying; Zhou, Shaobing

    2012-06-15

    The magnetic nanomicelles as a potential platform for dual targeted (folate-mediated and magnetic-guided) drug delivery were developed to enhance the efficiency and veracity of drug delivering to tumor site. The magnetic nanocarriers were synthesized based on superparamagnetic iron oxide nanoparticles (SPIONs), biocompatible Pluronic F127 and poly(dl-lactic acid) (F127-PLA) copolymer chemically conjugated with tumor-targeting ligand-folic acid (FA) via a facile chemical conjugation method. Doxorubicin hydrochloride (DOX·HCl) was selected as a model anticancer drug to investigate the in vitro drug release and antiproliferative effect of tumor cells in vitro and in vivo in the presence or absence of an external magnetic filed (MF) with strength of 0.1T. The Alamar blue assay exhibited that these magnetic nanomicelles possessed remarkable cell-specific targeting in vitro. Additionally this smart system enabling folate receptor-mediated uptake into tumor cells, showed strong responsiveness to MF. The primary in vivo tumor model study, which was carried out in VX2 tumor-bearing male New Zealand white rabbits, demonstrated that the nanomicelles could be guided into tumor site more efficiently by application of MF, and further represented significant therapeutic efficiency to solid tumor. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target.

    PubMed

    Chen, C-H; Fong, L W R; Yu, E; Wu, R; Trott, J F; Weiss, R H

    2017-06-22

    Targeted therapeutics, such as those abrogating hypoxia inducible factor (HIF)/vascular endothelial growth factor signaling, are initially effective against kidney cancer (or renal cell carcinoma, RCC); however, drug resistance frequently occurs via subsequent activation of alternative pathways. Through genome-scale integrated analysis of the HIF-α network, we identified the major protein kinase C substrate MARCKS (myristoylated alanine-rich C kinase substrate) as a potential target molecule for kidney cancer. In a screen of nephrectomy samples from 56 patients with RCC, we found that MARCKS expression and its phosphorylation are increased and positively correlate with tumor grade. Genetic and pharmacologic suppression of MARCKS in high-grade RCC cell lines in vitro led to a decrease in cell proliferation and migration. We further demonstrated that higher MARCKS expression promotes growth and angiogenesis in vivo in an RCC xenograft tumor. MARCKS acted upstream of the AKT/mTOR pathway, activating HIF-target genes, notably vascular endothelial growth factor-A. Following knockdown of MARCKS in RCC cells, the IC50 of the multikinase inhibitor regorafenib was reduced. Surprisingly, attenuation of MARCKS using the MPS (MARCKS phosphorylation site domain) peptide synergistically interacted with regorafenib treatment and decreased survival of kidney cancer cells through inactivation of AKT and mTOR. Our data suggest a major contribution of MARCKS to kidney cancer growth and provide an alternative therapeutic strategy of improving the efficacy of multikinase inhibitors.

  5. Researchers identify potential therapeutic targets for a rare childhood cancer | Center for Cancer Research

    Cancer.gov

    CCR researchers have identified the mechanism behind a rare but extremely aggressive childhood cancer called alveolar rhabdomyosarcoma (ARMS) and have pinpointed a potential drug target for its treatment. Learn more...

  6. Characterisation of Potential Antimicrobial Targets in Bacillus spp. I. Aminotransferases and Methionine Regeneration in Bacillus subtilis

    DTIC Science & Technology

    2002-07-01

    targets in Bacillus spp. I. Aminotransferases and methionine regeneration in Bacillus subtilis. Bradley J. Berger and Marvin H. Knodel Defence R&D...Characterisation of potential antimicrobial targets in Bacillus spp. I. Aminotransferases and methionine regeneration in Bacillus subtilis. Bradley J...examined in the gram-positive bacterium Bacillus subtilis. Homogenates of this bacterium were able to convert ketomethiobutyrate to methionine, utilising

  7. Redox Potential Ultrasensitive Nanoparticle for the Targeted Delivery of Camptothecin to HER2-Positive Cancer Cells

    PubMed Central

    2015-01-01

    Ideal “smart” nanoparticles for drug delivery should enhance therapeutic efficacy without introducing side effects. To achieve that, we developed a drug delivery system (HCN) based on a polymer–drug conjugate of poly[2-(pyridin-2-yldisulfanyl)]-graft-poly(ethylene glycol) and camptothecin with an intracellularly cleavable linker and human epidermal growth factor receptor 2 (HER2) targeting ligands. An in vitro drug release study found that HCN was stable in the physiological environment and supersensitive to the stimulus of elevated intracellular redox potential, releasing all payloads in less than 30 min. Furthermore, confocal microscopy revealed that HCN could specifically enter HER2-positive cancer cells. As a consequence, HCN could effectively kill HER2-positive cancer cells while not affecting HER2-negative cells. PMID:24779647

  8. Computational Prediction of CRISPR/Cas9 Target Sites Reveals Potential Off-Target Risks in Human and Mouse.

    PubMed

    Wang, Qingbo; Ui-Tei, Kumiko

    2017-01-01

    The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system is a prominent genome engineering technology. In the CRISPR/Cas system, the RNA-guided endonuclease Cas protein introduces a DNA double-stranded break at the genome position recognized by a guide RNA (gRNA) based on complementary base-pairing of about 20-nucleotides in length. The 8- or 12-mer gRNA sequence in the proximal region is especially important for target recognition, and the genes with sequence complementarity to such regions are often disrupted. To carry out target site-specific genome editing, we released the CRISPRdirect ( http://crispr.dbcls.jp /) website. This website allows us to select target site-specific gRNA sequences by performing exhaustive searches against entire genomic sequences. In this study, target site-specific gRNA sequences were designed for human, mouse, Drosophila melanogaster, and Caenorhabditis elegans. The calculation results revealed that at least five gRNA sequences, each of them having only one perfectly complementary site in the whole genome, could be designed for more than 95% of genes, regardless of the organism. Next, among those gRNAs, we selected gRNAs that did not have any other complementary site to the unique 12-mer proximal sequences to avoid possible off-target effects. This computational prediction revealed that target site-specific gRNAs are selectable for the majority of genes in D. melanogaster and C. elegans. However, for >50% of genes in humans and mice, there are no target sites without possible off-target effects.

  9. Myeloid-Biased Stem Cells as Potential Targets for Chronic Myelogeneous Leukemia

    DTIC Science & Technology

    2005-09-01

    AD Award Number: W81XWH-04-1-0798 TITLE: Myeloid-Biased Stem Cells as Potential Targets for Chronic Myelogeneous Leukemia PRINCIPAL INVESTIGATOR...Christa Muller-Sieburg, Ph.D. CONTRACTING ORGANIZATION: Sidney Kimmel Cancer Center San Diego, Ca 92121-1131 REPORT DATE: September 2005 TYPE OF REPORT...2005 4, TITLE AND SUBTITLE 5a. CONTRACT NUMBER Myeloid-Biased Stem Cells as Potential Targets for Chronic Myelogeneous Leukemia 5b. GRANT NUMBER W81

  10. Effect of functionalization on drug delivery potential of carbon nanotubes.

    PubMed

    Sharma, Sonam; Mehra, Neelesh Kumar; Jain, Keerti; Jain, Narendra Kumar

    2016-12-01

    The main aim of the present investigation was to explore the effect of functionalization on drug delivery potential of carbon nanotubes (CNTs) and to compare the in vitro and in vivo cancer targeting potential of doxorubicin HCL (DOX)-loaded ox-/multi-walled CNTs (MWCNTs), DOX-loaded PEG-MWCNTs and DOX-loaded FA-PEG-MWCNTs. The DOX/PEG-FA-MWCNTs showed enhanced cytotoxicity and were most preferentially taken up by the cancerous cells. The obtained results also support the extended resistance time and sustained release profile of drug-loaded surface-engineered MWCNTs. Overall, we concluded that the developed MWCNTs nanoformulations have higher cancer targeting potential.

  11. The periplasmic protein TolB as a potential drug target in Pseudomonas aeruginosa.

    PubMed

    Lo Sciuto, Alessandra; Fernández-Piñar, Regina; Bertuccini, Lucia; Iosi, Francesca; Superti, Fabiana; Imperi, Francesco

    2014-01-01

    The Gram-negative bacterium Pseudomonas aeruginosa is one of the most dreaded pathogens in the hospital setting, and represents a prototype of multi-drug resistant "superbug" for which effective therapeutic options are very limited. The identification and characterization of new cellular functions that are essential for P. aeruginosa viability and/or virulence could drive the development of anti-Pseudomonas compounds with novel mechanisms of action. In this study we investigated whether TolB, the periplasmic component of the Tol-Pal trans-envelope protein complex of Gram-negative bacteria, represents a potential drug target in P. aeruginosa. By combining conditional mutagenesis with the analysis of specific pathogenicity-related phenotypes, we demonstrated that TolB is essential for P. aeruginosa growth, both in laboratory and clinical strains, and that TolB-depleted P. aeruginosa cells are strongly defective in cell-envelope integrity, resistance to human serum and several antibiotics, as well as in the ability to cause infection and persist in an insect model of P. aeruginosa infection. The essentiality of TolB for P. aeruginosa growth, resistance and pathogenicity highlights the potential of TolB as a novel molecular target for anti-P. aeruginosa drug discovery.

  12. Self assembled hyaluronic acid nanoparticles as a potential carrier for targeting the inflamed intestinal mucosa.

    PubMed

    Vafaei, Seyed Yaser; Esmaeili, Motahareh; Amini, Mohsen; Atyabi, Fatemeh; Ostad, Seyed Naser; Dinarvand, Rassoul

    2016-06-25

    To develop a nanoparticulate drug carrier for targeting of the inflamed intestinal mucosa, amphiphilic hyaluronic acid (HA) conjugates were synthesized, which could form self-assembled nanoparticles (NPs) in aqueous solution and budesonide (BDS) was loaded into the HANPs. Their particle sizes were in the range of 177 to 293nm with negative surface charge. The model of inflammatory CACO-2 cells was utilized to investigate the therapeutic potential of budesonide loaded HA nanocarriers. The highest expression of CD44 receptors was found on inflamed Caco-2 cells, as determined by flow cytometry. FITC-labeled HANPs revealed greater uptake in inflamed CACO-2 cells compared to untreated CACO-2 and CD44-negative cell lines, NIH3T3. BDS loaded HANPs displayed almost no toxicity indicating HANPs are excellent biocompatible nano-carriers. BDS loaded HANPs demonstrated higher anti-inflammatory effect on IL-8 and TNF-α secretion in inflamed cell model compared to the same dose of free drug. These results revealed the promising potential of HA nanoparticles as a targeted drug delivery system for IBD treatment.

  13. Epigenetic Control and Cancer: The Potential of Histone Demethylases as Therapeutic Targets

    PubMed Central

    Lizcano, Fernando; Garcia, Jeison

    2012-01-01

    The development of cancer involves an immense number of factors at the molecular level. These factors are associated principally with alterations in the epigenetic mechanisms that regulate gene expression profiles. Studying the effects of chromatin structure alterations, which are caused by the addition/removal of functional groups to specific histone residues, are of great interest as a promising way to identify markers for cancer diagnosis, classify the disease and determine its prognosis, and these markers could be potential targets for the treatment of this disease in its different forms. This manuscript presents the current point of view regarding members of the recently described family of proteins that exhibit histone demethylase activity; histone demethylases are genetic regulators that play a fundamental role in both the activation and repression of genes and whose expression has been observed to increase in many types of cancer. Some fundamental aspects of their association with the development of cancer and their relevance as potential targets for the development of new therapeutic strategies at the epigenetic level are discussed in the following manuscript. PMID:24280700

  14. Monoacylglycerol Lipase: A Novel Potential Therapeutic Target and Prognostic Indicator for Hepatocellular Carcinoma

    PubMed Central

    Zhang, Junyong; Liu, Zuojin; Lian, Zhengrong; Liao, Rui; Chen, Yi; Qin, Yi; Wang, Jinlong; Jiang, Qing; Wang, Xiaobo; Gong, Jianping

    2016-01-01

    Monoacylglycerol lipase (MAGL) is a key enzyme in lipid metabolism that is demonstrated to be involved in tumor progression through both energy supply of fatty acid (FA) oxidation and enhancing cancer cell malignance. The aim of this study was to investigate whether MAGL could be a potential therapeutic target and prognostic indicator for hepatocellular carcinoma (HCC). To evaluate the relationship between MAGL levels and clinical characteristics, a tissue microarray (TMA) of 353 human HCC samples was performed. MAGL levels in HCC samples were closely linked to the degree of malignancy and patient prognosis. RNA interference, specific pharmacological inhibitor JZL-184 and gene knock-in of MAGL were utilized to investigate the effects of MAGL on HCC cell proliferation, apoptosis, and invasion. MAGL played important roles in both proliferation and invasion of HCC cells through mechanisms that involved prostaglandin E2 (PGE2) and lysophosphatidic acid (LPA). JZL-184 administration significantly inhibited tumor growth in mice. Furthermore, we confirmed that promoter methylation of large tumor suppressor kinase 1 (LATS1) resulted in dysfunction of the Hippo signal pathway, which induced overexpression of MAGL in HCC. These results indicate that MAGL could be a potentially novel therapeutic target and prognostic indicator for HCC. PMID:27767105

  15. Heat shock protein 90 as a potential drug target against surra.

    PubMed

    Rochani, Ankit K; Mithra, Chandan; Singh, Meetali; Tatu, Utpal

    2014-08-01

    Trypanosomiasis is caused by Trypanosoma species which affect both human and animal populations and pose a major threat to developing countries. The incidence of animal trypanosomiasis is on the rise. Surra is a type of animal trypanosomiasis, caused by Trypanosoma evansi, and has been included in priority list B of significant diseases by the World Organization of Animal Health (OIE). Control of surra has been a challenge due to the lack of effective drugs and vaccines and emergence of resistance towards existing drugs. Our laboratory has previously implicated Heat shock protein 90 (Hsp90) from protozoan parasites as a potential drug target and successfully demonstrated efficacy of an Hsp90 inhibitor in cell culture as well as a pre-clinical mouse model of trypanosomiasis. This article explores the role of Hsp90 in the Trypanosoma life cycle and its potential as a drug target. It appears plausible that the repertoire of Hsp90 inhibitors available in academia and industry may have value for treatment of surra and other animal trypanosomiasis.

  16. A C-code for the double folding interaction potential for reactions involving deformed target nuclei

    NASA Astrophysics Data System (ADS)

    Gontchar, I. I.; Chushnyakova, M. V.

    2013-01-01

    We present a C-code designed to obtain the interaction potential between a spherical projectile nucleus and an axial-symmetrical deformed target nucleus and in particular to find the Coulomb barrier, by using the double folding model (DFM). The program calculates the nucleus-nucleus potential as a function of the distance between the centers of mass of colliding nuclei as well as of the angle between the axis of symmetry of the target nucleus and the beam direction. The most important output parameters are the Coulomb barrier energy and the radius. Since many researchers use a Woods-Saxon profile for the nuclear term of the potential we provide an option in our code for fitting the DFM potential by such a profile near the barrier. Program summaryProgram title: DFMDEF Catalogue identifier: AENI_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AENI_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.html No. of lines in distributed program, including test data, etc.: 2245 No. of bytes in distributed program, including test data, etc.: 215442 Distribution format: tar.gz Programming language: C. Computer: PC, Mac. Operating system: Windows XP (with the GCC-compiler version 2), MacOS, Linux. RAM: 100 MB with average parameters set Classification: 17.9. Nature of problem: The code calculates in a semimicroscopic way the bare interaction potential between a spherical projectile nucleus and a deformed but axially symmetric target nucleus as a function of the center of mass distance as well as of the angle between the axis of symmetry of the target nucleus and the beam direction. The height and the position of the Coulomb barrier are found. The calculated potential is approximated by a conventional Woods-Saxon profile near the barrier. Dependence of the barrier parameters upon the characteristics of the effective NN forces (like, e

  17. The insect ecdysone receptor is a good potential target for RNAi-based pest control.

    PubMed

    Yu, Rong; Xu, Xinping; Liang, Yongkang; Tian, Honggang; Pan, Zhanqing; Jin, Shouheng; Wang, Na; Zhang, Wenqing

    2014-01-01

    RNA interference (RNAi) has great potential for use in insect pest control. However, some significant challenges must be overcome before RNAi-based pest control can become a reality. One challenge is the proper selection of a good target gene for RNAi. Here, we report that the insect ecdysone receptor (EcR) is a good potential target for RNAi-based pest control in the brown planthopper Nilaparvata lugens, a serious insect pest of rice plants. We demonstrated that the use of a 360 bp fragment (NlEcR-c) that is common between NlEcR-A and NlEcR-B for feeding RNAi experiments significantly decreased the relative mRNA expression levels of NlEcR compared with those in the dsGFP control. Feeding RNAi also resulted in a significant reduction in the number of offspring per pair of N. lugens. Consequently, a transgenic rice line expressing NlEcR dsRNA was constructed by Agrobacterium- mediated transformation. The results of qRT-PCR showed that the total copy number of the target gene in all transgenic rice lines was 2. Northern blot analysis showed that the small RNA of the hairpin dsNlEcR-c was successfully expressed in the transgenic rice lines. After newly hatched nymphs of N. lugens fed on the transgenic rice lines, effective RNAi was observed. The NlEcR expression levels in all lines examined were decreased significantly compared with the control. In all lines, the survival rate of the nymphs was nearly 90%, and the average number of offspring per pair in the treated groups was significantly less than that observed in the control, with a decrease of 44.18-66.27%. These findings support an RNAi-based pest control strategy and are also important for the management of rice insect pests.

  18. The apelin-APJ axis: A novel potential therapeutic target for organ fibrosis.

    PubMed

    Huang, Shifang; Chen, Linxi; Lu, Liqun; Li, Lanfang

    2016-05-01

    Apelin, an endogenous ligand of the G-protein-coupled receptor APJ, is expressed in a diverse number of organs. The apelin-APJ axis helps to control the processes of pathological and physiological fibrosis, including renal fibrosis, cardiac fibrosis, liver fibrosis and pulmonary fibrosis. However, the role of apelin-APJ in organ fibrosis remains controversial due to conflicting study results. The apelin-APJ axis is a detrimental mechanism which promotes liver fibrosis mainly via up-regulation the expression of collagen-II and platelet-derived growth factor receptor β (PDGFRβ). On the contrary, the apelin-APJ axis is beneficial for renal fibrosis, cardiac fibrosis and pulmonary fibrosis. The apelin-APJ axis alleviates renal fibrosis by restraining the expression of transforming growth factor-β1 (TGF-β1). In addition, the apelin-APJ axis attenuates cardiac fibrosis through multiple pathways. Furthermore, the apelin-APJ axis has beneficial effects on experimental bronchopulmonary dysplasia (BPD) and acute respiratory distress syndrome (ARDS) which suggest the apelin-APJ axis potentially alleviates pulmonary fibrosis. In this article, we review the controversies associated with apelin-APJ in organ fibrosis and introduce the drugs that target apelin-APJ. We conclude that future studies should place more emphasis on the relationship among apelin isoforms, APJ receptor subtypes and organ fibrosis. The apelin-APJ axis will be a potential therapeutic target and those drugs targeted for apelin-APJ may constitute a novel therapeutic strategy for renal fibrosis, cardiac fibrosis, liver fibrosis and pulmonary fibrosis. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Selective Mitochondrial Targeting Exerts Anxiolytic Effects In Vivo

    PubMed Central

    Nussbaumer, Markus; Asara, John M; Teplytska, Larysa; Murphy, Michael P; Logan, Angela; Turck, Christoph W; Filiou, Michaela D

    2016-01-01

    Current treatment strategies for anxiety disorders are predominantly symptom-based. However, a third of anxiety patients remain unresponsive to anxiolytics highlighting the need for more effective, mechanism-based therapeutic approaches. We have previously compared high vs low anxiety mice and identified changes in mitochondrial pathways, including oxidative phosphorylation and oxidative stress. In this work, we show that selective pharmacological targeting of these mitochondrial pathways exerts anxiolytic effects in vivo. We treated high anxiety-related behavior (HAB) mice with MitoQ, an antioxidant that selectively targets mitochondria. MitoQ administration resulted in decreased anxiety-related behavior in HAB mice. This anxiolytic effect was specific for high anxiety as MitoQ treatment did not affect the anxiety phenotype of C57BL/6N and DBA/2J mouse strains. We furthermore investigated the molecular underpinnings of the MitoQ-driven anxiolytic effect and found that MitoQ treatment alters the brain metabolome and that the response to MitoQ treatment is characterized by distinct molecular signatures. These results indicate that a mechanism-driven approach based on selective mitochondrial targeting has the potential to attenuate the high anxiety phenotype in vivo, thus paving the way for translational implementation as long-term MitoQ administration is well-tolerated with no reported side effects in mice and humans. PMID:26567514

  20. Selective Mitochondrial Targeting Exerts Anxiolytic Effects In Vivo.

    PubMed

    Nussbaumer, Markus; Asara, John M; Teplytska, Larysa; Murphy, Michael P; Logan, Angela; Turck, Christoph W; Filiou, Michaela D

    2016-06-01

    Current treatment strategies for anxiety disorders are predominantly symptom-based. However, a third of anxiety patients remain unresponsive to anxiolytics highlighting the need for more effective, mechanism-based therapeutic approaches. We have previously compared high vs low anxiety mice and identified changes in mitochondrial pathways, including oxidative phosphorylation and oxidative stress. In this work, we show that selective pharmacological targeting of these mitochondrial pathways exerts anxiolytic effects in vivo. We treated high anxiety-related behavior (HAB) mice with MitoQ, an antioxidant that selectively targets mitochondria. MitoQ administration resulted in decreased anxiety-related behavior in HAB mice. This anxiolytic effect was specific for high anxiety as MitoQ treatment did not affect the anxiety phenotype of C57BL/6N and DBA/2J mouse strains. We furthermore investigated the molecular underpinnings of the MitoQ-driven anxiolytic effect and found that MitoQ treatment alters the brain metabolome and that the response to MitoQ treatment is characterized by distinct molecular signatures. These results indicate that a mechanism-driven approach based on selective mitochondrial targeting has the potential to attenuate the high anxiety phenotype in vivo, thus paving the way for translational implementation as long-term MitoQ administration is well-tolerated with no reported side effects in mice and humans.

  1. Sci—Fri PM: Topics — 04: What if bystander effects influence cell kill within a target volume? Potential consequences of dose heterogeneity on TCP and EUD on intermediate risk prostate patients

    SciTech Connect

    Balderson, M.J.; Kirkby, C.

    2014-08-15

    In vitro evidence has suggested that radiation induced bystander effects may enhance non-local cell killing which may influence radiotherapy treatment planning paradigms. This work applies a bystander effect model, which has been derived from published in vitro data, to calculate equivalent uniform dose (EUD) and tumour control probability (TCP) and compare them with predictions from standard linear quadratic (LQ) models that assume a response due only to local absorbed dose. Comparisons between the models were made under increasing dose heterogeneity scenarios. Dose throughout the CTV was modeled with normal distributions, where the degree of heterogeneity was then dictated by changing the standard deviation (SD). The broad assumptions applied in the bystander effect model are intended to place an upper limit on the extent of the results in a clinical context. The bystander model suggests a moderate degree of dose heterogeneity yields as good or better outcome compared to a uniform dose in terms of EUD and TCP. Intermediate risk prostate prescriptions of 78 Gy over 39 fractions had maximum EUD and TCP values at SD of around 5Gy. The plots only dropped below the uniform dose values for SD ∼ 10 Gy, almost 13% of the prescribed dose. The bystander model demonstrates the potential to deviate from the common local LQ model predictions as dose heterogeneity through a prostate CTV is varies. The results suggest the potential for allowing some degree of dose heterogeneity within a CTV, although further investigations of the assumptions of the bystander model are warranted.

  2. Serotonin receptors as potential targets for modulation of nicotine use and dependence.

    PubMed

    Fletcher, Paul J; Lê, Anh Dzung; Higgins, Guy A

    2008-01-01

    Nicotine use carries considerable health risks and plays a major role in a variety of diseases. Current pharmacological treatments to aid in smoking cessation include nicotine-replacement therapy and non-nicotinic strategies such as bupropion and varenicline. While these treatments benefit some individuals there is still a need for better and more effective treatment strategies. Nicotine is the major psychoactive substance in tobacco. Some behavioural effects of nicotine, including its reinforcing efficacy result in part from activation of mesolimbic dopamine neurons. Modulation of dopamine function is one potential treatment strategy that could treat nicotine dependence. Serotonergic neurons modulate the functioning of dopamine neurons in a complex fashion. Much of this complexity arises from the fact that serotonin (5-HT) exerts its effects through multiple receptor subtypes, some of which even act in apparent functional opposition to each other. This article reviews evidence, primarily from animal experiments, using behavioural procedures relevant to nicotine use on the potential for 5-HT receptors as targets for treating nicotine dependence. The 5-HT(1A, 2A, 2C, 3, 4, 6) receptor subtypes have received most experimental attention, with the 5-HT(1A) and 5-HT(2C) receptors being the best studied. Several studies have now shown that 5-HT(1A) receptor antagonists alleviate some of the behavioural signs induced by nicotine withdrawal. Electrophysiological and neurochemical studies show that stimulation of 5-HT(2C) receptors reduces the function of the mesolimbic dopamine pathway. 5-HT(2C) receptor agonists block the stimulatory action of nicotine on midbrain dopamine function. They also reduce several behavioural effects of nicotine including its discriminative stimulus properties and reinforcing effects. Although more work remains to be done, 5-HT(2C) receptor agonists perhaps hold the most promise as potential therapies for smoking cessation.

  3. Perspectives and potential applications of mitochondria-targeted antioxidants in cardiometabolic diseases and type 2 diabetes.

    PubMed

    Rocha, Milagros; Apostolova, Nadezda; Herance, Jose Raul; Rovira-Llopis, Susana; Hernandez-Mijares, Antonio; Victor, Victor M

    2014-01-01

    There is abundant evidence to suggest that mitochondrial dysfunction is a main cause of insulin resistance and related cardiometabolic comorbidities. On the other hand, insulin resistance is one of the main characteristics of type 2 diabetes, obesity, and metabolic syndrome. Lipid and glucose metabolism require mitochondria to generate energy, and when O2 consumption is low due to inefficient nutrient oxidation, there is an increase in reactive oxygen species, which can impair different types of molecules, including DNA, lipids, proteins, and carbohydrates, thereby inducing proinflammatory processes. Factors which contribute to mitochondrial dysfunction, such as mitochondrial biogenesis and genetics, can also lead to insulin resistance in different insulin-target tissues, and its association with mitochondrial dysfunction can culminate in the development of cardiovascular diseases. In this context, therapies that improve mitochondrial function may also improve insulin resistance. This review explains mechanisms of mitochondrial function related to the pathological effects of insulin resistance in different tissues. The pathogenesis of cardiometabolic diseases will be explained from a mitochondrial perspective and the potential beneficial effects of mitochondria-targeted antioxidants as a therapy for modulating mitochondrial function in cardiometabolic diseases, especially diabetes, will also be considered.

  4. Evaluation of Acanthamoeba Myosin-IC as a Potential Therapeutic Target

    PubMed Central

    Lorenzo-Morales, Jacob; López-Arencibia, Atteneri; Reyes-Batlle, María; Piñero, José E.; Valladares, Basilio; Maciver, Sutherland K.

    2014-01-01

    Members of the genus Acanthamoeba are facultative pathogens of humans, causing a sight-threatening keratitis and a fatal encephalitis. We have targeted myosin-IC by using small interfering RNA (siRNA) silencing as a therapeutic approach, since it is known that the function of this protein is vital for the amoeba. In this work, specific siRNAs against the Acanthamoeba myosin-IC gene were developed. Treated and control amoebae were cultured in growth and encystment media to evaluate the induced effects after myosin-IC gene knockdown, as we have anticipated that cyst formation may be impaired. The effects of myosin-IC gene silencing were inhibition of cyst formation, inhibition of completion of cytokinesis, inhibition of osmoregulation under osmotic stress conditions, and death of the amoebae. The finding that myosin-IC silencing caused incompletion of cytokinesis is in agreement with earlier suggestions that the protein plays a role in cell locomotion, which is necessary to pull daughter cells apart after mitosis in a process known as “traction-mediated cytokinesis”. We conclude that myosin-IC is a very promising potential drug target for the development of much-needed antiamoebal drugs and that it should be further exploited for Acanthamoeba therapy. PMID:24468784

  5. Evaluation of Acanthamoeba myosin-IC as a potential therapeutic target.

    PubMed

    Martín-Navarro, Carmen M; Lorenzo-Morales, Jacob; López-Arencibia, Atteneri; Reyes-Batlle, María; Piñero, José E; Valladares, Basilio; Maciver, Sutherland K

    2014-01-01

    Members of the genus Acanthamoeba are facultative pathogens of humans, causing a sight-threatening keratitis and a fatal encephalitis. We have targeted myosin-IC by using small interfering RNA (siRNA) silencing as a therapeutic approach, since it is known that the function of this protein is vital for the amoeba. In this work, specific siRNAs against the Acanthamoeba myosin-IC gene were developed. Treated and control amoebae were cultured in growth and encystment media to evaluate the induced effects after myosin-IC gene knockdown, as we have anticipated that cyst formation may be impaired. The effects of myosin-IC gene silencing were inhibition of cyst formation, inhibition of completion of cytokinesis, inhibition of osmoregulation under osmotic stress conditions, and death of the amoebae. The finding that myosin-IC silencing caused incompletion of cytokinesis is in agreement with earlier suggestions that the protein plays a role in cell locomotion, which is necessary to pull daughter cells apart after mitosis in a process known as "traction-mediated cytokinesis". We conclude that myosin-IC is a very promising potential drug target for the development of much-needed antiamoebal drugs and that it should be further exploited for Acanthamoeba therapy.

  6. Inverse Target- and Cue-Priming Effects of Masked Stimuli

    ERIC Educational Resources Information Center

    Mattler, Uwe

    2007-01-01

    The processing of a visual target that follows a briefly presented prime stimulus can be facilitated if prime and target stimuli are similar. In contrast to these positive priming effects, inverse priming effects (or negative compatibility effects) have been found when a mask follows prime stimuli before the target stimulus is presented: Responses…

  7. Inverse Target- and Cue-Priming Effects of Masked Stimuli

    ERIC Educational Resources Information Center

    Mattler, Uwe

    2007-01-01

    The processing of a visual target that follows a briefly presented prime stimulus can be facilitated if prime and target stimuli are similar. In contrast to these positive priming effects, inverse priming effects (or negative compatibility effects) have been found when a mask follows prime stimuli before the target stimulus is presented: Responses…

  8. Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer

    PubMed Central

    Song, Lingqin; Wang, Weifeng; Liu, Di; Zhao, Yang; He, Jianjun; Wang, Xijing; Dai, Zhijun; Zhang, Huimin; Li, Xiao

    2016-01-01

    Breast cancer is the most common malignant cancer among women. The Hedgehog (Hh) signaling pathway serves a key role in malignant cancer cell growth and migration. However, little is known with regard to the specific function of the Hh signaling pathway in human breast cancer. The current study investigated the specific role of Hh signaling in the human breast cancer cell line MDA-MB-231. Expression of components of Shh-Gli signaling, as well as the Gli-responsive genes B-cell lymphoma 2 (Bcl-2) and cyclin D1, were investigated in MDA-MB-231 cells using western blotting. The effects of Shh-Gli signaling on MDA-MB-231 proliferation were analyzed by MTT assay. The role of E-cadherin in the epithelial-mesenchymal transition process was determined by western blot while matrix metalloproteinase (MMP)-9/MMP-2 secretion was studied by enzyme-linked immunosorbent assay. The results indicated that Shh-Gli signaling was activated in MDA-MB-231 cells, significantly enhancing cell viability. Overexpression of Gli positively regulated the transcription of Bcl-2 and cyclin D1 thereby regulating MDA-MB-231 cell proliferation and survival. Treatment of MDA-MB-231 cells with human sonic hedgehog, n-terminus for 72 h significantly reduced E-cadherin protein levels and enhanced secretion of MMP-9 and MMP-2. These findings suggest that Shh-Gli signaling is significantly activated in human breast cancer cells, and is accompanied by enhanced cell viability, proliferation and migration capacities. PMID:27446389

  9. Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer.

    PubMed

    Song, Lingqin; Wang, Weifeng; Liu, Di; Zhao, Yang; He, Jianjun; Wang, Xijing; Dai, Zhijun; Zhang, Huimin; Li, Xiao

    2016-08-01

    Breast cancer is the most common malignant cancer among women. The Hedgehog (Hh) signaling pathway serves a key role in malignant cancer cell growth and migration. However, little is known with regard to the specific function of the Hh signaling pathway in human breast cancer. The current study investigated the specific role of Hh signaling in the human breast cancer cell line MDA-MB-231. Expression of components of Shh-Gli signaling, as well as the Gli-responsive genes B-cell lymphoma 2 (Bcl-2) and cyclin D1, were investigated in MDA-MB-231 cells using western blotting. The effects of Shh-Gli signaling on MDA-MB-231 proliferation were analyzed by MTT assay. The role of E-cadherin in the epithelial-mesenchymal transition process was determined by western blot while matrix metalloproteinase (MMP)-9/MMP-2 secretion was studied by enzyme-linked immunosorbent assay. The results indicated that Shh-Gli signaling was activated in MDA-MB-231 cells, significantly enhancing cell viability. Overexpression of Gli positively regulated the transcription of Bcl-2 and cyclin D1 thereby regulating MDA-MB-231 cell proliferation and survival. Treatment of MDA-MB-231 cells with human sonic hedgehog, n-terminus for 72 h significantly reduced E-cadherin protein levels and enhanced secretion of MMP-9 and MMP-2. These findings suggest that Shh-Gli signaling is significantly activated in human breast cancer cells, and is accompanied by enhanced cell viability, proliferation and migration capacities.

  10. Review article: transient receptor potential channels as possible therapeutic targets in irritable bowel syndrome.

    PubMed

    Beckers, A B; Weerts, Z Z R M; Helyes, Z; Masclee, A A M; Keszthelyi, D

    2017-09-08

    Abdominal pain in irritable bowel syndrome (IBS) remains challenging to treat effectively. Researchers have attempted to elucidate visceral nociceptive processes in order to guide treatment development. Transient receptor potential (TRP) channels have been implied in the generation (TRPV1, TRPV4, TRPA1) and inhibition (TRPM8) of visceral pain signals. Pathological changes in their functioning have been demonstrated in inflammatory conditions, and appear to be present in IBS as well. To provide a comprehensive review of the current literature on TRP channels involved in visceral nociception. In particular, we emphasise the clinical implications of these nociceptors in the treatment of IBS. Evidence to support this review was obtained from an electronic database search via PubMed using the search terms "visceral nociception," "visceral hypersensitivity," "irritable bowel syndrome" and "transient receptor potential channels." After screening the abstracts the articles deemed relevant were cross-referenced for additional manuscripts. Recent studies have resulted in significant advances in our understanding of TRP channel mediated visceral nociception. The diversity of TRP channel sensitization pathways is increasingly recognised. Endogenous TRP agonists, including poly-unsaturated fatty acid metabolites and hydrogen sulphide, have been implied in augmented visceral pain generation in IBS. New potential targets for treatment development have been identified (TRPA1 and TRPV4,) and alternative means of affecting TRP channel signalling (partial antagonists, downstream targeting and RNA-based therapy) are currently being explored. The improved understanding of mechanisms involved in visceral nociception provides a solid basis for the development of new treatment strategies for abdominal pain in IBS. © 2017 John Wiley & Sons Ltd.

  11. Choroidal Proteins Involved in Cerebrospinal Fluid Production may be Potential Drug Targets for Alzheimer's Disease Therapy.

    PubMed

    Wostyn, Peter; Audenaert, Kurt; De Deyn, Peter Paul

    2011-02-23

    Alzheimer's disease is known to be the most common form of dementia in the elderly. It is clinically characterized by impairment of cognitive functions, as well as changes in personality, behavioral disturbances and an impaired ability to perform activities of daily living. To date, there are no effective ways to cure or reverse the disease. Genetic studies of early-onset familial Alzheimer's disease cases revealed causative mutations in the genes encoding β-amyloid precursor protein and the γ-secretase-complex components presenilin-1 and presenilin-2, supporting an important role of β-amyloid in the pathogenesis of Alzheimer's disease. Compromised function of the choroid plexus and defective cerebrospinal fluid production and turnover, with diminished clearance of β-amyloid, may play an important role in late-onset forms of Alzheimer's disease. If reduced cerebrospinal fluid turnover is a risk factor for Alzheimer's disease, then therapeutic strategies to improve cerebrospinal fluid flow are reasonable. However, the role of deficient cerebrospinal fluid dynamics in Alzheimer's disease and the relevance of choroidal proteins as potential therapeutic targets to enhance cerebrospinal fluid turnover have received relatively little research attention. In this paper, we discuss several choroidal proteins, such as Na(+)-K(+) ATPase, carbonic anhydrase, and aquaporin 1, that may be targets for pharmacological up-regulation of cerebrospinal fluid formation. The search for potentially beneficial drugs useful to ameliorate Alzheimer's disease by facilitating cerebrospinal fluid production and turnover may be an important area for future research. However, the ultimate utility of such modulators in the management of Alzheimer's disease remains to be determined. Here, we hypothesize that caffeine, the most commonly used psychoactive drug in the world, may be an attractive therapeutic candidate for treatment of Alzheimer's disease since long-term caffeine consumption may

  12. Crosstalk between bone niche and immune system: osteoimmunology signaling as a potential target for cancer treatment.

    PubMed

    Criscitiello, Carmen; Viale, Giulia; Gelao, Lucia; Esposito, Angela; De Laurentiis, Michele; De Placido, Sabino; Santangelo, Michele; Goldhirsch, Aron; Curigliano, Giuseppe

    2015-02-01

    There is a well recognized link between the bone and the immune system and in recent years there has been a major effort to elucidate the multiple functions of the molecules expressed in both bone and immune cells. Several molecules that were initially identified and studied in the immune system have been shown to have essential functions also in the bone. An interdisciplinary field embracing immune and bone biology has been brought together and called "osteoimmunology". The co-regulation of the skeletal and immune systems strikingly exemplifies the extreme complexity of such an interaction. Their interdependency must be considered in designing therapeutic approaches for either of the two systems. In other words, it is necessary to think of the osteoimmune system as a complex physiological unit. Denosumab was originally introduced to specifically target bone resorption, but it is now under evaluation for its effect on the long term immune response. Similarly, our current and still growing knowledge of the intimate link between the immune system and bone will be beneficial for the safety of drugs targeting either of these integrated systems. Given the large number of molecules exerting functions on both the skeletal and immune systems, osteoimmunological understanding is becoming increasingly important. Both bone and immune systems are frequently disrupted in cancer; and they may be crucial in regulating tumor growth and progression. Some therapies - such as bisphosphonates and receptor activator of NF-κB ligand (RANKL) targeted drugs - that aim at reducing pathologic osteolysis in cancer may interact with the immune system, thus providing potential favorable effects on survival. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Targeting luteinizing hormone-releasing hormone: A potential therapeutics to treat gynecological and other cancers.

    PubMed

    Ghanghoria, Raksha; Kesharwani, Prashant; Tekade, Rakesh K; Jain, Narendra K

    2016-11-10

    Cancer is a prime healthcare problem that is significantly responsible for universal mortality. Despite distinguished advancements in medical field, chemotherapy is still the mainstay for the treatment of cancers. During chemotherapy, approximately 90% of the administered dose goes to normal tissues, with mere 2-5% precisely reaching the cancerous tissues. Subsequently, the resultant side effects and associated complications lead to dose reduction or even discontinuance of the therapy. Tumor directed therapy therefore, represents a fascinating approach to augment the therapeutic potential of anticancer bioactives as well as overcomes its side effects. The selective overexpression of LHRH receptors on human tumors compared to normal tissues makes them a suitable marker for diagnostics, molecular probes and targeted therapeutics. These understanding enabled the rational to conjugate LHRH with various cytotoxic drugs (doxorubicin, DOX; camptothecin etc.), cytotoxic genes [small interfering RNA (siRNA), micro RNA (miRNA)], as well as therapeutic nanocarriers (nanoparticles, liposomes or dendrimers) to facilitate their tumor specific delivery. LHRH conjugation enhances their delivery via LHRH receptor mediated endocytosis. Numerous cytotoxic analogs of LHRH were developed over the past two decades to target various types of cancers. The potency of LHRH compound were reported to be as high as 5,00-10,00 folds compared to parent molecules. The objective of this review article is to discuss reports on various LHRH analogs with special emphasis on their prospective application in the medical field. The article also focuses on the attributes that must be taken into account while designing a LHRH therapeutics with special account to the biochemistry and applications of these conjugates. The record on various cytotoxic analogs of LHRH are also discussed. It is anticipated that the knowledge of therapeutic and toxicological aspects of LHRH compounds will facilitate the

  14. Modulation of actin dynamics as potential macrophage subtype-targeting anti-tumour strategy

    PubMed Central

    Pergola, Carlo; Schubert, Katrin; Pace, Simona; Ziereisen, Jana; Nikels, Felix; Scherer, Olga; Hüttel, Stephan; Zahler, Stefan; Vollmar, Angelika M.; Weinigel, Christina; Rummler, Silke; Müller, Rolf; Raasch, Martin; Mosig, Alexander; Koeberle, Andreas; Werz, Oliver

    2017-01-01

    Tumour-associated macrophages mainly comprise immunosuppressive M2 phenotypes that promote tumour progression besides anti-tumoural M1 subsets. Selective depletion or reprogramming of M2 may represent an innovative anti-cancer strategy. The actin cytoskeleton is central for cellular homeostasis and is targeted for anti-cancer chemotherapy. Here, we show that targeting G-actin nucleation using chondramide A (ChA) predominantly depletes human M2 while promoting the tumour-suppressive M1 phenotype. ChA reduced the viability of M2, with minor effects on M1, but increased tumour necrosis factor (TNF)α release from M1. Interestingly, ChA caused rapid disruption of dynamic F-actin filaments and polymerization of G-actin, followed by reduction of cell size, binucleation and cell division, without cellular collapse. In M1, but not in M2, ChA caused marked activation of SAPK/JNK and NFκB, with slight or no effects on Akt, STAT-1/-3, ERK-1/2, and p38 MAPK, seemingly accounting for the better survival of M1 and TNFα secretion. In a microfluidically-supported human tumour biochip model, circulating ChA-treated M1 markedly reduced tumour cell viability through enhanced release of TNFα. Together, ChA may cause an anti-tumoural microenvironment by depletion of M2 and activation of M1, suggesting induction of G-actin nucleation as potential strategy to target tumour-associated macrophages in addition to neoplastic cells. PMID:28134280

  15. Pyrimidine metabolism in schistosomes: A comparison with other parasites and the search for potential chemotherapeutic targets.

    PubMed

    El Kouni, Mahmoud H

    2017-11-01

    Schistosomes are responsible for the parasitic disease schistosomiasis, an acute and chronic parasitic ailment that affects >240 million people in 70 countries worldwide. It is the second most devastating parasitic disease after malaria. At least 200,000 deaths per year are associated with the disease. In the absence of the availability of vaccines, chemotherapy is the main stay for combating schistosomiasis. The antischistosomal arsenal is currently limited to a single drug, Praziquantel, which is quite effective with a single-day treatment and virtually no host-toxicity. Recently, however, the question of reduced activity of Praziquantel has been raised. Therefore, the search for alternative antischistosomal drugs merits the study of new approaches of chemotherapy. The rational design of a drug is usually based on biochemical and physiological differences between pathogens and host. Pyrimidine metabolism is an excellent target for such studies. Schistosomes, unlike most of the host tissues, require a very active pyrimidine metabolism for the synthesis of DNA and RNA. This is essential for the production of the enormous numbers of eggs deposited daily by the parasite to which the granulomas response precipitates the pathogenesis of schistosomiasis. Furthermore, there are sufficient differences between corresponding enzymes of pyrimidine metabolism from the host and the parasite that can be exploited to design specific inhibitors or "subversive substrates" for the parasitic enzymes. Specificities of pyrimidine transport also diverge significantly between parasites and their mammalian host. This review deals with studies on pyrimidine metabolism in schistosomes and highlights the unique characteristic of this metabolism that could constitute excellent potential targets for the design of safe and effective antischistosomal drugs. In addition, pyrimidine metabolism in schistosomes is compared with that in other parasites where studies on pyrimidine metabolism have

  16. Antibacterial Effects of Blackberry Extract Target Periodontopathogens

    PubMed Central

    González, Octavio A.; Escamilla, Carolina; Danaher, Robert J.; Dai, Jin; Ebersole, Jeffrey L.; Mumper, Russell J.; Miller, Craig S.

    2013-01-01

    Background and Objective Antimicrobial agents provide valuable adjunctive therapy for prevention and control of oral diseases. Limitations in their prolonged use have stimulated the search for new natural occurring agents with more specific activity and fewer adverse effects. Here we sought to determine the anti-bacterial properties of blackberry extract (BBE) in vitro against oral bacterial commensals and periodontopathogens. Material and Methods Effects of whole and fractionated BBE on the metabolism of 10 different oral bacteria were evaluated by colorimetric water-soluble tetrazolium-1 (WST-1) assay. Bactericidal effects of whole BBE against F. nucleatum were determined by quantitating colony forming units (CFUs). Cytotoxicity was determined in oral epithelial (OKF6) cells. Results BBE at 350-1,400 μg/mL reduced the metabolic activity of P. gingivalis, F. nucleatum and S. mutans. The reduced metabolic activity observed for F. nucleatum corresponded to a reduction in CFUs following exposure to BBE for as little as 1 hour, indicative of its bactericidal properties. An anthocyanin-enriched fraction of BBE reduced the metabolic activity of F. nucleatum but not P. gingivalis or S. mutans, suggesting the contribution of species specific agents in the whole BBE. Oral epithelial cell viability was not reduced following ≤ 6 h exposures to whole BBE (2.24-1400 μg/mL). Conclusion BBE alters the metabolic activity of oral periodontopathogens while demonstrating minimal effect on commensals. The specific antibacterial properties of BBE shown in this study along with its anti-inflammatory and antiviral properties previously demonstrated make this natural extract a promising target as an adjunct for prevention and/or complementary therapy of periodontal infections. PMID:22812456

  17. Is VEGF a key target of cotinine and other potential therapies against Alzheimer disease?

    PubMed

    Echeverria, Valentin; Barreto, George E; Ávila-Rodriguez, Marco; Tarasov, Vadim V; Aliev, Gjumrakch

    2017-03-29

    The vascular endothelial growth factor (VEGF) is a neuroprotective cytokine that promotes neurogenesis and angiogenesis in the brain. In animal models, it has been shown that environmental enrichment and exercise, two non-pharmacological interventions that are beneficial decreasing the progression of Alzheimer disease (AD) and depressive-like behavior, enhance hippocampal VEGF expression and neurogenesis. Furthermore, the stimulation of VEGF expression promotes neurotransmission and synaptic plasticity processes such as neurogenesis. It is thought that these VEGF actions in the brain, may underly its beneficial therapeutic effects against psychiatric and other neurological conditions. In this review, evidence linking VEGF deficit with the development of AD as well as the potential role of VEGF signaling as a therapeutic target for cotinine and other interventions in neurodegenerative conditions are discussed. .

  18. Interleukin-27 as a potential therapeutic target for rheumatoid arthritis: has the time come?

    PubMed

    Gong, Fang; Pan, Yu-Hong; Huang, Xuan; Chen, Jiang; Xiao, Jin-Hua; Zhu, Hua-Yan

    2013-10-01

    Interleukin (IL)-27 is a novel member of the IL-6/IL-12 family of cytokines with a broad range of pro- and anti-inflammatory properties. Recently, accumulating evidence has shown that IL-27 can play either a pathogenic or a protective role in animal models of inflammatory arthritis, depending upon the model and underlying pathogenic mechanisms. As to human system, elevated expression of IL-27 has clearly been detected in the synovial membranes and fluid from patients with rheumatoid arthritis (RA). Moreover, stimulation of IL-27 receptor with IL-27 of fibroblast-like synoviocytes from RA had a suppressive effect on the production of proinflammatory cytokines in vitro. All these findings suggest that IL-27 may have promise as a potential therapeutic target for RA. In this review, we will discuss the biological features of IL-27 and summarize recent advances on both pathogenic and protective roles of IL-27 in RA.

  19. Stress-induced molecules MICA as potential target for radioimmunotherapy of cancer

    NASA Astrophysics Data System (ADS)

    Abakushina, E. V.; Anokhin, Yu N.; Abakushin, D. N.; Kaprin, A. D.

    2017-01-01

    Improving the treatment of cancer, increasing their effectiveness and safety is the main objective in the medicine. Molecular nuclear medicine plays an important role in the therapy of cancer. Radioimmunotherapy (RIT) involves the use of antibodies conjugated with therapeutic radionuclides. More often for RIT use the radiolabeled monoclonal antibodies against tumor-associated antigens. Encouraging results have been achieved with this technology in the management of hematologic malignancies. On the contrary, solid tumors have been less responsive. Despite these encouraging results, new potential target for radioimmunodetection and RIT should be found. It was found to increase the level of tumor-associated molecules MICA in the serum of cancer patients. Use of anti-MICA monoclonal antibodies capable a specifically attach to cancer cell via NKG2D ligands and destroy it, is a very promising direction, both therapeutic and diagnostic standpoint.

  20. Potential prospects of nanomedicine for targeted therapeutics in inflammatory bowel diseases.

    PubMed

    Pichai, Madharasi V A; Ferguson, Lynnette R

    2012-06-21

    Inflammatory bowel diseases (IBDs) such as Crohn's disease are highly debilitating. There are inconsistencies in response to and side effects in the current conventional medications, failures in adequate drug delivery, and the lack of therapeutics to offer complete remission in the presently available treatments of IBD. This suggests the need to explore beyond the horizons of conventional approaches in IBD therapeutics. This review examines the arena of the evolving IBD nanomedicine, studied so far in animal and in vitro models, before comprehensive clinical testing in humans. The investigations carried out so far in IBD models have provided substantial evidence of the nanotherapeutic approach as having the potential to overcome some of the current drawbacks to conventional IBD therapy. We analyze the pros and cons of nanotechnology in IBD therapies studied in different models, aimed at different targets and mechanisms of IBD pathogenesis, in an attempt to predict its possible impact in humans.

  1. G protein-coupled receptors: potential therapeutic targets for diabetic nephropathy.

    PubMed

    Ding, Hai-Hua; Ni, Wei-Jian; Tang, Li-Qin; Wei, Wei

    2015-12-16

    Diabetic nephropathy, a lethal microvascular complication of diabetes mellitus, is characterized by progressive albuminuria, excessive deposition of extracellular matrix, thickened glomerular basement membrane, podocyte abnormalities, and podocyte loss. The G protein-coupled receptors (GPCRs) have attracted considerable attention in diabetic nephropathy, but the specific effects have not been elucidated yet. Likewise, abnormal signaling pathways are closely interrelated to the pathologic process of diabetic nephropathy, despite the fact that the mechanisms have not been explored clearly. Therefore, GPCRs and its mediated signaling pathways are essential for priority research, so that preventative strategies and potential targets might be developed for diabetic nephropathy. This article will give us comprehensive overview of predominant GPCR types, roles, and correlative signaling pathways in diabetic nephropathy.

  2. Reprogramming the oncogenic response: SET protein as a potential therapeutic target in cancer.

    PubMed

    Hung, Man-Hsin; Chen, Kuen-Feng

    2017-07-01

    SET is a multitask oncoprotein that promotes the initiation and progression of cancer. Overexpression of SET has been characterized as being tumor-specific and is associated with adverse clinical outcomes in many different human malignant diseases. Notably, SET has been shown to promote the development of therapeutic resistance in cancer cells. Area covered: In this review, we summarized the currently available evidence relating to the oncogenic roles, biological functions and clinical relevance of SET protein in cancer. The anti-cancer effects of three different SET antagonists undergoing preclinical investigation are also discussed. Expert opinion: Emerging evidence supports the critical role of SET in regulating various different cancer hallmarks. Targeting the SET-associated protein interfaces may be a potential anti-cancer strategy for future development. However, more studies are required to clarify the best strategy to combine SET antagonists with other anti-cancer treatments and to explore possible biomarkers that predict responsiveness.

  3. Individuals' attentional bias toward an envied target's name: an event-related potential study.

    PubMed

    Zhong, Jun; Liu, Yongfang; Zhang, Entao; Luo, Junlong; Chen, Jie

    2013-08-29

    Individuals may pay more attention to information about envied targets. Thus, we further investigate the neural correlates underlying the cognitive processing of envy-related stimuli. Participants read information about target persons characterized by two domains: levels of possession and self-relevance of comparison. Event-related potentials (ERPs) were then recorded for three target names (high-envy, moderate-envy, and low-envy) while participants performed a three-stimulus oddball task. The results showed that high- and moderate-envy target names elicited larger P300 amplitudes than did low-envy target names. Specifically, high-envy target names elicited larger P300 amplitudes than did low-envy target names at the left, central, and right sites; in contrast, moderate-envy target names elicited larger P300 amplitudes than did low-envy target names only at central sites. P300 amplitudes did not differ between high- and moderate-envy target names. Thus, we extend previous behavioral findings by showing that people preferentially attend toward envy-related stimuli, as reflected by enhanced P300 amplitudes.

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

    PubMed Central

    May, Felicity EB

    2014-01-01

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

  5. Identification of Cell Surface Proteins as Potential Immunotherapy Targets in 12 Pediatric Cancers

    PubMed Central

    Orentas, Rimas J.; Yang, James J.; Wen, Xinyu; Wei, Jun S.; Mackall, Crystal L.; Khan, Javed

    2012-01-01

    Technological advances now allow us to rapidly produce CARs and other antibody-derived therapeutics targeting cell surface receptors. To maximize the potential of these new technologies, relevant extracellular targets must be identified. The Pediatric Oncology Branch of the NCI curates a freely accessible database of gene expression data for both pediatric cancers and normal tissues, through which we have defined discrete sets of over-expressed transcripts in 12 pediatric cancer subtypes as compared to normal tissues. We coupled gene expression profiles to current annotation databases (i.e., Affymetrix, Gene Ontology, Entrez Gene), in order to categorize transcripts by their sub-cellular location. In this manner we generated a list of potential immune targets expressed on the cell surface, ranked by their difference from normal tissue. Global differences from normal between each of the pediatric tumor types studied varied, indicating that some malignancies expressed transcript sets that were more highly diverged from normal tissues than others. The validity of our approach is seen by our findings for pre-B cell ALL, where targets currently in clinical trials were top-ranked hits (CD19, CD22). For some cancers, reagents already in development could potentially be applied to a new disease class, as exemplified by CD30 expression on sarcomas. Moreover, several potential new targets shared among several pediatric solid tumors are herein identified, such as MCAM (MUC18), metadherin (MTDH), and glypican-2 (GPC2). These targets have been identified at the mRNA level and are yet to be validated at the protein level. The safety of targeting these antigens has yet to be demonstrated and therefore the identified transcripts should be considered preliminary candidates for new CAR and therapeutic antibody targets. Prospective candidate targets will be evaluated by proteomic analysis including Westerns and immunohistochemistry of normal and tumor tissues. PMID:23251904

  6. Global and Targeted Metabolomics of Esophageal Squamous Cell Carcinoma Discovers Potential Diagnostic and Therapeutic Biomarkers*

    PubMed Central

    Xu, Jing; Chen, Yanhua; Zhang, Ruiping; Song, Yongmei; Cao, Jianzhong; Bi, Nan; Wang, Jingbo; He, Jiuming; Bai, Jinfa; Dong, Lijia; Wang, Luhua; Zhan, Qimin; Abliz, Zeper

    2013-01-01

    Diagnostic and therapeutic biomarkers useful for esophageal squamous cell carcinoma (ESCC) have the ability to increase the long term survival of cancer patients. A metabolomics study, using plasma from four groups including ESCC patients before, during, and after chemoradiotherapy (CRT) and healthy controls, was originally carried out by LC-MS to determine global alterations in the metabolic profiles and find biomarkers potentially applicable to diagnosis and monitoring treatment effects. It is worth pointing out that a clear clustering and separation of metabolic data from the four groups was observed, which indicated that disease status and treatment intervention resulted in specific metabolic perturbations in the patients. A series of metabolites were found to be significantly altered in ESCC patients versus healthy controls and in pre- versus post-treatment patients based on multivariate statistical data analysis (MVDA). To further validate the reliability of these potential biomarkers, an independent validation was performed by using the selected reaction monitoring (SRM) based targeted approach. Finally, 18 most significantly altered plasma metabolites in ESCC patients, relative to healthy controls, were tentatively identified as lysophosphatidylcholines (lysoPCs), fatty acids, l-carnitine, acylcarnitines, organic acids, and a sterol metabolite. The classification performance of these metabolites were analyzed by receiver operating characteristic (ROC)1 analysis and a biomarker panel was generated. Together, biological significance of these metabolites was discussed. Comparison between pre- and post-treatment patients generated 11 metabolites as potential therapeutic biomarkers that were tentatively identified as amino acids, acylcarnitines, and lysoPCs. Levels of three of these (octanoylcarnitine, lysoPC(16:1), and decanoylcarnitine) were closely correlated with treatment effect. Moreover, variation of these three potential biomarkers was investigated over

  7. Targets of drugs are generally, and targets of drugs having side effects are specifically good spreaders of human interactome perturbations

    PubMed Central

    Perez-Lopez, Áron R.; Szalay, Kristóf Z.; Türei, Dénes; Módos, Dezső; Lenti, Katalin; Korcsmáros, Tamás; Csermely, Peter

    2015-01-01

    Network-based methods are playing an increasingly important role in drug design. Our main question in this paper was whether the efficiency of drug target proteins to spread perturbations in the human interactome is larger if the binding drugs have side effects, as compared to those which have no reported side effects. Our results showed that in general, drug targets were better spreaders of perturbations than non-target proteins, and in particular, targets of drugs with side effects were also better spreaders of perturbations than targets of drugs having no reported side effects in human protein-protein interaction networks. Colorectal cancer-related proteins were good spreaders and had a high centrality, while type 2 diabetes-related proteins showed an average spreading efficiency and had an average centrality in the human interactome. Moreover, the interactome-distance between drug targets and disease-related proteins was higher in diabetes than in colorectal cancer. Our results may help a better understanding of the network position and dynamics of drug targets and disease-related proteins, and may contribute to develop additional, network-based tests to increase the potential safety of drug candidates. PMID:25960144

  8. Targets of drugs are generally, and targets of drugs having side effects are specifically good spreaders of human interactome perturbations

    NASA Astrophysics Data System (ADS)

    Perez-Lopez, Áron R.; Szalay, Kristóf Z.; Türei, Dénes; Módos, Dezső; Lenti, Katalin; Korcsmáros, Tamás; Csermely, Peter

    2015-05-01

    Network-based methods are playing an increasingly important role in drug design. Our main question in this paper was whether the efficiency of drug target proteins to spread perturbations in the human interactome is larger if the binding drugs have side effects, as compared to those which have no reported side effects. Our results showed that in general, drug targets were better spreaders of perturbations than non-target proteins, and in particular, targets of drugs with side effects were also better spreaders of perturbations than targets of drugs having no reported side effects in human protein-protein interaction networks. Colorectal cancer-related proteins were good spreaders and had a high centrality, while type 2 diabetes-related proteins showed an average spreading efficiency and had an average centrality in the human interactome. Moreover, the interactome-distance between drug targets and disease-related proteins was higher in diabetes than in colorectal cancer. Our results may help a better understanding of the network position and dynamics of drug targets and disease-related proteins, and may contribute to develop additional, network-based tests to increase the potential safety of drug candidates.

  9. A critical evaluation of adenosine A2A receptors as potentially "druggable" targets in Huntington's disease.

    PubMed

    Popoli, Patrizia; Blum, David; Domenici, Maria Rosaria; Burnouf, Sylvie; Chern, Yijuang

    2008-01-01

    Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by the expansion of a polymorphic CAG trinucleotide repeat encoding a poly-glutamine tract within the Huntingtin protein. GABAergic enkephalin neurons of the basal ganglia, which show the highest levels of expression of adenosine A(2A) receptors, are the most vulnerable in HD. Such a selective neuronal vulnerability, which occurs despite ubiquitous expression of mutant and normal Huntingtin, has suggested that adenosine A(2A) receptors might play a pathogenetic role in HD. In agreement, changes in A(2A) receptor expression and signaling have been reported in various experimental models of HD. The interpretation of the functional significance of the aberrant A(2A) receptor phenotype in HD mice is however complicated by the conflicting data so far reported on the potential neuroprotective and neurodegenerative effects of these receptors in the brain, with some data suggesting a potential pathogenetic role and some other data suggesting activation of trophic or protective pathways in neurons. The same complex profile has emerged in experimental models of HD, in which both A(2A) receptor agonists and antagonists have shown beneficial effects. The main aim of this review is to critically evaluate whether adenosine A(2A) receptors may represent a suitable target to develop drugs against HD.

  10. Enantioselective Effects of Chiral Pesticides on their Primary Targets and Secondary Targets.

    PubMed

    Yang, Ye; Zhang, Jianyun; Yao, Yijun

    2017-01-01

    Enantioselectivity has been well recognized in the environmental fate and effects of chiral pesticides. Enantiospecific action of the optical enantiomers on the biological molecules establishes the mechanistic basis for the enantioselective toxicity of chiral pesticides to both target and non-target organisms. We undertook a structured search of bibliographic databases for research literature concerning the enantioselective effects of chiral pesticides, including insecticides, herbicides and fungicides, on biomolecules in various species by using some key words. The results of the relevant literatures were reviewed in the text and summarized in tables. Pesticides generally exert their activity on the target organisms via disrupting the primary target biomolecules. In non-target species, effects of pesticides on the secondary targets distinguished from the primary ones make great contribution to their toxicity. Recent investigations have provided convincing evidence of enantioselective toxicity of chiral pesticides to both target and non-target species which is recognized to result from their enantiospecific action on the primary or secondary targets in organisms. This review confirms that chiral pesticides have enantiospecific effects on both primary and secondary target biomolecules in organisms. Future studies regarding toxicological effects of chiral pesticides should focus on the relationship between the enantiomeric difference in the compound-biomolecules interaction and the enantioselectivity in their toxicity.

  11. USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy

    PubMed Central

    2013-01-01

    Reversible protein ubiquitination is emerging as a key process for maintaining cell homeostasis, and the enzymes that participate in this process, in particular E3 ubiquitin ligases and deubiquitinases (DUBs), are increasingly being regarded as candidates for drug discovery. Human DUBs are a group of approximately 100 proteins, whose cellular functions and regulatory mechanisms remain, with some exceptions, poorly characterized. One of the best-characterized human DUBs is ubiquitin-specific protease 1 (USP1), which plays an important role in the cellular response to DNA damage. USP1 levels, localization and activity are modulated through several mechanisms, including protein-protein interactions, autocleavage/degradation and phosphorylation, ensuring that USP1 function is carried out in a properly regulated spatio-temporal manner. Importantly, USP1 expression is deregulated in certain types of human cancer, suggesting that USP1 could represent a valid target in cancer therapy. This view has gained recent support with the finding that USP1 inhibition may contribute to revert cisplatin resistance in an in vitro model of non-small cell lung cancer (NSCLC). Here, we describe the current knowledge on the cellular functions and regulatory mechanisms of USP1. We also summarize USP1 alterations found in cancer, combining data from the literature and public databases with our own data. Finally, we discuss the emerging potential of USP1 as a target, integrating published data with our novel findings on the effects of the USP1 inhibitor pimozide in combination with cisplatin in NSCLC cells. PMID:23937906

  12. Anaplastic thyroid cancer: outcome and the mutation/expression profiles of potential targets.

    PubMed

    Wu, Hao; Sun, Yue; Ye, Huihui; Yang, Shi; Lee, Stephanie L; de las Morenas, Antonio

    2015-07-01

    Anaplastic thyroid cancer (ATC) is a rare but aggressive malignancy of the thyroid. No effective treatment modalities are currently available. Targeted therapy against protein kinases showed promising results in preclinical studies. Our goal was to assess the mutational status of potential therapeutic targets, as well as the biomarker for immunotherapy in the clinical context. Using allele specific PCR, Sanger sequencing, fragment analysis and immunohistochemistry, we assessed BRAF, KRAS, EGFR mutations and protein overexpression of C-KIT and PDL1 in anaplastic thyroid cancer specimens. Results were compared to clinical information and patient outcome to assess the utility of these biomarkers. There were 13 patients in our study with a median overall survival of 19 weeks. Of the 13 ATC patients, 3 (23 %) had BRAF V600E mutation. C-KIT overexpression was found in 1 (8 %) patient who responded well to a tyrosine kinase inhibitor. PDL1 expression was seen in 3 (23 %) patients, none of them were surgical candidates due to unresectability and poor performance status. KRAS codon 12/13 and EGFR exon 18, 19, 20 and 21 were all wild type in our patients. Protein kinase inhibitors and immunotherapy may be useful adjuvant therapies for ATC.

  13. Integrated network analysis reveals potentially novel molecular mechanisms and therapeutic targets of refractory epilepsies

    PubMed Central

    Liu, Guangming; Wang, Yiwei; Zhao, Pengyao; Zhu, Yizhun; Yang, Xiaohan; Zheng, Tiezheng; Zhou, Xuezhong; Jin, Weilin; Sun, Changkai

    2017-01-01

    Epilepsy is a complex neurological disorder and a significant health problem. The pathogenesis of epilepsy remains obscure in a significant number of patients and the current treatment options are not adequate in about a third of individuals which were known as refractory epilepsies (RE). Network medicine provides an effective approach for studying the molecular mechanisms underlying complex diseases. Here we integrated 1876 disease-gene associations of RE and located those genes to human protein-protein interaction (PPI) network to obtain 42 significant RE-associated disease modules. The functional analysis of these disease modules showed novel molecular pathological mechanisms of RE, such as the novel enriched pathways (e.g., “presynaptic nicotinic acetylcholine receptors”, “signaling by insulin receptor”). Further analysis on the relationships between current drug targets and the RE-related disease genes showed the rational mechanisms of most antiepileptic drugs. In addition, we detected ten potential novel drug targets (e.g., KCNA1, KCNA4-6, KCNC3, KCND2, KCNMA1, CAMK2G, CACNB4 and GRM1) located in three RE related disease modules, which might provide novel insights into the new drug discovery for RE therapy. PMID:28388656

  14. The sweet trap in tumors: aerobic glycolysis and potential targets for therapy

    PubMed Central

    Wang, Liantang; Chen, Shangwu

    2016-01-01

    Metabolic change is one of the hallmarks of tumor, which has recently attracted a great of attention. One of main metabolic characteristics of tumor cells is the high level of glycolysis even in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. The energy production is much less in glycolysis pathway than that in tricarboxylic acid cycle. The molecular mechanism of a high glycolytic flux in tumor cells remains unclear. A large amount of intermediates derived from glycolytic pathway could meet the biosynthetic requirements of the proliferating cells. Hypoxia-induced HIF-1α, PI3K-Akt-mTOR signaling pathway, and many other factors, such as oncogene activation and tumor suppressor inactivation, drive cancer cells to favor glycolysis over mitochondrial oxidation. Several small molecules targeting glycolytic pathway exhibit promising anticancer activity both in vitro and in vivo. In this review, we will focus on the latest progress in the regulation of aerobic glycolysis and discuss the potential targets for the tumor therapy. PMID:26918353

  15. Th17 Cells as Potential Probiotic Therapeutic Targets in Inflammatory Bowel Diseases.

    PubMed

    Owaga, Eddy; Hsieh, Rong-Hong; Mugendi, Beatrice; Masuku, Sakhile; Shih, Chun-Kuang; Chang, Jung-Su

    2015-09-01

    Inflammatory bowel diseases (IBD) are characterized by wasting and chronic intestinal inflammation triggered by various cytokine-mediated pathways. In recent years, it was shown that T helper 17 (Th17) cells are involved in the pathogenesis of IBD, which makes them an attractive therapeutic target. Th17 cells preferentially produce interleukin (IL)-17A-F as signature cytokines. The role of the interplay between host genetics and intestinal microbiota in the pathogenesis of IBD was demonstrated. Probiotics are live microorganisms that when orally ingested in adequate amounts, confer a health benefit to the host by modulating the enteric flora or by stimulating the local immune system. Several studies indicated the effectiveness of probiotics in preventing and treating IBD (ulcerative colitis, and Crohn's disease). Furthermore, there is mounting evidence of probiotics selectively targeting the Th17 lineage in the prevention and management of inflammatory and autoimmune diseases such as IBD. This review highlights critical roles of Th17 cells in the pathogenesis of IBD and the rationale for using probiotics as a novel therapeutic approach for IBD through manipulation of Th17 cells. The potential molecular mechanisms by which probiotics modulate Th17 cells differentiation and production are also discussed.

  16. Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast

    PubMed Central

    Gatalica, Zoran; Vranic, Semir; Ghazalpour, Anatole; Xiu, Joanne; Ocal, Idris Tolgay; McGill, John; Bender, Ryan P.; Discianno, Erin; Schlum, Aaron; Sanati, Souzan; Palazzo, Juan; Reddy, Sandeep; Pockaj, Barbara

    2016-01-01

    Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast. PMID:26625196

  17. Multiplatform molecular profiling identifies potentially targetable biomarkers in malignant phyllodes tumors of the breast.

    PubMed

    Gatalica, Zoran; Vranic, Semir; Ghazalpour, Anatole; Xiu, Joanne; Ocal, Idris Tolgay; McGill, John; Bender, Ryan P; Discianno, Erin; Schlum, Aaron; Sanati, Souzan; Palazzo, Juan; Reddy, Sandeep; Pockaj, Barbara

    2016-01-12

    Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast.

  18. Carbonic anhydrase IX correlates with survival and is a potential therapeutic target for neuroblastoma.

    PubMed

    Ameis, Helen M; Drenckhan, Astrid; Freytag, Morton; Izbicki, Jakob R; Supuran, Claudiu T; Reinshagen, Konrad; Holland-Cunz, Stefan; Gros, Stephanie J

    2016-01-01

    Carbonic anhydrase IX (CAIX) is involved in pathological processes including tumorgenicity, metastases and poor survival in solid tumors. Twenty-two neuroblastoma samples of patients who were surgically treated at the University Medical Center Hamburg-Eppendorf were evaluated immunohistochemically for expression of CAIX. Results were correlated with clinical parameters and outcome. Neuroblastoma Kelly and SH-EP-Tet-21/N cells were examined for CAIX expression and inhibited with specific inhibitors, FC5-207A and FC8-325A. 32% of neuroblastoma tumors expressed CAIX. This was significantly associated with poorer survival. Kelly and SH-EP-Tet-21/N cells showed a major increase of CAIX RNA under hypoxic conditions. Proliferation of Kelly cells was significantly decreased by CAIX inhibitors, FC5-207A and FC8-325A, while proliferation of SH-EP-Tet-21/N cells was only significantly affected by FC8-325A. CAIX is a potent biomarker that predicts survival in neuroblastoma patients. CAIX-targeted therapy in neuroblastoma cell lines is highly effective and strengthens the potential of CAIX as a clinical therapeutic target in a selected patient collective.

  19. MCT4 as a potential therapeutic target for metastatic gastric cancer with peritoneal carcinomatosis

    PubMed Central

    Chang, Won Jin; Ahn, Su Min; Lim, Sung Hee; Kim, Hae Su; Yoo, Kwai Han; Jung, Ki Sun; Song, Haa-Na; Cho, Jin Hyun; Kim, Sun Young; Kim, Kyoung-Mee; Lee, Soojin; Kim, Seung Tae; Park, Se Hoon; Lee, Jeeyun; Park, Joon Oh; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki

    2016-01-01

    Monocarboxylate transporters (MCTs) play a major role in up-regulation of glycolysis and adaptation to acidosis. However, the role of MCTs in gastric cancer (GC) is not fully understood. We investigated the potential utilization of a new cancer therapy for GC. We characterized the expression patterns of the MCT isoforms 1, 2, and 4 and investigated the role of MCT in GC through in vitro and in vivo tests using siRNA targeting MCTs. In GC cell lines, MCT1, 2, and 4 were up-regulated with different expression levels; MCT1 and MCT4 were more widely expressed in GC cell lines compared with MCT2. Inhibition of MCTs by siRNA or AR-C155858 reduced cell viability and lactate uptake in GC cell lines. The effect of inhibition of MCTs on tumor growth was also confirmed in xenograft models. Furthermore, MCT inhibition in GC cells increased the sensitivity of cells to radiotherapy or chemotherapy. Compared with normal gastric tissue, no significant alterations of expression levels in tumors were identified for MCT1 and MCT2, whereas a significant increase in MCT4 expression was observed. Most importantly, MCT4 was highly overexpressed in malignant cells of acsites and its silencing resulted in reduced tumor cell proliferation and lactate uptake in malignant ascites. Our study suggests that MCT4 is a clinically relevant target in GC with peritoneal carcinomatosis. PMID:27224918

  20. Radioprotective effect of transferrin targeted citicoline liposomes.

    PubMed

    Suresh Reddy, Jannapally; Venkateswarlu, Vobalaboina; Koning, Gerben A

    2006-01-01

    The high level of expression of transferrin receptors (Tf-R) on the surface of endothelial cells of the blood-brain-barrier (BBB) had been widely utilized to deliver drugs to the brain. The primary aim of this study was to use transferrin receptor mediated endocytosis as a pathway for the rational development of holo-transferrin coupled liposomes for drug targeting to the brain. Citicoline is a neuroprotective agent used clinically to treat for instance Parkinson disease, stroke, Alzheimer's disease and brain ischemia. Citicoline does not readily cross the BBB because of its strong polar nature. Hence, citicoline was used as a model drug. (Citicoline liposomes have been prepared using dipalmitoylphosphatidylcholine (DPPC) or distearoylphosphatidylcholine (DSPC) by dry lipid film hydration-extrusion method). The effect of the use of liposomes composed of DPPC or DSPC on their citicoline encapsulation efficiency and their stability in vitro were studied. Transferrin was coupled to liposomes by a technique which involves the prevention of scavenging diferric iron atoms of transferrin. The coupling efficiency of transferrin to the liposomes was studied. In vitro evaluation of transferrin-coupled liposomes was performed for their radioprotective effect in radiation treated cell cultures. In this study, OVCAR-3 cells were used as a model cell type over-expressing the Tf-R and human umbilical vein endothelial cells (HUVEC) as BBB endothelial cell model. The average diameter of DPPC and DSPC liposomes were 138 +/- 6.3 and 79.0 +/- 3.2 nm, respectively. The citicoline encapsulation capacity of DPPC and DSPC liposomes was 81.8 +/- 12.8 and 54.9 +/- 0.04 microg/micromol of phospholipid, respectively. Liposomes prepared from DSPC showed relatively better stability than DPPC liposomes at 37 degrees C and in the presence of serum. Hence, DSPC liposomes were used for transferrin coupling and an average of 46-55 molecules of transferrin were present per liposome. Free citicoline

  1. Controlled and in situ target strengths of the jumbo squid Dosidicus gigas and identification of potential acoustic scattering sources.

    PubMed

    Benoit-Bird, Kelly J; Gilly, William F; Au, Whitlow W L; Mate, Bruce

    2008-03-01

    This study presents the first target strength measurements of Dosidicus gigas, a large squid that is a key predator, a significant prey, and the target of an important fishery. Target strength of live, tethered squid was related to mantle length with values standardized to the length squared of -62.0, -67.4, -67.9, and -67.6 dB at 38, 70, 120, and 200 kHz, respectively. There were relatively small differences in target strength between dorsal and anterior aspects and none between live and freshly dead squid. Potential scattering mechanisms in squid have been long debated. Here, the reproductive organs had little effect on squid target strength. These data support the hypothesis that the pen may be an important source of squid acoustic scattering. The beak, eyes, and arms, probably via the sucker rings, also play a role in acoustic scattering though their effects were small and frequency specific. An unexpected source of scattering was the cranium of the squid which provided a target strength nearly as high as that of the entire squid though the mechanism remains unclear. Our in situ measurements of the target strength of free-swimming squid support the use of the values presented here in D. gigas assessment studies.

  2. Nuclease Target Site Selection for Maximizing On-target Activity and Minimizing Off-target Effects in Genome Editing

    PubMed Central

    Lee, Ciaran M; Cradick, Thomas J; Fine, Eli J; Bao, Gang

    2016-01-01

    The rapid advancement in targeted genome editing using engineered nucleases such as ZFNs, TALENs, and CRISPR/Cas9 systems has resulted in a suite of powerful methods that allows researchers to target any genomic locus of interest. A complementary set of design tools has been developed to aid researchers with nuclease design, target site selection, and experimental validation. Here, we review the various tools available for target selection in designing engineered nucleases, and for quantifying nuclease activity and specificity, including web-based search tools and experimental methods. We also elucidate challenges in target selection, especially in predicting off-target effects, and discuss future directions in precision genome editing and its applications. PMID:26750397

  3. Potential Ergogenic Effects of Saffron.

    PubMed

    Meamarbashi, Abbas; Rajabi, Ali

    2016-01-01

    Crocus sativus, commonly known as saffron, is a rich source of carotenoids with many health benefits. The muscular strength, pulmonary function, and reaction time are vital to the athlete's performance, and this study aimed to investigate an ergogenic effect of saffron. Twenty-eight nonactive and healthy male university students were randomly assigned into the saffron (n = 14) and control (n = 15) groups. The experimental group received dried saffron stigma (300 mg/day for 10 days) and the control group received a placebo. After one session, familiarization with the tests, anthropometric parameters, visual and audio reaction times, and the maximum isometric and isotonic forces on a leg press machine were measured accordingly, 1 day before and after the supplementation period. This study shows that 10 days of supplementation with saffron significantly increased (10.1%) the isometric force (p < .0001; effect size (EF) = 0.432) and increased 6.1% the isotonic force (p < .0001; effect size = 0.662), as well as effecting faster visual (p < .05; EF = 0.217) and audio (p < .05; EF = 0.214) reaction times. The ergogenic effect of saffron (increase in the forces) may contribute to increase in the muscle mitochondrial biogenesis and positive effect on the motor cortex, both of which may explain faster audio and visual reaction times. Saffron supplementation was also possibly responsible for improvement of muscle blood perfusion and facilitation in the oxygen transport.

  4. Therapeutic potentialities of EWS-Fli-1 mRNA-targeted vectorized antisense oligonucleotides.

    PubMed

    Maksimenko, A; Lambert, G; Bertrand, J R; Fattal, E; Couvreur, P; Malvy, C

    2003-12-01

    We have used structured antisense oligonucleotides (AON), which are protected against extra and intracellular degradation by their internal structure. We have shown that if correctly designed this structure does not prevent them from hybridizing to the mRNA target. This concept allows reducing the number of thioate groups in the oligonucleotide and therefore the potential toxicity. Junction oncogenes are found in cancers such as certain leukemias, Ewing sarcoma, and thyroid papillary carcinomas. Ewing sarcoma is a cancer of children and young adults with bone metastasis. It is caused by a chromosomic translocation t(11;22) (q24;q12) creating a fusion gene between the genes EWS and Fli-1 giving rise to a chimeric protein which is an unnatural transcription factor. Immortalized NIH/3T3 cells transfected by the EWS-Fli-1 cDNA under the control of the LTR retroviral promoter--which do not undergo apoptosis and which became tumoral--were used for this study. As a model of Ewing sarcoma in nude mice, we have used permanently expressing human EWS-Fli-1 cells grafted to nude mice. The nanospheres or nanocapsules have been used to deliver two different AON: a phosphorothioate, and a structured chimeric AON, both targeted toward the junction area of EWS-Fli-1. Both types of AON-loaded nanoparticles inhibited the growth of the xenografted tumor after intratumoral injections into nude mice, whereas similar nanoparticles with control oligonucleotides had no effect. With AON in nanospheres, we have shown after 24 hours that the mRNA of EWS-Fli-1 was specifically down-regulated, confirming the antisense activity of the targeted AON.

  5. Glycogen synthase kinase 3 is a potential drug target for African trypanosomiasis therapy.

    PubMed

    Ojo, Kayode K; Gillespie, J Robert; Riechers, Aaron J; Napuli, Alberto J; Verlinde, Christophe L M J; Buckner, Frederick S; Gelb, Michael H; Domostoj, Mathias M; Wells, Susan J; Scheer, Alexander; Wells, Timothy N C; Van Voorhis, Wesley C

    2008-10-01

    Development of a safe, effective, and inexpensive therapy for African trypanosomiasis is an urgent priority. In this study, we evaluated the validity of Trypanosoma brucei glycogen synthase kinase 3 (GSK-3) as a potential drug target. Interference with the RNA of either of two GSK-3 homologues in bloodstream-form T. brucei parasites led to growth arrest and altered parasite morphology, demonstrating their requirement for cell survival. Since the growth arrest after RNA interference appeared to be more profound for T. brucei GSK-3 "short" (Tb10.161.3140) than for T. brucei GSK-3 "long" (Tb927.7.2420), we focused on T. brucei GSK-3 short for further studies. T. brucei GSK-3 short with an N-terminal maltose-binding protein fusion was cloned, expressed, and purified in a functional form. The potency of a GSK-3-focused inhibitor library against the recombinant enzyme of T. brucei GSK-3 short, as well as bloodstream-form parasites, was evaluated with the aim of determining if compounds that inhibit enzyme activity could also block the parasites' growth and proliferation. Among the compounds active against the cell, there was an excellent correlation between activity inhibiting the T. brucei GSK-3 short enzyme and the inhibition of T. brucei growth. Thus, there is reasonable genetic and chemical validation of GSK-3 short as a drug target for T. brucei. Finally, selective inhibition may be required for therapy targeting the GSK-3 enzyme, and a molecular model of the T. brucei GSK-3 short enzyme suggests that compounds that selectively inhibit T. brucei GSK-3 short over the human GSK-3 enzymes can be found.

  6. Effective pair potentials for spherical nanoparticles

    NASA Astrophysics Data System (ADS)

    van Zon, Ramses

    2009-02-01

    An effective description for rigid spherical nanoparticles in a fluid of point particles is presented. The points inside the nanoparticles and the point particles are assumed to interact via spherically symmetric additive pair potentials, while the distribution of points inside the nanoparticles is taken to be spherically symmetric and smooth. The resulting effective pair interactions between a nanoparticle and a point particle, as well as between two nanoparticles, are then given by spherically symmetric potentials. If overlap between particles is allowed, as can occur for some forms of the pair potentials, the effective potential generally has non-analytic points. It is shown that for each effective potential the expressions for different overlapping cases can be written in terms of one analytic auxiliary potential. Even when only non-overlapping situations are possible, the auxiliary potentials facilitate the formulation of the effective potentials. Effective potentials for hollow nanoparticles (appropriate e.g. for buckyballs) are also considered and shown to be related to those for solid nanoparticles. For hollow nanoparticles overlap is more physical, since this covers the case of a smaller particle embedded in a larger, hollow nanoparticle. Finally, explicit expressions are given for the effective potentials derived from basic pair potentials of power law and exponential form, as well as from the commonly used London-van der Waals, Morse, Buckingham, and Lennard-Jones potentials. The applicability of the latter is demonstrated by comparison with an atomic description of nanoparticles with an internal face centered cubic structure.

  7. Identification of potential target genes of ROR-alpha in THP1 and HUVEC cell lines.

    PubMed

    Gulec, Cagri; Coban, Neslihan; Ozsait-Selcuk, Bilge; Sirma-Ekmekci, Sema; Yildirim, Ozlem; Erginel-Unaltuna, Nihan

    2017-04-01

    ROR-alpha is a nuclear receptor, activity of which can be modulated by natural or synthetic ligands. Due to its possible involvement in, and potential therapeutic target for atherosclerosis, we aimed to identify ROR-alpha target genes in monocytic and endothelial cell lines. We performed chromatin immunoprecipitation (ChIP) followed by tiling array (ChIP-on-chip) for ROR-alpha in monocytic cell line THP1 and endothelial cell line HUVEC. Following bioinformatic analysis of the array data, we tested four candidate genes in terms of dependence of their expression level on ligand-mediated ROR-alpha activity, and two of them in terms of promoter occupancy by ROR-alpha. Bioinformatic analyses of ChIP-on-chip data suggested that ROR-alpha binds to genomic regions near the transcription start site (TSS) of more than 3000 genes in THP1 and HUVEC. Potential ROR-alpha target genes in both cell types seem to be involved mainly in membrane receptor activity, signal transduction and ion transport. While SPP1 and IKBKA were shown to be direct target genes of ROR-alpha in THP1 monocytes, inflammation related gene HMOX1 and heat shock protein gene HSPA8 were shown to be potential target genes of ROR-alpha. Our results suggest that ROR-alpha may regulate signaling receptor activity, and transmembrane transport activity through its potential target genes. ROR-alpha seems also to play role in cellular sensitivity to environmental substances like arsenite and chloroprene. Although, the expression analyses have shown that synthetic ROR-alpha ligands can modulate some of potential ROR-alpha target genes, functional significance of ligand-dependent modulation of gene expression needs to be confirmed with further analyses. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Specific Targeting of Caspase-9/PP2A Interaction as Potential New Anti-Cancer Therapy

    PubMed Central

    Arrouss, Issam; Nemati, Fariba; Roncal, Fernando; Wislez, Marie; Dorgham, Karim; Vallerand, David; Rabbe, Nathalie; Karboul, Narjesse; Carlotti, Françoise; Bravo, Jeronimo; Mazier, Dominique

    2013-01-01

    Purpose PP2A is a serine/threonine phosphatase critical to physiological processes, including apoptosis. Cell penetrating peptides are molecules that can translocate into cells without causing membrane damage. Our goal was to develop cell-penetrating fusion peptides specifically designed to disrupt the caspase-9/PP2A interaction and evaluate their therapeutic potential in vitro and in vivo. Experimental Design We generated a peptide containing a penetrating sequence associated to the interaction motif between human caspase-9 and PP2A (DPT-C9h), in order to target their association. Using tumour cell lines, primary human cells and primary human breast cancer (BC) xenografts, we investigated the capacity of DPT-C9h to provoke apoptosis in vitro and inhibition of tumour growth (TGI) in vivo. DPT-C9h was intraperitonealy administered at doses from 1 to 25 mg/kg/day for 5 weeks. Relative Tumour Volume (RTV) was calculated. Results We demonstrated that DPT-C9h specifically target caspase-9/PP2A interaction in vitro and in vivo and induced caspase-9-dependent apoptosis in cancer cell lines. DPT-C9h also induced significant TGI in BC xenografts models. The mouse-specific peptide DPT-C9 also induced TGI in lung (K-Ras model) and breast cancer (PyMT) models. DPT-C9h has a specific effect on transformed B cells isolated from chronic lymphocytic leukemia patients without any effect on primary healthy cells. Finally, neither toxicity nor immunogenic responses were observed. Conclusion Using the cell-penetrating peptides blocking caspase-9/PP2A interactions, we have demonstrated that DPT-C9h had a strong therapeutic effect in vitro and in vivo in mouse models of tumour progression. PMID:23637769

  9. ACTP: A webserver for predicting potential targets and relevant pathways of autophagy-modulating compounds

    PubMed Central

    Ouyang, Liang; Cai, Haoyang; Liu, Bo

    2016-01-01

    Autophagy (macroautophagy) is well known as an evolutionarily conserved lysosomal degradation process for long-lived proteins and damaged organelles. Recently, accumulating evidence has revealed a series of small-molecule compounds that may activate or inhibit autophagy for therapeutic potential on human diseases. However, targeting autophagy for drug discovery still remains in its infancy. In this study, we developed a webserver called Autophagic Compound-Target Prediction (ACTP) (http://actp.liu-lab.com/) that could predict autophagic targets and relevant pathways for a given compound. The flexible docking of submitted small-molecule compound (s) to potential autophagic targets could be performed by backend reverse docking. The webpage would return structure-based scores and relevant pathways for each predicted target. Thus, these results provide a basis for the rapid prediction of potential targets/pathways of possible autophagy-activating or autophagy-inhibiting compounds without labor-intensive experiments. Moreover, ACTP will be helpful to shed light on identifying more novel autophagy-activating or autophagy-inhibiting compounds for future therapeutic implications. PMID:26824420

  10. Potential Diagnostic, Prognostic and Therapeutic Targets of MicroRNAs in Human Gastric Cancer

    PubMed Central

    Tsai, Ming-Ming; Wang, Chia-Siu; Tsai, Chung-Ying; Huang, Hsiang-Wei; Chi, Hsiang-Cheng; Lin, Yang-Hsiang; Lu, Pei-Hsuan; Lin, Kwang-Huei

    2016-01-01

    Human gastric cancer (GC) is characterized by a high incidence and mortality rate, largely because it is normally not identified until a relatively advanced stage owing to a lack of early diagnostic biomarkers. Gastroscopy with biopsy is the routine method for screening, and gastrectomy is the major therapeutic strategy for GC. However, in more than 30% of GC surgical patients, cancer has progressed too far for effective medical resection. Thus, useful biomarkers for early screening or detection of GC are essential for improving patients’ survival rate. MicroRNAs (miRNAs) play an important role in tumorigenesis. They contribute to gastric carcinogenesis by altering the expression of oncogenes and tumor suppressors. Because of their stability in tissues, serum/plasma and other body fluids, miRNAs have been suggested as novel tumor biomarkers with suitable clinical potential. Recently, aberrantly expressed miRNAs have been identified and tested for clinical application in the management of GC. Aberrant miRNA expression profiles determined with miRNA microarrays, quantitative reverse transcription-polymerase chain reaction and next-generation sequencing approaches could be used to establish sample specificity and to identify tumor type. Here, we provide an up-to-date summary of tissue-based GC-associated miRNAs, describing their involvement and that of their downstream targets in tumorigenic and biological processes. We examine correlations among significant clinical parameters and prognostic indicators, and discuss recurrence monitoring and therapeutic options in GC. We also review plasma/serum-based, GC-associated, circulating miRNAs and their clinical applications, focusing especially on early diagnosis. By providing insights into the mechanisms of miRNA-related tumor progression, this review will hopefully aid in the identification of novel potential therapeutic targets. PMID:27322246

  11. PLP-dependent enzymes as potential drug targets for protozoan diseases.

    PubMed

    Kappes, Barbara; Tews, Ivo; Binter, Alexandra; Macheroux, Peter

    2011-11-01

    The chemical properties of the B(6) vitamers are uniquely suited for wide use as cofactors in essential reactions, such as decarboxylations and transaminations. This review addresses current efforts to explore vitamin B(6) dependent enzymatic reactions as drug targets. Several current targets are described that are found amongst these enzymes. The focus is set on diseases caused by protozoan parasites. Comparison across a range of these organisms allows insight into the distribution of potential targets, many of which may be of interest in the development of broad range anti-protozoan drugs. This article is part of a Special Issue entitled: Pyridoxal Phosphate Enzymology.

  12. Targeting drug sensitivity predictors: New potential strategies to improve pharmacotherapy of human brain disorders.

    PubMed

    Kalueff, Allan V; Stewart, Adam Michael; Nguyen, Michael; Song, Cai; Gottesman, Irving I

    2015-12-03

    One of the main challenges in medicine is the lack of efficient drug therapies for common human disorders. For example, although depressed patients receive powerful antidepressants, many often remain resistant to psychopharmacotherapy. The growing recognition of complex interplay between the drug targets and the predictors of drug sensitivity requires an improved understanding of these two key aspects of drug action and their potentially shared molecular networks. Here, we apply the concept of endophenotypes and their interplay to drug action and sensitivity. Based on these analyses, we postulate that novel drugs may be developed by targeting specific molecular pathways that integrate drug targets with drug sensitivity predictors.

  13. Identification of multi-targeted anti-migraine potential of nystatin and development of its brain targeted chitosan nanoformulation.

    PubMed

    Girotra, Priti; Thakur, Aman; Kumar, Ajay; Singh, Shailendra Kumar

    2017-03-01

    The complex pathophysiology involved in migraine necessitates the drug treatment to act on several receptors simultaneously. The present investigation was an attempt to discover the unidentified anti-migraine activity of the already marketed drugs. Shared featured pharmacophore modeling was employed for this purpose on six target receptors (β2 adrenoceptor, Dopamine D3, 5HT1B, TRPV1, iGluR5 kainate and CGRP), resulting in the generation of five shared featured pharmacophores, which were further subjected to virtual screening of the ligands obtained from Drugbank database. Molecular docking, performed on the obtained hit compounds from virtual screening, indicated nystatin to be the only active lead against the receptors iGluR5 kainate receptor (1VSO), CGRP (3N7R), β2 adrenoceptor (3NYA) and Dopamine D3 (3PBL) with a high binding energy of -11.1, -10.9, -10.2 and -12kcal/mole respectively. The anti-migraine activity of nystatin was then adjudged by fabricating its brain targeted chitosan nanoparticles. Its brain targeting efficacy, analyzed qualitatively by confocal laser scanning microscopy, demonstrated a significant amount of drug reaching the brain. The pharmacodynamic models on Swiss male albino mice revealed significant anti-migraine activity of the nanoformulation. The present study reports for the first time the therapeutic potential of nystatin in migraine management, hence opening avenues for its future exploration.

  14. Cancer targeting potential of some ligand-anchored poly(propylene imine) dendrimers: a comparison.

    PubMed

    Kesharwani, Prashant; Tekade, Rakesh K; Gajbhiye, Virendra; Jain, Keerti; Jain, Narendra K

    2011-06-01

    The present investigation was aimed at developing and comparing the cancer-targeting potential of ligand-anchored dendrimers. Folate-, dextran-, and galactose-anchored poly(propylene imine) dendrimers were synthesized and characterized. Dendritic formulations were evaluated for ex vivo cytotoxicity on HeLa and SiHa cell lines. Flow cytometry studies were performed on the HeLa cell line. An ex vivo MTT assay on HeLa cells indicated IC(50) values of 0.05, 0.2, 0.8, and 0.08 μM for folate, dextran, and galactose formulations, and for free paclitaxel (PTX), respectively. An analogous observation was carried out in SiHa cells, where IC(50) values of 0.6, 0.8, 10, and 6 μM were observed by folate, dextran, and galactose formulations, and free PTX, respectively. The outcome of the MTT assay and flow cytometry suggested the order of targeting potential of various ligands under investigation as folate > dextran > galactose. The outcome is deemed to be of scientific value and is believed to assist drug delivery scientists during selection of targeting ligands. The cancer targeting potential of folate, dextran and galactose functionalized polypropyleneimine (PPI) dendrimers was studied by this group of investigators, reporting the order of targeting potential as folate > dextran > galactose. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. Enhanced antitumor effect of novel dual-targeted paclitaxel liposomes

    NASA Astrophysics Data System (ADS)

    Meng, Shuyan; Su, Bo; Li, Wei; Ding, Yongmei; Tang, Liang; Zhou, Wei; Song, Yin; Li, Heyan; Zhou, Caicun

    2010-10-01

    A novel dual-targeted peptide containing an alpha V integrins specific ligand and a neuropilin-1 specific motif was developed which showed an increased specific targeting affinity to tumors. Active dual-targeted liposomes were then produced with this peptide and exhibited greater binding activity than single-targeted liposomes in vitro. Paclitaxel entrapped in this formulation greatly increased the uptake of paclitaxel in the targeting cells and significantly suppressed the growth of HUVEC and A549 cells compared with general paclitaxel injections (Taxol) and single-targeted paclitaxel liposomes. The treatment of tumor xenograft models with dual-targeted paclitaxel liposomes also resulted in better tumor growth inhibition than any other treatment groups. Therefore, the dual-targeted paclitaxel liposomes prepared in the present study might be a more promising drug for cancer treatment. Furthermore, the dual-targeting approach may produce synergistic effects that can be applied in the development of new targeted drug delivery systems.

  16. Effects-Based Targeting: Another Empty Promise?

    DTIC Science & Technology

    2000-06-01

    actually need these capabilities, it will be too late. As Bertolt Brecht sagely noted, “The house will be built with the bricks that are there... played a significant role. Due to time and space 10 constraints, air operations in the Korean War, Bosnia, and numerous smaller contingencies are not... played a key role in target identification; however, selecting targets was one thing, actually hitting them from the air was something entirely

  17. IGF-binding protein 2 is a candidate target of therapeutic potential in cancer.

    PubMed

    Yao, Xiaofeng; Sun, Shanshan; Zhou, Xuan; Guo, Wenyu; Zhang, Lun

    2016-02-01

    Insulin-like growth factor (IGF)-binding protein 2(IGFBP2), a key member of IGF family, has been reported as a notable oncogene in most human epithelium cancers. Increasing evidences suggested that IGFBP2 might be a candidate target of therapuetic potential by regulating key cancer metastasis and invasion-associated signaling networks, but there is still confusion about the mechanism on how IGFBP2 takes part in these processes. In this review, we summarized the current points of view that IGFBP2 functions in signaling pathways during tumorigenesis and tumor progression and discussed its potential clinical applications as a therapeutic target.

  18. Transient receptor potential channels in sensory neurons are targets of the antimycotic agent clotrimazole.

    PubMed

    Meseguer, Victor; Karashima, Yuji; Talavera, Karel; D'Hoedt, Dieter; Donovan-Rodríguez, Tansy; Viana, Felix; Nilius, Bernd; Voets, Thomas

    2008-01-16

    Clotrimazole (CLT) is a widely used drug for the topical treatment of yeast infections of skin, vagina, and mouth. Common side effects of topical CLT application include irritation and burning pain of the skin and mucous membranes. Here, we provide evidence that transient receptor potential (TRP) channels in primary sensory neurons underlie these unwanted effects of CLT. We found that clinically relevant CLT concentrations activate heterologously expressed TRPV1 and TRPA1, two TRP channels that act as receptors of irritant chemical and/or thermal stimuli in nociceptive neurons. In line herewith, CLT stimulated a subset of capsaicin-sensitive and mustard oil-sensitive trigeminal neurons, and evoked nocifensive behavior and thermal hypersensitivity with intraplantar injection in mice. Notably, CLT-induced pain behavior was suppressed by the TRPV1-antagonist BCTC [(N-(-4-tertiarybutylphenyl)-4-(3-cholorpyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide)] and absent in TRPV1-deficient mice. In addition, CLT inhibited the cold and menthol receptor TRPM8, and blocked menthol-induced responses in capsaicin- and mustard oil-insensitive trigeminal neurons. The concentration for 50% inhibition (IC50) of inward TRPM8 current was approximately 200 nM, making CLT the most potent known TRPM8 antagonist and a useful tool to discriminate between TRPM8- and TRPA1-mediated responses. Together, our results identify TRP channels in sensory neurons as molecular targets of CLT, and offer means to develop novel CLT preparations with fewer unwanted sensory side effects.

  19. Molecular targets and anticancer potential of sanguinarine-a benzophenanthridine alkaloid.

    PubMed

    Galadari, Sehamuddin; Rahman, Anees; Pallichankandy, Siraj; Thayyullathil, Faisal

    2017-10-15

    Cancer is an enormous global health burden, and should be effectively addressed with better therapeutic strategies. Currently, over 60% of the clinically approved anticancer agents are either directly isolated from natural sources or are modified from natural lead molecules. Sanguinarine (SNG), a quaternary benzophenanthridine alkaloid has gained increasing attention in recent years as a potential anticancer agent. There is a large untapped source of phytochemical-based anticancer agents remaining to be explored. This review article aims to recapitulate different anticancer properties of SNG, and describes some of the molecular targets involved in exerting its effect. It also depicts the pharmacokinetic and toxicological properties of SNG, two parameters important in determining the druggability of a molecule. Numerous in vivo and in vitro published studies have signified the anticancer properties of SNG. In order to collate and decipher these properties, an extensive literature search was conducted in PubMed, ScienceDirect, and Scopus using keywords followed by the evaluation of the relevant articles where the relevant reports are integrated and analyzed. Apart from inducing cell death, SNG inhibits pro-tumorigenic processes such as invasion, angiogenesis, and metastasis in different cancers. Moreover, SNG has been shown to synergistically enhance the sensitivity of several chemotherapeutic agents and is effective against a variety of multi-drug resistant cancers. Copyright © 2017 Elsevier GmbH. All rights reserved.

  20. OmpW is a potential target for eliciting protective immunity against Acinetobacter baumannii infections.

    PubMed

    Huang, Weiwei; Wang, Shijie; Yao, Yufeng; Xia, Ye; Yang, Xu; Long, Qiong; Sun, Wenjia; Liu, Cunbao; Li, Yang; Ma, Yanbing

    2015-08-26

    Acinetobacter baumannii (A. baumannii) is an important conditioned pathogen that causes nosocomial and community-associated infections. In this study, we sought to investigate whether outer membrane protein W (OmpW) is a potential target for eliciting protective immunity against A. baumannii infections. Mice immunized with the fusion protein thioredoxin-OmpW generated strong OmpW-specific IgG responses. In a sepsis model, both active and passive immunizations against OmpW effectively protected mice from A. baumannii infections. This protection was demonstrated by a significantly improved survival rate, reduced bacterial burdens within organs, and the suppressed accumulation of inflammatory cytokines and chemokines in sera. Opsonophagocytic assays with murine macrophage RAW264.7 cells indicated that the bactericidal effects of the antisera derived from the immunized mice are mediated synergistically by specific antibodies and complement components. The antisera presented significant opsonophagocytic activities against homologous strains and clonally distinct clinical isolates in vitro. Protein data analysis showed that the sequence of OmpW, which has a molecule length of 183 amino acids, is more than 91% conserved in reported A. baumannii strains. In conclusion, we identified OmpW as a highly immunogenic and conserved protein as a valuable antigen candidate for the development of an effective vaccine or the preparation of antisera to control A. baumannii infections.

  1. Investigating the photosensitizer-potential of targeted gallium corrole using multimode optical imaging

    NASA Astrophysics Data System (ADS)

    Hwang, Jae Youn; Lubow, Jay; Chu, David; Gross, Zeev; Gray, Harry B.; Farkas, Daniel L.; Medina-Kauwe, Lali K.

    2011-02-01

    We recently developed a novel therapeutic particle, HerGa, for breast cancer treatment and detection. HerGa consists of a tumor-targeted cell penetration protein noncovalently assembled with a gallium-metallated corrole. The corrole is structurally similar to porphyrin, emits intense fluorescence, and has proven highly effective for breast tumor treatment preclinically, without light exposure. Here, we tested HerGa as a photosensitizer for photodynamic therapy and investigated its mechanism of action using multimode optical imaging. Using confocal fluorescence imaging, we observed that HerGa disrupts the mitochondrial membrane potential in situ, and this disruption is substantially augmented by light exposure. In addition, spectral and fluorescence lifetime imaging were utilized to both validate the mitochondrial membrane potential disruption and investigate HerGa internalization, allowing us to optimize the timing for light dosimetry. We observed, using advanced multimode optical imaging, that light at a specific wavelength promotes HerGa cytotoxicity, which is likely to cause disruption of mitochondrial function. Thus, we can identify for the first time the capacity of HerGa as a photosensitizer for photodynamic therapy and reveal its mechanism of action, opening possibilities for therapeutic intervention in human breast cancer management.

  2. Inhibition of cancer cell proliferation by midazolam by targeting transient receptor potential melastatin 7.

    PubMed

    Dou, Yunling; Li, Yuan; Chen, Jingkao; Wu, Sihan; Xiao, Xiao; Xie, Shanshan; Tang, Lipeng; Yan, Min; Wang, Youqiong; Lin, Jun; Zhu, Wenbo; Yan, Guangmei

    2013-03-01

    Transient receptor potential melastatin 7 (TRPM7), a Ca(2+)-permeable channel, has been demonstrated to be present in cancer cells and involved in their growth and proliferation. The present study used midazolam, a benzodiazepine class anesthesic, to pharmacologically intervene in the expression of TRPM7 and to inhibit cancer cell proliferation. Midazolam significantly inhibited the growth and proliferation of FaDu human hypopharyngeal squamous cell carcinoma cells, concurring with the induction of G(0)/G(1) cell cycle arrest and blockage of Rb activation. Central-type and peripheral-type benzodiazepine receptor antagonists did not abrogate proliferation inhibition by midazolam, while the specific TRPM7 agonist bradykinin reversed this effect. In addition, other benzodiazepines, diazepam and clonazepam also exhibited anti-proliferative activities. The inhibitory activity on cancer cell growth and proliferation, combined with the TRPM-dependent mechanism, reveals the anticancer potential of midazolam as a TRPM7 inhibitor and supports the suggestion that TRPM7 is a valuable target for pharmaceutical intervention.

  3. The Potential of Vitamin D-Regulated Intracellular Signaling Pathways as Targets for Myeloid Leukemia Therapy

    PubMed Central

    Gocek, Elzbieta; Studzinski, George P.

    2015-01-01

    The current standard regimens for the treatment of acute myeloid leukemia (AML) are curative in less than half of patients; therefore, there is a great need for innovative new approaches to this problem. One approach is to target new treatments to the pathways that are instrumental to cell growth and survival with drugs that are less harmful to normal cells than to neoplastic cells. In this review, we focus on the MAPK family of signaling pathways and those that are known to, or potentially can, interact with MAPKs, such as PI3K/AKT/FOXO and JAK/STAT. We exemplify the recent studies in this field with specific relevance to vitamin D and its derivatives, since they have featured prominently in recent scientific literature as having anti-cancer properties. Since microRNAs also are known to be regulated by activated vitamin D, this is also briefly discussed here, as are the implications of the emerging acquisition of transcriptosome data and potentiation of the biological effects of vitamin D by other compounds. While there are ongoing clinical trials of various compounds that affect signaling pathways, more studies are needed to establish the clinical utility of vitamin D in the treatment of cancer. PMID:26239344

  4. Inhibition of cancer cell proliferation by midazolam by targeting transient receptor potential melastatin 7

    PubMed Central

    DOU, YUNLING; LI, YUAN; CHEN, JINGKAO; WU, SIHAN; XIAO, XIAO; XIE, SHANSHAN; TANG, LIPENG; YAN, MIN; WANG, YOUQIONG; LIN, JUN; ZHU, WENBO; YAN, GUANGMEI

    2013-01-01

    Transient receptor potential melastatin 7 (TRPM7), a Ca2+-permeable channel, has been demonstrated to be present in cancer cells and involved in their growth and proliferation. The present study used midazolam, a benzodiazepine class anesthesic, to pharmacologically intervene in the expression of TRPM7 and to inhibit cancer cell proliferation. Midazolam significantly inhibited the growth and proliferation of FaDu human hypopharyngeal squamous cell carcinoma cells, concurring with the induction of G0/G1 cell cycle arrest and blockage of Rb activation. Central-type and peripheral-type benzodiazepine receptor antagonists did not abrogate proliferation inhibition by midazolam, while the specific TRPM7 agonist bradykinin reversed this effect. In addition, other benzodiazepines, diazepam and clonazepam also exhibited anti-proliferative activities. The inhibitory activity on cancer cell growth and proliferation, combined with the TRPM-dependent mechanism, reveals the anticancer potential of midazolam as a TRPM7 inhibitor and supports the suggestion that TRPM7 is a valuable target for pharmaceutical intervention. PMID:23426784

  5. Identification of potential inhibitors for oncogenic target of dihydroorotate dehydrogenase using in silico approaches

    NASA Astrophysics Data System (ADS)

    Surekha, Kanagarajan; Nachiappan, Mutharasappan; Prabhu, Dhamodharan; Choubey, Sanjay Kumar; Biswal, Jayashree; Jeyakanthan, Jeyaraman

    2017-01-01

    Dihydroorotate dehydrogenase (DHODH) plays a major role in the rate limiting step of de novo pyrimidine biosynthesis pathway and it is pronounced as a novel target for drug development of cancer. The currently available drugs against DHODH are ineffective and bear various side effects. Three-dimensional structure of the targeted protein was constructed using molecular modeling approach followed by 100 ns molecular dynamics simulations. In this study, High Throughput Virtual Screening (HTVS) was performed using various compound libraries to identify pharmacologically potential molecules. The top four identified lead molecules includes NCI_47074, HitFinder_7630, Binding_66981 and Specs_108872 with high docking score of -9.45, -8.29, -8.04 and -8.03 kcal/mol and the corresponding binding free energy were -16.25, -56.37, -26.93 and -48.04 kcal/mol respectively. Arg122, Arg185, Glu255 and Gly257 are the key residues found to be interacting with the ligands. Molecular dynamics simulations of DHODH-inhibitors complexes were performed to assess the stability of various conformations from complex structures of TtDHODH. Furthermore, stereoelectronic features of the ligands were explored to facilitate charge transfer during the protein-ligand interactions using Density Functional Theoretical approach. Based on in silico analysis, the ligand NCI_47074 ((2Z)-3-({6-[(2Z)-3-carboxylatoprop-2-enamido]pyridin-2-yl}carbamoyl)prop-2-enoate) was found to be the most potent lead molecule which was validated using energetic and electronic parameters and it could serve as a template for designing effective anticancerous drug molecule.

  6. Biosynthetic pathways of plastid-derived organelles as potential drug targets against parasitic apicomplexa.

    PubMed

    Seeber, Frank

    2003-06-01

    Apicomplexan parasites are a large phylum of unicellular and obligate intracellular organisms of great medical importance. They include the human pathogens Plasmodium spp., the causative agent of malaria, and Toxoplasma gondii, an opportunistic parasite of immunosuppressed individuals and a common cause of congenital disease, together affecting several hundred million people worldwide. The search for new and effective drugs against these pathogens has been boosted during the last years by an unexpected finding. Through molecular and cell biological analysis it was realized that probably most members of this phylum harbor a plastid-like organelle, called the apicoplast, which probably is derived from the engulfment of a red alga in ancient times. Although the apicoplast itself contains a small circular genome, most of the proteome of this organelle is encoded in the nuclear genome, and the proteins are subsequently transported to the apicoplast. It is assumed to contain a number of unique metabolic pathways not found in the vertebrate host, making it an ideal "playground" for those interested in drug targets. Recent reports have shown that the rationale of this approach is valid and that new drugs which are urgently needed especially for plasmodial infections, might be developed in the near future based on these targets. Amongst them are three enzymes of the plant-like fatty acid synthesis machinery and enzymes of the non-mevalonat isoprenoid biosynthesis pathway. From their presence in the apicoplast it can be concluded that fatty acid and lipid biosynthesis seems to be a major function of the apicoplast. Another recently described apicoplast enzyme, ferredoxin-NADP(+)-reductase and its redox partner, ferredoxin, points to another interesting organelle-specific biosynthetic pathway, namely [Fe-S] cluster biosynthesis. In the present review, the fundamental aspects of the apicoplast as drug target will be described, together with the specific pathways and their

  7. Non-Targeted Effects Models Predict Significantly Higher Mars Mission Cancer Risk than Targeted Effects Models.

    PubMed

    Cucinotta, Francis A; Cacao, Eliedonna

    2017-05-12

    Cancer risk is an important concern for galactic cosmic ray (GCR) exposures, which consist of a wide-energy range of protons, heavy ions and secondary radiation produced in shielding and tissues. Relative biological effectiveness (RBE) factors for surrogate cancer endpoints in cell culture models and tumor induction in mice vary considerable, including significant variations for different tissues and mouse strains. Many studies suggest non-targeted effects (NTE) occur for low doses of high linear energy transfer (LET) radiation, leading to deviation from the linear dose response model used in radiation protection. Using the mouse Harderian gland tumor experiment, the only extensive data-set for dose response modelling with a variety of particle types (>4), for the first-time a particle track structure model of tumor prevalence is used to investigate the effects of NTEs in predictions of chronic GCR exposure risk. The NTE model led to a predicted risk 2-fold higher compared to a targeted effects model. The scarcity of data with animal models for tissues that dominate human radiation cancer risk, including lung, colon, breast, liver, and stomach, suggest that studies of NTEs in other tissues are urgently needed prior to long-term space missions outside the protection of the Earth's geomagnetic sphere.

  8. Non-Targeted Effects Models Predict Significantly Higher Mars Mission Cancer Risk than Targeted Effects Models

    DOE PAGES

    Cucinotta, Francis A.; Cacao, Eliedonna

    2017-05-12

    Cancer risk is an important concern for galactic cosmic ray (GCR) exposures, which consist of a wide-energy range of protons, heavy ions and secondary radiation produced in shielding and tissues. Relative biological effectiveness (RBE) factors for surrogate cancer endpoints in cell culture models and tumor induction in mice vary considerable, including significant variations for different tissues and mouse strains. Many studies suggest non-targeted effects (NTE) occur for low doses of high linear energy transfer (LET) radiation, leading to deviation from the linear dose response model used in radiation protection. Using the mouse Harderian gland tumor experiment, the only extensive data-setmore » for dose response modelling with a variety of particle types (>4), for the first-time a particle track structure model of tumor prevalence is used to investigate the effects of NTEs in predictions of chronic GCR exposure risk. The NTE model led to a predicted risk 2-fold higher compared to a targeted effects model. The scarcity of data with animal models for tissues that dominate human radiation cancer risk, including lung, colon, breast, liver, and stomach, suggest that studies of NTEs in other tissues are urgently needed prior to long-term space missions outside the protection of the Earth’s geomagnetic sphere.« less

  9. Identification and validation of potential conserved microRNAs and their targets in peach (Prunus persica).

    PubMed

    Gao, Zhihong; Luo, Xiaoyan; Shi, Ting; Cai, Bin; Zhang, Zhen; Cheng, Zongming; Zhuang, Weibing

    2012-09-01

    MicroRNAs are a class of small, endogenous, non-coding RNA molecules that negatively regulate gene expression at the transcriptional or the post-transcriptional level. Although a large number of miRNAs have been identified in many plant species, especially from model plants and crops, they remain largely unknown in peach. In this study, 110 potential miRNAs belonging to 37 families were identified using computational methods. A total of 43 potential targets were found for 21 families based on near-perfect or perfect complementarity between the plant miRNA and the target sequences. A majority of the targets were transcription factors which play important roles in peach development. qRT-PCR analysis of RNA samples prepared from different peach tissues for 25 miRNA families revealed that miRNAs were differentially expressed in different tissues. Furthermore, two target genes were experimentally verified by detection of the miRNA-mediated mRNA cleavage sites in peach using RNA ligase-mediated 5' rapid amplification of cDNA ends (RLM-RACE). Finally, we studied the expression pattern of the two target genes in three different tissues of peach to further understand the mechanism of the interaction between miRNAs and their target genes.

  10. A systematic analysis of the RNA-targeting potential of secreted bacterial effector proteins.

    PubMed

    Tawk, Caroline; Sharan, Malvika; Eulalio, Ana; Vogel, Jörg

    2017-08-24

    Many pathogenic bacteria utilize specialized secretion systems to deliver proteins called effectors into eukaryotic cells for manipulation of host pathways. The vast majority of known effector targets are host proteins, whereas a potential targeting of host nucleic acids remains little explored. There is only one family of effectors known to target DNA directly, and effectors binding host RNA are unknown. Here, we take a two-pronged approach to search for RNA-binding effectors, combining biocomputational prediction of RNA-binding domains (RBDs) in a newly assembled comprehensive dataset of bacterial secreted proteins, and experimental screening for RNA binding in mammalian cells. Only a small subset of effectors were predicted to carry an RBD, indicating that if RNA targeting was common, it would likely involve new types of RBDs. Our experimental evaluation of effectors with predicted RBDs further argues for a general paucity of RNA binding activities amongst bacterial effectors. We obtained evidence that PipB2 and Lpg2844, effector proteins of Salmonella and Legionella species, respectively, may harbor novel biochemical activities. Our study presenting the first systematic evaluation of the RNA-targeting potential of bacterial effectors offers a basis for discussion of whether or not host RNA is a prominent target of secreted bacterial proteins.

  11. Investigating Mammalian Tyrosine Phosphatase Inhibitors as Potential ‘Piggyback’ Leads to Target Trypanosoma brucei Transmission

    PubMed Central

    Ruberto, Irene; Szoor, Balazs; Clark, Rachel; Matthews, Keith R.

    2014-01-01

    African trypanosomiasis is a neglected tropical disease affecting humans and animals across 36 sub-Saharan African countries. We have investigated the potential to exploit a ‘piggyback’ approach to inhibit Trypanosoma brucei transmission by targeting the key developmental regulator of transmission, T. brucei protein tyrosine phosphatase 1. This strategy took advantage of the extensive investment in inhibitors for human protein tyrosine phosphatase 1B, a key target for pharmaceutical companies for the treatment of obesity and diabetes. Structural predictions for human and trypanosome tyrosine phosphatases revealed the overall conservation of important functional motifs, validating the potential for exploiting cross specific compounds. Thereafter, nineteen inhibitors were evaluated; seventeen from a protein tyrosine phosphatase 1B-targeted inhibitor library and two from literature analysis – oleanolic acid and suramin, the latter of which is a front line drug against African trypanosomiasis. The compounds tested displayed similar inhibitory activities against the human and trypanosome enzymes, mostly behaving as noncompetitive inhibitors. However, their activity against T. brucei in culture was low, necessitating further chemical modification to improve their efficacy and specificity. Nonetheless, the results validate the potential to explore a ‘piggyback’ strategy targeting T. brucei protein tyrosine phosphatase 1 through exploiting the large pharmacological investment in therapies for obesity targeting protein tyrosine phosphatase 1B. PMID:23066974

  12. Investigating mammalian tyrosine phosphatase inhibitors as potential 'piggyback' leads to target Trypanosoma brucei transmission.

    PubMed

    Ruberto, Irene; Szoor, Balazs; Clark, Rachel; Matthews, Keith R

    2013-02-01

    African trypanosomiasis is a neglected tropical disease affecting humans and animals across 36 sub-Saharan African countries. We have investigated the potential to exploit a 'piggyback' approach to inhibit Trypanosoma brucei transmission by targeting the key developmental regulator of transmission, T. brucei protein tyrosine phosphatase 1. This strategy took advantage of the extensive investment in inhibitors for human protein tyrosine phosphatase 1B, a key target for pharmaceutical companies for the treatment of obesity and diabetes. Structural predictions for human and trypanosome tyrosine phosphatases revealed the overall conservation of important functional motifs, validating the potential for exploiting cross specific compounds. Thereafter, nineteen inhibitors were evaluated; seventeen from a protein tyrosine phosphatase 1B-targeted inhibitor library and two from literature analysis - oleanolic acid and suramin, the latter of which is a front line drug against African trypanosomiasis. The compounds tested displayed similar inhibitory activities against the human and trypanosome enzymes, mostly behaving as noncompetitive inhibitors. However, their activity against T. brucei in culture was low, necessitating further chemical modification to improve their efficacy and specificity. Nonetheless, the results validate the potential to explore a 'piggyback' strategy targeting T. brucei protein tyrosine phosphatase 1 through exploiting the large pharmacological investment in therapies for obesity targeting protein tyrosine phosphatase 1B. © 2012 John Wiley & Sons A/S.

  13. Potential Therapeutic Effects of Psilocybin.

    PubMed

    Johnson, Matthew W; Griffiths, Roland R

    2017-07-01

    Psilocybin and other 5-hydroxytryptamine2A agonist classic psychedelics have been used for centuries as sacraments within indigenous cultures. In the mid-twentieth century they were a focus within psychiatry as both probes of brain function and experimental therapeutics. By the late 1960s and early 1970s these scientific inquires fell out of favor because classic psychedelics were being used outside of medical research and in association with the emerging counter culture. However, in the twenty-first century, scientific interest in classic psychedelics has returned and grown as a result of several promising studies, validating earlier research. Here, we review therapeutic research on psilocybin, the classic psychedelic that has been the focus of most recent research. For mood and anxiety disorders, three controlled trials have suggested that psilocybin may decrease symptoms of depression and anxiety in the context of cancer-related psychiatric distress for at least 6 months following a single acute administration. A small, open-label study in patients with treatment-resistant depression showed reductions in depression and anxiety symptoms 3 months after two acute doses. For addiction, small, open-label pilot studies have shown promising success rates for both tobacco and alcohol addiction. Safety data from these various trials, which involve careful screening, preparation, monitoring, and follow-up, indicate the absence of severe drug-related adverse reactions. Modest drug-related adverse effects at the time of medication administration are readily managed. US federal funding has yet to support therapeutic psilocybin research, although such support will be important to thoroughly investigate efficacy, safety, and therapeutic mechanisms.

  14. MicroRNAs as potential target in human bone and soft tissue sarcoma therapeutics

    PubMed Central

    Varshney, Jyotika; Subramanian, Subbaya

    2015-01-01

    Sarcomas are highly aggressive heterogeneous tumors that are mesenchymal in origin. There have been vast advancements on identifying diagnostic markers for sarcomas including chromosomal translocations, but very little progress has been made to identify targeted therapies against them. The tumor heterogeneity, genetic complexity and the lack of drug studies make it challenging to recognize the potential targets and also accounts for the inadequate treatments in sarcomas. In recent years, microRNAs that are a part of small non-coding RNAs have shown promising results as potential diagnostic and prognostic biomarkers in multiple sarcoma types. This review focuses on the current knowledge of the microRNAs that are deregulated in sarcomas, and an insight on the strategies to target these microRNAs that are essential for developing improved therapies for various human sarcomas. PMID:26137468

  15. Recent Advances in Biomarkers and Potential Targeted Therapies in Head and Neck Squamous Cell Carcinoma

    PubMed Central

    Yavrouian, Eric J.; Sinha, Uttam K.

    2012-01-01

    Head and neck squamous cell carcinoma (HNSCC) is a devastating tumor of the upper aerodigestive tract with no significant change in treatment modality or improvement in survival over the last several decades. Biomarkers are important biological molecules that can be utilized in tumor detection, prognosis, and as targeted therapies. There are several important biomarkers and potential targets in the forefront, including biomarkers of tumorigenesis, signal transduction molecules, proteins involved in angiogenesis, and oncogenic viruses. The clinical applications of these biomarkers are in various states from in vitro and in vivo models, phase II and III clinical trials, to accepted modes of treatment in patients with HNSCC. Given the potential improvement in prognosis that biomarkers and their targeted therapies may have on the treatment of HNSCC, their investigation is both important and essential. PMID:22523710

  16. Mycothiol: a target for potentiation of rifampin and other antibiotics against Mycobacterium tuberculosis.

    PubMed

    Hernick, Marcy

    2013-01-01

    Actinomycetes, including Mycobacterium species, are Gram-positive bacteria that use the small molecule mycothiol (MSH) as their primary reducing agent and in the detoxification of xenobiotics. Due to these important functions, MSH is a potential target for the development of antibiotics for the treatment of tuberculosis. This review summarizes the progress to date on the viability of enzymes involved in MSH biosynthesis and MSH-dependent detoxification as drug targets, biochemical characterization of target enzymes (structure, mechanism and substrate specificity) and development of MSH biosynthesis and MSH-dependent detoxification enzyme inhibitors. In addition, the ability of MSH to influence the sensitivity of mycobacteria to existing antibiotics and potential of MSH biosynthesis and MSH-dependent detoxification enzyme inhibitors to modulate the activity of existing antibiotics are described.

  17. Bone-Targeted Acid-Sensitive Doxorubicin Conjugate Micelles as Potential Osteosarcoma Therapeutics

    PubMed Central

    2015-01-01

    Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy. The design features are the use of the hydrophilic d-aspartic acid octapeptide as both the effective targeting agent as well as the hydrophilic micelle corona. Micelle stabilization was accomplished by binding of model drug (doxorubicin) via an acid-sensitive hydrazone bond and incorporating one to four 11-aminoundecanoic acid (AUA) moieties to manipulate the hydrophobic/hydrophilic ratio. Four micelle-forming unimers have been synthesized and their self-assembly into micelles was evaluated. Size of the micelles could be modified by changing the architecture of the unimers from linear to branched. The stability of the micelles increased with increasing content of AUA moieties. Adsorption of all micelles to hydroxyapatite occurred rapidly. Doxorubicin release occurred at pH 5.5, whereas no release was detected at pH 7.4. Cytotoxicity toward human osteosarcoma Saos-2 cells correlated with drug release data. PMID:25291150

  18. Identification of potential targets for differentiation in human leukemia cells induced by diallyl disulfide.

    PubMed

    Ling, Hui; He, Jie; Tan, Hui; Yi, Lan; Liu, Fang; Ji, Xiaoxia; Wu, Youhua; Hu, Haobin; Zeng, Xi; Ai, Xiaohong; Jiang, Hao; Su, Qi

    2017-02-01

    Diallyl disulfide (DADS) is a primary component of garlic, which has chemopreventive potential. We previously found that moderate doses (15-120 µM) of DADS induced apoptosis and G2/M phase cell cycle arrest. In this study, we observed the effect of low doses (8 µM) of DADS on human leukemia HL-60 cells. We found that DADS could inhibit proliferation, migration and invasion in HL-60 cells, and arrested cells at G0/G1 stage. Then, cell differentiation was displayed by morphologic observation, NBT reduction activity and CD11b evaluation of cytometric flow. It showed that DADS induced differentiation, reduced the ability of NBT and increased CD11b expression. Likewise, DADS inhibited xenograft tumor growth and induced differentiation in vivo. In order to make sure how DADS induced differentiation, we compared the protein expression profile of DADS-treated cells with that of untreated control. Using high resolution mass spectrometry, we identified 18 differentially expressed proteins after treatment with DADS, including four upregulated and 14 downregulated proteins. RT-PCR and western blot assay showed that DJ-1, cofilin 1, RhoGDP dissociation inhibitor 2 (RhoGDI2), Calreticulin (CTR) and PCNA were decreased by DADS. These data suggest that the effects of DADS on leukemia may be due to multiple targets for intervention.

  19. Angiotensin-(1-7) and its receptor as a potential targets for new cardiovascular drugs.

    PubMed

    Santos, Robson A S; Ferreira, Anderson J; Pinheiro, Sérgio V B; Sampaio, Walkyria O; Touyz, Rhian; Campagnole-Santos, Maria José

    2005-08-01

    The identification of novel biochemical components of the renin-angiotensin system (RAS) has added a further layer of complexity to the classical concept of this cardiovascular regulatory system. It is now clear that there is a counter-regulatory arm within the RAS that is mainly formed by the angiotensin-converting enzyme 2-angiotensin (1-7)-receptor Mas axis. The functions of this axis are often opposite to those attributed to the major component of the RAS, angiotensin II. This review will highlight the current knowledge concerning the cardiovascular effects of angiotensin-(1-7) through a direct interaction with its receptor Mas or through an indirect interplay with the kallikrein-kinin system. In addition, there will be a discussion of its role in the beneficial effects of angiotensin-converting enzyme inhibitors and angio-tensin receptor type 1 (AT1) antagonists, and the potential of this peptide and its receptor as a novel targets for new cardiovascular drugs.

  20. Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics.

    PubMed

    Low, Stewart A; Yang, Jiyuan; Kopeček, Jindřich

    2014-11-19

    Osteosarcoma is a malignancy of the bone that primarily affects adolescents. Current treatments retain mortality rates, which are higher than average cancer mortality rates for the adolescent age group. We designed a micellar delivery system with the aim to increase drug accumulation in the tumor and potentially reduce side effects associated with chemotherapy. The design features are the use of the hydrophilic D-aspartic acid octapeptide as both the effective targeting agent as well as the hydrophilic micelle corona. Micelle stabilization was accomplished by binding of model drug (doxorubicin) via an acid-sensitive hydrazone bond and incorporating one to four 11-aminoundecanoic acid (AUA) moieties to manipulate the hydrophobic/hydrophilic ratio. Four micelle-forming unimers have been synthesized and their self-assembly into micelles was evaluated. Size of the micelles could be modified by changing the architecture of the unimers from linear to branched. The stability of the micelles increased with increasing content of AUA moieties. Adsorption of all micelles to hydroxyapatite occurred rapidly. Doxorubicin release occurred at pH 5.5, whereas no release was detected at pH 7.4. Cytotoxicity toward human osteosarcoma Saos-2 cells correlated with drug release data.

  1. Transient receptor potential ion channels in primary sensory neurons as targets for novel analgesics.

    PubMed

    Sousa-Valente, J; Andreou, A P; Urban, L; Nagy, I

    2014-05-01

    The last decade has witnessed an explosion in novel findings relating to the molecules involved in mediating the sensation of pain in humans. Transient receptor potential (TRP) ion channels emerged as the greatest group of molecules involved in the transduction of various physical stimuli into neuronal signals in primary sensory neurons, as well as, in the development of pain. Here, we review the role of TRP ion channels in primary sensory neurons in the development of pain associated with peripheral pathologies and possible strategies to translate preclinical data into the development of effective new analgesics. Based on available evidence, we argue that nociception-related TRP channels on primary sensory neurons provide highly valuable targets for the development of novel analgesics and that, in order to reduce possible undesirable side effects, novel analgesics should prevent the translocation from the cytoplasm to the cell membrane and the sensitization of the channels rather than blocking the channel pore or binding sites for exogenous or endogenous activators.

  2. Neuroprotective and neurorestorative potential of propargylamine derivatives in ageing: focus on mitochondrial targets.

    PubMed

    Bar-Am, Orit; Amit, Tamar; Youdim, Moussa B; Weinreb, Orly

    2016-02-01

    The mitochondrial theory of ageing proposes that accumulation of damage to mitochondrial function and DNA mutation lead to ageing of humans and animals. It has been suggested that mitochondria play dynamic roles in regulating synaptogenesis and morphological/functional responses of synaptic activity, and thus, deteriorating of mitochondrial function (e.g., deficits of the mitochondrial respiratory enzymes, reduced calcium influx, increased accumulation of mitochondrial DNA defects/apoptotic proteins and impairment of mitochondrial membrane potential) can lead to severe neuronal energy deficit, and in the long run, to modifications in neuronal synapses and neurodegeneration in the ageing brain. Hence, considering the mechanisms by which mitochondrial impairment can lead to neuronal death, the development of neuroprotective molecules that target various mitochondrial pathogenic processes can be effective in the treatment of ageing and age-related neurodegenerative diseases. This review addresses several aspects of the neuroprotective effects of propargylamine derivatives (e.g., the monoamine oxidase-B inhibitors, selegiline and rasagiline and the multifunctional drugs, ladostigil, M30 and VAR10303) in ageing with a special focus on mitochondrial molecular protective mechanisms.

  3. Target Essentiality and Centrality Characterize Drug Side Effects

    PubMed Central

    Yu, Haiyuan

    2013-01-01

    To investigate factors contributing to drug side effects, we systematically examine relationships between 4,199 side effects associated with 996 drugs and their 647 human protein targets. We find that it is the number of essential targets, not the number of total targets, that determines the side effects of corresponding drugs. Furthermore, within the context of a three-dimensional interaction network with atomic-resolution interaction interfaces, we find that drugs causing more side effects are also characterized by high degree and betweenness of their targets and highly shared interaction interfaces on these targets. Our findings suggest that both essentiality and centrality of a drug target are key factors contributing to side effects and should be taken into consideration in rational drug design. PMID:23874169

  4. Fatty acid synthase as a potential therapeutic target in feline oral squamous cell carcinoma.

    PubMed

    Walz, J Z; Saha, J; Arora, A; Khammanivong, A; O'Sullivan, M G; Dickerson, E B

    2017-09-04

    Oral squamous cell carcinoma (OSCC) is an aggressive and treatment-resistant malignancy in both feline and human patients. Recent work has demonstrated aberrant expression of fatty acid synthase (FASN) and an increased capacity for lipogenesis in human OSCC and other cancers. In human OSCC, inhibition of FASN decreased cell viability and growth in vitro, and diminished tumour growth and metastasis in murine preclinical models. This study aimed to characterize FASN as a therapeutic target in feline OSCC. Immunohistochemistry revealed high FASN expression in primary feline OSCC tumours, and FASN expression was detected in OSCC cell lines (3 feline and 3 human) by immunoblotting and quantitative real-time-polymerase chain reaction (qRT-PCR). Orlistat, a FASN inhibitor, substantially reduced cell viability in both feline and human OSCC lines, although feline cell lines consistently displayed higher sensitivity to the drug. FASN mRNA expression among cell lines mirrored sensitivity to orlistat, with feline cell lines expressing higher levels of FASN. Consistent with this observation, diminished sensitivity to orlistat treatment and decreased FASN mRNA expression were observed in feline OSCC cells following incubation under hypoxic conditions. Treatment with orlistat did not potentiate sensitivity to carboplatin in the cell lines investigated; instead, combinations of the 2 drugs resulted in additive to antagonistic effects. Our results suggest that FASN inhibition is a viable therapeutic target for feline OSCC. Furthermore, cats may serve as a spontaneous large animal model for human oral cancer, although differences in the regulation of lipogenesis between these 2 species require further investigation. © 2017 John Wiley & Sons Ltd.

  5. Oxidative stress and mitochondrial dysfunction in atherosclerosis: mitochondria-targeted antioxidants as potential therapy.

    PubMed

    Victor, V M; Apostolova, N; Herance, R; Hernandez-Mijares, A; Rocha, M

    2009-01-01

    Chronic and acute overproduction of reactive oxygen species (ROS) under pathophysiologic conditions forms an integral part of the development of cardiovascular diseases (CVD), and in particular atherosclerosis. These ROS are released from different sources, such as xanthine oxidase, lipoxygenase, nicotinamide adenine dinucleotide phosphate oxidase, the uncoupling of nitric oxide synthase and, in particular, mitochondria. Endothelial dysfunction, characterized by a loss of nitric oxide (NO) bioactivity, occurs early on in the development of atherosclerosis, and determines future vascular complications. Although the molecular mechanisms responsible for mitochondria-mediated disease processes are not clear, oxidative stress seems to play an important role. In general, ROS are essential to cell function, but adequate levels of antioxidant defenses are required in order to avoid the harmful effects of excessive ROS production. Mitochondrial oxidative stress damage and dysfunction contribute to a number of cell pathologies that manifest themselves through a range of conditions. This review considers the process of atherosclerosis from a mitochondrial perspective, and assesses strategies for the targeted delivery of antioxidants to mitochondria that are currently under development. We will provide a summary of the following areas: the cellular metabolism of reactive oxygen species (ROS) and its role in pathophysiological processes such as atherosclerosis; currently available antioxidants and possible reasons for their efficacy and inefficacy in ameliorating oxidative stress-mediated diseases; and recent developments in mitochondrially-targeted antioxidants that concentrate on the matrix-facing surface of the inner mitochondrial membrane in order to protect against mitochondrial oxidative damage, and their therapeutic potential as a treatment for atherosclerosis.

  6. The 5-HT7 receptor as a potential target for treating drug and alcohol abuse

    PubMed Central

    Hauser, Sheketha R.; Hedlund, Peter B.; Roberts, Amanda J.; Sari, Youssef; Bell, Richard L.; Engleman, Eric A.

    2015-01-01

    Alcohol and drug abuse take a large toll on society and affected individuals. However, very few effective treatments are currently available to treat alcohol and drug addiction. Basic and clinical research has begun to provide some insights into the underlying neurobiological systems involved in the addiction process. Several neurotransmitter pathways have been implicated and distinct reward neurocircuitry have been proposed—including the mesocorticolimbic dopamine (MCL-DA) system and the extended amygdala. The serotonin (5-HT) neurotransmitter system is of particular interest and multiple 5-HT receptors are thought to play significant roles in alcohol and drug self-administration and the development of drug dependence. Among the 5-HT receptors, the 5-HT7 receptor is currently undergoing characterization as a potential target for the treatment of several psychiatric disorders. Although this receptor has received only limited research regarding addictive behaviors, aspects of its neuroanatomical, biochemical, physiological, pharmacological, and behavioral profiles suggest that it could play a key role in the addiction process. For instance, genomic studies in humans have suggested a link between variants in the gene encoding the 5-HT7 receptor and alcoholism. Recent behavioral testing using high-affinity antagonists in mice and preliminary tests with alcohol-preferring rats suggest that this receptor could mediate alcohol consumption and/or reinforcement and play a role in seeking/craving behavior. Interest in the development of new and more selective pharmacological agents for this receptor will aid in examining the 5-HT7 receptor as a novel target for treating addiction. PMID:25628528

  7. The Ubiquitin-Proteasome System: Potential Therapeutic Targets for Alzheimer's Disease and Spinal Cord Injury.

    PubMed

    Gong, Bing; Radulovic, Miroslav; Figueiredo-Pereira, Maria E; Cardozo, Christopher

    2016-01-01

    The ubiquitin-proteasome system (UPS) is a crucial protein degradation system in eukaryotes. Herein, we will review advances in the understanding of the role of several proteins of the UPS in Alzheimer's disease (AD) and functional recovery after spinal cord injury (SCI). The UPS consists of many factors that include E3 ubiquitin ligases, ubiquitin hydrolases, ubiquitin and ubiquitin-like molecules, and the proteasome itself. An extensive body of work links UPS dysfunction with AD pathogenesis and progression. More recently, the UPS has been shown to have vital roles in recovery of function after SCI. The ubiquitin hydrolase (Uch-L1) has been proposed to increase cellular levels of mono-ubiquitin and hence to increase rates of protein turnover by the UPS. A low Uch-L1 level has been linked with Aβ accumulation in AD and reduced neuroregeneration after SCI. One likely mechanism for these beneficial effects of Uch-L1 is reduced turnover of the PKA regulatory subunit and consequently, reduced signaling via CREB. The neuron-specific F-box protein Fbx2 ubiquitinates β-secretase thus targeting it for proteasomal degradation and reducing generation of Aβ. Both Uch-L1 and Fbx2 improve synaptic plasticity and cognitive function in mouse AD models. The role of Fbx2 after SCI has not been examined, but abolishing ß-secretase reduces neuronal recovery after SCI, associated with reduced myelination. UBB+1, which arises through a frame-shift mutation in the ubiquitin gene that adds 19 amino acids to the C-terminus of ubiquitin, inhibits proteasomal function and is associated with increased neurofibrillary tangles in patients with AD, Pick's disease and Down's syndrome. These advances in understanding of the roles of the UPS in AD and SCI raise new questions but, also, identify attractive and exciting targets for potential, future therapeutic interventions.

  8. The 5-HT7 receptor as a potential target for treating drug and alcohol abuse.

    PubMed

    Hauser, Sheketha R; Hedlund, Peter B; Roberts, Amanda J; Sari, Youssef; Bell, Richard L; Engleman, Eric A

    2014-01-01

    Alcohol and drug abuse take a large toll on society and affected individuals. However, very few effective treatments are currently available to treat alcohol and drug addiction. Basic and clinical research has begun to provide some insights into the underlying neurobiological systems involved in the addiction process. Several neurotransmitter pathways have been implicated and distinct reward neurocircuitry have been proposed-including the mesocorticolimbic dopamine (MCL-DA) system and the extended amygdala. The serotonin (5-HT) neurotransmitter system is of particular interest and multiple 5-HT receptors are thought to play significant roles in alcohol and drug self-administration and the development of drug dependence. Among the 5-HT receptors, the 5-HT7 receptor is currently undergoing characterization as a potential target for the treatment of several psychiatric disorders. Although this receptor has received only limited research regarding addictive behaviors, aspects of its neuroanatomical, biochemical, physiological, pharmacological, and behavioral profiles suggest that it could play a key role in the addiction process. For instance, genomic studies in humans have suggested a link between variants in the gene encoding the 5-HT7 receptor and alcoholism. Recent behavioral testing using high-affinity antagonists in mice and preliminary tests with alcohol-preferring rats suggest that this receptor could mediate alcohol consumption and/or reinforcement and play a role in seeking/craving behavior. Interest in the development of new and more selective pharmacological agents for this receptor will aid in examining the 5-HT7 receptor as a novel target for treating addiction.

  9. The G Protein α Chaperone Ric-8 as a Potential Therapeutic Target

    PubMed Central

    Papasergi, Makaía M.; Patel, Bharti R.

    2015-01-01

    Resistance to inhibitors of cholinesterase (Ric-8)A and Ric-8B are essential genes that encode positive regulators of heterotrimeric G protein α subunits. Controversy persists surrounding the precise way(s) that Ric-8 proteins affect G protein biology and signaling. Ric-8 proteins chaperone nucleotide-free Gα-subunit states during biosynthetic protein folding prior to G protein heterotrimer assembly. In organisms spanning the evolutionary window of Ric-8 expression, experimental perturbation of Ric-8 genes results in reduced functional abundances of G proteins because G protein α subunits are misfolded and degraded rapidly. Ric-8 proteins also act as Gα-subunit guanine nucleotide exchange factors (GEFs) in vitro. However, Ric-8 GEF activity could strictly be an in vitro phenomenon stemming from the ability of Ric-8 to induce partial Gα unfolding, thereby enhancing GDP release. Ric-8 GEF activity clearly differs from the GEF activity of G protein–coupled receptors (GPCRs). G protein βγ is inhibitory to Ric-8 action but obligate for receptors. It remains an open question whether Ric-8 has dual functions in cells and regulates G proteins as both a molecular chaperone and GEF. Clearly, Ric-8 has a profound influence on heterotrimeric G protein function. For this reason, we propose that Ric-8 proteins are as yet untested therapeutic targets in which pharmacological inhibition of the Ric-8/Gα protein–protein interface could serve to attenuate the effects of disease-causing G proteins (constitutively active mutants) and/or GPCR signaling. This minireview will chronicle the understanding of Ric-8 function, provide a comparative discussion of the Ric-8 molecular chaperoning and GEF activities, and support the case for why Ric-8 proteins should be considered potential targets for development of new therapies. PMID:25319541

  10. Comparison of treecodes for computing electrostatic potentials in charged particle systems with disjoint targets and sources.

    PubMed

    Boateng, Henry A; Krasny, Robert

    2013-09-30

    In molecular simulations, it is sometimes necessary to compute the electrostatic potential at M target sites due to a disjoint set of N charged source particles. Direct summation requires O(MN) operations, which is prohibitively expensive when M and N are large. Here, we consider two alternative tree-based methods that reduce the cost. The standard particle-cluster treecode partitions the N sources into an octree and applies a far-field approximation, whereas a recently developed cluster-particle treecode instead partitions the M targets into an octree and applies a near-field approximation. We compare the two treecodes with direct summation and document their accuracy, CPU run time, and memory usage. We find that the particle-cluster treecode is faster when N > M, that is, when the sources outnumber the targets, and conversely, the cluster-particle treecode is faster when M > N, that is, when the targets outnumber the sources. Hence, the two treecodes provide useful tools for computing electrostatic potentials in charged particle systems with disjoint targets and sources.

  11. Genomic identification of potential targets unique to Candida albicans for the discovery of antifungal agents.

    PubMed

    Tripathi, Himanshu; Luqman, Suaib; Meena, Abha; Khan, Feroz

    2014-01-01

    Despite of modern antifungal therapy, the mortality rates of invasive infection with human fungal pathogen Candida albicans are up to 40%. Studies suggest that drug resistance in the three most common species of human fungal pathogens viz., C. albicans, Aspergillus fumigatus (causing mortality rate up to 90%) and Cryptococcus neoformans (causing mortality rate up to 70%) is due to mutations in the target enzymes or high expression of drug transporter genes. Drug resistance in human fungal pathogens has led to an imperative need for the identification of new targets unique to fungal pathogens. In the present study, we have used a comparative genomics approach to find out potential target proteins unique to C. albicans, an opportunistic fungus responsible for severe infection in immune-compromised human. Interestingly, many target proteins of existing antifungal agents showed orthologs in human cells. To identify unique proteins, we have compared proteome of C. albicans [SC5314] i.e., 14,633 total proteins retrieved from the RefSeq database of NCBI, USA with proteome of human and non-pathogenic yeast Saccharomyces cerevisiae. Results showed that 4,568 proteins were identified unique to C. albicans as compared to those of human and later when these unique proteins were compared with S. cerevisiae proteome, finally 2,161 proteins were identified as unique proteins and after removing repeats total 1,618 unique proteins (42 functionally known, 1,566 hypothetical and 10 unknown) were selected as potential antifungal drug targets unique to C. albicans.

  12. TargetHunter: an in silico target identification tool for predicting therapeutic potential of small organic molecules based on chemogenomic database.

    PubMed

    Wang, Lirong; Ma, Chao; Wipf, Peter; Liu, Haibin; Su, Weiwei; Xie, Xiang-Qun

    2013-04-01

    Target identification of the known bioactive compounds and novel synthetic analogs is a very important research field in medicinal chemistry, biochemistry, and pharmacology. It is also a challenging and costly step towards chemical biology and phenotypic screening. In silico identification of potential biological targets for chemical compounds offers an alternative avenue for the exploration of ligand-target interactions and biochemical mechanisms, as well as for investigation of drug repurposing. Computational target fishing mines biologically annotated chemical databases and then maps compound structures into chemogenomical space in order to predict the biological targets. We summarize the recent advances and applications in computational target fishing, such as chemical similarity searching, data mining/machine learning, panel docking, and the bioactivity spectral analysis for target identification. We then described in detail a new web-based target prediction tool, TargetHunter (http://www.cbligand.org/TargetHunter). This web portal implements a novel in silico target prediction algorithm, the Targets Associated with its MOst SImilar Counterparts, by exploring the largest chemogenomical databases, ChEMBL. Prediction accuracy reached 91.1% from the top 3 guesses on a subset of high-potency compounds from the ChEMBL database, which outperformed a published algorithm, multiple-category models. TargetHunter also features an embedded geography tool, BioassayGeoMap, developed to allow the user easily to search for potential collaborators that can experimentally validate the predicted biological target(s) or off target(s). TargetHunter therefore provides a promising alternative to bridge the knowledge gap between biology and chemistry, and significantly boost the productivity of chemogenomics researchers for in silico drug design and discovery.

  13. A novel nanobody specific for respiratory surfactant protein A has potential for lung targeting

    PubMed Central

    Wang, Shan-Mei; He, Xian; Li, Nan; Yu, Feng; Hu, Yang; Wang, Liu-Sheng; Zhang, Peng; Du, Yu-Kui; Du, Shan-Shan; Yin, Zhao-Fang; Wei, Ya-Ru; Mulet, Xavier; Coia, Greg; Weng, Dong; He, Jian-Hua; Wu, Min; Li, Hui-Ping

    2015-01-01

    Lung-targeting drugs are thought to be potential therapies of refractory lung diseases by maximizing local drug concentrations in the lung to avoid systemic circulation. However, a major limitation in developing lung-targeted drugs is the acquirement of lung-specific ligands. Pulmonary surfactant protein A (SPA) is predominantly synthesized by type II alveolar epithelial cells, and may serve as a potential lung-targeting ligand. Here, we generated recombinant rat pulmonary SPA (rSPA) as an antigen and immunized an alpaca to produce two nanobodies (the smallest naturally occurring antibodies) specific for rSPA, designated Nb6 and Nb17. To assess these nanobodies’ potential for lung targeting, we evaluated their specificity to lung tissue and toxicity in mice. Using immunohistochemistry, we demonstrated that these anti-rSPA nanobodies selectively bound to rat lungs with high affinity. Furthermore, we intravenously injected fluorescein isothiocyanate-Nb17 in nude mice and observed its preferential accumulation in the lung to other tissues, suggesting high affinity of the nanobody for the lung. Studying acute and chronic toxicity of Nb17 revealed its safety in rats without causing apparent histological alterations. Collectively, we have generated and characterized lung-specific nanobodies, which may be applicable for lung drug delivery. PMID:25926731

  14. Effective treatment of HER2-amplified breast cancer by targeting HER3 and β1 integrin

    PubMed Central

    Campbell, Marcia R.; Zhang, Hui; Ziaee, Shabnam; Ruiz-Saenz, Ana; Gulizia, Nathaniel; Oeffinger, Julie; Amin, Dhara N.; Ahuja, Deepika; Moasser, Mark M.; Park, Catherine C.

    2016-01-01

    The central role of HER2 as the disease driver and HER3 as its essential partner has made them rational targets for the treatment of HER2-amplifed breast cancers, and there is considerable interest in developing highly effective treatment regimens for this disease that consist of targeted therapies alone. Much of these efforts are focused on dual targeting approaches, particularly dual targeting of the HER2-HER3 tumor driver complex itself, or vertical combinations that target downstream PI3K or Akt in addition to HER2. There is also potential in lateral combinations based on evidence implicating cross-talk with other membrane receptor systems, particularly integrins, and such lateral combinations can potentially involve either HER2 or HER3. We established a preclinical model of targeting HER3 using doxycycline-inducible shRNA and determined the efficacy of a β1 integrin inhibitor in combination with targeting HER3. We report that targeting HER3 and β1 integrin provides a particularly effective combination therapy approach for HER2-amplified cancers, surpassing the combination of HER2 and β1 integrin targeting, and evading some of the safety concerns associated with direct HER2-targeting. This further validates HER3 as a major hub mediating the tumorigenic functions of HER2 and identifies it as a high value target for lateral combination therapy strategies. PMID:26860947

  15. Therapeutic potential of a peptide targeting BCL-2 cell guardians in cancer.

    PubMed

    Adams, Jerry M

    2012-06-01

    A promising approach to cancer therapy is to elicit apoptosis with "BH3 mimetic" drugs, which target proteins of the BCL-2 family. As of yet, however, such drugs can target only certain BCL-2 family proteins. Hence, in this issue of the JCI, LaBelle et al. assess instead the therapeutic potential of a "stapled" BH3 peptide from the BIM protein, which inactivates all its prosurvival relatives. The peptide killed cultured hematologic tumor cells and abated growth of a leukemia xenograft, without perturbing the hematopoietic compartment. Hence, such peptides might eventually provide a new way to treat refractory leukemias.

  16. SLC7A5 act as a potential leukemic transformation target gene in myelodysplastic syndrome

    PubMed Central

    Ma, Yan; Song, Jing; Chen, Bobin; Xu, Xiaoping; Lin, Guowei

    2016-01-01

    Objective Myelodysplastic syndromes (MDS) are a heterogenous group of clonal hematopoietic stem cell disorders characterized by increased risk of leukemic transformation. This study identifies microRNAs(miRNA) and miRNA targets that might represent leukemic transformation markers for MDS. Methods Based on our previously established nested case-control study cohort of MDS patients, we chose paired patients to undergo Angilent 8 × 15K human miRNA microarrays. Target prediction analysis was administrated using targetscan 5.1 software. We further investigated the function of target gene in MDS cell line using siRNA method, including cell proliferation, cell apoptosis, cell cycle and electron microscope. Results Finally we screened a subset of 7 miRNAs to be significantly differentially expressed between the case (at the end of follow up with leukemic transformation) and control group (at the end of follow up without leukemic transformation). Target prediction analysis revealed SLC7A5 was the common target gene of these 7 miRNAs. Further study on the function of SLC7A5 gene in SKM-1 cell line showed that downregulation of SLC7A5 inhibited SKM-1 cells proliferation, increased apoptosis and caused cell cycle arrest in the G0/G1 stage. Conclusion Our data indicate that SLC7A5 gene may act as a potential leukemic transformation target gene in MDS. PMID:26657287

  17. Dynamics of target and distractor processing in visual search: evidence from event-related brain potentials.

    PubMed

    Hilimire, Matthew R; Mounts, Jeffrey R W; Parks, Nathan A; Corballis, Paul M

    2011-05-20

    When multiple objects are present in a visual scene, salient and behaviorally relevant objects are attentionally selected and receive enhanced processing at the expense of less salient or less relevant objects. Here we examined three lateralized components of the event-related potential (ERP) - the N2pc, Ptc, and SPCN - as indices of target and distractor processing in a visual search paradigm. Participants responded to the orientation of a target while ignoring an attentionally salient distractor and ERPs elicited by the target and the distractor were obtained. Results indicate that both the target and the distractor elicit an N2pc component which may index the initial attentional selection of both objects. In contrast, only the distractor elicited a significant Ptc, which may reflect the subsequent suppression of distracting or irrelevant information. Thus, the Ptc component appears to be similar to another ERP component - the Pd - which is also thought to reflect distractor suppression. Furthermore, only the target elicited an SPCN component which likely reflects the representation of the target in visual short term memory.

  18. Conserved Fungal Genes as Potential Targets for Broad-Spectrum Antifungal Drug Discovery†

    PubMed Central

    Liu, Mengping; Healy, Matthew D.; Dougherty, Brian A.; Esposito, Kim M.; Maurice, Trina C.; Mazzucco, Charles E.; Bruccoleri, Robert E.; Davison, Daniel B.; Frosco, Marybeth; Barrett, John F.; Wang, Ying-Kai

    2006-01-01

    The discovery of novel classes of antifungal drugs depends to a certain extent on the identification of new, unexplored targets that are essential for growth of fungal pathogens. Likewise, the broad-spectrum capacity of future antifungals requires the target gene(s) to be conserved among key fungal pathogens. Using a genome comparison (or concordance) tool, we identified 240 conserved genes as candidates for potential antifungal targets in 10 fungal genomes. To facilitate the identification of essential genes in Candida albicans, we developed a repressible C. albicans MET3 (CaMET3) promoter system capable of evaluating gene essentiality on a genome-wide scale. The CaMET3 promoter was found to be highly amenable to controlled gene expression, a prerequisite for use in target-based whole-cell screening. When the expression of the known antifungal target C. albicans ERG1 was reduced via down-regulation of the CaMET3 promoter, the CaERG1 conditional mutant strain became hypersensitive, specifically to its inhibitor, terbinafine. Furthermore, parallel screening against a small compound library using the CaERG1 conditional mutant under normal and repressed conditions uncovered several hypersensitive compound hits. This work therefore demonstrates a streamlined process for proceeding from selection and validation of candidate antifungal targets to screening for specific inhibitors. PMID:16607011

  19. Potential nanotechnologies and molecular targets in the quest for efficient chemotherapy in ovarian cancer.

    PubMed

    Rhoda, Khadija; Choonara, Yahya E; Kumar, Pradeep; Bijukumar, Divya; du Toit, Lisa C; Pillay, Viness

    2015-04-01

    Ovarian cancer, considered one of the most fatal gynecological cancers, goes largely undiagnosed until metastasis presents itself, usually once the patient is in the final stages and thus, too late for worthwhile therapy. Targeting this elusive disease in its early stages would improve the outcome for most patients, while the information generated thereof would increase the possibility of preventative mechanisms of therapy. This review discusses various molecular targets as possible moieties to be incorporated in a holistic drug delivery system or the more aptly termed 'theranostic' system. These molecular targets can be used for targeting, visualizing, diagnosing, and ultimately, treating ovarian cancer in its entirety. Currently implemented nanoframeworks, such as nanomicelles and nanoliposomes, are described and the effectiveness of nanostructures in tumor targeting, treatment functions, and overcoming the drug resistance challenge is discussed. Novel nanotechnology strategies such as the development of nanoframeworks decorated with targeted ligands of a molecular nature may provide an efficient chemotherapy, especially when instituted in combination with imaging, diagnostic, and ultimately, therapeutic moieties. An imperative aspect of utilizing nanotechnology in the treatment of ovarian cancer is the flexibility of the drug delivery system and its ability to overcome standard obstacles such as: i) successfully treating the desired cells through direct targeting; ii) reducing toxicity levels of treatment by achieving direct targeting; and iii) delivery of targeted therapy using an efficient vehicle that is exceptionally degradable in response to a particular stimulus. The targeting of ovarian cancer in its early stages using imaging and diagnostic nanotechnology is an area that can be improved upon by combining therapeutic moieties with molecular biomarkers. The nanotechnology and molecular markers mentioned in this review have generally been used for either

  20. Vimentin as a potential molecular target in cancer therapy Or Vimentin, an overview and its potential as a molecular target for cancer therapy

    PubMed Central

    Satelli, Arun; Li, Shulin

    2011-01-01

    Vimentin, a major constituent of the intermediate filament (IF) family of proteins, is ubiquitously expressed in normal mesenchymal cells and is known to maintain cellular integrity and provide resistance against stress. Increased vimentin expression has been reported in various epithelial cancers including prostate cancer, gastrointestinal tumors, CNS tumors, breast cancer, malignant melanoma, lung cancer and other types of cancers. Vimentin's over-expression in cancer correlates well with increased tumor growth, invasion and poor prognosis; however, the role of vimentin in cancer progression remains obscure. In the recent years, vimentin has gained much importance as a marker for epithelial-mesenchymal transition (EMT). Although EMT is associated with a number of tumorigenic events, the role of vimentin in the underlying events mediating these processes remains unknown. Though majority of the literature findings indicate a future significance of vimentin as a biomarker for different cancers with clinical relevance, more research in to the molecular aspects will be crucial to particularly evaluate the function of vimentin in the process of tumorigenesis. By virtue of its over-expression in a large number of cancers and its role in mediating various tumorigenic events, vimentin serves as an attractive target for cancer therapy. Further, research directed toward elucidating the role of vimentin in various signaling pathways would open up new approaches for the development of promising therapeutic agents. This review summarizes the expression and functions of vimentin in cancers and also suggests some directions toward future cancer therapy utilizing vimentin as a potential target. PMID:21637948

  1. SERPINA4 is a novel independent prognostic indicator and a potential therapeutic target for colorectal cancer

    PubMed Central

    Sun, Hui-Min; Mi, Yu-Shuai; Yu, Fu-Dong; Han, Yang; Liu, Xi-Sheng; Lu, Su; Zhang, Yu; Zhao, Sen-Lin; Ye, Ling; Liu, Ting-Ting; Yang, Dao-Hua; Sun, Xiao-Feng; Qin, Xue-Bin; Zhou, Zong-Guang; Tang, Hua-Mei; Peng, Zhi-Hai

    2016-01-01

    Serpina family A member 4 (SERPINA4), also known as kallistatin, exerts important effects in inhibiting tumor growth and angiogenesis in many malignancies. However, the precise role of SERPINA4 in CRC has not been fully elucidated. The present study aimed to investigate the expression of SERPINA4 and its clinical significance in CRC. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analyses showed that the mRNA and protein expression of SERPINA4 in colorectal cancer (CRC) specimens was significantly decreased than that in adjacent normal mucosa. Immunohistochemistry (IHC) was conducted to characterize the expression pattern of SERPINA4 by using a tissue microarray (TMA) containing 327 archived paraffin-embedded CRC specimens. Statistical analyses revealed that decreased SERPINA4 expression was significantly associated with invasion depth, nodal involvement, distant metastasis, American Joint Committee on Cancer (AJCC) stage, and tumor differentiation. SERPINA4 was also an independent prognostic indicator of disease-free survival and overall survival in patients with CRC. Furthermore, the impact of altered SERPINA4 expression on CRC cells was analyzed with a series of in vitro and in vivo assays. The results demonstrated that SERPINA4 significantly inhibits malignant tumor progression and serves as a novel prognostic indicator and a potential therapeutic target for CRC. PMID:27648355

  2. Vandetanib and cabozantinib potentiate mitochondria-targeted agents to suppress medullary thyroid carcinoma cells.

    PubMed

    Starenki, Dmytro; Hong, Seung-Keun; Wu, Pui-Kei; Park, Jong-In

    2017-07-03

    Although the FDA-approved receptor tyrosine kinases inhibitors, vandetanib and cabozantinib, are used to treat surgically inoperable progressive medullary thyroid carcinoma (MTC), not all patients are responsive while the disease sometimes progresses after an initial response. To better understand MTC drug resistance at molecular and biochemical levels, we have generated drug-resistant subpopulations of the human MTC cell lines, TT and MZ-CRC-1, via prolonged exposure to vandetanib and cabozantinib. These drug-resistant progenies exhibited substantial cross-resistance to vandetanib and cabozantinib, suggesting that these inhibitors may invoke an overlapping resistance mechanism(s) in MTC cells. Of note, vandetanib and cabozantinib increased mitochondrial membrane potential (Δψm) in drug-naïve as well as drug-resistant cells but only drug-naïve cells exhibited substantially altered oxygen consumption and extracellular acidification rates. Therefore, these inhibitors appear to cause a bioenergetics stress to which drug-resistant MTC cells are more tolerant. Given the ability of vandetanib and cabozantinib to increase Δψm, we hypothesized that these inhibitors can augment growth inhibitory effects of mitochondria-targeted carboxy-proxyl and ubiquinone by increasing their Δψm-dependent uptake/retention in MTC cells. Indeed, our in vitro and mouse xenograft data strongly support this possibility.

  3. Cyclooxygenase-2 pathway as a potential therapeutic target in diabetic peripheral neuropathy.

    PubMed

    Kellogg, Aaron P; Cheng, Hsinlin Thomas; Pop-Busui, Rodica

    2008-01-01

    Diabetic peripheral neuropathy (DPN) is the most common diabetic complication and is the leading cause of diabetes-related hospital admissions and non-traumatic amputations. DPN is also associated with a poor quality of life and high economic costs for both type 1 and type 2 diabetic patients. An effective treatment for DPN, besides tight glycemic control, is not yet available. The pathogenesis of DPN is complex and involves an intertwined array of mechanisms. Glucose-mediated alteration of cyclooxygenase (COX) pathway activity with subsequent impaired production and function of prostaglandins (PGs) is one mechanism that is implicated in the pathogenesis of DPN. COX-2, the inducible COX isoform, is upregulated in a variety of pathophysiological conditions including diabetes. COX-2 upregulation has tissue-specific consequences and is associated with activation of downstream inflammatory reactions. We have previously reported that COX-2 is upregulated in the peripheral nerves and dorsal root ganglia neurons in experimental diabetes and that COX-2 gene inactivation and/or selective COX-2 inhibition provides protection against various DPN deficits. This review will summarize current evidence supporting the role of COX-2 activation in inducing diabetic neurovascular dysfunction and that modulation of the COX-2 pathway is a potential therapeutic target for DPN.

  4. Regulation of the norepinephrine transporter by endothelins: a potential therapeutic target.

    PubMed

    Vatta, Marcelo S; Bianciotti, Liliana G; Guil, María J; Hope, Sandra I

    2015-01-01

    Neuronal norepinephrine (NE) uptake is a crucial step in noradrenergic neurotransmission that regulates NE concentration in the synaptic cleft. It is a key mechanism mediated by the NE transporter (NET) which takes the neurotransmitter into the presynaptic neuron terminal or the adrenal medulla chromaffin cell. The activity of NET is short and long terms modulated by phosphorylation mediated by protein kinases A, C, and G and calcium-calmodulin-dependent protein kinase, whereas the transporter availability at the cell surface is regulated by glycosylation. Several neuropeptides like angiotensins II, III, and 1-7, bradykinin, natriuretic peptides, as well as endothelins (ETs) regulate a wide variety of biological effects, including noradrenergic transmission and in particular neuronal NE uptake. Diverse reports, including studies from our laboratory, show that ETs differentially modulate the activity and expression of NET not only in normal conditions but also in diverse cardiovascular diseases such as congestive heart failure and hypertension. Current literature supports a key role for the interaction between ETs and NE in maintaining neurotransmission homeostasis and further suggests that this interaction may represent a potential therapeutic target for various diseases, particularly hypertension.

  5. Polymeric micellar nanocarriers of benzoyl peroxide as potential follicular targeting approach for acne treatment.

    PubMed

    Kahraman, Emine; Özhan, Gül; Özsoy, Yıldız; Güngör, Sevgi

    2016-10-01

    The aim of this work was to optimize polymeric nano-sized micellar carriers of the anti-acne compound benzoyl peroxide (BPO) and to examine the ability of these carriers to deposit into hair follicles with the objective of improving skin delivery of BPO. BPO loaded polymeric micelles composed of Pluronic(®) F127 were prepared by the thin film hydration method and characterized in terms of size, loading capacity, morphology and physical stability. The optimized micelle formulation was then selected for skin delivery studies. The penetration of BPO loaded micellar carriers into skin and skin appendages across full thickness porcine skin was examined in vitro. Confocal microscopy images confirmed the penetration of Nile Red into hair follicles, which was loaded into micellar carriers as a model fluorescent compound. The relative safety of the polymeric micelles was evaluated with the MTT viability test using mouse embryonic fibroblasts. The results indicated that nano-sized polymeric micelles of BPO composed of Pluronic(®) F127 offer a potential approach to enhance skin delivery of BPO and that targeting of micelles into hair follicles may be an effective and safe acne treatment.

  6. Cancer Targeting Potential of (99m)Tc-Finasteride in Experimental Model of Prostate Carcinogenesis.

    PubMed

    Jan, Gowsia; Passi, Neelima D; Dhawan, Devinder Kumar; Chadha, Vijayta Dani

    2017-03-01

    This study aimed to radiolabel finasteride, a novel 5α-reductase inhibitor, to evaluate its cancer targeting potential in experimental model of prostate carcinogenesis. Finasteride was effectively radiolabeled with (99m)Tc and showed >90% labeling efficiency. The radiopharmaceutical was found to be stable up to 6 hours in rat serum at 37°C. The blood kinetics of the (99m)Tc-finasteride followed a biphasic release pattern, whereby fast-release phase was observed at 15 seconds and a slow-release phase was observed after 30 minutes of administration. The plasma protein binding of the radio complex observed was 83.89%. For biodistribution studies, the rats were divided into two groups. Group I served as normal controls, while group II was subjected to carcinogen N-methyl-N-nitrosourea (MNU) and hormone testosterone propionate (T) for induction of prostate carcinogenesis, which was confirmed histopathologically. The biodistribution studies on control and carcinogen-treated rats revealed a significant percent-specific uptake in prostate, which was found to be increased significantly as a function of time. The most significant finding of the study was an increase in the percent-specific uptake in prostate of carcinogen-treated animals when compared to the percent-specific uptake in prostate of normal rats after 2 and 4 hours postinjection. The study concludes that (99m)Tc-finasteride possesses selectively toward prostate cancer tissue and can be explored further for its role in detection of prostate cancer.

  7. Inosine 5'-Monophosphate Dehydrogenase (IMPDH) as a Potential Target for the Development of a New Generation of Antiprotozoan Agents.

    PubMed

    Fotie, Jean

    2016-06-19

    Inosine-5'-monophosphate dehydrogenase (IMPDH) is a metabolic enzyme that catalyzes the critical step in guanine nucleotide biosynthesis, and thus is at the center of cell growth and proliferation. However, although this enzyme has been exploited as potential target for the development of immunosuppressive, anticancer, and antiviral agents, the functional importance of IMPDH as a promising antiprotozoan drug target is still in its infancy mainly because of the availability of alternative nucleotides metabolic pathways in many of these parasites. This situation suggests that the inhibition of IMPDH might have little to no effect on the survival of protozoan parasites. As a result, no IMPDH inhibitor is currently commercially available or has advanced to clinical trials as a potential antiprotozoan drug. Nevertheless, recent advances toward the development of selective inhibitors of the IMPDH enzyme from Crystosporidium parvum as potential drug candidates against cryptosporidiosis should revive further investigations of this drug target in other protozoa parasites. The current review examines the chemical structures and biological activities of reported protozoan's IMPDH inhibitors. SciFinder was used to broadly pinpoint reports published on the topic in the chemical literature, with no specific time frame. Opportunities and challenges towards the development of inhibitors of IMPDH enzymes from protozoa parasites as potential chemotherapies toward the respective diseases they cause are also discussed.

  8. Identification of immunodominant regions of Brassica juncea glyoxalase I as potential antitumor immunomodulation targets.

    PubMed

    Deswal, Renu; Singh, Rohini; Lynn, Andrew M; Frank, Ronald

    2005-03-01

    Glyoxalase I activity has been shown to be directly related to cancer and its inhibitors have been used as anti-cancer drugs. Immunochemical studies have shown immunochemical relatedness among animal and plant glyoxalase I, but its potential application for biomedical research has not been investigated. In order to understand the conserved immunochemical regions of the protein and to determine probable immunomodulation targets, a cellulose-bound scanning peptide library for Brassica juncea glyoxalase I was made using the spot synthesis method. Immuno-probing of the library, using B. juncea anti-glyoxalase I monospecific polyclonal antibodies, revealed three immunodominant regions, epitope I, II, and III. In the homology model of B. juncea glyoxalase I generated by threading its sequence onto the human glyoxalase I, the high accessible surface area and the hydrophilic nature of the epitopes confirmed their surface localization and hence their accessibility for antigen-antibody interaction. Epitopes I and II were specific to B. juncea glyoxalase I. Localizing the epitopes on available glyoxalase I sequences showed that epitope III containing the active site region was conserved across phyla. Therefore, this could be used as a potential immunomodulation target for cancer therapy. Moreover, as the most immunogenic epitopes were mapped on the surface of the protein, this method could be used to discover potential therapeutic targets. It is a simple and fast approach for such investigations. This study, to our knowledge, is the first in epitope mapping of glyoxalase I and has great biomedical potential.

  9. Glo1 genetic amplification as a potential therapeutic target in hepatocellular carcinoma.

    PubMed

    Zhang, Shirong; Liang, Xiaodong; Zheng, Xiaoliang; Huang, Haixiu; Chen, Xufeng; Wu, Kan; Wang, Bing; Ma, Shenglin

    2014-01-01

    Glyoxalase 1 (Glo1) gene aberrations is associated with tumorigenesis and progression in numerous cancers. In this study, we explored the role of Glo1 genetic amplification and expression in Chinese patients with hepatocellular carcinoma (HCC), and Glo1 genetic amplification as potential therapeutic target for HCC. We used fluorescence in situ hybridization (FISH) analysis and qRT-PCR to examine Glo1 genetic aberrations and Glo1 mRNA expression in paired tumor samples obtained from HCC patients. Glo1 genetic amplification was identified in a subset of HCC patient (6%, 3/50), and up-regulation of Glo1 expression was found in 48% (24/50) of tumor tissues compared with adjacent non-tumorous tissues. Statistic analysis showed that Glo1-upregulation significantly correlated with high serum level of alpha-fetoprotein (AFP). Interfering Glo1 expression with shRNA knocking-down led to significant inhibition of cell growth and induced apoptosis in primarily cultured HCC cells carrying genetic amplified Glo1 gene, while no inhibitory effects on cell proliferation were observed in HCC cells with normal copies of Glo1 gene. Glo1 knockdown also inhibited tumor growth and induced apoptosis in xenograft tumors established from primarily cultured HCC cells with Glo1 gene amplification. In addition, Glo1 knocking-down with shRNA interfering caused cellular accumulation of methylglyoxal, a Glo1 cytotoxic substrate. Our data suggested Glo1 pathway activation is required for cell proliferation and cell survival of HCC cells carrying Glo1 genetic amplification. Intervention of Glo1 activation could be a potential therapeutic option for patients with HCC carrying Glo1 gene amplification.

  10. Non target effects in Biological control (in French)

    USDA-ARS?s Scientific Manuscript database

    Only recently the ecological non target effects of biocontrol have been recognized and studies. This chapter presents examples that were highlighted in the past 3 decades as non target effects in biocontrol. Two main examples are for weeds, the prickly pear in Central America, and for insect pests, ...

  11. Dynamic effects of interaction of composite projectiles with targets

    SciTech Connect

    Zakharov, V. M.

    2016-01-15

    The process of high-speed impact of projectiles against targets of finite thickness is experimentally investigated. Medium-hard steel plates are used as targets. The objective of this research is to carry out a comparative analysis of dynamic effects of interaction of various types of projectiles with targets, such as characteristics of destruction of the target, the state of the projectile behind the target, and particularities of the after-penetration stream of fragments after the target has been pierced. The projectiles are made of composites on the basis of tungsten carbide obtained by caking and the SHS-technology. To compare effectiveness of composite projectiles steel projectiles are used. Their effectiveness was estimated in terms of the ballistic limit. High density projectiles obtained by means of the SHS-technology are shown to produce results comparable in terms of the ballistic limit with high-strength projectiles that contain tungsten received by caking.

  12. Dynamic effects of interaction of composite projectiles with targets

    NASA Astrophysics Data System (ADS)

    Zakharov, V. M.

    2016-01-01

    The process of high-speed impact of projectiles against targets of finite thickness is experimentally investigated. Medium-hard steel plates are used as targets. The objective of this research is to carry out a comparative analysis of dynamic effects of interaction of various types of projectiles with targets, such as characteristics of destruction of the target, the state of the projectile behind the target, and particularities of the after-penetration stream of fragments after the target has been pierced. The projectiles are made of composites on the basis of tungsten carbide obtained by caking and the SHS-technology. To compare effectiveness of composite projectiles steel projectiles are used. Their effectiveness was estimated in terms of the ballistic limit. High density projectiles obtained by means of the SHS-technology are shown to produce results comparable in terms of the ballistic limit with high-strength projectiles that contain tungsten received by caking.

  13. Optical Imaging and Gene Therapy with Neuroblastoma-Targeting Polymeric Nanoparticles for Potential Theranostic Applications.

    PubMed

    Lee, Jangwook; Jeong, Eun Ju; Lee, Yeon Kyung; Kim, Kwangmeyung; Kwon, Ick Chan; Lee, Kuen Yong

    2016-03-02

    Recently, targeted delivery systems based on functionalized polymeric nanoparticles have attracted a great deal of attention in cancer diagnosis and therapy. Specifically, as neuroblastoma occurs in infancy and childhood, targeted delivery may be critical to reduce the side effects that can occur with conventional approaches, as well as to achieve precise diagnosis and efficient therapy. Thus, biocompatible poly(d,l-lactide-co-glycolide) (PLG) nanoparticles containing an imaging probe and therapeutic gene are prepared, followed by modification with rabies virus glycoprotein (RVG) peptide for neuroblastoma-targeting delivery. RVG peptide is a well-known neuronal targeting ligand and is chemically conjugated to PLG nanoparticles without changing their size or shape. RVG-modified nanoparticles are effective in specifically targeting neuroblastoma both in vitro and in vivo. RVG-modified nanoparticles loaded with a fluorescent probe are useful to detect the tumor site in a neuroblastoma-bearing mouse model, and those encapsulating a therapeutic gene cocktail (siMyc, siBcl-2, and siVEGF) significantly suppressed tumor growth in the mouse model. This approach to designing and tailoring of polymeric nanoparticles for targeted delivery may be useful in the development of multimodality systems for theranostic approaches.

  14. Orphan G protein-coupled receptors (GPCRs): biological functions and potential drug targets

    PubMed Central

    Tang, Xiao-long; Wang, Ying; Li, Da-li; Luo, Jian; Liu, Ming-yao

    2012-01-01

    The superfamily of G protein-coupled receptors (GPCRs) includes at least 800 seven-transmembrane receptors that participate in diverse physiological and pathological functions. GPCRs are the most successful targets of modern medicine, and approximately 36% of marketed pharmaceuticals target human GPCRs. However, the endogenous ligands of more than 140 GPCRs remain unidentified, leaving the natural functions of those GPCRs in doubt. These are the so-called orphan GPCRs, a great source of drug targets. This review focuses on the signaling transduction pathways of the adhesion GPCR family, the LGR subfamily, and the PSGR subfamily, and their potential functions in immunology, development, and cancers. In this review, we present the current approaches and difficulties of orphan GPCR deorphanization and characterization. PMID:22367282

  15. The Sphingolipid Biosynthetic Pathway Is a Potential Target for Chemotherapy against Chagas Disease

    PubMed Central

    Koeller, Carolina Macedo; Heise, Norton

    2011-01-01

    The protozoan parasite Trypanosoma cruzi is the causative agent of human Chagas disease, for which there currently is no cure. The life cycle of T. cruzi is complex, including an extracellular phase in the triatomine insect vector and an obligatory intracellular stage inside the vertebrate host. These phases depend on a variety of surface glycosylphosphatidylinositol-(GPI-) anchored glycoconjugates that are synthesized by the parasite. Therefore, the surface expression of GPI-anchored components and the biosynthetic pathways of GPI anchors are attractive targets for new therapies for Chagas disease. We identified new drug targets for chemotherapy by taking the available genome sequence information and searching for differences in the sphingolipid biosynthetic pathways (SBPs) of mammals and T. cruzi. In this paper, we discuss the major steps of the SBP in mammals, yeast and T. cruzi, focusing on the IPC synthase and ceramide remodeling of T. cruzi as potential therapeutic targets for Chagas disease. PMID:21603271

  16. Tumor-targeting bacterial therapy: A potential treatment for oral cancer (Review)

    PubMed Central

    LIU, SAI; XU, XIAOPING; ZENG, XIN; LI, LONGJIANG; CHEN, QIANMING; LI, JING

    2014-01-01

    Certain obligate or facultative anaerobic bacteria, which exhibit an inherent ability to colonize solid tumors in vivo, may be used in tumor targeting. As genetically manipulated bacteria may actively and specifically penetrate into the tumor tissue, bacterial therapy is becoming a promising approach in the treatment of tumors. However, to the best of our knowledge, no reports have been published thus far regarding the bacterial treatment of oral cancer, one of the most common types of cancer worldwide. In this review, the progress in the understanding of bacterial strategies used in tumor-targeted therapy is discussed and particular bacterial strains that may have great therapeutic potential in oral squamous cell carcinoma (OSCC) tumor-targeted therapy are predicted as determined by previous studies. PMID:25364397

  17. The Hot and Potential Targets of Type 2 Diabetes Mellitus Treatment in Recent Decade.

    PubMed

    Shi, Dayong; Luo, Jiao; Wang, Lijun; Xu, Qi

    2017-03-07

    Type 2 diabetes mellitus (T2DM) has been a great burden to the world and it's urgent to develop new treatment strategies. Many targets are currently available to aid in the drug discovery of this disease as our understanding of the pathophysiology of T2DM develops. This article is intended to provide a broad ranging overview of 14 prominent molecule targets currently being pursued for the treatment of diabetes, with regard to their therapeutic rationale, small molecule modulators and application prospects. These targets are roughly divided into four general areas that correlate with insulin secretion, act on the insulin sensitivity, and have an effect on the complications. This article could provides the medicinal chemist interested in discovering novel therapeutic small molecules with a myriad of promising diabetes targets and broader development space for treating T2DM.

  18. Limbic, associative, and motor territories within the targets for deep brain stimulation: potential clinical implications.

    PubMed

    Sudhyadhom, Atchar; Bova, Frank J; Foote, Kelly D; Rosado, Christian A; Kirsch-Darrow, Lindsey; Okun, Michael S

    2007-07-01

    The use of deep brain stimulation (DBS) has recently been expanding for the treatment of many neurologic disorders such as Parkinson disease, dystonia, essential tremor, Tourette's syndrome, cluster headache, epilepsy, depression, and obsessive compulsive disorder. The target structures for DBS include specific segregated territories within limbic, associative, or motor regions of very small subnuclei. In this review, we summarize current clinical techniques for DBS, the cognitive/mood/motor outcomes, and the relevant neuroanatomy with respect to functional territories within specific brain targets. Future development of new techniques and technology that may include a more direct visualization of "motor" territories within target structures may prove useful for avoiding side effects that may result from stimulation of associative and limbic regions. Alternatively, newer procedures may choose and specifically target non-motor territories for chronic electrical stimulation.

  19. Odorranalectin Is a Small Peptide Lectin with Potential for Drug Delivery and Targeting

    PubMed Central

    Xu, Xueqing; Yang, Hailong; Wu, Bingxian; Wang, Yipeng; Zhu, Jianhua; Lai, Ren; Jiang, Xinguo; Lin, Donghai; Prescott, Mark C.; Rees, Huw H.

    2008-01-01

    Background Lectins are sugar-binding proteins that specifically recognize sugar complexes. Based on the specificity of protein–sugar interactions, different lectins could be used as carrier molecules to target drugs specifically to different cells which express different glycan arrays. In spite of lectin's interesting biological potential for drug targeting and delivery, a potential disadvantage of natural lectins may be large size molecules that results in immunogenicity and toxicity. Smaller peptides which can mimic the function of lectins are promising candidates for drug targeting. Principal Findings Small peptide with lectin-like behavior was screened from amphibian skin secretions and its structure and function were studied by NMR, NMR-titration, SPR and mutant analysis. A lectin-like peptide named odorranalectin was identified from skin secretions of Odorrana grahami. It was composed of 17 aa with a sequence of YASPKCFRYPNGVLACT. L-fucose could specifically inhibit the haemagglutination induced by odorranalectin. 125I-odorranalectin was stable in mice plasma. In experimental mouse models, odorranalectin was proved to mainly conjugate to liver, spleen and lung after i.v. administration. Odorranalectin showed extremely low toxicity and immunogenicity in mice. The small size and single disulfide bridge of odorranalectin make it easy to manipulate for developing as a drug targeting system. The cyclic peptide of odorranalectin disclosed by solution NMR study adopts a β-turn conformation stabilized by one intramolecular disulfide bond between Cys6-Cys16 and three hydrogen bonds between Phe7-Ala15, Tyr9-Val13, Tyr9-Gly12. Residues K5, C6, F7, C16 and T17 consist of the binding site of L-fucose on odorranalectin determined by NMR titration and mutant analysis. The structure of odorranalectin in bound form is more stable than in free form. Conclusion These findings identify the smallest lectin so far, and show the application potential of odorranalectin for drug

  20. Evaluation of potential RNA-interference-target genes to control cotton mealybug, Phenacoccus solenopsis (Hemiptera: Pseudococcuidae).

    PubMed

    Khan, Arif M; Ashfaq, Muhammad; Khan, Azhar A; Naseem, Muhammad T; Mansoor, Shahid

    2017-03-18

    RNA interference (RNAi) of vital insect genes is a potential tool for targeted pest control. However, selection of the right target genes is a challenge because the RNAi efficacy is known to vary among insect species. Cotton mealybug, Phenacoccus solenopsis, is a phloem-feeding economically important crop pest. We evaluated the RNAi of two vital genes, Bursicon (PsBur) and V-ATPase (PsV-ATPase) as potential targets in P. solenopsis for its control. PCR fragments of PsBur and PsV-ATPase were amplified using cDNA synthesized from the total RNA. The PCR amplicons were cloned into Potato virus X (PVX) to develop recombinant PVX for the inoculation of Nicotiana tabacum plants for bioassays with healthy P. solenopsis. Reverse-transcription-polymerase chain reaction (RT-PCR) was used to validate the expression of transgenes in the recombinant-PVX-inoculated plants (treated), and suppression of the target genes in the mealybugs exposed to them. The RT-PCR confirmed the expression of transgenes in the treated plants. Mealybug individuals on treated plants either died or showed physical deformities. Further, the population of mealybug was significantly reduced by feeding on N. tabacum expressing RNAi triggers against PsBur and PsV-ATPase. The results conclude that RNAi is activated in P. solenopsis by feeding on N. tabacum expressing RNAi triggering elements of PsBur and PsV-ATPase genes through recombinant PVX vector. Further, V-ATPase and Bursicon genes are potential targets for RNAi mediated control of P. solenopsis. This article is protected by copyright. All rights reserved.

  1. Formulation of temozolomide-loaded nanoparticles and their targeting potential to melanoma cells.

    PubMed

    Jiang, Guan; Li, Ronghua; Tang, Jianqin; Ma, Yafeng; Hou, Xiaoyang; Yang, Chunsheng; Guo, Wenwen; Xin, Yong; Liu, Yanqun

    2017-02-01

    The present study was carried out to prepare and evaluate a temozolomide (TMZ)-loaded polyamide-amine dendrimer (PAMAM)‑based nanodrug delivery system, and to explore its ability to target human melanoma (A375) cells in vitro. Firstly, PAMAM-PEG and PAMAM-PEG-GE11 were synthesized by substitution and addition reactions, and their products were identified and characterized by fourier transform-infrared (FTIR), proton nuclear magnetic resonance (1H-NMR) and transmission electron microscopy (TEM), as well as differential light scattering (DLS). Using fluorescein isothiocyanate (FITC)-modified PAMAM, we synthesized FITC-PAMAM, FITC-PAMAM-PEG and FITC-PAMAM-PEG-GE11. Fluorescence microscopy and flow cytometry were used to monitor the uptake of A375 cells of these three nanomaterials. Secondly, TMZ-PAMAM‑PEG‑GE11-HA drug complexes were prepared by ultrasonic emulsification, and their particle size, zeta potential and morphology were evaluated by DLS and TEM. Drug loading (DL) and encapsulation efficiency (EE) were assayed by ultraviolet spectrophotometry. Thirdly, we ascertained whether TMZ-PAMAM-PEG-GE11-HA conjugates could target A375 cells in vitro. The TMZ-PAMAM‑PEG‑GE11-HA nanodrug delivery system was successfully synthesized according to FTIR and 1H-NMR. Its mean particle size was 183.2 nm and zeta potential was -0.01 mV. It was a regular sphere with good uniformity. The EE of TMZ-PAMAM-PEG-GE11-HA was ~50.63% and DL ~10.4%. TMZ-PAMAM-PEG-GE11-HA targeted A375 cells in vitro. In conclusion, the TMZ-PAMAM‑PEG-GE11-HA nanodrug delivery system was successfully prepared, and demonstrated its potential for targeting A375 cells in vitro. This system enhanced the sensitivity of A375 cells to TMZ, and provided a novel targeted strategy for the treatment of metastatic melanoma.

  2. Potential Health Effects from Groundwater Pollution.

    ERIC Educational Resources Information Center

    Goyer, Robert A.

    1985-01-01

    Discusses the growing awareness of potential toxicological effects of synthetic organic chemicals contaminating groundwater. Problems concerning pesticides, chlorination, epidemiologic studies, cancer, nephrotoxicity, and considerations of risk are addressed. Additional research in this area is advocated. (DH)

  3. Potential Health Effects from Groundwater Pollution.

    ERIC Educational Resources Information Center

    Goyer, Robert A.

    1985-01-01

    Discusses the growing awareness of potential toxicological effects of synthetic organic chemicals contaminating groundwater. Problems concerning pesticides, chlorination, epidemiologic studies, cancer, nephrotoxicity, and considerations of risk are addressed. Additional research in this area is advocated. (DH)

  4. PT symmetric interpretation of effective potentials

    NASA Astrophysics Data System (ADS)

    Sarkar, Sarben

    2017-07-01

    Conventional systems in equilibrium should have convex effective potentials. PT symmetry applies to systems which are in between open and closed systems. A PT symmetric interpretation can allow some non-convex effective potentials to be entirely physical. The oneloop effective potentials of the Higgs field in the Standard Model and the gravitino condensate in dynamically broken supergravity are conventionally unstable at large field values. In the specially simple case of space-independent and time-independent fields, the effective potentials are governed by PT-symmetric quantum mechanics. The PT-symmetric reinterpretation of these models at a quantum-mechanical level eliminates these instabilities and involves unusual semi-classical analysis involving many Riemann sheets. This interpretation is based on a combination of numerical analysis and semi-classical asymptotics.

  5. Clostridium-DT(DB): a comprehensive database for potential drug targets of Clostridium difficile.

    PubMed

    Jadhav, Ankush; Ezhilarasan, Vijayalakshmi; Prakash Sharma, Om; Pan, Archana

    2013-05-01

    Clostridium difficile is considered to be one of the most important causes of health care-associated infections currently. The prevalence and severity of C. difficile infection have increased significantly worldwide in the past decade which has led to the increased research interest. Here, using comparative genomics strategy coupled with bioinformatics tools we have identified potential drug targets in C. difficile and determined their three-dimensional structures in order to develop a database, named Clostridium-DT(DB). Currently, the database comprises the potential drug targets with their structural information from three strains of C. difficile, namely hypervirulent PCR-ribotype 027 strain R20291, PCR-ribotype 012 strain 630, and PCR-ribotype 027 strain CD196. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Identification of potential cellular targets of aloisine A by affinity chromatography.

    PubMed

    Corbel, Caroline; Haddoub, Rose; Guiffant, Damien; Lozach, Olivier; Gueyrard, David; Lemoine, Jérôme; Ratin, Morgane; Meijer, Laurent; Bach, Stéphane; Goekjian, Peter

    2009-08-01

    Affinity chromatography was used to identify potential cellular targets of aloisine A (7-n-butyl-6-(4'-hydroxyphenyl)-5H-pyrrolo[2,3b]pyrazine), a potent inhibitor of cyclin-dependent kinases. This technique is based on the immobilization of the drug on a solid matrix, followed by identification of specifically bound proteins. To this end, both aloisine A and the protein-kinase inactive control N-methyl aloisine, bearing extended linker chains have been synthesized. We present the preparation of such analogues having the triethylene glycol chain at different positions of the molecule, as well as their immobilization on an agarose-based matrix. Affinity chromatography of various biological extracts on the aloisine matrices allowed the identification of both protein kinases and non-kinase proteins as potential cellular targets of aloisine.

  7. Adipokines: Potential Therapeutic Targets for Vascular Dysfunction in Type II Diabetes Mellitus and Obesity

    PubMed Central

    El husseny, Mostafa Wanees Ahmed; Mamdouh, Mediana; Shaban, Sara; Zaki, Marwa Mostafa Mohamed; Ahmed, Osama M.

    2017-01-01

    Adipokines are bioactive molecules that regulate several physiological functions such as energy balance, insulin sensitization, appetite regulation, inflammatory response, and vascular homeostasis. They include proinflammatory cytokines such as adipocyte fatty acid binding protein (A-FABP) and anti-inflammatory cytokines such as adiponectin, as well as vasodilator and vasoconstrictor molecules. In obesity and type II diabetes mellitus (DM), insulin resistance causes impairment of the endocrine function of the perivascular adipose tissue, an imbalance in the secretion of vasoconstrictor and vasodilator molecules, and an increased production of reactive oxygen species. Recent studies have shown that targeting plasma levels of adipokines or the expression of their receptors can increase insulin sensitivity, improve vascular function, and reduce the risk of cardiovascular morbidity and mortality. Several reviews have discussed the potential of adipokines as therapeutic targets for type II DM and obesity; however, this review is the first to focus on their therapeutic potential for vascular dysfunction in type II DM and obesity. PMID:28286779

  8. Identification of potential miRNAs and their targets in Vriesea carinata (Poales, Bromeliaceae).

    PubMed

    Guzman, Frank; Almerão, Mauricio Pereira; Korbes, Ana Paula; Christoff, Ana Paula; Zanella, Camila Martini; Bered, Fernanda; Margis, Rogério

    2013-09-01

    The miRNAs play important roles in regulation of gene expression at the post-transcriptional level. A small RNA and RNA-seq of libraries were constructed to identify miRNAs in Vriesea carinata, a native bromeliad species from Brazilian Atlantic Rainforest. Illumina technology was used to perform high throughput sequencing and data was analyzed using bioinformatics tools. We obtained 2,191,509 mature miRNAs sequences representing 54 conserved families in plant species. Further analysis allowed the prediction of secondary structures for 19 conserved and 16 novel miRNAs. Potential targets were predicted from pre-miRNAs by sequence homology and validated using RTqPCR approach. This study provides the first identification of miRNAs and their potential targets of a bromeliad species.

  9. Potential clinical insights into microRNAs and their target genes in esophageal carcinoma.

    PubMed

    Li, Su Q; Wang, He M; Cao, Xiu F

    2011-12-01

    Esophageal carcinoma (EC) are characterized by dysregulation of microRNAs, which play an important roles as a posttranscriptional regulators in protein synthesis, and are involved in cellular processes, such as proliferation, apoptosis, and differentiation. Recently, altered miRNAs expression has been comprehensively studied in EC by high-throughput technology. Increased understanding of miRNAs target genes and their potential regulatory mechanisms have clarified the miRNAs activities and may provide exciting opportunities for cancer diagnosis and miRNA-based genetherapy. Here, we reviewed the most recently discovered miRNA target genes, with particular emphasis on the deciphering of their possible mechanisms and the potential roles in miRNAs-based tumour therapeutics.

  10. Adipokines: Potential Therapeutic Targets for Vascular Dysfunction in Type II Diabetes Mellitus and Obesity.

    PubMed

    El Husseny, Mostafa Wanees Ahmed; Mamdouh, Mediana; Shaban, Sara; Ibrahim Abushouk, Abdelrahman; Zaki, Marwa Mostafa Mohamed; Ahmed, Osama M; Abdel-Daim, Mohamed M

    2017-01-01

    Adipokines are bioactive molecules that regulate several physiological functions such as energy balance, insulin sensitization, appetite regulation, inflammatory response, and vascular homeostasis. They include proinflammatory cytokines such as adipocyte fatty acid binding protein (A-FABP) and anti-inflammatory cytokines such as adiponectin, as well as vasodilator and vasoconstrictor molecules. In obesity and type II diabetes mellitus (DM), insulin resistance causes impairment of the endocrine function of the perivascular adipose tissue, an imbalance in the secretion of vasoconstrictor and vasodilator molecules, and an increased production of reactive oxygen species. Recent studies have shown that targeting plasma levels of adipokines or the expression of their receptors can increase insulin sensitivity, improve vascular function, and reduce the risk of cardiovascular morbidity and mortality. Several reviews have discussed the potential of adipokines as therapeutic targets for type II DM and obesity; however, this review is the first to focus on their therapeutic potential for vascular dysfunction in type II DM and obesity.

  11. Basic calcium phosphate crystals and osteoarthritis pathogenesis: novel pathways and potential targets.

    PubMed

    Stack, John; McCarthy, Geraldine

    2016-03-01

    Basic calcium phosphate (BCP) crystals have long been associated with the pathogenesis of osteoarthritis. As our knowledge concerning BCP crystals in osteoarthritis expands, so does the potential to develop targeted therapies. The present review discusses recent advances in this field and attempts to summarize our current understanding regarding the role of BCP crystals in osteoarthritis pathogenesis. BCP crystals injected into the knees of mice induce osteoarthritis-like changes, further evidence of their pathogenic properties. Interleukin-6 has emerged as a key cytokine involved in BCP crystal-induced inflammation that could represent a potential therapeutic target. The role of BCP crystal-induced osteoclastogenesis has also recently been explored and may also hold the key to future targeted therapies. Although tools to detect BCP crystals remain limited, dual energy computerized tomography scanning has emerged as a useful noninvasive means of quantifying intra-articular calcium crystal deposition. BCP crystals can activate a number of inflammatory pathways which in turn may lead to cartilage degradation and osteoarthritis. Understanding of these pathways may ultimately yield targeted therapies for osteoarthritis, for which none currently exists.

  12. MRI-visible liposome nanovehicles for potential tumor-targeted delivery of multimodal therapies

    NASA Astrophysics Data System (ADS)

    Ren, Lili; Chen, Shizhen; Li, Haidong; Zhang, Zhiying; Ye, Chaohui; Liu, Maili; Zhou, Xin

    2015-07-01

    Real-time diagnosis and monitoring of disease development, and therapeutic responses to treatment, are possible by theranostic magnetic resonance imaging (MRI). Here we report the synthesis of a multifunctional liposome, which contains Gd-DOTA (an MRI probe), paclitaxel and c(RGDyk) (a targeted peptide). This nanoparticle overcame the insolubility of paclitaxel, reduced the side effects of FDA-approved formulation of PTX-Cre (Taxol®) and improved drug delivery efficiency to the tumor. c(RGDyk) modification greatly enhanced the cytotoxicity of the drug in tumor cells A549. The T1 relaxivity in tumor cells treated with the targeted liposome formulation was increased 16-fold when compared with the non-targeted group. In vivo, the tumors in mice were visualized using T1-weighted imaging after administration of the liposome. Also the tumor growth could be inhibited well after the treatment. Fluorescence images in vitro and ex vivo also showed the targeting effect of this liposome in tumor cells, indicating that this nanovehicle could limit the off-target side effects of anticancer drugs and contrast agents. These findings lay the foundation for further tumor inhibition study and application of this delivery vehicle in cancer therapy settings.

  13. Shikimate kinase: a potential target for development of novel antitubercular agents.

    PubMed

    Pereira, José H; Vasconcelos, Igor B; Oliveira, Jaim S; Caceres, Rafael A; de Azevedo, Walter F; Basso, Luis A; Santos, Diógenes S

    2007-03-01

    Tuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. However, no new classes of drugs for TB have been developed in the past 30 years. Therefore there is an urgent need to develop faster acting and effective new antitubercular agents, preferably belonging to new structural classes, to better combat TB, including MDR-TB, to shorten the duration of current treatment to improve patient compliance, and to provide effective treatment of latent tuberculosis infection. The enzymes in the shikimate pathway are potential targets for development of a new generation of antitubercular drugs. The shikimate pathway has been shown by disruption of aroK gene to be essential for the Mycobacterium tuberculosis. The shikimate kinase (SK) catalyses the phosphorylation of the 3-hydroxyl group of shikimic acid (shikimate) using ATP as a co-substrate. SK belongs to family of nucleoside monophosphate (NMP) kinases. The enzyme is an alpha/beta protein consisting of a central sheet of five parallel beta-strands flanked by alpha-helices. The shikimate kinases are composed of three domains: Core domain, Lid domain and Shikimate-binding domain. The Lid and Shikimate-binding domains are responsible for large conformational changes during catalysis. More recently, the precise interactions between SK and substrate have been elucidated, showing the binding of shikimate with three charged residues conserved among the SK sequences. The elucidation of interactions between MtSK and their substrates is crucial for the development of a new generation of drugs against tuberculosis through rational drug design.

  14. FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib.

    PubMed

    Hibi, Masaaki; Kaneda, Hiroyasu; Tanizaki, Junko; Sakai, Kazuko; Togashi, Yosuke; Terashima, Masato; De Velasco, Marco Antonio; Fujita, Yoshihiko; Banno, Eri; Nakamura, Yu; Takeda, Masayuki; Ito, Akihiko; Mitsudomi, Tetsuya; Nakagawa, Kazuhiko; Okamoto, Isamu; Nishio, Kazuto

    2016-11-01

    Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non-small cell lung cancer. We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined in vitro, and its effects on tumor formation were examined in vivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway in vitro and in vivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.

  15. Assessing potential introduction of universal or targeted hepatitis A vaccination in the Netherlands.

    PubMed

    Suijkerbuijk, A W M; Lugnér, A K; van Pelt, W; Wallinga, J; Verhoef, L P B; de Melker, H E; de Wit, G A

    2012-07-27

    In many industrialized countries, hepatitis A incidence rates have declined steadily in the past decades. Since future cohorts of non-vaccinated elderly will lack protection against disease and the burden of hepatitis A is higher with increasing age, this could be an argument in favour of taking preventive measures such as including hepatitis A vaccine into the National Immunisation Program, or offering hepatitis A vaccine to the elderly only. Using a vaccination evaluation scheme, we assessed the potential benefits and drawbacks of introducing hepatitis A vaccine in the National Immunisation Program in the Netherlands. The average number of annual hepatitis A notifications is declining, from 957 in the period 1991 to 1995 to 211 over the period 2006 to 2010. The direct health care costs and costs due to productivity losses per patient are rising, because the age at infection increases and older patients require a relatively higher number of hospitalizations. Initiating a vaccination program would most likely not be cost-effective yet. The annual costs of mass-vaccination are large: about €10 million for infants and €13 million for older people (and only in the first year €210 million), based on current retail prices. The annual effects of mass-vaccination are small: the cost-of-illness in recent years attributed to hepatitis A infection is estimated to be €650,000 per year, and the disease burden is on average 17 DALYs. Given the current low hepatitis A incidence, and the continuing decline in incidence, targeted preventive measures such as vaccinating travellers and other high-risk groups and timely vaccination of close contacts of hepatitis A patients are adequate. However, because susceptibility to hepatitis A is increasing in the group with the highest risk of developing severe complications upon infections, careful monitoring of the epidemiology of hepatitis A remains important. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. Internal combustion engine run on biogas is a potential solution to meet Indonesia emission target

    NASA Astrophysics Data System (ADS)

    Ambarita, Himsar

    2017-09-01

    Indonesia has released two different Greenhouse Gas (GHG) emissions reduction targets. The first target, released in 2009, is reduction GHG emissions 26% from Business-as-Usual (BAU) level using own budget and up 41% if supported international aids by 2020. The second target is reduction 29% and 41% from BAU by 2030 using own budget and with international support, respectively. In this paper, the BAU emissions and emissions reduction target of these two targets are elaborated. In addition, the characteristics of emissions from transportation sector are discussed. One of the potential mitigation actions is switching fuel in transportation sector. The results the most promising mitigation action in the transportation is switching oil fuel with biofuel. The Government of Indonesia (GoI) focuses on using biodiesel and bioethanol to run internal combustion engine in transportation sector and biogas is aimed to fuel power plant unit. However, there is very limited of success stories on using biogas in the power plant. The barriers and challenges will be discussed here. It is suggested to run internal combustion engine with biogas.

  17. Genetic Determinants of Target and Novelty Related Event-related Potentials in the Auditory Oddball Response

    PubMed Central

    Liu, Jingyu; Kiehl, Kent A.; Pearlson, Godfrey; Perrone-Bizzozero, Nora I.; Eichele, Tom; Calhoun, Vince D.

    2009-01-01

    Processing of novel and target stimuli in the auditory target detection or ‘oddball’ task encompasses the chronometry of perception, attention and working memory and is reflected in scalp recorded event-related potentials (ERPs). A variety of ERP components related to target and novelty processing have been described and extensively studied, and linked to deficits of cognitive processing. However, little is known about associations of genotypes with ERP endophenotypes. Here we sought to elucidate the genetic underpinnings of auditory oddball ERP components using a novel data analysis technique. A parallel independent component analysis of the electrophysiology and single nucleotide polymorphism (SNP) data was used to extract relations between patterns of ERP components and SNP associations purely based on an analysis incorporating higher order statistics. The method allows for broader associations of genotypes with phenotypes than traditional hypothesis-driven univariate correlational analyses. We show that target detection and processing of novel stimuli are both associated with a shared cluster of genes linked to the adrenergic and dopaminergic pathways. These results provide evidence of genetic influences on normal patterns of ERP generation during auditory target detection and novelty processing at the SNP association level. PMID:19285141

  18. The Potential of Targeting Ribosome Biogenesis in High-Grade Serous Ovarian Cancer

    PubMed Central

    Yan, Shunfei; Frank, Daniel; Son, Jinbae; Hannan, Katherine M.; Hannan, Ross D.; Chan, Keefe T.; Pearson, Richard B.; Sanij, Elaine

    2017-01-01

    Overall survival for patients with ovarian cancer (OC) has shown little improvement for decades meaning new therapeutic options are critical. OC comprises multiple histological subtypes, of which the most common and aggressive subtype is high-grade serous ovarian cancer (HGSOC). HGSOC is characterized by genomic structural variations with relatively few recurrent somatic mutations or dominantly acting oncogenes that can be targeted for the development of novel therapies. However, deregulation of pathways controlling homologous recombination (HR) and ribosome biogenesis has been observed in a high proportion of HGSOC, raising the possibility that targeting these basic cellular processes may provide improved patient outcomes. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has been approved to treat women with defects in HR due to germline BRCA mutations. Recent evidence demonstrated the efficacy of targeting ribosome biogenesis with the specific inhibitor of ribosomal RNA synthesis, CX-5461 in v-myc avian myelocytomatosis viral oncogene homolog (MYC)-driven haematological and prostate cancers. CX-5461 has now progressed to a phase I clinical trial in patients with haematological malignancies and phase I/II trial in breast cancer. Here we review the currently available targeted therapies for HGSOC and discuss the potential of targeting ribosome biogenesis as a novel therapeutic approach against HGSOC. PMID:28117679

  19. Mechanistic study of IR-780 dye as a potential tumor targeting and drug delivery agent.

    PubMed

    Zhang, Erlong; Luo, Shenglin; Tan, Xu; Shi, Chunmeng

    2014-01-01

    IR-780 iodide, a near-infrared fluorescent heptamethine dye, has been recently characterized to exhibit preferential accumulation property in the mitochondria of tumor cells. In this study, we investigated the possible mechanisms for its tumor selective activity and its potential as a drug delivery carrier. Results showed that the energy-dependent uptake of IR-780 iodide into the mitochondria of tumor cells was affected by glycolysis and plasma membrane potential. Moreover, OATP1B3 subtype of organic anion transporter peptides (OATPs) may play a dominant role in the transportation of IR-780 iodide into tumor cells, while cellular endocytosis, mitochondrial membrane potential and the ATP-binding cassette transporters did not show significant influence to its accumulation. We further evaluated the potential of IR-780 iodide as a drug delivery carrier by covalent conjugation of IR-780 with nitrogen mustard (IR-780NM). In vivo imaging showed that IR-780NM remained the tumor targeting property, indicating that IR-780 iodide could be potentially applied as a drug delivery agent for cancer targeted imaging and therapy.

  20. Action Potential Dynamics in Fine Axons Probed with an Axonally Targeted Optical Voltage Sensor.

    PubMed

    Ma, Yihe; Bayguinov, Peter O; Jackson, Meyer B

    2017-01-01

    The complex and malleable conduction properties of axons determine how action potentials propagate through extensive axonal arbors to reach synaptic terminals. The excitability of axonal membranes plays a major role in neural circuit function, but because most axons are too thin for conventional electrical recording, their properties remain largely unexplored. To overcome this obstacle, we used a genetically encoded hybrid voltage sensor (hVOS) harboring an axonal targeting motif. Expressing this probe in transgenic mice enabled us to monitor voltage changes optically in two populations of axons in hippocampal slices, the large axons of dentate granule cells (mossy fibers) in the stratum lucidum of the CA3 region and the much finer axons of hilar mossy cells in the inner molecular layer of the dentate gyrus. Action potentials propagated with distinct velocities in each type of axon. Repetitive firing broadened action potentials in both populations, but at an intermediate frequency the degree of broadening differed. Repetitive firing also attenuated action potential amplitudes in both mossy cell and granule cell axons. These results indicate that the features of use-dependent action potential broadening, and possible failure, observed previously in large nerve terminals also appear in much finer unmyelinated axons. Subtle differences in the frequency dependences could influence the propagation of activity through different pathways to excite different populations of neurons. The axonally targeted hVOS probe used here opens up the diverse repertoire of neuronal processes to detailed biophysical study.

  1. Revealing potential molecular targets bridging colitis and colorectal cancer based on multidimensional integration strategy

    PubMed Central

    Hu, Yongfei; Li, Xiaobo; Wang, Xishan; Fan, Huihui; Wang, Guiyu; Wang, Dong

    2015-01-01

    Chronic inflammation may play a vital role in the pathogenesis of inflammation-associated tumors. However, the underlying mechanisms bridging ulcerative colitis (UC) and colorectal cancer (CRC) remain unclear. Here, we integrated multidimensional interaction resources, including gene expression profiling, protein-protein interactions (PPIs), transcriptional and post-transcriptional regulation data, and virus-host interactions, to tentatively explore potential molecular targets that functionally link UC and CRC at a systematic level. In this work, by deciphering the overlapping genes, crosstalking genes and pivotal regulators of both UC- and CRC-associated functional module pairs, we revealed a variety of genes (including FOS and DUSP1, etc.), transcription factors (including SMAD3 and ETS1, etc.) and miRNAs (including miR-155 and miR-196b, etc.) that may have the potential to complete the connections between UC and CRC. Interestingly, further analyses of the virus-host interaction network demonstrated that several virus proteins (including EBNA-LP of EBV and protein E7 of HPV) frequently inter-connected to UC- and CRC-associated module pairs with their validated targets significantly enriched in both modules of the host. Together, our results suggested that multidimensional integration strategy provides a novel approach to discover potential molecular targets that bridge the connections between UC and CRC, which could also be extensively applied to studies on other inflammation-related cancers. PMID:26461477

  2. Detection of Moving Targets Using Soliton Resonance Effect

    NASA Technical Reports Server (NTRS)

    Kulikov, Igor K.; Zak, Michail

    2013-01-01

    The objective of this research was to develop a fundamentally new method for detecting hidden moving targets within noisy and cluttered data-streams using a novel "soliton resonance" effect in nonlinear dynamical systems. The technique uses an inhomogeneous Korteweg de Vries (KdV) equation containing moving-target information. Solution of the KdV equation will describe a soliton propagating with the same kinematic characteristics as the target. The approach uses the time-dependent data stream obtained with a sensor in form of the "forcing function," which is incorporated in an inhomogeneous KdV equation. When a hidden moving target (which in many ways resembles a soliton) encounters the natural "probe" soliton solution of the KdV equation, a strong resonance phenomenon results that makes the location and motion of the target apparent. Soliton resonance method will amplify the moving target signal, suppressing the noise. The method will be a very effective tool for locating and identifying diverse, highly dynamic targets with ill-defined characteristics in a noisy environment. The soliton resonance method for the detection of moving targets was developed in one and two dimensions. Computer simulations proved that the method could be used for detection of singe point-like targets moving with constant velocities and accelerations in 1D and along straight lines or curved trajectories in 2D. The method also allows estimation of the kinematic characteristics of moving targets, and reconstruction of target trajectories in 2D. The method could be very effective for target detection in the presence of clutter and for the case of target obscurations.

  3. sgRNAcas9: a software package for designing CRISPR sgRNA and evaluating potential off-target cleavage sites.

    PubMed

    Xie, Shengsong; Shen, Bin; Zhang, Chaobao; Huang, Xingxu; Zhang, Yonglian

    2014-01-01

    Although the CRISPR/Cas9/sgRNA system efficiently cleaves intracellular DNA at desired target sites, major concerns remain on potential "off-target" cleavage that may occur throughout the whole genome. In order to improve CRISPR-Cas9 specificity for targeted genome editing and transcriptional control, we describe a bioinformatics tool "sgRNAcas9", which is a software package developed for fast design of CRISPR sgRNA with minimized off-target effects. This package consists of programs to perform a search for CRISPR target sites (protospacers) with user-defined parameters, predict genome-wide Cas9 potential off-target cleavage sites (POT), classify the POT into three categories, batch-design oligonucleotides for constructing 20-nt (nucleotides) or truncated sgRNA expression vectors, extract desired length nucleotide sequences flanking the on- or off-target cleavage sites for designing PCR primer pairs to validate the mutations by T7E1 cleavage assay. Importantly, by identifying potential off-target sites in silico, the sgRNAcas9 allows the selection of more specific target sites and aids the identification of bona fide off-target sites, significantly facilitating the design of sgRNA for genome editing applications. sgRNAcas9 software package is publicly available at BiooTools website (www.biootools.com) under the terms of the GNU General Public License.

  4. Exploring the Trypanosoma brucei Hsp83 potential as a target for structure guided drug design.

    PubMed

    Pizarro, Juan Carlos; Hills, Tanya; Senisterra, Guillermo; Wernimont, Amy K; Mackenzie, Claire; Norcross, Neil R; Ferguson, Michael A J; Wyatt, Paul G; Gilbert, Ian H; Hui, Raymond

    2013-01-01

    Human African trypanosomiasis is a neglected parasitic disease that is fatal if untreated. The current drugs available to eliminate the causative agent Trypanosoma brucei have multiple liabilities, including toxicity, increasing problems due to treatment failure and limited efficacy. There are two approaches to discover novel antimicrobial drugs--whole-cell screening and target-based discovery. In the latter case, there is a need to identify and validate novel drug targets in Trypanosoma parasites. The heat shock proteins (Hsp), while best known as cancer targets with a number of drug candidates in clinical development, are a family of emerging targets for infectious diseases. In this paper, we report the exploration of T. brucei Hsp83--a homolog of human Hsp90--as a drug target using multiple biophysical and biochemical techniques. Our approach included the characterization of the chemical sensitivity of the parasitic chaperone against a library of known Hsp90 inhibitors by means of differential scanning fluorimetry (DSF). Several compounds identified by this screening procedure were further studied using isothermal titration calorimetry (ITC) and X-ray crystallography, as well as tested in parasite growth inhibitions assays. These experiments led us to the identification of a benzamide derivative compound capable of interacting with TbHsp83 more strongly than with its human homologs and structural rationalization of this selectivity. The results highlight the opportunities created by subtle structural differences to develop new series of compounds to selectively target the Trypanosoma brucei chaperone and effectively kill the sleeping sickness parasite.

  5. Identification of potential drug targets by subtractive genome analysis of Escherichia coli O157:H7: an in silico approach

    PubMed Central

    Mondal, Shakhinur Islam; Ferdous, Sabiha; Jewel, Nurnabi Azad; Akter, Arzuba; Mahmud, Zabed; Islam, Md Muzahidul; Afrin, Tanzila; Karim, Nurul

    2015-01-01

    Bacterial enteric infections resulting in diarrhea, dysentery, or enteric fever constitute a huge public health problem, with more than a billion episodes of disease annually in developing and developed countries. In this study, the deadly agent of hemorrhagic diarrhea and hemolytic uremic syndrome, Escherichia coli O157:H7 was investigated with extensive computational approaches aimed at identifying novel and broad-spectrum antibiotic targets. A systematic in silico workflow consisting of comparative genomics, metabolic pathways analysis, and additional drug prioritizing parameters was used to identify novel drug targets that were essential for the pathogen’s survival but absent in its human host. Comparative genomic analysis of Kyoto Encyclopedia of Genes and Genomes annotated metabolic pathways identified 350 putative target proteins in E. coli O157:H7 which showed no similarity to human proteins. Further bio-informatic approaches including prediction of subcellular localization, calculation of molecular weight, and web-based investigation of 3D structural characteristics greatly aided in filtering the potential drug targets from 350 to 120. Ultimately, 44 non-homologous essential proteins of E. coli O157:H7 were prioritized and proved to have the eligibility to become novel broad-spectrum antibiotic targets and DNA polymerase III alpha (dnaE) was the top-ranked among these targets. Moreover, druggability of each of the identified drug targets was evaluated by the DrugBank database. In addition, 3D structure of the dnaE was modeled and explored further for in silico docking with ligands having potential druggability. Finally, we confirmed that the compounds N-coeleneterazine and N-(1,4-dihydro-5H-tetrazol-5-ylidene)-9-oxo-9H-xanthene-2-sulfon-amide were the most suitable ligands of dnaE and hence proposed as the potential inhibitors of this target protein. The results of this study could facilitate the discovery and release of new and effective drugs against E

  6. Discovering potential drug-targets for personalized treatment of autoimmune disorders - what we learn from epidermolysis bullosa acquisita.

    PubMed

    Witte, Mareike; Koga, Hiroshi; Hashimoto, Takashi; Ludwig, Ralf J; Bieber, Katja

    2016-08-01

    Epidermolysis bullosa acquisita (EBA) is a chronic autoimmune bullous dermatosis (AIBD). Treatment of EBA is challenging and mostly relies on systemic immunosuppression. During the last decade, intensive research led to the identification of new potential therapeutic targets that interfere in different phases of disease progression. Therapeutic interventions acting upon these candidate drug targets in animal models of EBA, such as cytokine-modulating biologics and small molecules, have validated them as potential new therapeutic strategies for EBA patients. In this paper, we review the current treatments for EBA, describe the pathogenesis of the disease, and finally specify new drug candidates for the development of a more specific therapy with minimized side-effects for EBA and potentially other autoimmune diseases. We currently understand EBA as a disease that evolves from the interplay of many different signaling pathways. These signaling pathways, which are described in this review, provide new targets for EBA treatment. The ultimate goal of this research field is the development of specific, pathogenesis-based therapeutic strategies. Through identification of up- or downregulated pathways that dominate disease progression in individual patients, we expect therapy in EBA to become more and more precise and move towards a patient-based therapy.

  7. Vitiligo blood transcriptomics provides new insights into disease mechanisms and identifies potential novel therapeutic targets.

    PubMed

    Dey-Rao, Rama; Sinha, Animesh A

    2017-01-28

    Significant gaps remain regarding the pathomechanisms underlying the autoimmune response in vitiligo (VL), where the loss of self-tolerance leads to the targeted killing of melanocytes. Specifically, there is incomplete information regarding alterations in the systemic environment that are relevant to the disease state. We undertook a genome-wide profiling approach to examine gene expression in the peripheral blood of VL patients and healthy controls in the context of our previously published VL-skin gene expression profile. We used several in silico bioinformatics-based analyses to provide new insights into disease mechanisms and suggest novel targets for future therapy. Unsupervised clustering methods of the VL-blood dataset demonstrate a "disease-state"-specific set of co-expressed genes. Ontology enrichment analysis of 99 differentially expressed genes (DEGs) uncovers a down-regulated immune/inflammatory response, B-Cell antigen receptor (BCR) pathways, apoptosis and catabolic processes in VL-blood. There is evidence for both type I and II interferon (IFN) playing a role in VL pathogenesis. We used interactome analysis to identify several key blood associated transcriptional factors (TFs) from within (STAT1, STAT6 and NF-kB), as well as "hidden" (CREB1, MYC, IRF4, IRF1, and TP53) from the dataset that potentially affect disease pathogenesis. The TFs overlap with our reported lesional-skin transcriptional circuitry, underscoring their potential importance to the disease. We also identify a shared VL-blood and -skin transcriptional "hot spot" that maps to chromosome 6, and includes three VL-blood dysregulated genes (PSMB8, PSMB9 and TAP1) described as potential VL-associated genetic susceptibility loci. Finally, we provide bioinformatics-based support for prioritizing dysregulated genes in VL-blood or skin as potential therapeutic targets. We examined the VL-blood transcriptome in context with our (previously published) VL-skin transcriptional profile to address

  8. Atmospheric electromagnetic pulse propagation effects from thick targets in a terawatt laser target chamber

    SciTech Connect

    Remo, John L.; Adams, Richard G.; Jones, Michael C

    2007-08-20

    Generation and effects of atmospherically propagated electromagnetic pulses (EMPs)initiated by photoelectrons ejected by the high density and temperature target surface plasmas from multiterawatt laser pulses are analyzed. These laser radiation pulse interactions can significantly increase noise levels, thereby obscuring data (sometimes totally) and may even damage sensitive probe and detection instrumentation. Noise effects from high energy density (approximately multiterawatt) laser pulses(?300-400 ps pulse widths)interacting with thick(?1 mm) metallic and dielectric solid targets anddielectric-metallic powder mixtures are interpreted as transient resonance radiation associated with surface charge fluctuations on the target chamber that functions as a radiating antenna. Effective solutions that minimize atmospheric EMP effects on internal and proximate electronic and electro-optical equipment external to the system based on systematic measurements using Moebius loop antennas, interpretations of signal periodicities, and dissipation indicators determining transient noise origin characteristics from target emissions are described.Analytic models for the effect of target chamber resonances and associated noise current and temperature in a probe diode laser are described.

  9. Atmospheric electromagnetic pulse propagation effects from thick targets in a terawatt laser target chamber.

    PubMed

    Remo, John L; Adams, Richard G; Jones, Michael C

    2007-08-20

    Generation and effects of atmospherically propagated electromagnetic pulses (EMPs) initiated by photoelectrons ejected by the high density and temperature target surface plasmas from multiterawatt laser pulses are analyzed. These laser radiation pulse interactions can significantly increase noise levels, thereby obscuring data (sometimes totally) and may even damage sensitive probe and detection instrumentation. Noise effects from high energy density (approximately multiterawatt) laser pulses (approximately 300-400 ps pulse widths) interacting with thick approximately 1 mm) metallic and dielectric solid targets and dielectric-metallic powder mixtures are interpreted as transient resonance radiation associated with surface charge fluctuations on the target chamber that functions as a radiating antenna. Effective solutions that minimize atmospheric EMP effects on internal and proximate electronic and electro-optical equipment external to the system based on systematic measurements using Moebius loop antennas, interpretations of signal periodicities, and dissipation indicators determining transient noise origin characteristics from target emissions are described. Analytic models for the effect of target chamber resonances and associated noise current and temperature in a probe diode laser are described.

  10. Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration

    PubMed Central

    Andreas, Kristin; Häupl, Thomas; Lübke, Carsten; Ringe, Jochen; Morawietz, Lars; Wachtel, Anja; Sittinger, Michael; Kaps, Christian

    2009-01-01

    Introduction Rheumatoid arthritis (RA) leads to progressive destruction of articular cartilage. This study aimed to disclose major mechanisms of antirheumatic drug action on human chondrocytes and to reveal marker and pharmacological target genes that are involved in cartilage dysfunction and regeneration. Methods An interactive in vitro cultivation system composed of human chondrocyte alginate cultures and conditioned supernatant of SV40 T-antigen immortalised human synovial fibroblasts was used. Chondrocyte alginate cultures were stimulated with supernatant of RA synovial fibroblasts, of healthy donor synovial fibroblasts, and of RA synovial fibroblasts that have been antirheumatically treated with disease-modifying antirheumatic drugs (DMARDs) (azathioprine, gold sodium thiomalate, chloroquine phosphate, and methotrexate), nonsteroidal anti-inflammatory drugs (NSAIDs) (piroxicam and diclofenac), or steroidal anti-inflammatory drugs (SAIDs) (methylprednisolone and prednisolone). Chondrocyte gene expression profile was analysed using microarrays. Real-time reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were performed for validation of microarray data. Results Genome-wide expression analysis revealed 110 RA-related genes in human chondrocytes: expression of catabolic mediators (inflammation, cytokines/chemokines, and matrix degradation) was induced, and expression of anabolic mediators (matrix synthesis and proliferation/differentiation) was repressed. Potential marker genes to define and influence cartilage/chondrocyte integrity and regeneration were determined and include already established genes (COX-2, CXCR-4, IL-1RN, IL-6/8, MMP-10/12, and TLR-2) and novel genes (ADORA2A, BCL2-A1, CTGF, CXCR-7, CYR-61, HSD11B-1, IL-23A, MARCKS, MXRA-5, NDUFA4L2, NR4A3, SMS, STS, TNFAIP-2, and TXNIP). Antirheumatic treatment with SAIDs showed complete and strong reversion of RA-related gene expression in human chondrocytes, whereas

  11. Accurate effective pair potentials for polymer solutions

    NASA Astrophysics Data System (ADS)

    Bolhuis, P. G.; Louis, A. A.; Hansen, J. P.; Meijer, E. J.

    2001-03-01

    Dilute or semidilute solutions of nonintersecting self-avoiding walk (SAW) polymer chains are mapped onto a fluid of "soft" particles interacting via an effective pair potential between their centers of mass. This mapping is achieved by inverting the pair distribution function of the centers of mass of the original polymer chains, using integral equation techniques from the theory of simple fluids. The resulting effective pair potential is finite at all distances, has a range of the order of the radius of gyration, and turns out to be only moderately concentration-dependent. The dependence of the effective potential on polymer length is analyzed in an effort to extract the scaling limit. The effective potential is used to derive the osmotic equation of state, which is compared to simulation data for the full SAW segment model, and to the predictions of renormalization group calculations. A similar inversion procedure is used to derive an effective wall-polymer potential from the center of mass density profiles near the wall, obtained from simulations of the full polymer segment model. The resulting wall-polymer potential turns out to depend strongly on bulk polymer concentration when polymer-polymer correlations are taken into account, leading to a considerable enhancement of the effective repulsion with increasing concentration. The effective polymer-polymer and wall-polymer potentials are combined to calculate the depletion interaction induced by SAW polymers between two walls. The calculated depletion interaction agrees well with the "exact" results from much more computer-intensive direct simulation of the full polymer-segment model, and clearly illustrates the inadequacy—in the semidilute regime—of the standard Asakura-Oosawa approximation based on the assumption of noninteracting polymer coils.

  12. Effective Potential in Noncommutative BTZ Black Hole

    NASA Astrophysics Data System (ADS)

    Sadeghi, Jafar; Shajiee, Vahid Reza

    2016-02-01

    In this paper, we investigated the noncommutative rotating BTZ black hole and showed that such a space-time is not maximally symmetric. We calculated effective potential for the massive and the massless test particle by geodesic equations, also we showed effect of non-commutativity on the minimum mass of BTZ black hole.

  13. Lipids: a key for hepatitis C virus entry and a potential target for antiviral strategies.

    PubMed

    Blaising, Julie; Pécheur, Eve-Isabelle

    2013-01-01

    Viruses have evolved to complex relationship with their host cells. Many viruses modulate the lipid composition, lipid synthesis and signaling of their host cell. Lipids are also an essential part of the life cycle of the hepatitis C virus (HCV). HCV is a major human pathogen, persistently infecting 170 million people worldwide, with no currently effective treatment available for all patients. HCV appears to make use of the host lipid metabolism and one common feature of chronic hepatitis C is the steatosis, characterized by excessive accumulation of triglycerides and lipid content in the liver. Thus, HCV lifecycle appears to be closely connected to host cell lipid metabolism, from cell entry, through viral RNA replication to viral particle production and formation/assembly. HCV particles have a unique lipid composition, certainly distinct from other viruses. In the blood of chronically-infected patients, viral particles are bound to serum lipoproteins and are thus called lipo-viro-particles. The density of these circulating viral particles is heterogeneous. Specific infectivity and fusion of low density particles are greater than those of high density particles. Lipids and association to lipoproteins therefore play a key role in HCV life cycle. The purpose of this review is to make a state of the art on recent findings on the contribution of lipids in cell entry and membrane fusion of HCV. The influence of lipids as chemically-defined entities will be analyzed, as well as the role played by cholesterol transporters and lipoprotein receptors in HCV entry and fusion. Since viral entry would constitute a key target for antiviral strategies, inhibitor molecules interacting with viral and/or cellular membranes or interfering with the function of lipid metabolism regulators of HCV entry could offer strong antiviral potential. This will be lastly discussed in this review. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

  14. Phosphoprotein enriched in astrocytes (PEA)-15: A potential therapeutic target in multiple disease states

    PubMed Central

    Greig, Fiona H.; Nixon, Graeme F.

    2014-01-01

    Phosphoprotein enriched in astrocytes-15 (PEA-15) is a cytoplasmic protein that sits at an important junction in intracellular signalling and can regulate diverse cellular processes, such as proliferation and apoptosis, dependent upon stimulation. Regulation of these processes occurs by virtue of the unique interaction of PEA-15 with other signalling proteins. PEA-15 acts as a cytoplasmic tether for the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2 (ERK1/2) preventing nuclear localisation. In order to release ERK1/2, PEA-15 requires to be phosphorylated via several potential pathways. PEA-15 (and its phosphorylation state) therefore regulates many ERK1/2-dependent processes, including proliferation, via regulating ERK1/2 nuclear translocation. In addition, PEA-15 contains a death effector domain (DED) which allows interaction with other DED-containing proteins. PEA-15 can bind the DED-containing apoptotic adaptor molecule, Fas-associated death domain protein (FADD) which is also dependent on the phosphorylation status of PEA-15. PEA-15 binding of FADD can inhibit apoptosis as bound FADD cannot participate in the assembly of apoptotic signalling complexes. Through these protein–protein interactions, PEA-15-regulated cellular effects have now been investigated in a number of disease-related studies. Changes in PEA-15 expression and regulation have been observed in diabetes mellitus, cancer, neurological disorders and the cardiovascular system. These changes have been suggested to contribute to the pathology related to each of these disease states. As such, new therapeutic targets based around PEA-15 and its associated interactions are now being uncovered and could provide novel avenues for treatment strategies in multiple diseases. PMID:24657708

  15. Identification of potential therapeutic targets for colorectal cancer by bioinformatics analysis

    PubMed Central

    Yan, Ming; Song, Maomin; Bai, Rixing; Cheng, Shi; Yan, Wenmao

    2016-01-01

    The aim of the present study was to identify potential therapeutic targets for colorectal cancer (CRC). The gene expression profile GSE32323, containing 34 samples, including 17 specimens of CRC tissues and 17 of paired normal tissues from CRC patients, was downloaded from the Gene Expression Omnibus database. Following data preprocessing using the Affy and preprocessCore packages, the differentially-expressed genes (DEGs) between the two types of samples were identified with the Linear Models for Microarray Analysis package. Next, functional and pathway enrichment analysis of the DEGs was performed using the Database for Annotation Visualization and Integrated Discovery. The protein-protein interaction (PPI) network was established using the Search Tool for the Retrieval of Interacting Genes database. Utilizing WebGestalt, the potential microRNAs (miRNAs/miRs) of the DEGs were screened and the integrated miRNA-target network was built. A cohort of 1,347 DEGs was identified, the majority of which were mainly enriched in cell cycle-related biological processes and pathways. Cyclin-dependent kinase 1 (CDK1), cyclin B1 (CCNB1), MAD2 mitotic arrest deficient-like 1 (MAD2L1) and BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) were prominent in the PPI network, while the over-represented genes in the integrated miRNA-target network were SRY (sex determining region Y)-box 4 (SOX4; targeted by hsa-mir-129), v-myc avian myelocytomatosis viral oncogene homolog (MYC; targeted by hsa-let-7c and hsa-mir-145) and cyclin D1 (CCND1; targeted by hsa-let-7b). CDK1, CCNB1 and CCND1 were also associated with the p53 signaling pathway. Overall, several genes associated with the cell cycle and p53 pathway were identified as biomarkers for CRC. CDK1, CCNB1, MAD2L1, BUB1B, SOX4, collagen type I α2 chain and MYC may play significant roles in CRC progression by affecting the cell cycle-related pathways, while CDK1, CCNB1 and CCND1 may serve as crucial regulators in the p53

  16. Realizing the Potential of Vascular Targeted Therapy: The Rationale for Combining Vascular Disrupting Agents and Anti-Angiogenic Agents to Treat Cancer.

    PubMed

    Siemann, D W; Chaplin, D J; Horsman, M R

    2017-09-14

    Vascular targeted therapies (VTTs) are agents that target tumor vasculature and can be classified into two categories: those that inhibit angiogenesis and those that directly interfere with established tumor vasculature. Although both the anti-angiogenic agents (AAs) and the vascular disrupting agents (VDAs) target tumor vasculature, they differ in their mechanism of action and therapeutic application. Combining these two agents may realize the full potential of VTT and produce an effective therapeutic regimen. Here, we review AAs and VDAs (monotherapy and in combination with conventional therapies). We also discuss the rationale of combined VTT and its potential to treat cancer.

  17. Molecular Pathways: Targeting the CXCR4-CXCL12 Axis--Untapped Potential in the Tumor Microenvironment.

    PubMed

    Scala, Stefania

    2015-10-01

    Evidence suggests that the CXC-chemokine receptor-4 pathway plays a role in cancer cell homing and metastasis, and thus represents a potential target for cancer therapy. The homeostatic microenvironment chemokine CXCL12 binds the CXCR4 and CXCR7 receptors, activating divergent signals on multiple pathways, such as ERK1/2, p38, SAPK/JNK, AKT, mTOR, and the Bruton tyrosine kinase (BTK). An activating mutation in CXCR4 is responsible for a rare disease, WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), and dominant CXCR4 mutations have also been reported in Waldenstrom macroglobulinemia. The CXCR4-CXCL12 axis regulates the hematopoietic stem cell niche--a property that has led to the approval of the CXCR4 antagonist plerixafor (AMD3100) for mobilization of hematopoietic precursors. In preclinical models, plerixafor has shown antimetastatic potential in vivo, offering proof of concept. Other antagonists are in preclinical and clinical development. Recent evidence demonstrates that inhibiting CXCR4 signaling restores sensitivity to CTLA-4 and PD-1 checkpoint inhibitors, creating a new line for investigation. Targeting the CXCR4-CXCL12 axis thus offers the possibility of affecting CXCR4-expressing primary tumor cells, modulating the immune response, or synergizing with other targeted anticancer therapies. ©2015 American Association for Cancer Research.

  18. A double-targeted magnetic nanocarrier with potential application in hydrophobic drug delivery.

    PubMed

    Ding, Guobin; Guo, Yi; Lv, Yanyun; Liu, Xiaofeng; Xu, Li; Zhang, Xuezhong

    2012-03-01

    A double-targeted magnetic nanocarrier based with potential applications in the delivery of hydrophobic drugs has been developed. It consists of magnetite (Fe(3)O(4)) nanoparticles encapsulated in self-assembled micelles of the amphiphilic copolymer MPEG-PLGA [methoxy poly (ethylene glycol)-poly (d,l-lactide-co-glycolide)], and was fabricated using the solvent-evaporation technique. The magnetic nanocarrier has a very stable core-shell structure and is superparamagnetic. Its cytotoxicity was evaluated using the MTT assay with three cell lines-HeLa, MCF-7, and HT1080; it exhibited no cytotoxicity against any tested line at concentrations of up to 400 μg/mL after incubation for 24 h. Its cellular uptake was studied by Prussian blue staining and by fluorescence microscopy after encapsulating a fluorescent probe (hydrophobic quantum dots) into the nanocarrier. Finally, the magnetic targeting property of the magnetic nanocarrier was confirmed by an in vitro test. Overall, the results obtained demonstrate the potential of the double-targeted nanocarrier for the intracellular delivery of hydrophobic drugs.

  19. Tp53 and its potential therapeutic role as a target in bladder cancer.

    PubMed

    Ciccarese, Chiara; Massari, Francesco; Blanca, Ana; Tortora, Giampaolo; Montironi, Rodolfo; Cheng, Liang; Scarpelli, Marina; Raspollini, Maria R; Vau, Nuno; Fonseca, Jorge; Lopez-Beltran, Antonio

    2017-04-01

    Despite more than 30 years of research on p53 resulting in >50,000 publications, we are now beginning to figure out the complexity of the p53 pathway, gene ontology and conformational structure of the molecule. Recent years brought great advances in p53 related drugs and the potencial ways in which p53 is inactivated in cancer. Areas covered: We searched for related publications on Pubmed and ClinicalTrial.gov using the following keywords 'p53, Tp53, p53 and bladder cancer, p53 and therapeutic target'. Relevant articles improved the understanding on p53 pathways and their potential as candidate to targeted therapy in bladder cancer. Expert opinion: Novel strategies developed to restore the function of mutants with chemical chaperones or by using compounds to improved pharmacokinetic properties are in development with potential to be applied in the oncology clinic. Other strategies targeting aberrantly overexpressed p53 regulators with wild-type p53 are also an active area of research. In particular, studies inhibiting the interaction of p53 with its negative regulators MDMX and MDM2 are an important field in drug discovery. Small molecules for inhibition of MDM2 are now in clinical trials process. However, personalized anticancer therapy might eventually advance through analyses of p53 status in cancer patients.

  20. Epidermal growth factor (EGF) as a potential targeting agent for delivery of boron to malignant gliomas

    SciTech Connect

    Capala, J.; Barth, R.F.; Adams, D.M.; Bailey, M.Q.; Soloway, A.H.; Carlsson, J.

    1994-12-31

    The majority of high grade gliomas express an amplified epidermal growth factor receptor (EGFR) gene, and this often is associated with an increase in cell surface receptor expression. The rapid internalization and degradation of EGF-EGFR complexes, as well as their high affinity make EGF a potential targeting agent for delivery of {sup 10}B to tumor cells with an amplified number of EGFR. Human glioma cells can expresses as many as 10{sup 5} {minus}10{sup 6} EGF receptors per cell, and if these could be saturated with boronated EGF, then > 10{sup 8} boron atoms would be delivered per cell. Since EGF has a comparatively low molecular weight ({approximately} 6 kD), this has allowed us to construct relatively small bioconjugates containing {approximately} 900 boron atoms per EGF molecule{sup 3}, which also had high affinity for EGFR on tumor cells. In the present study, the feasibility of using EGF receptors as a potential target for therapy of gliomas was investigated by in vivo scintigraphic studies using {sup 131}I{minus} or {sup 99m}{Tc}-labeled EGF in a rat brain tumor model. Our results indicate that intratumorally delivered boron- EGF conjugates might be useful for targeting EGFR on glioma cells if the boron containing moiety of the conjugates persisted intracellularly. Further studies are required, however, to determine if this approach can be used for BNCT of the rat glioma.