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Sample records for doxorubicin potential therapeutic

  1. 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.

  2. Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: potential therapeutic relevance

    PubMed Central

    2010-01-01

    Background Ovarian carcinoma is a rarely curable disease, for which new treatment options are required. As agents that block HMG-CoA reductase and the mevalonate pathway, the statin family of drugs are used in the treatment of hypercholesterolemia and have been shown to trigger apoptosis in a tumor-specific manner. Recent clinical trials show that the addition of statins to traditional chemotherapeutic strategies can increase efficacy of targeting statin-sensitive tumors. Our goal was to assess statin-induced apoptosis of ovarian cancer cells, either alone or in combination with chemotherapeutics, and then determine these mechanisms of action. Methods The effect of lovastatin on ovarian cancer cell lines was evaluated alone and in combination with cisplatin and doxorubicin using several assays (MTT, TUNEL, fixed PI, PARP cleavage) and synergy determined by evaluating the combination index. The mechanisms of action were evaluated using functional, molecular, and pharmacologic approaches. Results We demonstrate that lovastatin induces apoptosis of ovarian cancer cells in a p53-independent manner and synergizes with doxorubicin, a chemotherapeutic agent used to treat recurrent cases of ovarian cancer. Lovastatin drives ovarian tumor cell death by two mechanisms: first, by blocking HMG-CoA reductase activity, and second, by sensitizing multi-drug resistant cells to doxorubicin by a novel mevalonate-independent mechanism. This inhibition of drug transport, likely through inhibition of P-glycoprotein, potentiates both DNA damage and tumor cell apoptosis. Conclusions The results of this research provide pre-clinical data to warrant further evaluation of statins as potential anti-cancer agents to treat ovarian carcinoma. Many statins are inexpensive, off-patent generic drugs that are immediately available for use as anti-cancer agents. We provide evidence that lovastatin triggers apoptosis of ovarian cancer cells as a single agent by a mevalonate-dependent mechanism

  3. 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

  4. 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.

  5. The Therapeutic Potential of AN-7, a Novel Histone Deacetylase Inhibitor, for Treatment of Mycosis Fungoides/Sezary Syndrome Alone or with Doxorubicin.

    PubMed

    Moyal, Lilach; Feldbaum, Nataly; Goldfeiz, Neta; Rephaeli, Ada; Nudelman, Abraham; Weitman, Michal; Tarasenko, Nataly; Gorovitz, Batia; Maron, Leah; Yehezkel, Shiran; Amitay-Laish, Iris; Lubin, Ido; Hodak, Emmilia

    2016-01-01

    The 2 histone deacetylase inhibitors (HDACIs) approved for the treatment of cutaneous T-cell lymphoma (CTCL) including mycosis fungoides/sezary syndrome (MF/SS), suberoylanilide hydroxamic acid (SAHA) and romidepsin, are associated with low rates of overall response and high rates of adverse effects. Data regarding combination treatments with HDACIs is sparse. Butyroyloxymethyl diethylphosphate (AN-7) is a novel HDACI, which was found to have selective anticancer activity in several cell lines and animal models. The aim of this study was to compare the anticancer effects of AN-7 and SAHA, either alone or combined with doxorubicin, on MF/SS cell lines and peripheral blood lymphocytes (PBL) from patients with Sezary syndrome (SPBL). MyLa cells, Hut78 cells, SPBL, and PBL from healthy normal individuals (NPBL) were exposed to the test drugs, and the findings were analyzed by a viability assay, an apoptosis assay, and Western blot. AN-7 was more selectively toxic to MyLa cells, Hut78 cells, and SPBL (relative to NPBL) than SAHA and also acted more rapidly. Both drugs induced apoptosis in MF/SS cell lines, SAHA had a greater effect on MyLa cell line, while AN-7 induced greater apoptosis in SPBL; both caused an accumulation of acetylated histone H3, but AN-7 was associated with earlier kinetics; and both caused a downregulation of the HDAC1 protein in MF/SS cell lines. AN-7 acted synergistically with doxorubicin in both MF/SS cell lines and SPBL, and antagonistically with doxorubicin in NPBL. By contrast, SAHA acted antagonistically with doxorubicin on MF/SS cell lines, SPBL, and NPBL, leaving <50% viable cells. In conclusion, AN-7 holds promise as a therapeutic agent in MF/SS and has several advantages over SAHA. Our data provide a rationale for combining AN-7, but not SAHA, with doxorubicin to induce the cell death in MF/SS.

  6. Potential therapeutic strategies for non - muscle invasive bladder cancer based on association of intravesical immunotherapy with p - mapa and systemic administration of cisplatin and doxorubicin.

    PubMed

    Dias, Queila Cristina; Nunes, Iseu da Silva; Garcia, Patrick Vianna; Favaro, Wagner Jose

    2016-01-01

    The present study describes the histopathological and molecular effects of P-MAPA (Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride) intravesical immunotherapy combined with systemic doxorubicin or cisplatin for treatment of non-muscle invasive bladder cancer (NMIBC) in an appropriate animal model. Our results showed an undifferentiated tumor, characterizing a tumor invading mucosa or submucosa of the bladder wall (pT1) and papillary carcinoma in situ (pTa) in the Cancer group. The histopathological changes were similar between the combined treatment with intravesical P-MAPA plus systemic Cisplatin and P-MAPA immunotherapy alone, showing decrease of urothelial neoplastic lesions progression and histopathological recovery in 80% of the animals. The animals treated systemically with cisplatin or doxorubicin singly, showed 100% of malignant lesions in the urinary bladder. Furthemore, the combined treatment with P-MAPA and Doxorubicin showed no decrease of urothelial neoplastic lesions progression and histopathological recovery. Furthermore, Akt, PI3K, NF-kB and VEGF protein levels were significantly lower in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments than other groups. In contrast, PTEN protein levels were significantly higher in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments. Thus, it could be concluded that combination of intravesical P-MAPA immunotherapy and systemic cisplatin in the NMIBC animal model was effective, well tolerated and showed no apparent signs of antagonism between the drugs. In addition, intravesical P-MAPA immunotherapy may be considered as a valuable option for treatment of BCG unresponsive patients that unmet the criteria for early cystectomy. Copyright® by the International Brazilian Journal of Urology.

  7. Potential therapeutic strategies for non - muscle invasive bladder cancer based on association of intravesical immunotherapy with P-MAPA and systemic administration of cisplatin and doxorubicin

    PubMed Central

    Dias, Queila Cristina; Nunes, Iseu da Silva; Garcia, Patrick Vianna; Fávaro, Wagner José

    2016-01-01

    ABSTRACT The present study describes the histopathological and molecular effects of P-MAPA (Protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride) intravesical immunotherapy combined with systemic doxorubicin or cisplatin for treatment of non-muscle invasive bladder cancer (NMIBC) in an appropriate animal model. Our results showed an undifferentiated tumor, characterizing a tumor invading mucosa or submucosa of the bladder wall (pT1) and papillary carcinoma in situ (pTa) in the Cancer group. The histopathological changes were similar between the combined treatment with intravesical P-MAPA plus systemic Cisplatin and P-MAPA immunotherapy alone, showing decrease of urothelial neoplastic lesions progression and histopathological recovery in 80% of the animals. The animals treated systemically with cisplatin or doxorubicin singly, showed 100% of malignant lesions in the urinary bladder. Furthemore, the combined treatment with P-MAPA and Doxorubicin showed no decrease of urothelial neoplastic lesions progression and histopathological recovery. Furthermore, Akt, PI3K, NF-kB and VEGF protein levels were significantly lower in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments than other groups. In contrast, PTEN protein levels were significantly higher in intravesical P-MAPA plus systemic cisplatin and in intravesical P-MAPA alone treatments. Thus, it could be concluded that combination of intravesical P-MAPA immunotherapy and systemic cisplatin in the NMIBC animal model was effective, well tolerated and showed no apparent signs of antagonism between the drugs. In addition, intravesical P-MAPA immunotherapy may be considered as a valuable option for treatment of BCG unresponsive patients that unmet the criteria for early cystectomy. PMID:24893914

  8. Effect of intratumoral injection on the biodistribution and therapeutic potential of novel chemophor EL-modified single-walled nanotube loading doxorubicin.

    PubMed

    Liu, Hongzhuo; Xu, Hui; Wang, Yan; He, Zhonggui; Li, Sanming

    2012-09-01

    The purpose of this study is to evaluate in vivo efficacy and loco-regional distribution of a doxorubicin (DOX)-loaded Polyoxyl 35 Castor Oil (Cremophor EL, CrEL) noncovalent modified single-walled carbon nanotubes (SWNTs) formulation in a sarcoma tumor model after intratumoral injection. The drug loaded SWNTs were successfully prepared via physical absorption, which was confirmed by UV-vis-NIR absorbance spectra and dynamic light scattering assay. Solid tumor models were obtained by injecting mouse sarcoma 180 cells into the thighs of ICR mice. CrEL-SWNTs-DOX, CrEL-SWNTs, free DOX and saline (control) were intratumorally injected after 5 days post transplantation. The biodistribution studies demonstrated that intratumoral delivery of CrEL-SWNTs-DOX resulted in longer drug retention time in tumor, higher tumor level (27.6-fold than that of free DOX), as well as less accumulation in other solid tissues, especially in heart. Furthermore, in vivo anti-tumor activity results showed that CrEL-SWNTs-DOX could effectively suppress the tumor growth than free DOX and the control, attributing to its enhanced intratumoral DOX level. The histopathological findings revealed that the new carbon nanomaterials were a safe vehicle for topical drug delivery systems. It is concluded that this noncovalent modification of carbon nanotubes by CrEL for anticancer agents might be a promising alternative for cancer treatment.

  9. EGCG/gelatin-doxorubicin gold nanoparticles enhance therapeutic efficacy of doxorubicin for prostate cancer treatment.

    PubMed

    Tsai, Li-Chu; Hsieh, Hao-Ying; Lu, Kun-Ying; Wang, Sin-Yu; Mi, Fwu-Long

    2016-01-01

    Development of epigallocatechin gallate (EGCG) and gelatin-doxorubicin conjugate (GLT-DOX)-coated gold nanoparticles (DOX-GLT/EGCG AuNPs) for fluorescence imaging and inhibition of prostate cancer cell growth. AuNPs alternatively coated with EGCG and DOX-GLT conjugates were prepared by a layer-by-layer assembly method. The physicochemical properties of the AuNPs and the effect of Laminin 67R receptor-mediated endocytosis on the anticancer efficacy of the AuNPs were examined. The AuNPs significantly inhibit the proliferation of PC-3 cancer cell and the enzyme-responsive intracellular release of DOX could be tracked by monitoring the recovery of the fluorescence signal of DOX. Laminin 67R receptor-mediated delivery of DOX using the AuNPs enhanced cellular uptake of DOX and improved apoptosis of PC-3 cells.

  10. N-acetylcysteine potentiates doxorubicin-induced ATM and p53 activation in ovarian cancer cells.

    PubMed

    Brum, Gabriella; Carbone, Thomas; Still, Eric; Correia, Vendita; Szulak, Kevin; Calianese, David; Best, Charles; Cammarata, Garret; Higgins, Katelyn; Ji, Fang; Di, Wen; Wan, Yinsheng

    2013-01-01

    Doxorubicin has been used clinically to treat various types of cancer, and yet the molecular mode of actions of doxorubicin remains to be fully unraveled. In this study, we investigated the effect of doxorubicin on cultured ovarian cancer cells (CaOV3). MTT assay data showed that doxorubicin inhibits cell proliferation in a time- and dose-dependent manner. Phagokinetic cell motility assay data indicated that doxorubicin inhibits both basal level and EGF-induced cell migration in CaOV3 cells. Confocal microscopic data revealed that doxorubicin induces reorganization of cytoskeletal proteins including actin, tubulin and vimentin. Doxorubicin induces phosphorylation of p53 at Ser15 and 20, acetylation of p53 and ATM activation. Doxorubicin also induces phosphorylation of histone H2AX at Ser139. Interestingly, doxorubicin also inhibits mTOR activity, measured by phosphorylation of S6 ribosomal protein. Pretreatment of CaOV3 cells with antioxidant N-acetylcysteine (NAC), but not pyrrolidine dithiocarbamate (PDTC) potentiates doxorubicin-induced phosphorylation of p53 and ATM. Collectively, we conclude that doxorubicin induces ATM/p53 activation leading to reorganization of cytoskeletal networks, inhibition of mTOR activity, and inhibition of cell proliferation and migration. Our data also suggest that removal of oxidants by antioxidants such as NAC may enhance the efficacy of doxorubicin in vivo.

  11. Doxorubicin conjugated functionalizable carbon dots for nucleus targeted delivery and enhanced therapeutic efficacy

    NASA Astrophysics Data System (ADS)

    Yang, Lei; Wang, Zheran; Wang, Ju; Jiang, Weihua; Jiang, Xuewei; Bai, Zhaoshi; He, Yunpeng; Jiang, Jianqi; Wang, Dongkai; Yang, Li

    2016-03-01

    Carbon dots (CDs) have shown great potential in imaging and drug/gene delivery applications. In this work, CDs functionalized with a nuclear localization signal peptide (NLS-CDs) were employed to transport doxorubicin (DOX) into cancer cells for enhanced antitumor activity. DOX was coupled to NLS-CDs (DOX-CDs) through an acid-labile hydrazone bond, which was cleavable in the weakly acidic intracellular compartments. The cytotoxicity of DOX-CD complexes was evaluated by the MTT assay and the cellular uptake was monitored using flow cytometry and confocal laser scanning microscopy. Cell imaging confirmed that DOX-CDs were mainly located in the nucleus. Furthermore, the complexes could efficiently induce apoptosis in human lung adenocarcinoma A549 cells. The in vivo therapeutic efficacy of DOX-CDs was investigated in an A549 xenograft nude mice model and the complexes exhibited an enhanced ability to inhibit tumor growth compared with free DOX. Thus, the DOX-CD conjugates may be exploited as promising drug delivery vehicles in cancer therapy.Carbon dots (CDs) have shown great potential in imaging and drug/gene delivery applications. In this work, CDs functionalized with a nuclear localization signal peptide (NLS-CDs) were employed to transport doxorubicin (DOX) into cancer cells for enhanced antitumor activity. DOX was coupled to NLS-CDs (DOX-CDs) through an acid-labile hydrazone bond, which was cleavable in the weakly acidic intracellular compartments. The cytotoxicity of DOX-CD complexes was evaluated by the MTT assay and the cellular uptake was monitored using flow cytometry and confocal laser scanning microscopy. Cell imaging confirmed that DOX-CDs were mainly located in the nucleus. Furthermore, the complexes could efficiently induce apoptosis in human lung adenocarcinoma A549 cells. The in vivo therapeutic efficacy of DOX-CDs was investigated in an A549 xenograft nude mice model and the complexes exhibited an enhanced ability to inhibit tumor growth compared

  12. Gef gene therapy enhances the therapeutic efficacy of doxorubicin to combat growth of MCF-7 breast cancer cells.

    PubMed

    Prados, Jose; Melguizo, Consolación; Rama, Ana Rosa; Ortiz, Rául; Segura, Ana; Boulaiz, Houria; Vélez, Celia; Caba, Octavio; Ramos, Juan Luís; Aránega, Antonia

    2010-05-01

    The potential use of combined therapy is under intensive study including the association between classical cytotoxic and genes encoding toxic proteins which enhanced the antitumour activity. The main aim of this work was to evaluate whether the gef gene, a suicide gene which has a demonstrated antiproliferative activity in tumour cells, improved the antitumour effect of chemotherapeutic drugs used as first-line treatment in the management of advanced breast cancer. MCF-7 human breast cancer cells were transfected with gef gene using pcDNA3.1-TOPO expression vector. To determine the effect of the combined therapy, MCF-7 transfected and non-transfected cells were exposed to paclitaxel, docetaxel and doxorubicin at different concentrations. The growth-inhibitory effect of gef gene and/or drugs was assessed by MTT assay. Apoptosis modulation was determined by flow cytometric analysis, DNA fragmentation and morphological analysis. Multicellular tumour spheroids (MTS) from MCF-7 cells were used to confirm effectiveness of combined therapy (gef gene and drug). Our results demonstrate that combined therapy gef gene/drugs (paclitaxel, docetaxel or doxurubicin) caused a decrease in cell viability. However, only the gef-doxorubicin (10 microM) combination induced a greater enhancement in the antitumour activity in MCF-7 cells. Most importantly, this combined strategy resulted in a significant synergistic effect, thus allowing lower doses of the drug to be used to achieve the same therapeutic effect. These results were confirmed using MTS in which volume decrease with combined therapy was greater than obtained using the gene therapy or chemotherapy alone, or the sum of both therapies. The cytotoxic effect of gef gene in breast cancer cells enhances the chemotherapeutic effect of doxorubicin. This therapeutic approach has the potential to overcome some of the major limitations of conventional chemotherapy, and may therefore constitute a promising strategy for future

  13. Stabilization of mitochondrial membrane potential prevents doxorubicin-induced cardiotoxicity in isolated rat heart

    SciTech Connect

    Montaigne, David; Marechal, Xavier; Baccouch, Riadh; Modine, Thomas; Preau, Sebastien; Zannis, Konstantinos; Marchetti, Philippe; Lancel, Steve; Neviere, Remi

    2010-05-01

    The present study was undertaken to examine the effects of doxorubicin on left ventricular function and cellular energy state in intact isolated hearts, and, to test whether inhibition of mitochondrial membrane potential dissipation would prevent doxorubicin-induced mitochondrial and myocardial dysfunction. Myocardial contractile performance and mitochondrial respiration were evaluated by left ventricular tension and its first derivatives and cardiac fiber respirometry, respectively. NADH levels, mitochondrial membrane potential and glucose uptake were monitored non-invasively via epicardial imaging of the left ventricular wall of Langendorff-perfused rat hearts. Heart performance was reduced in a time-dependent manner in isolated rat hearts perfused with Krebs-Henseleit solution containing 1 muM doxorubicin. Compared with controls, doxorubicin induced acute myocardial dysfunction (dF/dt{sub max} of 105 +- 8 mN/s in control hearts vs. 49 +- 7 mN/s in doxorubicin-treated hearts; *p < 0.05). In cardiac fibers prepared from perfused hearts, doxorubicin induced depression of mitochondrial respiration (respiratory control ratio of 4.0 +- 0.2 in control hearts vs. 2.2 +- 0.2 in doxorubicin-treated hearts; *p < 0.05) and cytochrome c oxidase kinetic activity (24 +- 1 muM cytochrome c/min/mg in control hearts vs. 14 +- 3 muM cytochrome c/min/mg in doxorubicin-treated hearts; *p < 0.05). Acute cardiotoxicity induced by doxorubicin was accompanied by NADH redox state, mitochondrial membrane potential, and glucose uptake reduction. Inhibition of mitochondrial permeability transition pore opening by cyclosporine A largely prevented mitochondrial membrane potential dissipation, cardiac energy state and dysfunction. These results suggest that in intact hearts an impairment of mitochondrial metabolism is involved in the development of doxorubicin cardiotoxicity.

  14. Stabilization of mitochondrial membrane potential prevents doxorubicin-induced cardiotoxicity in isolated rat heart.

    PubMed

    Montaigne, David; Marechal, Xavier; Baccouch, Riadh; Modine, Thomas; Preau, Sebastien; Zannis, Konstantinos; Marchetti, Philippe; Lancel, Steve; Neviere, Remi

    2010-05-01

    The present study was undertaken to examine the effects of doxorubicin on left ventricular function and cellular energy state in intact isolated hearts, and, to test whether inhibition of mitochondrial membrane potential dissipation would prevent doxorubicin-induced mitochondrial and myocardial dysfunction. Myocardial contractile performance and mitochondrial respiration were evaluated by left ventricular tension and its first derivatives and cardiac fiber respirometry, respectively. NADH levels, mitochondrial membrane potential and glucose uptake were monitored non-invasively via epicardial imaging of the left ventricular wall of Langendorff-perfused rat hearts. Heart performance was reduced in a time-dependent manner in isolated rat hearts perfused with Krebs-Henseleit solution containing 1 microM doxorubicin. Compared with controls, doxorubicin induced acute myocardial dysfunction (dF/dt(max) of 105+/-8 mN/s in control hearts vs. 49+/-7 mN/s in doxorubicin-treated hearts; p<0.05). In cardiac fibers prepared from perfused hearts, doxorubicin induced depression of mitochondrial respiration (respiratory control ratio of 4.0+/-0.2 in control hearts vs. 2.2+/-0.2 in doxorubicin-treated hearts; p<0.05) and cytochrome c oxidase kinetic activity (24+/-1 microM cytochrome c/min/mg in control hearts vs. 14+/-3 microM cytochrome c/min/mg in doxorubicin-treated hearts; p<0.05). Acute cardiotoxicity induced by doxorubicin was accompanied by NADH redox state, mitochondrial membrane potential, and glucose uptake reduction. Inhibition of mitochondrial permeability transition pore opening by cyclosporine A largely prevented mitochondrial membrane potential dissipation, cardiac energy state and dysfunction. These results suggest that in intact hearts an impairment of mitochondrial metabolism is involved in the development of doxorubicin cardiotoxicity. Copyright 2010 Elsevier Inc. All rights reserved.

  15. Encapsulation of doxorubicin in liver-targeted erythrocytes increases the therapeutic index of the drug in a murine metastatic model.

    PubMed Central

    Zocchi, E; Tonetti, M; Polvani, C; Guida, L; Benatti, U; De Flora, A

    1989-01-01

    Doxorubicin-loaded, glutaraldehyde-treated murine erythrocytes, once reinjected into circulation, are rapidly taken up by liver and lungs and behave as an organ-targeted, slow delivery system for the encapsulated drug. The antitumor activity of encapsulated doxorubicin (former generic name, adriamycin) was compared with that of the free drug in a murine hepatic and pulmonary tumor model. This was obtained by intrasplenic injection of L1210 lymphoma cells followed by splenectomy. Different schedules of treatment of tumor-bearing mice with erythrocyte-encapsulated or free doxorubicin were investigated. The optimal schedule of treatment for free doxorubicin proved to be i.v. bolus administration on the day of splenectomy. Under these conditions, the dose producing 50% inhibition of metastatic growth in the liver, as measured by inhibition of 5-[125I]iodo-2'-deoxyuridine uptake 9 days after tumor induction, was 6.3 mg/kg for free doxorubicin and 0.48 mg/kg for the encapsulated drug. In these conditions pulmonary tumor development was even more efficiently prevented by encapsulated doxorubicin as compared with the free drug. The values of the therapeutic index (TI), defined as the ratio between the maximal tolerated dose (LD10) and the minimal effective dose (ED90, producing 90% inhibition of liver metastatic growth), were 4.2 and 1.8 for encapsulated and free doxorubicin, respectively. PMID:2928317

  16. Chemoradionuclide Therapy with 186Re-Labeled Liposomal Doxorubicin: Toxicity, Dosimetry, and Therapeutic Response

    PubMed Central

    Soundararajan, Anuradha; Bao, Ande; Phillips, William T.; McManus, Linda M.

    2011-01-01

    Abstract This study was performed to determine the maximum tolerated dose (MTD) and therapeutic effects of rhenium-186 (186Re)-labeled liposomal doxorubicin (Doxil), investigate associated toxicities, and calculate radiation absorbed dose in head and neck tumor xenografts and normal organs. Doxil and control polyethylene glycol (PEG)-liposomes were labeled using 186Re-N,N-bis(2-mercaptoethyl)-N′,N′-diethylethylenediamine (BMEDA) method. Tumor-bearing rats received either no therapy (n=6), intravenous Doxil (n=4), or escalating radioactivity of 186Re-Doxil (185–925 MBq/kg) or 186Re-PEG-liposomes (1110–1665 MBq/kg) and were monitored for 28 days. Based on body weight loss and systemic toxicity, MTD for 186Re-Doxil and 186Re-PEG-liposomes were established at injected radioactivity/body weight of 740 and 1480 MBq/kg, respectively. 186Re-injected radioactivity/body weight for therapy studies was determined to be 555 MBq/kg for 186Re-Doxil and 1295 MBq/kg for 186Re-PEG-liposomes. All groups recovered from their body weight loss, leucopenia, and thrombocytopenia by 28 days postinjection. Normalized radiation absorbed dose to tumor was significantly higher for 186Re-Doxil (0.299±0.109 Gy/MBq) compared with 186Re-PEG-liposomes (0.096±0.120 Gy/MBq) (p<0.05). In a separate therapy study, tumor volumes were significantly smaller for 186Re-Doxil (555 MBq/kg) compared with 186Re-PEG-liposomes (1295 MBq/kg) (p<0.01) at 42 days postinjection. In conclusion, combination chemoradionuclide therapy with 186Re-Doxil has promising potential, because good tumor control was achieved with limited associated toxicity. PMID:21834653

  17. Nanodiamonds enhance therapeutic efficacy of doxorubicin in treating metastatic hormone-refractory prostate cancer

    NASA Astrophysics Data System (ADS)

    Salaam, Amanee D.; Hwang, Patrick T. J.; Poonawalla, Aliza; Green, Hadiyah N.; Jun, Ho-wook; Dean, Derrick

    2014-10-01

    Enhancing therapeutic efficacy is essential for successful treatment of chemoresistant cancers such as metastatic hormone-refractory prostate cancer (HRPC). To improve the efficacy of doxorubicin (DOX) for treating chemoresistant disease, the feasibility of using nanodiamond (ND) particles was investigated. Utilizing the pH responsive properties of ND, a novel protocol for complexing NDs and DOX was developed using a pH 8.5 coupling buffer. The DOX loading efficiency, loading on the NDs, and pH responsive release characteristics were determined utilizing UV-Visible spectroscopy. The effects of the ND-DOX on HRPC cell line PC3 were evaluated with MTS and live/dead cell viability assays. ND-DOX displayed exceptional loading efficiency (95.7%) and drug loading on NDs (23.9 wt%) with optimal release at pH 4 (80%). In comparison to treatment with DOX alone, cell death significantly increased when cells were treated with ND-DOX complexes demonstrating a 50% improvement in DOX efficacy. Of the tested treatments, ND-DOX with 2.4 μg mL-1 DOX exhibited superior efficacy (60% cell death). ND-DOX with 1.2 μg mL-1 DOX achieved 42% cell death, which was comparable to cell death in response to 2.4 μg mL-1 of free DOX, suggesting that NDs aid in decreasing the DOX dose necessary to achieve a chemotherapeutic efficacy. Due to its enhanced efficacy, ND-DOX can be used to successfully treat HRPC and potentially decrease the clinical side effects of DOX.

  18. Doxorubicin-polyphosphazene conjugate hydrogels for locally controlled delivery of cancer therapeutics.

    PubMed

    Chun, Changju; Lee, Sun M; Kim, Chang W; Hong, Ki-Yun; Kim, Sang Y; Yang, Han K; Song, Soo-Chang

    2009-09-01

    Poly(organophosphazene)-doxorubicin (DOX) conjugate bearing hydrophobic L-isoleucine ethyl ester (IleOEt) and hydrophilic alpha-amino-omega-methoxy-poly(ethylene glycol) with molecular weight of 550 Da (AMPEG 550) along with carboxylic acid as a functional group was synthesized to create a drug delivery system, which is based on locally injectable, biodegradable, and thermosensitive hydrogels. In addition to the evaluation of the in vitro and in vivo antitumor activities, the physicochemical properties, hydrolytic degradation, and DOX release profile of the poly(organophosphazene)-DOX conjugate were determined. The aqueous solution of the polymer-DOX conjugate showed a sol-gel transition behavior depending on temperature changes. Based on the in vivo antitumor activities of the locally injected poly(organophosphazene)-DOX conjugate into the tumor-induced nude mice, the conjugate hydrogel after the local injection at the tumor site was shown to inhibit tumor growth more effectively with less toxicity and much longer than doxorubicin and saline as controls, indicating that tumor active DOX from the conjugate hydrogel is released slowly over a longer period of time and effectively accumulated locally in the tumor sites. These results suggest that the poly(organophosphazene)-doxorubicin conjugates hold great potential for use in preclinical and clinical studies as single and/or combination therapies.

  19. Redox nanoparticle therapeutics to cancer--increase in therapeutic effect of doxorubicin, suppressing its adverse effect.

    PubMed

    Yoshitomi, Toru; Ozaki, Yuki; Thangavel, Sindhu; Nagasaki, Yukio

    2013-11-28

    The ultimate goal of cancer chemotherapy is to achieve a cure without causing any adverse effects. We have developed a pH-sensitive redox nanoparticle (RNP(N)), which disintegrates under acidic conditions and exposes nitroxide radicals, leading to strongly scavenging reactive oxygen species (ROS). After intravenous administration of RNP(N) to tumor bearing mice, it effectively accumulated in tumors due to the leaky neovascular and immature lymphatic system and scavenged ROS, resulting in suppression of inflammation and activation of NF-кB, after disintegration of RNP(N) in the tumors. Pre-administration of RNP(N) prior to treatments with anticancer agents, doxorubicin, to tumor-bearing mice significantly suppressed the progression of tumor size, compared to low-molecular weight 4-hydroxy-TEMPO. Interestingly, the administration of RNP(N) suppressed adverse effects of doxorubicin to normal organs due to the scavenging ROS and suppression of inflammation, which was confirmed by reduction in lactate dehydrogenase and creatine phosphokinase activities in plasma. RNP(N) is thus anticipated as a novel and ideal adjuvant for cancer chemotherapy.

  20. Antimicrobial peptides: therapeutic potentials.

    PubMed

    Kang, Su-Jin; Park, Sung Jean; Mishig-Ochir, Tsogbadrakh; Lee, Bong-Jin

    2014-12-01

    The increasing appearance of multidrug-resistant pathogens has created an urgent need for suitable alternatives to current antibiotics. Antimicrobial peptides (AMPs), which act as defensive weapons against microbes, have received great attention because of broad-spectrum activities, unique action mechanisms and rare antibiotic-resistant variants. Despite desirable characteristics, they have shown limitations in pharmaceutical development due to toxicity, stability and manufacturing costs. Because of these drawbacks, only a few AMPs have been tested in Phase III clinical trials and no AMPs have been approved by the US FDA yet. However, these obstacles could be overcome by well-known methods such as changing physicochemical characteristics and introducing nonnatural amino acids, acetylation or amidation, as well as modern techniques like molecular targeted AMPs, liposomal formulations and drug delivery systems. Thus, the current challenge in this field is to develop therapeutic AMPs at a reasonable cost as well as to overcome the limitations.

  1. Amphiphilic dendritic nanomicelle-mediated co-delivery of 5-fluorouracil and doxorubicin for enhanced therapeutic efficacy.

    PubMed

    Han, Rui; Sun, Yuan; Kang, Chen; Sun, Huijing; Wei, Wenguang

    2017-02-01

    Combination cancer therapy has attracted considerable attention due to its enhanced antitumor efficacy and reduced toxicity granted by synergistic effects over monotherapy. The application of nanotechnology is expected to achieve coencapsulation of multiple anticancer agents with enhanced therapeutic efficacy. Herein, a unique nanomicelle based on amphiphilic dendrimer (AmD) consisting of a hydrophilic polyamidoamine dendritic shell and a hydrophobic polylactide core is developed for effectively loading and shuttling 5-fluorouracil (5-Fu) and doxorubicin (Dox). The yielded drug-encapsulated dendritic nanomicelle (5-Fu/Dox-DNM) has a modest average size of 68.6 ± 3.3 nm and shows pH-sensitive drug release manner. The parallel activity of 5-Fu and Dox show synergistic anticancer efficacy. The IC50 value of 5-Fu/Dox-DNM toward human breast cancer (MDA-MB-231) cells was 0.25 μg/mL, presenting an 11.2-fold and 6.1-fold increase in cytotoxicity compared to Dox-DNM and 5-Fu-DNM, respectively. Furthermore, 5-Fu/Dox-DNM significantly inhibits the progression of tumor growth in the MDA-MB-231 xenograft tumor mice model. In conclusion, we have demonstrated that our AmD-based combination therapeutic system has promising potential to open an avenue for coencapsulation of multiple chemotherapeutic agents to promote superior anticancer effect.

  2. Therapeutically blocking Interleukin-11 Receptor-α enhances doxorubicin cytotoxicity in high grade type I endometrioid tumours.

    PubMed

    Winship, Amy; Van Sinderen, Michelle; Rainczuk, Katarzyna; Dimitriadis, Evdokia

    2017-04-04

    High grade type I endometrial cancers have poor prognosis. Interleukin (IL)11 is elevated in tumours and uterine lavage with increasing tumour grade in women. IL11 regulates cell cycle, invasion and migration and we recently demonstrated that IL11 receptor (R)α inhibition impaired low and moderate grade endometrial tumourigenesis in vivo. In this report, we hypothesized that micro-RNA(miR)-1 regulates IL11 and that IL11 promotes high grade endometrial tumour growth. We aimed to determine whether combination treatment using an anti-human IL11Rα blocking antibody (Ab) and doxorubicin chemotherapeutic impairs high grade tumour growth. MiR-1 was absent in human endometrial tumours versus human benign endometrium (n = 10/group). Transfection with miR-1 mimic restored miR-1 expression, down-regulated IL11 mRNA and impaired cell viability in grade 3-derived AN3CA human endometrial epithelial cancer cells. AN3CA cell proliferation was reduced in response to Ab and doxorubicin combination treatment versus Ab, IgG control, or doxorubicin alone. Subcutaneous xenograft tumours were established in female Balb/c athymic nude mice using AN3CA cells expressing IL11 and IL11Rα. Administration of recombinant human IL11 to mice (n = 4/group) activated IL11 downstream target, signal transducers and activators of transcription (STAT3) and significantly increased tumour growth (p < 0.05), suggesting that IL11 promotes high grade tumour growth. IL11Rα blocking Ab reduced STAT3 phosphorylation and combination treatment with doxorubicin resulted in a significant reduction in tumour growth (p < 0.05) compared to Ab, doxorubicin, or IgG control. Our data suggest that therapeutically targeting IL11Rα in combination with doxorubicin chemotherapy could inhibit high grade type I endometrioid cancer growth.

  3. Increase of therapeutic activity of doxorubicin by long circulating liposomes in combination with curcumin.

    PubMed

    Wang, Hong; Hu, Liandong; Li, Chunlei; Zhang, Jingguo; Zhang, Tao

    2011-11-01

    In this study, doxorubicin (DOX)-loaded long circulating liposomes combined with curcumin (CUR) (DOX-CUR-LCLs) were successfully prepared as a novel formulation for cancer treatment. The particle size and distribution, zeta potential, drug loading capacity, and entrapment efficiency (EE) of the preparation were characterized. The in vitro anti-tumor activities of DOX-CUR-LCLs and DOX-LCLs against A549 cells were then evaluated and compared with that of free DOX. Cytotoxicity evaluation showed that DOX-CUR-LCLs had a significantly higher antitumor activity than other DOX preparations. These results suggest that novel DOX-CUR-LCLs, combination of DOX and CUR administered in long-circulating liposomes, could improve antitumor activity.

  4. MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity.

    PubMed

    Holmgren, Gustav; Synnergren, Jane; Andersson, Christian X; Lindahl, Anders; Sartipy, Peter

    2016-08-01

    Anthracyclines, such as doxorubicin, are well-established, highly efficient anti-neoplastic drugs used for treatment of a variety of cancers, including solid tumors, leukemia, lymphomas, and breast cancer. The successful use of doxorubicin has, however, been hampered by severe cardiotoxic side-effects. In order to prevent or reverse negative side-effects of doxorubicin, it is important to find early biomarkers of heart injury and drug-induced cardiotoxicity. The high stability under extreme conditions, presence in various body fluids, and tissue-specificity, makes microRNAs very suitable as clinical biomarkers. The present study aimed towards evaluating the early and late effects of doxorubicin on the microRNA expression in cardiomyocytes derived from human pluripotent stem cells. We report on several microRNAs, including miR-34a, miR-34b, miR-187, miR-199a, miR-199b, miR-146a, miR-15b, miR-130a, miR-214, and miR-424, that are differentially expressed upon, and after, treatment with doxorubicin. Investigation of the biological relevance of the identified microRNAs revealed connections to cardiomyocyte function and cardiotoxicity, thus supporting the findings of these microRNAs as potential biomarkers for drug-induced cardiotoxicity. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Presence of Cx43 in extracellular vesicles reduces the cardiotoxicity of the anti-tumour therapeutic approach with doxorubicin

    PubMed Central

    Martins-Marques, Tania; Pinho, Maria Joao; Zuzarte, Monica; Oliveira, Carla; Pereira, Paulo; Sluijter, Joost P. G.; Gomes, Celia; Girao, Henrique

    2016-01-01

    Extracellular vesicles (EVs) are major conveyors of biological information, mediating local and systemic cell-to-cell communication under physiological and pathological conditions. These endogenous vesicles have been recognized as prominent drug delivery vehicles of several therapeutic cargoes, including doxorubicin (dox), presenting major advantages over the classical approaches. Although dox is one of the most effective anti-tumour agents in the clinical practice, its use is very often hindered by its consequent dramatic cardiotoxicity. Despite significant advances witnessed in the past few years, more comprehensive studies, supporting the therapeutic efficacy of EVs, with decreased side effects, are still scarce. The main objective of this study was to evaluate the role of the gap junction protein connexin43 (Cx43) in mediating the release of EV content into tumour cells. Moreover, we investigated whether Cx43 improves the efficiency of dox-based anti-tumour treatment, with a concomitant decrease of cardiotoxicity. In the present report, we demonstrate that the presence of Cx43 in EVs increases the release of luciferin from EVs into tumour cells in vitro and in vivo. In addition, using cell-based approaches and a subcutaneous mouse tumour model, we show that the anti-tumour effect of dox incorporated into EVs is similar to the administration of the free drug, regardless the presence of Cx43. Strikingly, we demonstrate that the presence of Cx43 in dox-loaded EVs reduces the cardiotoxicity of the drug. Altogether, these results bring new insights into the concrete potential of EVs as therapeutic vehicles and open new avenues toward the development of strategies that help to reduce unwanted side effects. PMID:27702427

  6. Potential therapeutic applications of biosurfactants.

    PubMed

    Gudiña, Eduardo J; Rangarajan, Vivek; Sen, Ramkrishna; Rodrigues, Lígia R

    2013-12-01

    Biosurfactants have recently emerged as promising molecules for their structural novelty, versatility, and diverse properties that are potentially useful for many therapeutic applications. Mainly due to their surface activity, these molecules interact with cell membranes of several organisms and/or with the surrounding environments, and thus can be viewed as potential cancer therapeutics or as constituents of drug delivery systems. Some types of microbial surfactants, such as lipopeptides and glycolipids, have been shown to selectively inhibit the proliferation of cancer cells and to disrupt cell membranes causing their lysis through apoptosis pathways. Moreover, biosurfactants as drug delivery vehicles offer commercially attractive and scientifically novel applications. This review covers the current state-of-the-art in biosurfactant research for therapeutic purposes, providing new directions towards the discovery and development of molecules with novel structures and diverse functions for advanced applications.

  7. Quercetin Potentiates Doxorubicin Mediated Antitumor Effects against Liver Cancer through p53/Bcl-xl

    PubMed Central

    Wang, Guanyu; Sharma, Sherven; Dong, Qinghua

    2012-01-01

    Background The dose-dependent toxicities of doxorubicin (DOX) limit its clinical applications, particularly in drug-resistant cancers, such as liver cancer. In this study, we investigated the role of quercetin on the antitumor effects of DOX on liver cancer cells and its ability to provide protection against DOX-mediated liver damage in mice. Methodology and Results The MTT and Annexin V/PI staining assay demonstrated that quercetin selectively sensitized DOX-induced cytotoxicity against liver cancer cells while protecting normal liver cells. The increase in DOX-mediated apoptosis in hepatoma cells by quercetin was p53-dependent and occurred by downregulating Bcl-xl expression. Z-VAD-fmk (caspase inhibitor), pifithrin-α (p53 inhibitor), or overexpressed Bcl-xl decreased the effects of quercetin on DOX-mediated apoptosis. The combined treatment of quercetin and DOX significantly reduced the growth of liver cancer xenografts in mice. Moreover, quercetin decreased the serum levels of alanine aminotransferase and aspartate aminotransferase that were increased in DOX-treated mice. Quercetin also reversed the DOX-induced pathological changes in mice livers. Conclusion and Significance These results indicate that quercetin potentiated the antitumor effects of DOX on liver cancer cells while protecting normal liver cells. Therefore, the development of quercetin may be beneficial in a combined treatment with DOX for increased therapeutic efficacy against liver cancer. PMID:23240061

  8. Bicontinuous cubic liquid crystalline nanoparticles for oral delivery of Doxorubicin: implications on bioavailability, therapeutic efficacy, and cardiotoxicity.

    PubMed

    Swarnakar, Nitin K; Thanki, Kaushik; Jain, Sanyog

    2014-05-01

    The present study explores the potential of bicontinous cubic liquid crystalline nanoparticles (LCNPs) for improving therapeutic potential of doxorubicin. Phytantriol based Dox-LCNPs were prepared using hydrotrope method, optimized for various formulation components, process variables and lyophilized. Structural elucidation of the reconstituted formulation was performed using HR-TEM and SAXS analysis. The developed formulation was subjected to exhaustive cell culture experiments for delivery potential (Caco-2 cells) and efficacy (MCF-7 cells). Finally, in vivo pharmacokinetics, pharmacodynamic studies in DMBA induced breast cancer model and cardiotoxicity were also evaluated. The reconstituted formulation exhibited Pn3m type cubic structure, evident by SAXS and posed stability in simulated gastrointestinal fluids and at accelerated stability conditions for 6 months. Dox-LCNPs revealed significantly higher cell cytotoxicity (16.23-fold) against MCF-7 cell lines as compared to free drug owing to its preferential localization in the vicinity of nucleus. Furthermore, Caco-2 cell experiments revealed formation of reversible "virtual pathways" in the cell membrane for Dox-LCNPs and hence posed significantly higher relative oral bioavailability (17.74-fold). Subsequently, Single dose of Dox-LCNPs (per oral) led to significant reduction in % tumor burden (~42%) as compared that of ~31% observed in case of Adriamycin® (i.v.) when evaluated in DMBA induced breast cancer model. Moreover, Dox induced cardiotoxicity was also found to be significantly lower in case of Dox-LCNPs as compared to clinical formulations (Adriamycin® and Lipodox®). Incorporation of Dox in the novel LCNPs demonstrated improved antitumor efficacy and safety profile and can be a viable option for oral chemotherapy.

  9. The tumor accumulation and therapeutic efficacy of doxorubicin carried in calcium phosphate-reinforced polymer nanoparticles.

    PubMed

    Min, Kyung Hyun; Lee, Hong Jae; Kim, Kwangmeyung; Kwon, Ick Chan; Jeong, Seo Young; Lee, Sang Cheon

    2012-08-01

    A mineral (calcium phosphate, CaP)-reinforced core-shell-corona micelle was evaluated as a nanocarrier of doxorubicin (DOX) for cancer therapy. The polymer micelles of poly(ethylene glycol)-b-poly(L-aspartic acid)-b-poly(L-phenylalanine) (PEG-PAsp-PPhe) in the aqueous phase provided the three distinct functional domains: the hydrated PEG outer corona for prolonged circulation, the anionic PAsp middle shell for CaP mineralization, and the hydrophobic PPhe inner core for DOX loading. CaP mineralization was performed by initial electrostatic localization of calcium ions at anionic PAsp shells, and the consequent addition of phosphate anions to trigger the growth of CaP. The mineralization did not affect the micelle size or the spherical morphology. The CaP-mineralized micelles exhibited enhanced serum stability. The DOX release from the DOX-loaded mineralized micelles (DOX-CaP-PM) at physiological pH was efficiently inhibited, whereas at an endosomal pH (pH 4.5), DOX release was facilitated due to the rapid dissolution of the CaP mineral layers in the middle shell domains. The in vivo tissue distribution and tumor accumulation of the DOX-CaP-PM that were labeled with a near-infrared fluorescent (NIRF) dye, Cy5.5, were monitored in MDA-MB231 tumor-bearing mice. Non-invasive real-time optical imaging results indicated that the DOX-CaP-PM exhibited enhanced tumor specificity due to the prolonged stable circulation in the blood and an enhanced permeation and retention (EPR) effect compared with the DOX-loaded nonmineralized polymer micelles (DOX-NPM). The DOX-CaP-PM exhibited enhanced therapeutic efficacy in tumor-bearing mice compared with free DOX and DOX-NPM. The CaP mineralization on assembled nanoparticles may serve as a useful guide for enhancing the antitumor therapeutic efficacy of various polymer micelles and nano-aggregates. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Doxorubicin in Combination with a Small TGFβ Inhibitor: A Potential Novel Therapy for Metastatic Breast Cancer in Mouse Models

    PubMed Central

    Bandyopadhyay, Abhik; Wang, Long; Agyin, Joseph; Tang, Yuping; Lin, Shu; Yeh, I-Tien; De, Keya; Sun, Lu-Zhe

    2010-01-01

    Background Recent studies suggested that induction of epithelial-mesenchymal transition (EMT) might confer both metastatic and self-renewal properties to breast tumor cells resulting in drug resistance and tumor recurrence. TGFβ is a potent inducer of EMT and has been shown to promote tumor progression in various breast cancer cell and animal models. Principal Findings We report that chemotherapeutic drug doxorubicin activates TGFβ signaling in human and murine breast cancer cells. Doxorubicin induced EMT, promoted invasion and enhanced generation of cells with stem cell phenotype in murine 4T1 breast cancer cells in vitro, which were significantly inhibited by a TGFβ type I receptor kinase inhibitor (TβRI-KI). We investigated the potential synergistic anti-tumor activity of TβR1-KI in combination with doxorubicin in animal models of metastatic breast cancer. Combination of Doxorubicin and TβRI-KI enhanced the efficacy of doxorubicin in reducing tumor growth and lung metastasis in the 4T1 orthotopic xenograft model in comparison to single treatments. Doxorubicin treatment alone enhanced metastasis to lung in the human breast cancer MDA-MB-231 orthotopic xenograft model and metastasis to bone in the 4T1 orthotopic xenograft model, which was significantly blocked when TβR1-KI was administered in combination with doxorubicin. Conclusions These observations suggest that the adverse activation of TGFβ pathway by chemotherapeutics in the cancer cells together with elevated TGFβ levels in tumor microenvironment may lead to EMT and generation of cancer stem cells resulting in the resistance to the chemotherapy. Our results indicate that the combination treatment of doxorubicin with a TGFβ inhibitor has the potential to reduce the dose and consequently the toxic side-effects of doxorubicin, and improve its efficacy in the inhibition of breast cancer growth and metastasis. PMID:20442777

  11. Microparticles in angiogenesis: therapeutic potential.

    PubMed

    Martinez, M Carmen; Andriantsitohaina, Ramaroson

    2011-06-24

    Considered during the past decades as cell dust, microparticles are now deemed true biomarkers and vectors of biological information between cells. Depending on their origin, the composition of microparticles varies and the subsequent message transported by them, such as proteins, mRNA, or miRNA, can differ. Recent studies have described microparticles as "cargos" of deleterious information in blood vessel wall under pathological situations such as hypertension, myocardial infarction, and metabolic syndrome. In addition, it has been reported that depending on their origin, microparticles also possess a therapeutic potential regarding angiogenesis. Microparticles can act directly through the interaction ligand/receptor or indirectly on angiogenesis by modulating soluble factor production involved in endothelial cell differentiation, proliferation, migration, and adhesion; by reprogramming endothelial mature cells; and by inducing changes in levels, phenotype, and function of endothelial progenitor cells. This results in an increase in formation of in vitro capillary-like tubes and the generation of new vessels in vivo under ischemic conditions, for instance. Taking into consideration these properties of microparticles, recent evidence provides new basis to expand the possibility that microparticles might be used as therapeutic tools in pathologies associated with an alteration of angiogenesis.

  12. Therapeutic potential of cannabinoid medicines.

    PubMed

    Robson, P J

    2014-01-01

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

  13. Potentiation of Methoxymorpholinyl Doxorubicin Anti-Tumor Activity by P450 3A4 Gene Transfer#

    PubMed Central

    Lu, Hong; Chen, Chong-Sheng; Waxman, David J.

    2008-01-01

    Summary Preclinical and clinical studies of CYP gene-directed enzyme-prodrug therapy have focused on anticancer prodrugs activated by CYP2B enzymes, which have low endogenous expression in human liver; however, the gene therapeutic potential of CYP3A enzymes, which are highly expressed in human liver, remains unknown. This study investigated methoxymorpholinyl-doxorubicin (MMDX), a novel CYP3A-activated anticancer prodrug. Retroviral transfer of CYP3A4 increased 9L gliosarcoma cell chemosensitivity to MMDX 120-fold (IC50=0.2nM). In CHO cells, overexpression of P450 reductase in combination with CYP3A4 enhanced chemosensitivity to MMDX, and to ifosfamide, another CYP3A4 prodrug, 11–23-fold compared to CYP3A4 expression alone. CYP3A4 expression and MMDX chemosensitivity were increased in human lung (A549) and brain (U251) tumor cells infected with replication-defective adenovirus encoding CYP3A4. Co-infection with Onyx-017, a replication-conditional adenovirus that co-amplifies and co-replicates the Adeno-3A4 virus, led to large increases in CYP3A4 RNA but only modest increases in CYP3A4 protein and activity. MMDX induced remarkable growth delay of 9L/3A4 tumors, but not 9L tumors, in immunodeficient mice administered low-dose MMDX either i.v. or by direct intratumoral injection (60µg/kg, every 7-days ×3), with the intratumoral route being substantially less toxic to the mouse host. No antitumor activity was observed with i.p. MMDX treatment, suggesting a substantial hepatic first pass effect, and with activated MMDX metabolites formed in the liver having poor access to the tumor site. These studies demonstrate that human CYP3A4 has strong potential for MMDX prodrug activation therapy, and suggest that endogenous tumor cell expression of CYP3A4, and not hepatic CYP3A4 activity, is a key determinant of responsiveness to MMDX therapy in cancer patients in vivo. PMID:19011599

  14. Improved drug delivery and therapeutic efficacy of PEgylated liposomal doxorubicin by targeting anti-HER2 peptide in murine breast tumor model.

    PubMed

    Zahmatkeshan, Masoumeh; Gheybi, Fatemeh; Rezayat, Seyed Mahdi; Jaafari, Mahmoud Reza

    2016-04-30

    Targeted cancer therapy is a powerful therapeutic strategy to management of cancer. HER2 as an anticancer target has long been studied. Its overexpression plays an important role in the pathogenesis and progressiveness of breast and other cancers. To establish efficient and reliable drug delivery to HER2-overexpressing cells, the authors of this study have developed anti-HER2 (ErbB2) peptide-liposomal formulations of doxorubicin (DOX) by an engineered breast tumor-targeting peptide ligand, AHNP, Anti-HER2/neu peptide, (FCDGFYACYADV) with three glycine amino acids as spacer before its original sequencing. Towards this goal, PEGylated liposome doxorubicin (PLD) bearing different ligand densities of AHNP was prepared and characterized for their size, zeta potential and peptide conjugation. The AHNP functionalization and density effects on breast tumor cell uptake, selective cytotoxicity, prevention of tumor growth and the tissue biodistribution of encapsulated DOX were studied in mice bearing TUBO breast cancer tumor model. The findings demonstrated that increasing the ligand density of AHNP increases cytotoxicity and cell-uptake in SKBR3 and TUBO cells which overexpress HER2 but not in MDA-MB-231with low HER2 expression profile. The anticancer activity was also superior for targeted liposomal DOX with more AHNP densities. Overall, the results showed that optimum AHNP density functionalization of PLD can significantly improve selectivity and the therapeutic index of liposomal DOX in the treatment of HER2 positive breast cancer and merits further investigation. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Development, characterization and evaluation of doxorubicin nanostructured lipid carriers for prostate cancer.

    PubMed

    Zhang, Hong-Wei; Dang, Qiang; Zhang, Zheng-Wei; Wu, Fu-Shun

    2017-01-01

    The purpose of this study was to develop an optimised formulation for a nanostructured lipid carrier (NLC) loaded with doxorubicin. A doxorubicin-loaded NLC was prepared using an emulsification solidification method. The Box-Behnken design response surface methodology was used to optimise formulations of the doxorubicin-loaded NLC. The drug entrapment efficiency, drug loading efficiency, particle size, and zeta potential of the doxorubicin- loaded NLC were 74.18%, 13.28%, 170 nm, and -14.8 mV, respectively. Transmission electron microscopy of the optimised NLC showed spherical particles. Furthermore, the doxorubicin-loaded NLC was found to exhibit good therapeutic efficacy with remarkably improved oral bioavailability of doxorubicin. The NLC system demonstrated potential for the targeted delivery of doxorubicin in prostate cancer.

  16. 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.

  17. Tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity: Potential role of tannins in cancer chemotherapy

    SciTech Connect

    Tikoo, Kulbhushan Sane, Mukta Subhash; Gupta, Chanchal

    2011-03-15

    Doxorubicin, an anthracycline antibiotic, is widely used in the treatment of various solid tumors including breast cancer. However, its use is limited due to a variety of toxicities including cardiotoxicity. The present study aimed to evaluate the effect of tannic acid, a PARG/PARP inhibitor and an antioxidant, on doxorubicin-induced cardiotoxicity in H9c2 embryonic rat heart myoblasts and its anti-cancer activity in MDA-MB-231 human breast cancer cells as well as in DMBA-induced mammary tumor animals. Doxorubicin-induced cardiotoxicity was assessed by measurement of heart weight, plasma LDH level and histopathology. Bcl-2, Bax, PARP-1 and p53 expression were examined by western blotting. Our results show that tannic acid prevents activation of PARP-1, reduces Bax and increases Bcl-2 expression in H9c2 cells, thus, preventing doxorubicin-induced cell death. Further, it reduces the cell viability of MDA-MB-231 breast cancer cells, increases p53 expression in mammary tumors and shows maximum tumor volume reduction, suggesting that tannic acid potentiates the anti-cancer activity of doxorubicin. To the best of our knowledge, this is the first report which shows that tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity both in vitro (H9c2 and MDA-MB-231 cells) as well as in in vivo model of DMBA-induced mammary tumor animals.

  18. 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.

  19. Zinc is a potential therapeutic for chemoresistant ovarian cancer.

    PubMed

    Bastow, Max; Kriedt, Christopher L; Baldassare, Joseph; Shah, Maulik; Klein, Claudette

    2011-01-01

    Ovarian cancer is the leading cause of death from gynecological cancer. The high mortality rate reflets the lack of early diagnosis and limited treatment alternatives. We have observed a number of properties of zinc cytotoxicity that make it attractive from a therapeutic standpoint. Using SKOV3 and ES2 cells, ovarian cancer cell lines that demonstrate varied degrees of resistance to known therapeutics, we show that zinc killing is time and concentration dependent. Death is preceded by distinct changes in cell shape and size. The effects of zinc are additive with cisplatin or doxorubicin, whose morphological effects are distinct from those of zinc. Cytotoxicity of paclitaxel is minimal, making it difficult to determine additivity with zinc. Paclitaxel results in changes in cell shape and size similar to those of zinc but has different effects on cell cycle progression and cyclin expression. The data indicate that the means by which zinc kills ovarian cancer cells is distinct from currently used chemotherapeutics. Based on the properties reported here, zinc has the potential to be developed as either a primary treatment or as a second line of defense against cancers that have developed resistance to currently used chemotherapeutics.

  20. Evaluation of the potential of doxorubicin loaded microbubbles as a theranostic modality using a murine tumor model.

    PubMed

    Abdalkader, Rodi; Kawakami, Shigeru; Unga, Johan; Suzuki, Ryo; Maruyama, Kazuo; Yamashita, Fumiyoshi; Hashida, Mitsuru

    2015-06-01

    In this study, a novel phospholipid-based microbubble formulation containing doxorubicin and perfluoropropane gas (DLMB) was developed. The DLMBs were prepared by mechanical agitation of a phospholipid dispersion in the presence of perfluoropropane (PFP) gas. An anionic phospholipid, distearoyl phosphatidylglycerol (DSPG) was selected to load doxorubicin in the microbubbles by means of electrostatic interaction. The particle size, zeta potential, echogenicity and stability of the DLMBs were measured. Drug loading was ⩾ 92%. The potential of the DLMBs for use as a theranostic modality was evaluated in tumor bearing mice. Gas chromatography analysis of PFP showed significant enhancement of PFP retention when doxorubicin was used at concentrations of 10-82% equivalent to DSPG. The inhibitory effects on the proliferation of B16BL6 melanoma murine cells in vitro were enhanced using a combination of ultrasound (US) irradiation and DLMBs. Moreover, in vivo DLMBs in combination with (US) irradiation significantly inhibited the growth of B16BL6 melanoma tumor in mice. Additionally, US echo imaging showed high contrast enhancement of the DLMBs in the tumor vasculature. These results suggest that DLMBs could serve as US triggered carriers of doxorubicin as well as tumor imaging agents in cancer therapy.

  1. Curcumin: therapeutical potential in ophthalmology.

    PubMed

    Pescosolido, Nicola; Giannotti, Rossella; Plateroti, Andrea Maria; Pascarella, Antonia; Nebbioso, Marcella

    2014-03-01

    Curcumin (diferuloylmethane) is the main curcuminoid of the popular Indian spice turmeric (Curcuma longa). In the last 50 years, in vitro and in vivo experiments supported the main role of polyphenols and curcumin for the prevention and treatment of many different inflammatory diseases and tumors.The anti-inflammatory, antioxidant, and antitumor properties of curcumin are due to different cellular mechanisms: this compound, in fact, produces different responses in different cell types. Unfortunately, because of its low solubility and oral bioavailability, the biomedical potential of curcumin is not easy to exploit; for this reason more attention has been given to nanoparticles and liposomes, which are able to improve curcumin's bioavailability. Pharmacologically, curcumin does not show any dose-limiting toxicity when it is administered at doses of up to 8 g/day for three months. It has been demonstrated that curcumin has beneficial effects on several ocular diseases, such as chronic anterior uveitis, diabetic retinopathy, glaucoma, age-related macular degeneration, and dry eye syndrome. The purpose of this review is to report what has so far been elucidated about curcumin properties and its potential use in ophthalmology.

  2. Didox potentiates the cytotoxic profile of doxorubicin and protects from its cardiotoxicity.

    PubMed

    Al-Abd, Ahmed M; Al-Abbasi, Fahad A; Asaad, Gihan F; Abdel-Naim, Ashraf B

    2013-10-15

    The use of adjuvant therapies in cancer treatment is rationalized by potentiating the efficacy and/or protecting from the major side effects of chemotherapeutics. Didox, besides its antioxidant properties, is an inhibitor for DNA synthesis and repair which might recommend its use as adjuvant therapy. Herein, we have studied the effect of didox in potentiating the efficacy of doxorubicin (DOX) against liver cancer cells and protecting from its dose-limiting cardiotoxic effects. Didox combination with DOX significantly decreased in the IC50 of DOX to half its original value in Huh7 and HepG2 liver cancer cell lines. The calculated combination index (CI-value) indicated additive type of drug interaction (CI-value ranged from 0.81 to 0.9). Both didox and DOX significantly blocked the cell cycle in S-phase and their combination significantly increased cell cycle blockade. Also, didox combination significantly increase the caspase-3 level compared to DOX treatment alone. On the other hand, didox (150 mg/kg daily) significantly protected the cardiomyocyte membrane integrity and decreased the intra-cardiac oxidative stress induced by DOX treatment (15 mg/kg). This protective effect was reflected in reverting the cardiomegaly and cardio-pathological features induced by DOX treatment. Also didox prolonged the median survival time of mice treated with DOX and decreased the mortality risk by 3.7 folds. In conclusion, didox significantly potentiated the cytotoxicity of DOX in liver cancer cells and protected from its cardiotoxicity.

  3. Doxorubicin loaded polymeric gold nanoparticles targeted to human folate receptor upon laser photothermal therapy potentiates chemotherapy in breast cancer cell lines.

    PubMed

    Banu, Hussaina; Sethi, Dipinder Kaur; Edgar, Andre; Sheriff, Adhnaan; Rayees, Nuthan; Renuka, N; Faheem, S M; Premkumar, Kumpati; Vasanthakumar, Geetha

    2015-08-01

    The current research focuses on the application of folate conjugated and doxorubicin loaded polymeric gold nanoparticles (GNPs) for the targeted treatment of folate receptor overexpressing breast cancers, augmented by adjunctive laser photothermal therapy. Herein, GNPs surface modified with folate, drug doxorubicin and polyethylene glycol were engineered and were used as vehicles for folate receptor targeted delivery of doxorubicin into cancer cells. Subsequently, the GNPs were photo-excited using laser light for mediating hyperthermia in the cancer cells. In vitro studies were performed to validate the efficacy of the combined modality of folate conjugated and doxorubicin loaded polymeric GNP mediated chemotherapy followed by photothermal therapy in comparison to treatment with free drug; and the combination modality showed better therapeutic efficacy than that of plain doxorubicin treatment in MDA-MB-231 breast cancer cells that express increased levels of surface folate receptors when compared to MCF-7 breast cancer cells that express low levels of folate receptor. The mechanism of cell death was investigated using fluorescent microscopy. Immunoassays showed the up-regulation of the pro-apoptotic protein p53 and down-regulation of the anti-apoptotic protein Bcl-2. Collectively, these results suggest that the folate tagged doxorubicin loaded GNPs are an attractive platform for targeted delivery of doxorubicin and are agents suitable for photothermal cancer therapy. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Pentoxifylline as a modulator of anticancer drug doxorubicin. Part II: Reduction of doxorubicin DNA binding and alleviation of its biological effects.

    PubMed

    Gołuński, Grzegorz; Borowik, Agnieszka; Derewońko, Natalia; Kawiak, Anna; Rychłowski, Michał; Woziwodzka, Anna; Piosik, Jacek

    2016-04-01

    Anticancer drug doxorubicin is commonly used in cancer treatment. However, drug's severe side effects make toxicity reduction important matter. Another biologically active aromatic compound, pentoxifylline, can sequester aromatic compounds in stacking complexes reducing their bioactivity. This work deals with the problem of alleviating doxorubicin side effects by pentoxifylline. We employed a wide spectrum of prokaryotic and eukaryotic cellular assays. In addition, we used the doxorubicin-pentoxifylline mixed association constant to quantitatively assess pentoxifylline influence on the doxorubicin mutagenic activity. Obtained results indicate strong protective effects of pentoxifylline towards doxorubicin, observed on bacteria and human keratinocytes with no such effects observed on the cancer cells. It may be hypothesized that, considering much shorter half-life of pentoxifylline than doxorubicin, simultaneous administration of doxorubicin and pentoxifylline will lead to gradual release of doxorubicin from complexes with pentoxifylline to reach desired therapeutic concentration. Proposed results shed light on the possible doxorubicin chemotherapy modification and its side effects reduction without the loss of its therapeutic potential.

  5. Coating doxorubicin-loaded nanocapsules with alginate enhances therapeutic efficacy against Leishmaniain hamsters by inducing Th1-type immune responses

    PubMed Central

    Kansal, S; Tandon, R; Verma, A; Misra, P; Choudhary, A K; Verma, R; Verma, P R P; Dube, A; Mishra, P R

    2014-01-01

    Background and Purpose The aim of the present study was to evaluate the immunomodulatory and chemotherapeutic potential of alginate-(SA) coated nanocapsule (NCs) loaded with doxorubicin (SA-NCs-DOX) against visceral leishmaniasis in comparison with nano-emulsions containing doxorubicin (NE-DOX). Experimental Approach NE-DOX was prepared using low-energy emulsification methods. Stepwise addition of protamine sulphate and SA in a layer-by-layer manner was used to form SA-NCs-DOX. SA-NCs-DOX, NE-DOX and Free DOX were compared for their cytotoxicity against Leishmania donovani-infected macrophages in vitro and generation of T-cell responses in infected hamsters in vivo. Key Results Size and ζ potential of the NE-DOX and SA-NCs-DOX formulations were 310 ± 2.1 nm and (−)32.6 ± 2.1 mV, 342 ± 4.1 nm and (−)29.3 ± 1.2 mV respectively. SA-NCs-DOX was better (1.5 times) taken up by J774A.1 macrophages compared with NE-DOX. SA-NCs -DOX showed greater efficacy than NE-DOX against intramacrophagic amastigotes. SA-NCs-DOX treatment exhibited enhanced apoptotic efficiency than NE-DOX and free DOX as evident by cell cycle analysis, decrease in mitochondrial membrane potential, ROS and NO production. T-cell responses, when assessed through lymphoproliferative responses, NO production along with enhanced levels of iNOS, TNF-α, IFN-γ and IL-12 were found to be up-regulated after SA-NCs-DOX, compared with responses to NE-DOX in vivo. Parasitic burden was decreased in Leishmania-infected hamsters treated with SA-NCs-DOX, compared with NE-DOX. Conclusions and Implications Our results provide insights into the development of an alternative approach to improved management of leishmaniasis through a combination of chemotherapy with stimulation of the innate immune system. PMID:24837879

  6. Tea nanoparticle, a safe and biocompatible nanocarrier, greatly potentiates the anticancer activity of doxorubicin

    PubMed Central

    Wang, Yi-Jun; Huang, Yujian; Anreddy, Nagaraju; Zhang, Guan-Nan; Zhang, Yun-Kai; Xie, Meina; Lin, Derrick; Yang, Dong-Hua; Zhang, Mingjun; Chen, Zhe-Sheng

    2016-01-01

    An infusion-dialysis based procedure has been developed as an approach to isolate organic nanoparticles from green tea. Tea nanoparticle (TNP) can effectively load doxorubicin (DOX) via electrostatic and hydrophobic interactions. We established an ABCB1 overexpressing tumor xenograft mouse model to investigate whether TNP can effectively deliver DOX into tumors and bypass the efflux function of the ABCB1 transporter, thereby increasing the intratumoral accumulation of DOX and potentiating the anticancer activity of DOX. MTT assays suggested that DOX-TNP showed higher cytotoxicity toward CCD-18Co, SW620 and SW620/Ad300 cells than DOX. Animal study revealed that DOX-TNP resulted in greater inhibitory effects on the growth of SW620 and SW620/Ad300 tumors than DOX. In pharmacokinetics study, DOX-TNP greatly increased the SW620 and SW620/Ad300 intratumoral concentrations of DOX. But DOX-TNP had no effect on the plasma concentrations of DOX. Furthermore, TNP is a safe nanocarrier with excellent biocompatibility and minimal toxicity. Ex vivo IHC analysis of SW620 and SW620/Ad300 tumor sections revealed evidence of prominent antitumor activity of DOX-TNP. In conclusion, our findings suggested that natural nanomaterials could be useful in combating multidrug resistance (MDR) in cancer cells and potentiating the anticancer activity of chemotherapeutic agents in cancer treatment. PMID:26716507

  7. Chondroitin sulfate-capped super-paramagnetic iron oxide nanoparticles as potential carriers of doxorubicin hydrochloride.

    PubMed

    Mallick, Neha; Anwar, Mohammed; Asfer, Mohammed; Mehdi, Syed Hassan; Rizvi, Mohammed Moshahid Alam; Panda, Amulya Kumar; Talegaonkar, Sushama; Ahmad, Farhan Jalees

    2016-10-20

    Chondroitin-4-sulfate (CS), a glycosaminoglycan, was used to prepare CS-capped super-paramagnetic iron oxide nanoparticles, which were further employed for loading a water-soluble chemotherapeutic agent (doxorubicin hydrochloride, DOX). CS-capped SPIONs have potential biomedical application in cancer targeting. The optimized formulation had a hydrodynamic size of 91.2±0.8nm (PDI; 0.228±0.004) and zeta potential of -49.1±1.66mV. DOX was loaded onto the formulation up to 2% (w/w) by physical interaction with CS. TEM showed nano-sized particles having a core-shell structure. XRD confirmed crystal phase of iron oxide. FT-IR conceived the interaction of iron oxide with CS as bidentate chelation and also confirmed DOX loading. Vibration sample magnetometry confirmed super-paramagnetic nature of nanoparticles, with saturation magnetization of 0.238emug(-1). In vitro release profile at pH 7.4 showed that 96.67% of DOX was released within 24h (first order kinetics). MTT assay in MCF7 cells showed significantly higher (p<0.0001) cytotoxicity for DOX in SPIONs than DOX solution (IC50 values 6.294±0.4169 and 11.316±0.1102μgmL(-1), respectively).

  8. Monoclonal antibody-targeted PEGylated liposome-ICG encapsulating doxorubicin as a potential theranostic agent.

    PubMed

    Lozano, Neus; Al-Ahmady, Zahraa S; Beziere, Nicolas S; Ntziachristos, Vasilis; Kostarelos, Kostas

    2015-03-30

    Indocyanine green (ICG) is an FDA-approved, strongly photo-absorbent/fluorescent probe that has been incorporated into a clinically-relevant PEGylated liposome as a flexible optoacoustic contrast agent platform. This study describes the engineering of targeted PEGylated liposome-ICG using the anti-MUC-1 "humanized" monoclonal antibody (MoAb) hCTM01 as a tumour-specific theranostic system. We aimed to visualise non-invasively the tumour accumulation of these MoAb-targeted liposomes over time in tumour-bearing mice using multispectral optoacoustic tomography (MSOT). Preferential accumulation of targeted PEGylated liposome-ICG was studied after intravenous administration in comparison to non-targeted PEGylated liposome-ICG using both fast growing (4T1) and slow growing (HT-29) MUC-1 positive tumour models. Monitoring liposomal ICG in the tumour showed that both targeted and non-targeted liposome-ICG formulations preferentially accumulated into the tumour models studied. Rapid accumulation was observed for targeted liposomes at early time points mainly in the periphery of the tumour volume suggesting binding to available MUC-1 receptors. In contrast, non-targeted PEGylated liposomes showed accumulation at the centre of the tumour at later time points. In an attempt to take this a step further, we successfully encapsulated the anticancer drug, doxorubicin (DOX) into both targeted and non-targeted PEGylated liposome-ICG. The engineering of DOX-loaded targeted ICG liposome systems present a novel platform for combined tumour-specific therapy and diagnosis. This can open new possibilities in the design of advanced image-guided cancer therapeutics.

  9. Role of xanthine oxidase in the potentiation of doxorubicin-induced cardiotoxicity by mitomycin C.

    PubMed

    Gustafson, D L; Swanson, J D; Pritsos, C A

    1991-09-01

    Clinical evidence has suggested that mitomycin C (MMC) potentiates doxorubicin (DOX) induced cardiotoxicity. In this study a mouse model was used to examine the effect of DOX on the ability of cardiac tissue to bioactivate MMC to generate oxygen radicals. Cardiac damage was assessed by measuring serum CPK-MB isoenzyme levels and thiobarbituric acid reactive substances (TBARS) in the cardiac tissue. The exposure of animals to DOX or DOX and MMC over a three week period led to an increase in serum CPK-MB isoenzyme levels as well as TBARS. Treatment with DOX led to an increase in MMC-dependent, NADH-dependent, cyanide insensitive oxygen consumption, compared to control animals, thereby suggesting increased MMC-dependent oxygen radical generation. Levels of xanthine oxidase (XO; EC 1.1.3.22) and NADPH:cytochrome C reductase, two enzymes known to bioactivate MMC with subsequent oxygen radical generation, were measured in cardiac tissue with a 4.5 x increase in XO activity seen in DOX treated animals vs controls and no change in NADPH:cytochrome C reductase activity. Cardiac levels of xanthine dehydrogenase (XDH; EC 1.1.1.204) activity in DOX treated animals decreased while the XO/XDH ratio increased, suggesting a conversion of XDH to XO following DOX treatment.

  10. L-Canavanine potentiates the cytotoxicity of doxorubicin and cisplatin in arginine deprived human cancer cells

    PubMed Central

    Wink, Michael

    2016-01-01

    The non-protein amino acid L-canavanine (L-CAV), an antimetabolite of L-arginine (L-ARG), can alter the 3D conformation of proteins when incorporated into a protein instead of L-ARG. L-CAV inhibits the proliferation of some tumour cells. The deprivation of L-ARG in the culture medium enhances the response of cells to L-CAV. This study aimed to investigate the interaction of L-CAV in combination with the chemotherapeutic drugs, doxorubicin (DOX) or cisplatin (CIS), in cancer cells, especially in the absence of L-ARG. A combination method based on the median-effect principle and mass-action law was used. The following cancer cells were employed: HeLa and Caco-2 cells, overexpressing argininosuccinate synthase (ASS), pancreatic cells (MIA PaCa-2 and BxPC-3) and hepatocellular carcinoma cells (Hep G2 and SK-HEP-1), with down-regulated ASS. When constant and non-constant ratios of L-CAV were combined with DOX and CIS, a synergistic potentiation of cytotoxicity was recorded. Cells expressing high levels of ASS were more sensitive to the treatment as compared to the cells with reduced ASS levels. Overall, this study may provide a new approach to targeting some cancer cells with L-CAV in combination with DNA-targeting drugs such as DOX and CIS, especially those cells which overexpress ASS, such as human cervical and colorectal carcinoma cells. PMID:26839743

  11. Cardioprotective Potentials of Plant-Derived Small Molecules against Doxorubicin Associated Cardiotoxicity

    PubMed Central

    Ojha, Shreesh; Al Taee, Hasan; Goyal, Sameer; Mahajan, Umesh B.; Patil, Chandrgouda R.; Arya, D. S.; Rajesh, Mohanraj

    2016-01-01

    Doxorubicin (DOX) is a potent and widely used anthracycline antibiotic for the treatment of several malignancies. Unfortunately, the clinical utility of DOX is often restricted due to the elicitation of organ toxicity. Particularly, the increased risk for the development of dilated cardiomyopathy by DOX among the cancer survivors warrants major attention from the physicians as well as researchers to develop adjuvant agents to neutralize the noxious effects of DOX on the healthy myocardium. Despite these pitfalls, the use of traditional cytotoxic drugs continues to be the mainstay treatment for several types of cancer. Recently, phytochemicals have gained attention for their anticancer, chemopreventive, and cardioprotective activities. The ideal cardioprotective agents should not compromise the clinical efficacy of DOX and should be devoid of cumulative or irreversible toxicity on the naïve tissues. Furthermore, adjuvants possessing synergistic anticancer activity and quelling of chemoresistance would significantly enhance the clinical utility in combating DOX-induced cardiotoxicity. The present review renders an overview of cardioprotective effects of plant-derived small molecules and their purported mechanisms against DOX-induced cardiotoxicity. Phytochemicals serve as the reservoirs of pharmacophore which can be utilized as templates for developing safe and potential novel cardioprotective agents in combating DOX-induced cardiotoxicity. PMID:27313831

  12. Smac therapeutic Peptide nanoparticles inducing apoptosis of cancer cells for combination chemotherapy with Doxorubicin.

    PubMed

    Li, Mingxing; Liu, Peng; Gao, Guanhui; Deng, Jizhe; Pan, Zhengyin; Wu, Xu; Xie, Gaofeng; Yue, Caixia; Cho, Chi Hin; Ma, Yifan; Cai, Lintao

    2015-04-22

    Smac-conjugated nanoparticle (Smac-NP) was designed to induce the apoptosis of cancer cells and as a drug carrier for combination therapy. It contained three parts, a SmacN7 peptide which could induce apoptosis of cancer cells by interacting with XIAPs, the cell penetrating domain rich in arginine, and four hydrophobic tails for self-assembled Smac-NP. We demonstrated that Smac-NPs exerted an antitumor effect in breast cancer cell MDA-MB-231 and nonsmall lung cancer (NSCLC) cell H460, which efficiently inhibited cancer cells proliferation without influencing normal liver cell lines LO2. Smac-NPs also significantly induced apoptosis of MDA-MB-231 and H460 cells through activating pro-caspase-3, down-regulating the expression of antiapoptotic protein Bcl-2 and up-regulating the pro-apoptotic protein Bax. Furthermore, Smac-NPs could be explored as a drug delivery system to load hydrophobic drug such as DOX for combination therapy. The DOX-loaded nanoparticles (DOX-Smac-NPs) exhibited higher cellular uptake efficiency and antitumor effect. Our work provided a new insight into therapeutic peptides integrated with drug simultaneously in one system for cancer combination treatment.

  13. An Engineered Bivalent Neuregulin Protects Against Doxorubicin-Induced Cardiotoxicity with Reduced Pro-Neoplastic Potential

    PubMed Central

    Jay, Steven M.; Murthy, Ashwin C.; Hawkins, Jessica F.; Wortzel, Joshua R.; Steinhauser, Matthew L.; Alvarez, Luis M.; Gannon, Joseph; Macrae, Calum A.; Griffith, Linda G.; Lee, Richard T.

    2013-01-01

    Background Doxorubicin (DOXO) is an effective anthracycline chemotherapeutic, but its use is limited by cumulative dose-dependent cardiotoxicity. Neuregulin-1β (NRG1B) is an ErbB receptor family ligand that is effective against DOXO-induced cardiomyopathy in experimental models but is also pro-neoplastic. We previously showed that an engineered bivalent neuregulin-1β (NN) has reduced pro-neoplastic potential compared to the epidermal growth factor (EGF)-like domain of NRG1B (NRG), an effect mediated by receptor biasing towards ErbB3 homotypic interactions uncommonly formed by native NRG1B. Here, we hypothesized that a newly formulated, covalent NN would be cardioprotective with reduced pro-neoplastic effects compared to NRG. Methods and Results NN was expressed as a maltose-binding protein fusion in E. coli. As established previously, NN stimulated anti-neoplastic or cytostatic signaling and phenotype in cancer cells, whereas NRG stimulated pro-neoplastic signaling and phenotype. In neonatal rat cardiomyocytes (NRCM), NN and NRG induced similar downstream signaling. NN, like NRG, attenuated the double-stranded DNA breaks associated with DOXO exposure in NRCM and human cardiomyocytes derived from induced pluripotent stem cells. NN treatment significantly attenuated DOXO-induced decrease in fractional shortening as measured by blinded echocardiography in mice in a chronic cardiomyopathy model (57.7% ± 0.6% vs. 50.9% ± 2.6%, P=0.004), whereas native NRG had no significant effect (49.4% ± 3.7% vs. 50.9% ± 2.6%, P=0.813). Conclusions NN is a cardioprotective agent that promotes cardiomyocyte survival and improves cardiac function in DOXO-induced cardiotoxicity. Given the reduced pro-neoplastic potential of NN versus NRG, NN has translational potential for cardioprotection in cancer patients receiving anthracyclines. PMID:23757312

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

    PubMed

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

    2016-01-01

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

  15. Therapeutic potential of curcumin in gastrointestinal diseases

    PubMed Central

    Rajasekaran, Sigrid A

    2011-01-01

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

  16. A simple route to develop transparent doxorubicin-loaded nanodiamonds/cellulose nanocomposite membranes as potential wound dressings.

    PubMed

    Luo, Xiaogang; Zhang, Hao; Cao, Zhenni; Cai, Ning; Xue, Yanan; Yu, Faquan

    2016-06-05

    The objective of this study is to develop transparent porous nanodiamonds/cellulose nanocomposite membranes with controlled release of doxorubicin for potential applications as wound dressings, which were fabricated by tape casting method from dispersing carboxylated nanodiamonds and dissolving cellulose homogeneously in 7 wt% NaOH/12 wt% urea aqueous solution. By adjusting the carboxylated nanodiamonds content, various nanocomposite membranes were obtained. The structure and properties of these membranes have been investigated by light transmittance measurements, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), tensile tests, water loss analyses, etc. The drug loading and release was investigated using doxorubicin hydrochloride as a model drug. In vitro cytotoxicity assay of the membranes was also studied. This work presented a proof-of-concept utility of these membranes for loading and release of bioactive compounds to be employed as a candidate for wound dressing.

  17. Mechanisms of doxorubicin resistance in hepatocellular carcinoma

    PubMed Central

    Cox, Josiah; Weinman, Steven

    2015-01-01

    Hepatocellular carcinoma, one of the most common solid tumors worldwide, is poorly responsive to available chemotherapeutic approaches. While systemic chemotherapy is of limited benefit, intra-arterial delivery of doxorubicin to the tumor frequently produces tumor shrinkage. Its utility is limited, in part, by the frequent emergence of doxorubicin resistance. The mechanisms of this resistance include increased expression of multidrug resistance efflux pumps, alterations of the drug target, topoisomerase, and modulation of programmed cell death pathways. Many of these effects result from changes in miRNA expression and are particularly prominent in tumor cells with a stem cell phenotype. This review will summarize the current knowledge on the mechanisms of doxorubicin resistance of hepatocellular carcinoma and the potential for approaches toward therapeutic chemosensitization. PMID:26998221

  18. Doxorubicin Conjugated to Glutathione Stabilized Gold Nanoparticles (Au-GSH-Dox) as an Effective Therapeutic Agent for Feline Injection-Site Sarcomas-Chick Embryo Chorioallantoic Membrane Study.

    PubMed

    Zabielska-Koczywąs, Katarzyna; Dolka, Izabella; Król, Magdalena; Żbikowski, Artur; Lewandowski, Wiktor; Mieczkowski, Józef; Wójcik, Michał; Lechowski, Roman

    2017-02-08

    Feline injection-site sarcomas are malignant skin tumours with a high local recurrence rate, ranging from 14% to 28%. The treatment of feline injection-site sarcomas includes radical surgery, radiotherapy and/or chemotherapy. In our previous study it has been demonstrated that doxorubicin conjugated to glutathione-stabilized gold nanoparticles (Au-GSH-Dox) has higher cytotoxic effects than free doxorubicin for feline fibrosarcoma cell lines with high glycoprotein P activity (FFS1, FFS3). The aim of the present study was to assess the effectiveness of intratumoural injection of Au-GSH-Dox on the growth of tumours from the FFS1 and FFS3 cell lines on chick embryo chorioallantoic membrane. This model has been utilized both in human and veterinary medicine for preclinical oncological studies. The influence of intratumoural injections of Au-GSH-Dox, glutathione-stabilized gold nanoparticles and doxorubicin alone on the Ki-67 proliferation marker was also checked. We demonstrated that the volume ratio of tumours from the FFS1 and FFS3 cell lines was significantly (p < 0.01) decreased after a single intratumoural injection of Au-GSH-Dox, which confirms the positive results of in vitro studies and indicates that Au-GSH-Dox may be a potent new therapeutic agent for feline injection-site sarcomas.

  19. Nanoceria: a Potential Therapeutic for Dry AMD.

    PubMed

    Cai, Xue; McGinnis, James F

    2016-01-01

    Age-related macular degeneration (AMD) is the leading cause of blinding diseases. The "dry" form of AMD is the most common form of AMD. In contrast to the treatable neovascular (wet) AMD, no effective treatment is available for dry AMD. In this review, we summarize the animal models and therapeutic strategies for dry AMD. The novel candidates as potential treatment targets and the potential effectiveness of nanoceria as a treatment of dry AMD are also discussed.

  20. Circulating miR-1 as a potential biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients

    PubMed Central

    Oliveira-Carvalho Vagner, Rigaud; Ferreira, Ludmila R.P; Ayub-Ferreira, Silvia M; Ávila, Mônica S; Brandão, Sara M.G; Cruz, Fátima D; Santos, Marília H.H; Cruz, Cecilia B.B.V; Alves, Marco S.L; Issa, Victor S; Guimarães, Guilherme V; Cunha-Neto, Edécio; Bocchi, Edimar A

    2017-01-01

    Cardiotoxicity is associated with the chronic use of doxorubicin leading to cardiomyopathy and heart failure. Identification of cardiotoxicity-specific miRNA biomarkers could provide clinicians with a valuable prognostic tool. The aim of the study was to evaluate circulating levels of miRNAs in breast cancer patients receiving doxorubicin treatment and to correlate with cardiac function. This is an ancillary study from “Carvedilol Effect on Chemotherapy-induced Cardiotoxicity” (CECCY trial), which included 56 female patients (49.9±3.3 years of age) from the placebo arm. Enrolled patients were treated with doxorubicin followed by taxanes. cTnI, LVEF, and miRNAs were measured periodically. Circulating levels of miR-1, -133b, -146a, and -423-5p increased during the treatment whereas miR-208a and -208b were undetectable. cTnI increased from 6.6±0.3 to 46.7±5.5 pg/mL (p<0.001), while overall LVEF tended to decrease from 65.3±0.5 to 63.8±0.9 (p=0.053) over 12 months. Ten patients (17.9%) developed cardiotoxicity showing a decrease in LVEF from 67.2±1.0 to 58.8±2.7 (p=0.005). miR-1 was associated with changes in LVEF (r=-0.531, p<0.001). In a ROC curve analysis miR-1 showed an AUC greater than cTnI to discriminate between patients who did and did not develop cardiotoxicity (AUC = 0.851 and 0.544, p= 0.0016). Our data suggest that circulating miR-1 might be a potential new biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients. PMID:28052002

  1. Therapeutic potential for microRNAs.

    PubMed

    Esau, Christine C; Monia, Brett P

    2007-03-30

    MiRNAs are a conserved class of non-coding RNAs that negatively regulate gene expression post-transcriptionally. Although their biological roles are largely unknown, examples of their importance in cancer, metabolic disease, and viral infection are accumulating, suggesting that they represent a new class of drug targets in these and likely many other therapeutic areas. Antisense oligonucleotide approaches for inhibiting miRNA function and siRNA-like technologies for replacement of miRNAs are currently being explored as tools for uncovering miRNA biology and as potential therapeutic agents. The next few years should see significant progress in our understanding of miRNA biology and the advancement of the technology for therapeutic modulation of miRNA activity.

  2. Potential interaction of green tea extract with hydrochlorothiazide against doxorubicin-induced myocardial damage.

    PubMed

    Chakraborty, Manodeep; Kamath, Jagadish V; Bhattacharjee, Ananya

    2015-01-01

    Treatment of ischemic hypertensive patients with hydrochlorothiazide can precipitate cardiac arrhythmias. Green tea, by virtue of its antioxidant potential, is responsible for cardio-protective activity. The present study was under taken to evaluate the pharmacodynamic interaction of green tea extract with hydrochlorothiazide (HCTZ) against doxorubicin (DOX)-induced myocardial toxicity. Rats were treated with high (500 mg/kg, p.o.) and low (100 mg/kg, p.o.) dose of green tea extract in alone and interactive groups for 28 days. Standard, high and low dose of interactive groups received hydrochlorothiazide (10 mg/kg, p.o.) for the last 7 days. Apart from normal controls, all other groups were subjected to DOX (3 mg/kg, i.p.) toxicity on Days 1, 7, 14, 21 and 28, and the effect of different treatments was evaluated by changes in electrocardiographic parameters, serum biomarkers and tissue antioxidant levels. Apart from that, lipid profile and histological studies were also carried out. Compared with the DOX control group, both high and low dose of green tea exhibited a significant decrease in serum biomarkers and increase in tissue antioxidant levels. Green tea treatment was also responsible for significant improvement in ECG parameter, lipid profile and histological score. Incorporation of high and low dose of green tea with HCTZ exhibited significant protection compared with the HCTZ alone treated group. The present findings clearly suggest that the green tea extract dose-dependently reduces DOX-induced myocardial toxicity. Green tea when combined with HCTZ can reduce the associated side-effects and exhibits myocardial protection.

  3. Brown adipose tissue and its therapeutic potential.

    PubMed

    Lidell, M E; Betz, M J; Enerbäck, S

    2014-10-01

    Obesity and related diseases are a major cause of human morbidity and mortality and constitute a substantial economic burden for society. Effective treatment regimens are scarce, and new therapeutic targets are needed. Brown adipose tissue, an energy-expending tissue that produces heat, represents a potential therapeutic target. Its presence is associated with low body mass index, low total adipose tissue content and a lower risk of type 2 diabetes mellitus. Knowledge about the development and function of thermogenic adipocytes in brown adipose tissue has increased substantially in the last decade. Important transcriptional regulators have been identified, and hormones able to modulate the thermogenic capacity of the tissue have been recognized. Intriguingly, it is now clear that humans, like rodents, possess two types of thermogenic adipocytes: the classical brown adipocytes found in the interscapular brown adipose organ and the so-called beige adipocytes primarily found in subcutaneous white adipose tissue after adrenergic stimulation. The presence of two distinct types of energy-expending adipocytes in humans is conceptually important because these cells might be stimulated and recruited by different signals, raising the possibility that they might be separate potential targets for therapeutic intervention. In this review, we will discuss important features of the energy-expending brown adipose tissue and highlight those that may serve as potential targets for pharmacological intervention aimed at expanding the tissue and/or enhancing its function to counteract obesity.

  4. Doxorubicin Cardiomyopathy

    PubMed Central

    Chatterjee, Kanu; Zhang, Jianqing; Honbo, Norman; Karliner, Joel S.

    2010-01-01

    Established doxorubicin cardiomyopathy is a lethal disease. When congestive heart failure develops, mortality is approximately 50%. Extensive research has been done to understand the mechanism and pathophysiology of doxorubicin cardiomyopathy, and considerable knowledge and experience has been gained. Unfortunately, no effective treatment for established doxorubicin cardiomyopathy is presently available. Extensive research has been done and is being done to discover preventive treatments. However an effective and clinically applicable preventive treatment is yet to be discovered. PMID:20016174

  5. Use of Anionic Liposomes for the Reduction of Chronic Doxorubicin-Induced Cardiotoxicity

    NASA Astrophysics Data System (ADS)

    Forssen, Eric A.; Tokes, Zoltan A.

    1981-03-01

    Anionic liposomes containing doxorubicin were evaluated in mice for therapeutic potential in reducing the risks of chronic cardiotoxicity characteristic of long-term high-dose anthracycline therapy. Doxorubicin first was complexed to phosphatidylcholine and then entrapped in anionic vesicles. Quantitation of myocardial injury was accomplished through examination of thin sections of cardiac tissue by light microscopy. At treatment levels of either 20 or 40 mg/kg (total dose), mice receiving liposomal doxorubicin had toxicity scores indistinguishable from or only slightly greater than those of saline-treated controls. Similar total doses of free drug produced moderate to severe myocardial damage and yielded much higher toxicity scores. Mixture of free doxorubicin with empty liposomes did not alleviate cardiac toxicity, indicating that the drug must be entrapped within phospholipid vesicles for reduction in toxicity. The inhibition of body growth produced by free doxorubicin at both dose levels was also completely eliminated by encapsulation in liposomes. Doxorubicin liposomes were also tested for chemotherapeutic potential against L-1210 and P-388 murine leukemias. In all cases, treatment with liposomal doxorubicin produced increases in life-span greater than that observed for free drug. We conclude that anionic liposomes can function as efficacious carriers of doxorubicin. These vesicles possess improved therapeutic action as reflected by their ability to reduce cardiac toxicity, overcome growth inhibition, and increase antileukemic activity.

  6. Hyperthermic potentiation of doxorubicin and 4'-EPI-doxorubicin in a transplantable neurogenic rat tumor (BT/sub 4/A) in BD IX rats

    SciTech Connect

    Dahl, O.

    1983-02-01

    The combined effect of hyperthermia and doxorubicin on the neurogenic rat cell line BT/sub 4/C was found to be synergistic in vitro. The present investigation was initiated to study if this synergistic effect also could be obtained in vivo. An enhanced effect occurred when doxorubicin and 4'-epi-doxorubicin 7 mg/kg body weight were given 30 minutes prior to local water bath hyperthermia (one hour at 44.0 degrees C). The local side effects of the combined treatment did not increase above that of hyperthermia alone. Therefore, local hyperthermia may become a useful modality for enhancement of the effect of anthracyclines on tumors with marginal drug sensitivity or bulky tumors with poor drug penetration.

  7. Therapeutic potential of cannabis-related drugs.

    PubMed

    Alexander, Stephen P H

    2016-01-04

    In this review, I will consider the dual nature of Cannabis and cannabinoids. The duality arises from the potential and actuality of cannabinoids in the laboratory and clinic and the 'abuse' of Cannabis outside the clinic. The therapeutic areas currently best associated with exploitation of Cannabis-related medicines include pain, epilepsy, feeding disorders, multiple sclerosis and glaucoma. As with every other medicinal drug of course, the 'trick' will be to maximise the benefit and minimise the cost. After millennia of proximity and exploitation of the Cannabis plant, we are still playing catch up with an understanding of its potential influence for medicinal benefit. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Therapeutic Efficacy of Combining PEGylated Liposomal Doxorubicin and Radiofrequency (RF) Ablation: Comparison between Slow-Drug-Releasing, Non-Thermosensitive and Fast-Drug-Releasing, Thermosensitive Nano-Liposomes

    PubMed Central

    Andriyanov, Alexander V.; Koren, Erez; Barenholz, Yechezkel

    2014-01-01

    Aims To determine how the accumulation of drug in mice bearing an extra-hepatic tumor and its therapeutic efficacy are affected by the type of PEGylated liposomal doxorubicin used, treatment modality, and rate of drug release from the liposomes, when combined with radiofrequency (RF) ablation. Materials and Methods Two nano-drugs, both long-circulating PEGylated doxorubicin liposomes, were formulated: (1) PEGylated doxorubicin in thermosensitive liposomes (PLDTS), having a burst-type fast drug release above the liposomes’ solid ordered to liquid disordered phase transition (at 42°C), and (2) non-thermosensitive PEGylated doxorubicin liposomes (PLDs), having a slow and continuous drug release. Both were administered intravenously at 8 mg/kg doxorubicin dose to tumor-bearing mice. Animals were divided into 6 groups: no treatment, PLD, RF, RF+PLD, PLDTS, and PLDTS+RF, for intra-tumor doxorubicin deposition at 1, 24, and 72 h post-injection (in total 41, mice), and 31 mice were used for randomized survival studies. Results Non-thermosensitive PLD combined with RF had the least tumor growth and the best end-point survival, better than PLDTS+RF (p<0.005) or all individual therapies (p<0.001). Although at 1 h post-treatment the greatest amount of intra-tumoral doxorubicin was seen following PLDTS+RF (p<0.05), by 24 and 72 h the greatest doxorubicin amount was seen for PLD+RF (p<0.05); in this group the tumor also has the longest exposure to doxorubicin. Conclusion Optimizing therapeutic efficacy of PLD requires a better understanding of the relationship between the effect of RF on tumor microenvironment and liposome drug release profile. If drug release is too fast, the benefit of changing the microenvironment by RF on tumor drug localization and therapeutic efficacy may be much smaller than for PLDs having slow and temperature-independent drug release. Thus the much longer circulation time of doxorubicin from PLD than from PLDTS may be beneficial in many therapeutic

  9. Therapeutic efficacy of combining pegylated liposomal doxorubicin and radiofrequency (RF) ablation: comparison between slow-drug-releasing, non-thermosensitive and fast-drug-releasing, thermosensitive nano-liposomes.

    PubMed

    Andriyanov, Alexander V; Koren, Erez; Barenholz, Yechezkel; Goldberg, S Nahum

    2014-01-01

    To determine how the accumulation of drug in mice bearing an extra-hepatic tumor and its therapeutic efficacy are affected by the type of PEGylated liposomal doxorubicin used, treatment modality, and rate of drug release from the liposomes, when combined with radiofrequency (RF) ablation. Two nano-drugs, both long-circulating PEGylated doxorubicin liposomes, were formulated: (1) PEGylated doxorubicin in thermosensitive liposomes (PLDTS), having a burst-type fast drug release above the liposomes' solid ordered to liquid disordered phase transition (at 42°C), and (2) non-thermosensitive PEGylated doxorubicin liposomes (PLDs), having a slow and continuous drug release. Both were administered intravenously at 8 mg/kg doxorubicin dose to tumor-bearing mice. Animals were divided into 6 groups: no treatment, PLD, RF, RF+PLD, PLDTS, and PLDTS+RF, for intra-tumor doxorubicin deposition at 1, 24, and 72 h post-injection (in total 41, mice), and 31 mice were used for randomized survival studies. Non-thermosensitive PLD combined with RF had the least tumor growth and the best end-point survival, better than PLDTS+RF (p<0.005) or all individual therapies (p<0.001). Although at 1 h post-treatment the greatest amount of intra-tumoral doxorubicin was seen following PLDTS+RF (p<0.05), by 24 and 72 h the greatest doxorubicin amount was seen for PLD+RF (p<0.05); in this group the tumor also has the longest exposure to doxorubicin. Optimizing therapeutic efficacy of PLD requires a better understanding of the relationship between the effect of RF on tumor microenvironment and liposome drug release profile. If drug release is too fast, the benefit of changing the microenvironment by RF on tumor drug localization and therapeutic efficacy may be much smaller than for PLDs having slow and temperature-independent drug release. Thus the much longer circulation time of doxorubicin from PLD than from PLDTS may be beneficial in many therapeutic instances, especially in extra-hepatic tumors.

  10. Mn-porphyrin conjugated Au nanoshells encapsulating doxorubicin for potential magnetic resonance imaging and light triggered synergistic therapy of cancer.

    PubMed

    Jing, Lijia; Liang, Xiaolong; Li, Xiaoda; Lin, Li; Yang, Yongbo; Yue, Xueli; Dai, Zhifei

    2014-01-01

    A theranostic agent was successfully fabricated by the formation of Au nanoshell around poly(lactic acid) nanoparticles entrapping doxorubicin, followed by linking a Mn-porphyrin derivative on the Au shell surface through polyethylene glycol. The resulted agent exhibited excellent colloidal stability and long blood circulation time due to introducing polyethylene glycol. The grafting Mn-porphyrin onto the nanoparticle surface endowed a greatly improved relaxivity (r1 value of 22.18 mM(-1)s(-1) of Mn(3+)), favorable for accurate cancer diagnosing and locating the tumor site to guide the external near infrared (NIR) laser irradiation for photothermal ablation of tumors. The in vitro experiments confirmed that the agent exhibited an efficient photohyperthermia and a light triggered and stepwise release behavior of doxorubicin due to the high NIR light absorption coefficient of Au nanoshell. The in vivo experiments showed that the combination of chemotherapy and photothermal therapy through such theranostic agent offered a synergistically improved therapeutic outcome compared with either therapy alone, making it a promising approach for cancer therapy. Therefore, such theranostic agent can be developed as a smart and promising nanosystemplatform that integrates multiple capabilities for both effective contrast enhanced magnetic resonance imaging and synergistic therapy.

  11. Mn-porphyrin Conjugated Au Nanoshells Encapsulating Doxorubicin for Potential Magnetic Resonance Imaging and Light Triggered Synergistic Therapy of Cancer

    PubMed Central

    Jing, Lijia; Liang, Xiaolong; Li, Xiaoda; Lin, Li; Yang, Yongbo; Yue, Xueli; Dai, Zhifei

    2014-01-01

    A theranostic agent was successfully fabricated by the formation of Au nanoshell around poly(lactic acid) nanoparticles entrapping doxorubicin, followed by linking a Mn-porphyrin derivative on the Au shell surface through polyethylene glycol. The resulted agent exhibited excellent colloidal stability and long blood circulation time due to introducing polyethylene glycol. The grafting Mn-porphyrin onto the nanoparticle surface endowed a greatly improved relaxivity (r1 value of 22.18 mM-1s-1 of Mn3+), favorable for accurate cancer diagnosing and locating the tumor site to guide the external near infrared (NIR) laser irradiation for photothermal ablation of tumors. The in vitro experiments confirmed that the agent exhibited an efficient photohyperthermia and a light triggered and stepwise release behavior of doxorubicin due to the high NIR light absorption coefficient of Au nanoshell. The in vivo experiments showed that the combination of chemotherapy and photothermal therapy through such theranostic agent offered a synergistically improved therapeutic outcome compared with either therapy alone, making it a promising approach for cancer therapy. Therefore, such theranostic agent can be developed as a smart and promising nanosystemplatform that integrates multiple capabilities for both effective contrast enhanced magnetic resonance imaging and synergistic therapy. PMID:25057312

  12. Antioxidants as potential therapeutics for neuropsychiatric disorders

    PubMed Central

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

    2012-01-01

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

  13. Biopharmaceutics and Therapeutic Potential of Engineered Nanomaterials

    PubMed Central

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

    2009-01-01

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

  14. Ayahuasca: Pharmacology, neuroscience and therapeutic potential.

    PubMed

    Domínguez-Clavé, Elisabet; Soler, Joaquim; Elices, Matilde; Pascual, Juan C; Álvarez, Enrique; de la Fuente Revenga, Mario; Friedlander, Pablo; Feilding, Amanda; Riba, Jordi

    2016-09-01

    Ayahuasca is the Quechua name for a tea obtained from the vine Banisteriopsis caapi, and used for ritual purposes by the indigenous populations of the Amazon. The use of a variation of the tea that combines B. caapi with the leaves of the shrub Psychotria viridis has experienced unprecedented expansion worldwide for its psychotropic properties. This preparation contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT) from P. viridis, plus β-carboline alkaloids with monoamine-oxidase-inhibiting properties from B. caapi. Acute administration induces a transient modified state of consciousness characterized by introspection, visions, enhanced emotions and recollection of personal memories. A growing body of evidence suggests that ayahuasca may be useful to treat substance use disorders, anxiety and depression. Here we review the pharmacology and neuroscience of ayahuasca, and the potential psychological mechanisms underlying its therapeutic potential. We discuss recent findings indicating that ayahuasca intake increases certain mindfulness facets related to acceptance and to the ability to take a detached view of one's own thoughts and emotions. Based on the available evidence, we conclude that ayahuasca shows promise as a therapeutic tool by enhancing self-acceptance and allowing safe exposure to emotional events. We postulate that ayahuasca could be of use in the treatment of impulse-related, personality and substance use disorders and also in the handling of trauma. More research is needed to assess the full potential of ayahuasca in the treatment of these disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Cannabidiol and epilepsy: Rationale and therapeutic potential.

    PubMed

    Leo, Antonio; Russo, Emilio; Elia, Maurizio

    2016-05-01

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

  16. Therapeutic Potential of α-Crystallin

    PubMed Central

    Nagaraj, Ram H.; Nahomi, Rooban B.; Mueller, Niklaus H.; Raghavan, Cibin T.; Ammar, David A.; Petrash, J. Mark

    2015-01-01

    Background The findings that α-crystallins are multi-functional proteins with diverse biological functions have generated considerable interest in understanding their role in health and disease. Recent studies have shown that chaperone peptides of α-crystallin could be delivered into cultured cells and in experimental animals with beneficial effects against protein aggregation, oxidation, inflammation and apoptosis. Scope of Review In this review, we will summarize the latest developments on the therapeutic potential of α-crystallins and their functional peptides. Major conclusions α-Crystallins and their functional peptides have shown significant favorable effects against several diseases. Their targeted delivery to tissues would be of great therapeutic benefit. However, α-crystallins can also function as disease-causing proteins. These seemingly contradictory functions must be carefully considered prior to their therapeutic use. General significance αA and αB-Crystallin are members of the small heat shock protein family. These proteins exhibit molecular chaperone and anti-apoptotic activities. The core crystallin domain within these proteins is largely responsible for these prosperities. Recent studies have identified peptides within the crystallin domain of both α- and αB-crystallins with remarkable chaperone and anti-apoptotic activities. Administration of α-crystallin or their functional peptides have shown substantial inhibition of pathologies in several diseases. However, α-crystallins have been shown to promote disease-causing pathways. These two sides of the proteins are discussed in this review. PMID:25840354

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

    PubMed

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

    2016-01-01

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

  18. Natural toxins and their therapeutic potential.

    PubMed

    Kapoor, V K

    2010-03-01

    Plants have been extensively investigated for exploring their therapeutic potentials, but there are comparatively scanty reports on drugs derived from animal kingdom, except for hormones. During last decade, the toxins that are used for defense by the animals, have been isolated and found useful tools for physiological and pharmacological studies, besides giving valuable leads to drug development. Toxins with interesting results have been isolated from the venoms of snakes, scorpions, spiders, snails, lizards, frogs and fish. The present review describe about some toxins as drugs and their biological activities. Some fungal, bacterial and marine toxins have also been covered in this article.

  19. Potential therapeutic approaches for Angelman syndrome

    PubMed Central

    Bi, Xiaoning; Sun, Jiandong; Ji, Angela X.; Baudry, Michel

    2016-01-01

    INTRODUCTION Angelman syndrome (AS) is a neurodevelopmental disorder caused by deficiency of maternally inherited UBE3A, an ubiquitin E3 ligase. Despite recent progress in understanding the mechanism underlying UBE3A imprinting, there is no effective treatment. Further investigation of the roles played by UBE3A in the central nervous system (CNS) is needed for developing effective therapies. AREA COVERED This review covers the literature related to genetic classifications of AS, recent discoveries regarding the regulation of UBE3A imprinting, alterations in cell signaling in various brain regions, and potential therapeutic approaches. Since a large proportion of AS patients exhibit comorbid autism spectrum disorder (ASD), potential common molecular bases are discussed. EXPERT OPINION Advances in understanding UBE3A imprinting provide a unique opportunity to induce paternal UBE3A expression, thus targeting the syndrome at its “root.” However, such efforts have yielded less-than-expected rescue effects in AS mouse models, raising the concern that activation of paternal UBE3A after a critical period cannot correct all the CNS defects that developed in a UBE3A-deficient environment. On the other hand, targeting abnormal downstream cell signaling pathways has provided promising rescue effects in preclinical research. Thus, combined reinstatement of paternal UBE3A expression with targeting abnormal signaling pathways should provide better therapeutic effects. PMID:26558806

  20. 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.

  1. Melissa officinalis Protects against Doxorubicin-Induced Cardiotoxicity in Rats and Potentiates Its Anticancer Activity on MCF-7 Cells

    PubMed Central

    Hamza, Alaaeldin Ahmed; Ahmed, Mahguob Mohamed; Elwey, Hanan Mohamed; Amin, Amr

    2016-01-01

    Cardiotoxicity is a limiting factor of doxorubicin (DOX)-based anticancer therapy. Due to its beneficial effects, we investigated whether standardized extract of Melissa officinalis (MO) can attenuate doxorubicin-induced cardiotoxicity and can potentiate the efficacy of DOX against human breast cancer cells. MO was administered orally to male albino rats once daily for 10 consecutive days at doses of 250, 500 and 750 mg/kg b.wt. DOX (15 mg/kg b.wt. i.p.) was administered on the 8th day. MO protected against DOX-induced leakage of cardiac enzymes and histopathological changes. MO ameliorated DOX-induced oxidative stress as evidenced by decreasing lipid peroxidation, protein oxidation and total oxidant capacity depletion and by increasing antioxidant capacity. Additionally, MO pretreatment inhibited inflammatory responses to DOX by decreasing the expressions of nuclear factor kappa-B, tumor necrosis factor-alpha and cyclooxygenase-2 and the activity of myeloperoxidase. MO ameliorated DOX-induced apoptotic tissue damage in heart of rats. In vitro study showed that MO augmented the anticancer efficacy of DOX in human breast cancer cells (MCF-7) and potentiated oxidative damage and apoptosis. Thus, combination of DOX and MO may prove future cancer treatment protocols safer and more efficient. PMID:27880817

  2. Chemical screening identifies the β-Carboline alkaloid harmine to be synergistically lethal with doxorubicin.

    PubMed

    Atteya, Reham; Ashour, Mohamed E; Ibrahim, Elsayed E; Farag, Mohamed A; El-Khamisy, Sherif F

    2017-01-01

    Despite being an invaluable chemotherapeutic agent for several types of cancer, the clinical utility of doxorubicin is hampered by its age-related and dose-dependent cardiotoxicity. Co-administration of dexrazoxane as a cardioprotective agent has been proposed, however recent studies suggest that it attenuates doxorubicin-induced antitumor activity. Since compounds of natural origin present a rich territory for drug discovery, we set out to identify putative natural compounds with the view to mitigate or minimize doxorubicin cardiotoxicity. We identify the DYRK1A kinase inhibitor harmine, which phosphorylates Tau that is deregulated in Alzheimer's disease, as a potentiator of cell death induced by non-toxic doses of doxorubicin. These observations suggest that harmine or other compounds that target the DYRK1A kinase my offer a new therapeutic opportunity to suppress doxorubicin age-related and dose-dependent cardiotoxicity. Copyright © 2016 The Author(s). Published by Elsevier B.V. All rights reserved.

  3. The intratumoral administration of ferucarbotran conjugated with doxorubicin improved therapeutic effect by magnetic hyperthermia combined with pharmacotherapy in a hepatocellular carcinoma model

    PubMed Central

    2014-01-01

    Background Local hyperthermia of tumor in conjunction with chemotherapy is a promising strategy for cancer treatment. The aim of this study was to evaluate the efficacy of intratumoral delivery of clinically approved magnetic nanoparticles (MNPs) conjugated with doxorubicin to simultaneously induce magnetic hyperthermia and drug delivery in a hepatocellular carcinoma (HCC) model. Materials and methods HCC cells expressing luciferase were implanted into the flank of BALB/c-nu mice (n = 19). When the tumor diameter reached 7–8 mm, the animals were divided into four groups according to the injected agents: group A (normal saline, n = 4), group B (doxorubicin, n = 5), group C (MNP, n = 5), and group D (MNP/doxorubicin complex, n = 5). Animals were exposed to an alternating magnetic field (AMF) to receive magnetic hyperthermia, and intratumoral temperature changes were measured. Bioluminescence imagings (BLIs) were performed before treatment and at 3, 7, and 14 days after treatment to measure the tumoral activities. The relative signal intensity (RSI) of each tumor was calculated by dividing the BLI signal at each time point by the value measured before treatment. At day 14 post-treatment, all tumor tissues were harvested to assess the apoptosis rates by pathological examination. Results The rise in temperature of the tumors was 1.88 ± 0.21°C in group A, 0.96 ± 1.05°C in B, 7.93 ± 1.99°C in C, and 8.95 ± 1.31°C in D. The RSI of the tumors at day 14 post-treatment was significantly lower in group D (0.31 ± 0.20) than in group A (2.23 ± 1.14), B (0.94 ± 0.47), and C (1.02 ± 0.21). The apoptosis rates of the tumors were 11.52 ± 3.10% in group A, 23.0 ± 7.68% in B, 25.4 ± 3.36% in C, and 39.0 ± 13.2% in D, respectively. Conclusions The intratumoral injection of ferucarbotran conjugated with doxorubicin shows an improved therapeutic effect compared with doxorubicin or ferucarbotran alone

  4. Chaperones as potential therapeutics for Krabbe disease.

    PubMed

    Graziano, Adriana Carol Eleonora; Pannuzzo, Giovanna; Avola, Rosanna; Cardile, Venera

    2016-11-01

    Krabbe's disease (KD) is an autosomal recessive, neurodegenerative disorder. It is classified among the lysosomal storage diseases (LSDs). It was first described in , but the genetic defect for the galactocerebrosidase (GALC) gene was not discovered until the beginning of the 1970s, 20 years before the GALC cloning. Recently, in 2011, the crystal structures of the GALC enzyme and the GALC-product complex were obtained. For this, compared with other LSDs, the research on possible therapeutic interventions is much more recent. Thus, it is not surprising that some treatment options are still under preclinical investigation, whereas their relevance for other pathologies of the same group has already been tested in clinical studies. This is specifically the case for pharmacological chaperone therapy (PCT), a promising strategy for selectively correcting defective protein folding and trafficking and for enhancing enzyme activity by small molecules. These compounds bind directly to a partially folded biosynthetic intermediate, stabilize the protein, and allow completion of the folding process to yield a functional protein. Here, we review the chaperones that have demonstrated potential therapeutics during preclinical studies for KD, underscoring the requirement to invigorate research for KD-addressed PCT that will benefit from recent insights into the molecular understanding of GALC structure, drug design, and development in cellular models. © 2016 Wiley Periodicals, Inc.

  5. Garlic: a review of potential therapeutic effects

    PubMed Central

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

    2014-01-01

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

  6. Potential therapeutic interventions for fragile X syndrome

    PubMed Central

    Levenga, Josien; de Vrij, Femke M.S.; Oostra, Ben A.; Willemsen, Rob

    2010-01-01

    Fragile X syndrome (FXS) is caused by a lack of the fragile X mental retardation protein (FMRP); FMRP deficiency in neurons of patients with FXS causes intellectual disability (IQ<70) and several behavioural problems, including hyperactivity and autistic-like features. In the brain, no gross morphological malformations have been found, although subtle spine abnormalities have been reported. FXS has been linked to altered group I metabotropic glutamate receptor (mGluR)-dependent and independent forms of synaptic plasticity. Here, we discuss potential targeted therapeutic strategies developed to specifically correct disturbances in the excitatory mGluR and the inhibitory gamma-aminobutyric (GABA) receptor pathways that have been tested in animal models and/or in clinical trials with patients with FXS. PMID:20864408

  7. Antioxidants as Potential Therapeutics for Lung Fibrosis

    PubMed Central

    DAY, BRIAN J.

    2009-01-01

    Interstitial lung disease encompasses a large group of chronic lung disorders associated with excessive tissue remodeling, scarring, and fibrosis. The evidence of a redox imbalance in lung fibrosis is substantial, and the rationale for testing antioxidants as potential new therapeutics for lung fibrosis is appealing. Current animal models of lung fibrosis have clear involvement of ROS in their pathogenesis. New classes of antioxidant agents divided into catalytic antioxidant mimetics and antioxidant scavengers are being developed. The catalytic antioxidant class is based on endogenous antioxidant enzymes and includes the manganese-containing macrocyclics, porphyrins, salens, and the non–metal-containing nitroxides. The antioxidant scavenging class is based on endogenous antioxidant molecules and includes the vitamin E analogues, thiols, lazaroids, and polyphenolic agents. Numerous studies have shown oxidative stress to be associated with many interstitial lung diseases and that these agents are effective in attenuating fibroproliferative responses in the lung of animals and humans. PMID:17999627

  8. The role of milk thistle extract in breast carcinoma cell line (MCF-7) apoptosis with doxorubicin.

    PubMed

    Rastegar, Hussein; Ahmadi Ashtiani, Hamidreza; Anjarani, Soghra; Bokaee, Saeed; Khaki, Arash; Javadi, Leila

    2013-01-01

    Breast cancer is the most commonly diagnosed invasive malignancy and first leading cause of cancer-related deaths in Iranian women. Based on silymarin's unique characteristics, its application in chemotherapy combined with doxorubicin can be effective to enhance the efficacy together with a reduced toxicity on normal tissues. The present study focus on evaluate the efficacy of silymarin in combination with doxorubicin, on viability and apoptosis of estrogen-dependent breast carcinoma cell line (MCF-7). After being cultured, MCF-7 cells were divided into 8 groups and treated as follows: 1st group received 75 μg silymarin, groups 2, 3, and 4 were treated with 10, 25, and 50 nM doxorubicin, respectively, and groups 5, 6, and 7 respectively received 10, 25, and 50 nM doxorubicin as well as 75 μg silymarin. Viability percentage and apoptosis of the cells were assessed with Trypan Blue staining after 16, 24, and 48 hours. Silymarin has a synergistic effect on the therapeutic potential of doxorubicin. Use of silymarin in combination with doxorubicin can be more effective on the therapeutic potential of doxorubicin and decreases its dose-limiting side effects.

  9. Pharmacology and therapeutic potential of interferons.

    PubMed

    George, Peter M; Badiger, Rekha; Alazawi, William; Foster, Graham R; Mitchell, Jane A

    2012-07-01

    Interferon (IFN) is widely recognised to be an integral part of the innate immune response to viral infection. Since its initial discovery in 1957 by Isaacs and Lindenmann, various IFN sub-types have been identified and there are now three distinct classes recognised-Type I (IFN-α and IFN-β), Type II (IFN-γ) and Type III (IFN-λ), distinguished by their differing receptors. As well as displaying profound antiviral activity in vivo, IFN has anti-proliferative, cytotoxic and anti-tumoural roles. In an attempt to harness their immunomodulatory potential, investigators and clinicians have investigated the use of IFNs for the treatment of human diseases with considerable success. For example, IFN-α preparations are now a critical component in the treatment of chronic Hepatitis C infection and IFN-β therapy is now the first line treatment for relapsing remitting multiple sclerosis. However, IFN therapy is also associated with significant morbidity and in some patients is poorly tolerated. In this review, we explore the scientific basis for IFN therapy and outline its therapeutic scope. We describe the commonly encountered side effects and attempt to explain the less well recognised pulmonary complications including emerging evidence of life threatening and irreversible pulmonary vascular pathology. Finally, we look to the future of interferon drug treatment, examining the potential for emerging therapies.

  10. Cyclic depsipeptides as potential cancer therapeutics.

    PubMed

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

    2015-03-01

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

  11. Therapeutic potential of fecal microbiota transplantation.

    PubMed

    Smits, Loek P; Bouter, Kristien E C; de Vos, Willem M; Borody, Thomas J; Nieuwdorp, Max

    2013-11-01

    There has been growing interest in the use of fecal microbiota for the treatment of patients with chronic gastrointestinal infections and inflammatory bowel diseases. Lately, there has also been interest in its therapeutic potential for cardiometabolic, autoimmune, and other extraintestinal conditions that were not previously considered to be associated with the intestinal microbiota. Although it is not clear if changes in the microbiota cause these conditions, we review the most current and best methods for performing fecal microbiota transplantation and summarize clinical observations that have implicated the intestinal microbiota in various diseases. We also discuss case reports of fecal microbiota transplantations for different disorders, including Clostridium difficile infection, irritable bowel syndrome, inflammatory bowel diseases, insulin resistance, multiple sclerosis, and idiopathic thrombocytopenic purpura. There has been increasing focus on the interaction between the intestinal microbiome, obesity, and cardiometabolic diseases, and we explore these relationships and the potential roles of different microbial strains. We might someday be able to mine for intestinal bacterial strains that can be used in the diagnosis or treatment of these diseases. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

  12. TRIB3 downregulation enhances doxorubicin-induced cytotoxicity in gastric cancer cells.

    PubMed

    Wu, I-Jung; Lin, Rong-Jaan; Wang, Hsin-Chiao; Yuan, Tein-Ming; Chuang, Show-Mei

    2017-05-15

    TRIB3, which is a pseudokinase known to regulate multiple pro-survival pathways, appears to be a potential therapeutic target for the treatment of human tumors. However, its precise role in cancer is controversial, as TRIB3 protein levels have been associated with both good and poor prognosis in cancer patients. Here, we investigated the significance of TRIB3 expression in the survival of gastric cancer cells exposed to anticancer drugs. We found that the tested anticancer drug, doxorubicin, induced cytotoxicity by decreasing TRIB3 transcription, which was followed by apoptotic cell death. Moreover, TRIB3 siRNA knockdown appeared to enhance doxorubicin-induced apoptosis in gastric cancer cells, concurrently with altering the expression of downstream apoptotic factors. Conversely, overexpression of TRIB3 significantly protected cells against doxorubicin-induced apoptosis. Our results indicate that downregulation of TRIB3 appears to promote cell death and enhance doxorubicin-induced apoptosis, supporting the anti-apoptotic role of TRIB3. The inductions of three classes of MAPKs failed to affect doxorubicin-mediated TRIB3 downregulation, while TRIB3 overexpression did not affect doxorubicin-induced MAPK activation. In sum, our findings indicate that TRIB3 plays an anti-apoptotic role in doxorubicin-treated gastric cancer cell lines, perhaps indicating that the status of TRIB3 expression in response to anticancer drugs, such as doxorubicin, irinotecan or oxaliplatin, may reflect the efficiency for cancer therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Galectin-3 as a Potential Therapeutic Target in Tumors Arising from Malignant Endothelia1

    PubMed Central

    Johnson, Kim D; Glinskii, Olga V; Mossine, Valeri V; Turk, James R; Mawhinney, Thomas P; Anthony, Douglas C; Henry, Carolyn J; Huxley, Virginia H; Glinsky, Gennadi V; Pienta, Kenneth J; Raz, Avraham; Glinsky, Vladislav V

    2007-01-01

    Angiosarcoma (ASA) in humans and hemangiosarcoma (HSA) in dogs are deadly neoplastic diseases characterized by an aggressive growth of malignant cells with endothelial phenotype, widespread metastasis, and poor response to chemotherapy. Galectin-3 (Gal-3), a β-galactoside-binding lectin implicated in tumor progression and metastasis, endothelial cell biology and angiogenesis, and regulation of apoptosis and neoplastic cell response to cytotoxic drugs, has not been studied before in tumors arising from malignant endothelia. Here, we tested the hypothesis that Gal-3 could be widely expressed in human ASA and canine HSA and could play an important role in malignant endothelial cell biology. Immunohistochemical analysis demonstrated that 100% of the human ASA (10 of 10) and canine HSA (17 of 17) samples analyzed expressed Gal-3. Two carbohydrate-based Gal-3 inhibitors, modified citrus pectin (MCP) and lactulosyl-l-leucine (LL), caused a dose-dependent reduction of SVR murine ASA cell clonogenic survival through the inhibition of Gal-3 antiapoptotic function. Furthermore, both MCP and LL sensitized SVR cells to the cytotoxic drug doxorubicin to a degree sufficient to reduce the in vitro IC50 of doxorubicin by 10.7-fold and 3.6-fold, respectively. These results highlight the important role of Gal-3 in the biology of ASA and identify Gal-3 as a potential therapeutic target in tumors arising from malignant endothelial cells. PMID:17786185

  14. Therapeutic potential of chalcones as cardiovascular agents.

    PubMed

    Mahapatra, Debarshi Kar; Bharti, Sanjay Kumar

    2016-03-01

    Cardiovascular diseases are the leading cause of death affecting 17.3 million people across the globe and are estimated to affect 23.3 million people by year 2030. In recent years, about 7.3 million people died due to coronary heart disease, 9.4 million deaths due to high blood pressure and 6.2 million due to stroke, where obesity and atherosclerotic progression remain the chief pathological factors. The search for newer and better cardiovascular agents is the foremost need to manage cardiac patient population across the world. Several natural and (semi) synthetic chalcones deserve the credit of being potential candidates to inhibit various cardiovascular, hematological and anti-obesity targets like angiotensin converting enzyme (ACE), cholesteryl ester transfer protein (CETP), diacylglycerol acyltransferase (DGAT), acyl-coenzyme A: cholesterol acyltransferase (ACAT), pancreatic lipase (PL), lipoprotein lipase (LPL), calcium (Ca(2+))/potassium (K(+)) channel, COX-1, TXA2 and TXB2. In this review, a comprehensive study of chalcones, their therapeutic targets, structure activity relationships (SARs), mechanisms of actions (MOAs) have been discussed. Chemically diverse chalcone scaffolds, their derivatives including structural manipulation of both aryl rings, replacement with heteroaryl scaffold(s) and hybridization through conjugation with other pharmacologically active scaffold have been highlighted. Chalcones which showed promising activity and have a well-defined MOAs, SARs must be considered as prototype for the design and development of potential anti-hypertensive, anti-anginal, anti-arrhythmic and cardioprotective agents. With the knowledge of these molecular targets, structural insights and SARs, this review may be helpful for (medicinal) chemists to design more potent, safe, selective and cost effective chalcone derivatives as potential cardiovascular agents. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Therapeutic efficacy of the combination of doxorubicin-loaded liposomes with inertial cavitation generated by confocal ultrasound in AT2 Dunning rat tumour model.

    PubMed

    Mestas, Jean-Louis; Fowler, R Andrew; Evjen, Tove J; Somaglino, Lucie; Moussatov, Alexei; Ngo, Jacqueline; Chesnais, Sabrina; Røgnvaldsson, Sibylla; Fossheim, Sigrid L; Nilssen, Esben A; Lafon, Cyril

    2014-09-01

    The combination of liposomal doxorubicin (DXR) and confocal ultrasound (US) was investigated for the enhancement of drug delivery in a rat tumour model. The liposomes, based on the unsaturated phospholipid dierucoylphosphocholine, were designed to be stable during blood circulation in order to maximize accumulation in tumour tissue and to release drug content upon US stimulation. A confocal US setup was developed for delivering inertial cavitation to tumours in a well-controlled and reproducible manner. In vitro studies confirm drug release from liposomes as a function of inertial cavitation dose, while in vivo pharmacokinetic studies show long blood circulation times and peak tumour accumulation at 24-48 h post intravenous administration. Animals injected 6 mg kg(-1) liposomal DXR exposed to US treatment 48 h after administration show significant tumour growth delay compared to control groups. A liposomal DXR dose of 3 mg kg(-1), however, did not induce any significant therapeutic response. This study demonstrates that inertial cavitation can be generated in such a fashion as to disrupt drug carrying liposomes which have accumulated in the tumour, and thereby increase therapeutic effect with a minimum direct effect on the tissue. Such an approach is an important step towards a therapeutic application of cavitation-induced drug delivery and reduced chemotherapy toxicity.

  16. An oxidative stress-based mechanism of doxorubicin cytotoxicity suggests new therapeutic strategies in ABC-DLBCL.

    PubMed

    Mai, Yun; Yu, J Jessica; Bartholdy, Boris; Xu-Monette, Zijun Y; Knapp, Esther E; Yuan, Fei; Chen, Hongshan; Ding, B Belinda; Yao, Zhihua; Das, Bhaskar; Zou, Yiyu; Young, Ken He; Parekh, Samir; Ye, B Hilda

    2016-12-15

    Diffuse large B-cell lymphomas (DLBCLs) contain 2 major molecular subtypes; namely, the germinal center B-cell-like (GCB) and the activated B-cell-like (ABC) DLBCLs. It is well documented that ABC-DLBCL cases have a significantly poorer survival response than GCB-DLBCLs in both the CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) and the rituximab (R)-CHOP eras. However, the underlying cause of this subtype disparity is poorly understood. Nevertheless, these clinical observations raise the possibility for an ABC-DLBCL-specific resistance mechanism that is directed toward 1 of the CHOP components and is inadequately addressed by rituximab. Here, we report that the main cytotoxic ingredient in CHOP, doxorubicin (Dox), has subtype-specific mechanisms of cytotoxicity in DLBCLs resulting from differences in the subcellular distribution pattern. Specifically, in cell line models of ABC-DLBCL, Dox is often enriched in the cytoplasm away from the nuclear DNA. As a result, Dox-induced cytotoxicity in ABC-DLBCLs is often dependent on oxidative stress, rather than DNA damage response. These findings are corroborated by gene signature analysis, which demonstrates that basal oxidative stress status predicts treatment outcome among patients with ABC-DLBCL, but not patients with GCB-DLBCL. In terms of redox-related resistance mechanism, our results suggest that STAT3 confers Dox resistance in ABC-DLBCLs by reinforcing an antioxidant program featuring upregulation of the SOD2 gene. Furthermore, a small-molecule STAT3 inhibitor synergizes with CHOP to trigger oxidative stress and kill ABC-DLBCL cells in preclinical models. These results provide a mechanistic basis for development of novel therapies that target either STAT3 or redox homeostasis to improve treatment outcomes for ABC-DLBCLs. © 2016 by The American Society of Hematology.

  17. Caffeic Acid Phenethyl Ester and Therapeutic Potentials

    PubMed Central

    Karim, Sabiha; Akram, Muhammad Rouf; Khan, Shujaat Ali; Azhar, Saira; Mumtaz, Amara; Bin Asad, Muhammad Hassham Hassan

    2014-01-01

    Caffeic acid phenethyl ester (CAPE) is a bioactive compound of propolis extract. The literature search elaborates that CAPE possesses antimicrobial, antioxidant, anti-inflammatory, and cytotoxic properties. The principal objective of this review article is to sum up and critically assess the existing data about therapeutic effects of CAPE in different disorders. The findings elaborate that CAPE is a versatile therapeutically active polyphenol and an effective adjuvant of chemotherapy for enhancing therapeutic efficacy and diminishing chemotherapy-induced toxicities. PMID:24971312

  18. Essential Oil from Myrica rubra Leaves Potentiated Antiproliferative and Prooxidative Effect of Doxorubicin and its Accumulation in Intestinal Cancer Cells.

    PubMed

    Ambrož, Martin; Hanušová, Veronika; Skarka, Adam; Boušová, Iva; Králová, Věra; Langhasová, Lenka; Skálová, Lenka

    2016-01-01

    Essential oil from the leaves of Myrica rubra, a subtropical Asian fruit tree traditionally used in folk medicines, has a significant antiproliferative effect in several intestinal cancer cell lines. Doxorubicin belongs to the most important cytostatics used in cancer therapy. The present study was designed to evaluate the effects of defined essential oil from M. rubra leaves on efficacy, prooxidative effect, and accumulation of doxorubicin in cancer cell lines and in non-cancerous cells. For this purpose, intestinal adenocarcinoma CaCo2 cells were used. Human fibroblasts (periodontal ligament) and a primary culture of rat hepatocytes served as models of non-cancerous cells. The results showed that the sole essential oil from M. rubra has a strong prooxidative effect in cancer cells while it acts as a mild antioxidant in hepatocytes. Combined with doxorubicin, the essential oil enhanced the antiproliferative and prooxidative effects of doxorubicin in cancer cells. At higher concentrations, synergism of doxorubicin and essential oil from M. rubra was proved. In non-cancerous cells, the essential oil did not affect the toxicity of doxorubicin and the doxorubicin-mediated reactive oxygen species formation. The essential oil increased the intracellular concentration of doxorubicin and enhanced selectively the doxorubicin accumulation in nuclei of cancer cells. Taken together, essential oil from M. rubra leaves could be able to improve the doxorubicin efficacy in cancer cells due to an increased reactive oxygen species production, and the doxorubicin accumulation in nuclei of cancer cells. Georg Thieme Verlag KG Stuttgart · New York.

  19. Therapeutic potential of argan oil: a review.

    PubMed

    Monfalouti, Hanae El; Guillaume, Dom; Denhez, Clément; Charrouf, Zoubida

    2010-12-01

    The therapeutic benefits of argan oil consumption have been claimed by natives of Morocco and explorers for more than eight centuries. However, argan oil has remained unresearched for a long time. Traditionally, argan oil has been well known for its cardioprotective properties and it is also used in the treatment of skin infections. Argan oil is principally composed of mono-unsaturated (up to 80%) and saturated (up to 20%) fatty acids. As minor components, it contains polyphenols, tocopherols, sterols, squalene, and triterpene alcohols. Together with the mono-unsaturated fatty acids, these minor components are likely to be responsible for its beneficial effects. This review aims to present an overview of the known pharmacological properties of argan oil. Antiproliferative, antidiabetic, and cardiovascular-protective effects of argan oil have been particularly actively evaluated over the last 5 years in order to build on phytochemical studies that indicate the presence of large amounts of possibly pharmacologically active compounds. This review shows that a lack of clinical data constitutes a serious weakness in our knowledge about argan oil, therefore it is difficult to correlate the reported pharmacological activities to any potential clinical relevance. © 2010 The Authors. JPP © 2010 Royal Pharmaceutical Society of Great Britain.

  20. Therapeutic potential of dental stem cells

    PubMed Central

    Chalisserry, Elna Paul; Nam, Seung Yun; Park, Sang Hyug; Anil, Sukumaran

    2017-01-01

    Stem cell biology has become an important field in regenerative medicine and tissue engineering therapy since the discovery and characterization of mesenchymal stem cells. Stem cell populations have also been isolated from human dental tissues, including dental pulp stem cells, stem cells from human exfoliated deciduous teeth, stem cells from apical papilla, dental follicle progenitor cells, and periodontal ligament stem cells. Dental stem cells are relatively easily obtainable and exhibit high plasticity and multipotential capabilities. The dental stem cells represent a gold standard for neural-crest-derived bone reconstruction in humans and can be used for the repair of body defects in low-risk autologous therapeutic strategies. The bioengineering technologies developed for tooth regeneration will make substantial contributions to understand the developmental process and will encourage future organ replacement by regenerative therapies in a wide variety of organs such as the liver, kidney, and heart. The concept of developing tooth banking and preservation of dental stem cells is promising. Further research in the area has the potential to herald a new dawn in effective treatment of notoriously difficult diseases which could prove highly beneficial to mankind in the long run. PMID:28616151

  1. Therapeutic potential of naringin: an overview.

    PubMed

    Chen, Rui; Qi, Qiao-Ling; Wang, Meng-Ting; Li, Qi-Yan

    2016-12-01

    Naringin is a natural flavanone glycoside that is found in the Chinese herbal medicines and citrus fruits. Studies have demonstrated that naringin possesses numerous biological and pharmacological properties, but few reviews of these studies have been performed. The present review gathers the fragmented information available in the literature describing the extraction of naringin, its pharmacology and its controlled release formulations. Current research progress and the therapeutic potential of naringin are also discussed. A literature survey for relevant information regarding the biological and pharmacological properties of naringin was conducted using Pubmed, Sciencedirect, MEDLINE, Springerlink and Google Scholar electronic databases from the year 2007-2015. Naringin modulates signalling pathways and interacts with signalling molecules and thus has a wide range of pharmacological activities, including anti-inflammatory, anti-cancer activities, as well as effects on bone regeneration, metabolic syndrome, oxidative stress, genetic damage and central nervous system (CNS) diseases. Information was gathered that showed the extraction of naringin can be improved using several modifications. There has been some progress in the development of controlled release formulations of naringin. Naringin is a promising candidate for further in vivo studies and clinical use. More detailed studies regarding its mechanism of action are required.

  2. Therapeutic potential of dental stem cells.

    PubMed

    Chalisserry, Elna Paul; Nam, Seung Yun; Park, Sang Hyug; Anil, Sukumaran

    2017-01-01

    Stem cell biology has become an important field in regenerative medicine and tissue engineering therapy since the discovery and characterization of mesenchymal stem cells. Stem cell populations have also been isolated from human dental tissues, including dental pulp stem cells, stem cells from human exfoliated deciduous teeth, stem cells from apical papilla, dental follicle progenitor cells, and periodontal ligament stem cells. Dental stem cells are relatively easily obtainable and exhibit high plasticity and multipotential capabilities. The dental stem cells represent a gold standard for neural-crest-derived bone reconstruction in humans and can be used for the repair of body defects in low-risk autologous therapeutic strategies. The bioengineering technologies developed for tooth regeneration will make substantial contributions to understand the developmental process and will encourage future organ replacement by regenerative therapies in a wide variety of organs such as the liver, kidney, and heart. The concept of developing tooth banking and preservation of dental stem cells is promising. Further research in the area has the potential to herald a new dawn in effective treatment of notoriously difficult diseases which could prove highly beneficial to mankind in the long run.

  3. Therapeutic potential of manipulating suicidal erythrocyte death.

    PubMed

    Lang, Florian; Jilani, Kashif; Lang, Elisabeth

    2015-01-01

    Eryptosis, the suicidal erythrocyte death, is characterized by erythrocyte shrinkage and phosphatidylserine translocation to the erythrocyte surface. Eryptosis is triggered by cell stress such as energy depletion and oxidative stress, by Ca(2+)-entry, ceramide, caspases, calpain and/or altered activity of several kinases. Phosphatidylserine-exposing erythrocytes adhere to the vascular wall and may thus impede microcirculation. Eryptotic cells are further engulfed by phagocytes and thus rapidly cleared from circulation. Stimulation of eryptosis contributes to anemia of several clinical conditions such as metabolic syndrome, diabetes, malignancy, hepatic failure, heart failure, uremia, hemolytic uremic syndrome, sepsis, fever, dehydration, mycoplasma infection, malaria, iron deficiency, sickle cell anemia, thalassemia, glucose-6-phosphate dehydrogenase deficiency and Wilson's disease. On the other hand, eryptosis with subsequent clearance of infected erythrocytes in malaria may counteract parasitemia. In theory, anemia due to excessive eryptosis could be alleviated by treatment with small molecules inhibiting eryptosis. In malaria, stimulators of eryptosis may accelerate death of infected erythrocytes and thus favorably influence the clinical course of the disease. Many small molecules inhibit or stimulate eryptosis. Several stimulators favorably influence murine malaria. Further preclinical and subsequent clinical studies are required to elucidate the therapeutic potential of stimulators or inhibitors of eryptosis.

  4. Coadsorption of Doxorubicin and Selected Dyes on Carbon Nanotubes. Theoretical Investigation of Potential Application as a pH-Controlled Drug Delivery System.

    PubMed

    Panczyk, Tomasz; Wolski, Pawel; Lajtar, Leszek

    2016-05-17

    This work shows results of a theoretical survey, based on molecular dynamics simulation, of potential applicability of doxorubicin coadsorption with various dyes molecules on/in carbon nanotubes as a drug delivery system. The central idea is to take advantage of the dyes charge distribution change upon switching the pH of the environment from neutral (physiological 7.4) to acidic one (∼5.5 which is typical for tumor tissues). This work discusses results obtained for four dye molecules revealing more or less interesting behavior. These were bromothymol blue, methyl red, neutral red, and p-phenylenediamine. All of them reveal pKa in the range 5-7 and thus will undergo protonation in that pH range. We considered coadsorption on external walls of carbon nanotubes and sequential filling of the nanotubes inner hollow space by drug and dyes. The latter approach, with the application of neutral red and p-phenylenediamine as blockers of doxorubicin, led to the most promising results. Closer analysis of these systems allowed us to state that neutral red can be particularly useful as a long-term blocker of doxorubicin encapsulated in the inner cavity of (30,0) carbon nanotube at neutral pH. At acidic pH we observed a spontaneous release of neutral red from the nanotube and unblocking of doxorubicin. We also confirmed, by analysis of free energy profiles, that unblocked doxorubicin can spontaneously leave the nanotube interior at the considered conditions. Thus, that system can realize pH controlled doxorubicin release in acidic environment of tumor tissues.

  5. First In Vivo Evaluation of Liposome-encapsulated 223Ra as a Potential Alpha-particle-emitting Cancer Therapeutic Agent

    SciTech Connect

    Jonasdottir, Thora J.; Fisher, Darrell R.; Borrebaek, Jorgen; Bruland, Oyvind S.; Larsen, Roy H.

    2006-09-13

    Liposomes carrying chemotherapeutics have had some success in cancer treatment and may be suitable carriers for therapeutic radionuclides. This study was designed to evaluate the biodistribution of and to estimate the radiation doses from the alpha emitter 223Ra loaded into pegylated liposomes in selected tissues. 223Ra was encapsulated in pegylated liposomal doxorubicin by ionophore-mediated loading. The biodistribution of liposomal 223Ra was compared to free cationic 223Ra in Balb/C mice. We showed that liposomal 223 Ra circulated in the blood with an initial half-time in excess of 24 hours, which agreed well with that reported for liposomal doxorubicin in rodents, while the blood half-time of cationic 223Ra was considerably less than one hour. When liposomal 223 Ra was catabolized, the released 223Ra was either excreted or taken up in the skeleton. This skeletal uptake increased up to 14 days after treatment, but did not reach the level seen with free 223Ra. Pre-treatment with non-radioactive liposomal doxorubicin 4 days in advance lessened the liver uptake of liposomal 223 Ra. Dose estimates showed that the spleen, followed by bone surfaces, received the highest absorbed doses. Liposomal 223 Ra was relatively stable in vivo and may have potential for radionuclide therapy and combination therapy with chemotherapeutic agents.

  6. Therapeutic potential of monoacylglycerol lipase inhibitors.

    PubMed

    Mulvihill, Melinda M; Nomura, Daniel K

    2013-03-19

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

  7. EGF-modified mPEG-PLGA-PLL nanoparticle for delivering doxorubicin combined with Bcl-2 siRNA as a potential treatment strategy for lung cancer.

    PubMed

    Zhang, Xiangyu; Wang, Qi; Qin, Liubing; Fu, Hao; Fang, Yiwei; Han, Baoshan; Duan, Yourong

    2016-10-01

    Nanoparticles (NPs) have been widely used as carriers to deliver siRNA and chemotherapeutic agents. Bcl-2 siRNA has been widely used to induce cancer cell apoptosis, and doxorubicin (Dox) can destroy cancer cells by binding with cancer cell DNA. To investigate the therapeutic effect on lung cancer of simultaneously delivering Dox and Bcl-2-siRNA using epidermal growth factor (EGF) modified monomethoxy (polyethylene glycol)-poly (D, L-lactide-co-glycolide)-poly(L-lysine) (mPEG-PLGA-PLL, PEAL) NPs (EGF-PEAL). EGF-PEAL NPs were characterized with respect to size, zeta potential and morphology. Cytotoxicity and drug (or siRNA) loading capacity of EGF-PEAL NPs were analyzed. Cellular uptake, drug release profile, cell killing effects of Dox and Bcl-2-siRNA-loaded EGF-PEAL NPs were assessed. Biodistribution and therapeutic effects of Dox and Bcl-2-siRNA EGF-PEAL NPs were evaluated in H1299 tumor-bearing mice. EGF-PEAL NPs or PEAL NPs had nearly negligible cytotoxicity toward H1299 cells. Dox and Bcl-2-siRNA gradually released from EGF-PEAL NPs and exhibited sustained release patterns. Dox and Bcl-2-siRNA-loaded NPs were taken up by cells and induced the apoptosis of H1299 cells more effectively than using Dox or Bcl-2 siRNA alone. With the intravenous injection of PEAL NPs into H1299 xenografted mice, we found that combination treatment suppressed lung cancer growth and reduced Bcl-2 expression in tumor tissue, and EGF-PEAL NPs concentrated in lung tumor much more than non-targeted PEAL NPs. We conclude that co-delivery of Dox and Bcl-2-siRNA by tumor-targeted EGF-PEAL NPs could significantly inhibit lung cancer growth.

  8. Trichostatin A accentuates doxorubicin-induced hypertrophy in cardiac myocytes

    PubMed Central

    Karagiannis, Tom C; Lin, Ann JE; Ververis, Katherine; Chang, Lisa; Tang, Michelle M; Okabe, Jun; El-Osta, Assam

    2010-01-01

    Histone deacetylase inhibitors represent a new class of anticancer therapeutics and the expectation is that they will be most effective when used in combination with conventional cancer therapies, such as the anthracycline, doxorubicin. The dose-limiting side effect of doxorubicin is severe cardiotoxicity and evaluation of the effects of combinations of the anthracycline with histone deacetylase inhibitors in relevant models is important. We used a well-established in vitro model of doxorubicin-induced hypertrophy to examine the effects of the prototypical histone deacetylase inhibitor, Trichostatin A. Our findings indicate that doxorubicin modulates the expression of the hypertrophy-associated genes, ventricular myosin light chain-2, the alpha isoform of myosin heavy chain and atrial natriuretic peptide, an effect which is augmented by Trichostatin A. Furthermore, we show that Trichostatin A amplifies doxorubicin-induced DNA double strand breaks, as assessed by γH2AX formation. More generally, our findings highlight the importance of investigating potential side effects that may be associated with emerging combination therapies for cancer. PMID:20930262

  9. PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects.

    PubMed

    Rincón, Raúl; Cristóbal, Ion; Zazo, Sandra; Arpí, Oriol; Menéndez, Silvia; Manso, Rebeca; Lluch, Ana; Eroles, Pilar; Rovira, Ana; Albanell, Joan; García-Foncillas, Jesús; Madoz-Gúrpide, Juan; Rojo, Federico

    2015-02-28

    The protein phosphatase 2A (PP2A) is a key tumor suppressor which has emerged as a novel molecular target in some human cancers. Here, we show that PP2A inhibition is a common event in breast cancer and identified PP2A phosphorylation and deregulation SET and CIP2A as molecular contributing mechanisms to inactivate PP2A. Interestingly, restoration of PP2A activity after FTY720 treatment reduced cell growth, induced apoptosis and decreased AKT and ERK activation. Moreover, FTY720 led to PP2A activation then enhancing doxorubicin-induced antitumor effects both in vitro and in vivo. PP2A inhibition (CPscore: PP2A phosphorylation and/or CIP2A overexpression) was detected in 27% of cases (62/230), and associated with grade (p = 0.017), relapse (p < 0.001), negative estrogen (p < 0.001) and progesterone receptor expression (p < 0.001), HER2-positive tumors (p = 0.049), Ki-67 expression (p < 0.001), and higher AKT (p < 0.001) and ERK (p < 0.001) phosphorylation. Moreover, PP2A inhibition determined shorter overall (p = 0.006) and event-free survival (p = 0.003), and multivariate analysis confirmed its independent prognostic impact. Altogether, our results indicate that PP2A is frequently inactivated in breast cancer and determines worse outcome, and its restoration using PP2A activators represents an alternative therapeutic strategy in this disease.

  10. PP2A inhibition determines poor outcome and doxorubicin resistance in early breast cancer and its activation shows promising therapeutic effects

    PubMed Central

    Zazo, Sandra; Arpí, Oriol; Menéndez, Silvia; Manso, Rebeca; Lluch, Ana; Eroles, Pilar; Rovira, Ana; Albanell, Joan; García-Foncillas, Jesús; Madoz-Gúrpide, Juan; Rojo, Federico

    2015-01-01

    The protein phosphatase 2A (PP2A) is a key tumor suppressor which has emerged as a novel molecular target in some human cancers. Here, we show that PP2A inhibition is a common event in breast cancer and identified PP2A phosphorylation and deregulation SET and CIP2A as molecular contributing mechanisms to inactivate PP2A. Interestingly, restoration of PP2A activity after FTY720 treatment reduced cell growth, induced apoptosis and decreased AKT and ERK activation. Moreover, FTY720 led to PP2A activation then enhancing doxorubicin-induced antitumor effects both in vitro and in vivo. PP2A inhibition (CPscore: PP2A phosphorylation and/or CIP2A overexpression) was detected in 27% of cases (62/230), and associated with grade (p = 0.017), relapse (p < 0.001), negative estrogen (p < 0.001) and progesterone receptor expression (p < 0.001), HER2-positive tumors (p = 0.049), Ki-67 expression (p < 0.001), and higher AKT (p < 0.001) and ERK (p < 0.001) phosphorylation. Moreover, PP2A inhibition determined shorter overall (p = 0.006) and event-free survival (p = 0.003), and multivariate analysis confirmed its independent prognostic impact. Altogether, our results indicate that PP2A is frequently inactivated in breast cancer and determines worse outcome, and its restoration using PP2A activators represents an alternative therapeutic strategy in this disease. PMID:25726524

  11. Smac Mimetic SM-164 Potentiates APO2L/TRAIL- and Doxorubicin-Mediated Anticancer Activity in Human Hepatocellular Carcinoma Cells

    PubMed Central

    Zhang, Shuijun; Li, Gongquan; Zhao, Yongfu; Liu, Guangzhi; Wang, Yu; Ma, Xiuxian; Li, Dexu; Wu, Yang; Lu, Jianfeng

    2012-01-01

    Background The members of inhibitor of apoptosis proteins (IAPs) family are key negative regulators of apoptosis. Overexpression of IAPs are found in hepatocellular carcinoma (HCC), and can contribute to chemotherapy resistance and recurrence of HCC. Small-molecule Second mitochondria-derived activator of caspases (Smac) mimetics have recently emerged as novel anticancer drugs through targeting IAPs. The specific aims of this study were to 1) examine the anticancer activity of Smac mimetics as a single agent and in combination with chemotherapy in HCC cells, and 2) investigate the mechanism of anticancer action of Smac mimetics. Methods Four HCC cell lines, including SMMC-7721, BEL-7402, HepG2 and Hep3B, and 12 primary HCC cells were used in this study. Smac mimetic SM-164 was used to treat HCC cells. Cell viability, cell death induction and clonal formation assays were used to evaluate the anticancer activity. Western blotting analysis and a pancaspase inhibitor were used to investigate the mechanisms. Results Although SM-164 induced complete cIAP-1 degradation, it displayed weak inhibitory effects on the viability of HCC cells. Nevertheless, SM-164 considerably potentiated Apo2 ligand or TNF-related apoptosis-inducing ligand (APO2L/TRAIL)- and Doxorubicin-mediated anticancer activity in HCC cells. Mechanistic studies demonstrated that SM-164 in combination with chemotherapeutic agents resulted in enhanced activation of caspases-9, -3 and cleavage of poly ADP-ribose polymerase (PARP), and also led to decreased AKT activation. Conclusions Smac mimetics can enhance chemotherapeutic-mediated anticancer activity by enhancing apoptosis signaling and suppressing survival signaling in HCC cells. This study suggests Smac mimetics are potential therapeutic agents for HCC. PMID:23240027

  12. [Potential therapeutic usefulness of cannabis and cannabinoids].

    PubMed

    Lorenzo Fernández, P

    2000-01-01

    Diseases in which Cannabis and cannabinoids have demonstrated some medicinal putative properties are: nausea and vomiting associated with cancer chemotherapy, muscle spasticity (multiple sclerosis, movement disorders), pain, anorexia, epilepsy, glaucoma, bronchial asthma, neuroegenerative diseases, cancer, etc. Although some of the current data comes from clinical controlled essays, the majority are based on anecdotic reports. Basic pharmacokinetic and pharmacodynamic studies and more extensive controlled clinical essays with higher number of patients and long term studies are necessary to consider these compounds useful since a therapeutical point of view.

  13. Therapeutic potential of curcumin in digestive diseases

    PubMed Central

    Dulbecco, Pietro; Savarino, Vincenzo

    2013-01-01

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

  14. Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice

    SciTech Connect

    Guenancia, Charles; Li, Na; Hachet, Olivier; Rigal, Eve; Cottin, Yves; Dutartre, Patrick; Rochette, Luc; Vergely, Catherine

    2015-04-15

    Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran–iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran–iron (15 mg/kg) for 3 weeks (D0–D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6 mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran–iron (125–1000 μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+ 22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice. - Highlights: • The effects of iron on cardiomyocytes were opposite to those on cancer cell lines. • In our model, iron overload did not potentiate anthracycline cardiotoxicity. • Chronic oxidative stress induced by iron could mitigate doxorubicin cardiotoxicity. • The role of iron in

  15. Actions of sesquiterpene lactones isolated from Moquiniastrum polymorphum subsp. floccosum in MCF7 cell line and their potentiating action on doxorubicin.

    PubMed

    de Oliveira Mauro, Mariana; Matuo, Renata; de David, Natan; Strapasson, Regiane Lauriano Batista; Oliveira, Rodrigo Juliano; Stefanello, Maria Élida Alves; Kassuya, Cândida Aparecida Leite; de Cepa Matos, Maria de Fátima; Faria, Fábio José Carvalho; Costa, Deiler Sampaio

    2017-06-29

    In order to obtain better clinical results in anticancer therapies, polychemotherapy or combination therapies are used. For this, the combinations are required to increase the efficacy and reduce the adverse reactions of the associated chemotherapies. The aim of this study was to evaluate the cytotoxic, apoptotic and (anti)proliferative potential of two sesquiterpene lactones isolated from Moquiniastrum polymorphum, 11,13-diidrozaluzanin C (1) and gochnatiolide C (2), and their associations with chemotherapeutic agents irinotecan, tamoxifen, cisplatin, 5-fluouracyl and doxorubicin in the tumoral lineage of MCF-7 breast adenocarcinoma. The analyses were performed by MTT cytotoxicity assays, drug combination index (CI), apoptosis morphological assay and cell proliferation assay. Treatments were evaluated with short exposure times (4 h), followed or not by recovery in drug-free medium for 24 h. For the cell viability assay the statistical analysis was performed using software INSTAT, and the ANOVA/Tukey test was applied. Combination Indices (CI) was made using CompuSyn software and demonstrated through isoboles. The assays that evaluated cell death and proliferation used statistical analysis SAS 9.4 (Statistical Analysis System), and the procedure adopted was PROC NPAR1WAY. The Wilcoxon test at 5% level was applied for comparing statistical differences. The results demonstrated that the compounds decrease cell viability and increase their action when associated with irinotecan, tamoxifen and doxorubicin (CI < 1 and CI = 1). In periods of 4 h-exposure, the compounds cause cell death by apoptosis and after 24 h, they increase the mean number of cells in programmed cell death, especially when treated with 2. In addition, the association with doxorubicin increases the apoptotic potential induced by tested compounds. Both isolates had effect on the reduction of the number of mitoses, especially when 2 at its highest concentration is associated with doxorubicin

  16. Therapeutic Potential of Epigallocatechin Gallate Nanodelivery Systems

    PubMed Central

    Granja, Andreia; Frias, Iúri; Neves, Ana Rute; Reis, Salette

    2017-01-01

    Nowadays, the society is facing a large health problem with the rising of new diseases, including cancer, heart diseases, diabetes, neurodegenerative diseases, and obesity. Thus, it is important to invest in substances that enhance the health of the population. In this context, epigallocatechin gallate (EGCG) is a flavonoid found in many plants, especially in tea. Several studies support the notion that EGCG has several benefits in fighting cancer, heart diseases, diabetes, and obesity, among others. Nevertheless, the poor intestinal absorbance and instability of EGCG constitute the main drawback to use this molecule in prevention and therapy. The encapsulation of EGCG in nanocarriers leads to its enhanced stability and higher therapeutic effects. A comprehensive review of studies currently available on the encapsulation of EGCG by means of nanocarriers will be addressed. PMID:28791306

  17. Therapeutic Potential of Epigallocatechin Gallate Nanodelivery Systems.

    PubMed

    Granja, Andreia; Frias, Iúri; Neves, Ana Rute; Pinheiro, Marina; Reis, Salette

    2017-01-01

    Nowadays, the society is facing a large health problem with the rising of new diseases, including cancer, heart diseases, diabetes, neurodegenerative diseases, and obesity. Thus, it is important to invest in substances that enhance the health of the population. In this context, epigallocatechin gallate (EGCG) is a flavonoid found in many plants, especially in tea. Several studies support the notion that EGCG has several benefits in fighting cancer, heart diseases, diabetes, and obesity, among others. Nevertheless, the poor intestinal absorbance and instability of EGCG constitute the main drawback to use this molecule in prevention and therapy. The encapsulation of EGCG in nanocarriers leads to its enhanced stability and higher therapeutic effects. A comprehensive review of studies currently available on the encapsulation of EGCG by means of nanocarriers will be addressed.

  18. 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

  19. Gaq proteins: molecular pharmacology and therapeutic potential.

    PubMed

    Kamato, Danielle; Mitra, Partha; Davis, Felicity; Osman, Narin; Chaplin, Rebecca; Cabot, Peter J; Afroz, Rizwana; Thomas, Walter; Zheng, Wenhua; Kaur, Harveen; Brimble, Margaret; Little, Peter J

    2017-04-01

    Seven transmembrane G protein-coupled receptors (GPCRs) have gained much interest in recent years as it is the largest class among cell surface receptors. G proteins lie in the heart of GPCRs signalling and therefore can be therapeutically targeted to overcome complexities in GPCR responses and signalling. G proteins are classified into four families (Gi, Gs, G12/13 and Gq); Gq is further subdivided into four classes. Among them Gαq and Gαq/11 isoforms are most crucial and ubiquitously expressed; these isoforms are almost 88% similar at their amino acid sequence but may exhibit functional divergences. However, uncertainties often arise about Gαq and Gαq/11 inhibitors, these G proteins might also have suitability to the invention of novel-specific inhibitors for each isoforms. YM-254890 and UBO-QIC are discovered as potent inhibitors of Gαq functions and also investigated in thrombin protease-activated receptor (PAR)-1 inhibitors and platelet aggregation inhibition. The most likely G protein involved in PAR-1 stimulates responses is one of the Gαq family isoforms. In this review, we highlight the molecular structures and pharmacological responses of Gαq family which may reflect the biochemical and molecular role of Gαq and Gαq/11. The advanced understanding of Gαq and Gαq/11 role in GPCR signalling may shed light on our understanding on cell biology, cellular physiology and pathophysiology and also lead to the development of novel therapeutic agents for a number of diseases.

  20. Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors

    PubMed Central

    Yu, Man; Lee, Carol; Wang, Marina; Tannock, Ian F

    2015-01-01

    Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined the effects of the PPI lansoprazole to modify the activity of doxorubicin. To gain insight into its mechanisms, we studied the effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole showed concentration-dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances the therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors. PMID:26212113

  1. Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors.

    PubMed

    Yu, Man; Lee, Carol; Wang, Marina; Tannock, Ian F

    2015-10-01

    Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined the effects of the PPI lansoprazole to modify the activity of doxorubicin. To gain insight into its mechanisms, we studied the effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole showed concentration-dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances the therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors.

  2. 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

  3. HAMLET: functional properties and therapeutic potential.

    PubMed

    Ho C S, James; Rydström, Anna; Trulsson, Maria; Bålfors, Johannes; Storm, Petter; Puthia, Manoj; Nadeem, Aftab; Svanborg, Catharina

    2012-10-01

    Human α-lactalbumin made lethal to tumor cells (HAMLET) is the first member in a new family of protein-lipid complexes that kills tumor cells with high selectivity. The protein component of HAMLET is α-lactalbumin, which in its native state acts as a substrate specifier in the lactose synthase complex, thereby defining a function essential for the survival of lactating mammals. In addition, α-lactalbumin acquires tumoricidal activity after partial unfolding and binding to oleic acid. The lipid cofactor serves the dual role as a stabilizer of the altered fold of the protein and a coactivator of specific steps in tumor cell death. HAMLET is broadly tumoricidal, suggesting that the complex identifies conserved death pathways suitable for targeting by novel therapies. Sensitivity to HAMLET is defined by oncogene expression including Ras and c-Myc and by glycolytic enzymes. Cellular targets are located in the cytoplasmic membrane, cytoskeleton, mitochondria, proteasomes, lysosomes and nuclei, and specific signaling pathways are rapidly activated, first by interactions of HAMLET with the cell membrane and subsequently after HAMLET internalization. Therapeutic effects of HAMLET have been demonstrated in human skin papillomas and bladder cancers, and HAMLET limits the progression of human glioblastomas, with no evidence of toxicity for normal brain or bladder tissue. These findings open up new avenues for cancer therapy and the understanding of conserved death responses in tumor cells.

  4. Therapeutic potential of cannabis in pain medicine.

    PubMed

    Hosking, R D; Zajicek, J P

    2008-07-01

    Advances in cannabis research have paralleled developments in opioid pharmacology whereby a psychoactive plant extract has elucidated novel endogenous signalling systems with therapeutic significance. Cannabinoids (CBs) are chemical compounds derived from cannabis. The major psychotropic CB delta-9-tetrahydrocannabinol (Delta(9)-THC) was isolated in 1964 and the first CB receptor (CB(1)R) was cloned in 1990. CB signalling occurs via G-protein-coupled receptors distributed throughout the body. Endocannabinoids are derivatives of arachidonic acid that function in diverse physiological systems. Neuronal CB(1)Rs modulate synaptic transmission and mediate psychoactivity. Immune-cell CB(2) receptors (CB(2)R) may down-regulate neuroinflammation and influence cyclooxygenase-dependent pathways. Animal models demonstrate that CBRs play a fundamental role in peripheral, spinal, and supraspinal nociception and that CBs are effective analgesics. Clinical trials of CBs in multiple sclerosis have suggested a benefit in neuropathic pain. However, human studies of CB-mediated analgesia have been limited by study size, heterogeneous patient populations, and subjective outcome measures. Furthermore, CBs have variable pharmacokinetics and can manifest psychotropism. They are currently licensed as antiemetics in chemotherapy and can be prescribed on a named-patient basis for neuropathic pain. Future selective peripheral CB(1)R and CB(2)R agonists will minimize central psychoactivity and may synergize opioid anti-nociception. This review discusses the basic science and clinical aspects of CB pharmacology with a focus on pain medicine.

  5. 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

  6. The therapeutic potential of cannabis and cannabinoids.

    PubMed

    Grotenhermen, Franjo; Müller-Vahl, Kirsten

    2012-07-01

    Cannabis-based medications have been a topic of intense study since the endogenous cannabinoid system was discovered two decades ago. In 2011, for the first time, a cannabis extract was approved for clinical use in Germany. Selective literature review. Cannabis-based medications exert their effects mainly through the activation of cannabinoid receptors (CB1 and CB2). More than 100 controlled clinical trials of cannabinoids or whole-plant preparations for various indications have been conducted since 1975. The findings of these trials have led to the approval of cannabis-based medicines (dronabinol, nabilone, and a cannabis extract [THC:CBD=1:1]) in several countries. In Germany, a cannabis extract was approved in 2011 for the treatment of moderate to severe refractory spasticity in multiple sclerosis. It is commonly used off label for the treatment of anorexia, nausea, and neuropathic pain. Patients can also apply for government permission to buy medicinal cannabis flowers for self-treatment under medical supervision. The most common side effects of cannabinoids are tiredness and dizziness (in more than 10% of patients), psychological effects, and dry mouth. Tolerance to these side effects nearly always develops within a short time. Withdrawal symptoms are hardly ever a problem in the therapeutic setting. There is now clear evidence that cannabinoids are useful for the treatment of various medical conditions.

  7. Therapeutic potential of resveratrol in Alzheimer's disease.

    PubMed

    Vingtdeux, Valérie; Dreses-Werringloer, Ute; Zhao, Haitian; Davies, Peter; Marambaud, Philippe

    2008-12-03

    Several epidemiological studies indicate that moderate consumption of red wine is associated with a lower incidence of dementia and Alzheimer's disease. Red wine is enriched in antioxidant polyphenols with potential neuroprotective activities. Despite scepticism concerning the bioavailability of these polyphenols, in vivo data have clearly demonstrated the neuroprotective properties of the naturally occurring polyphenol resveratrol in rodent models for stress and diseases. Furthermore, recent work in cell cultures and animal models has shed light on the molecular mechanisms potentially involved in the beneficial effects of resveratrol intake against the neurodegenerative process in Alzheimer's disease.

  8. Novel bifunctional natriuretic peptides as potential therapeutics.

    PubMed

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

    2008-12-12

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

  9. [Development of a new type intelligent high potential therapeutic apparatus].

    PubMed

    Gao, Tiedan; Wang, Huafeng; Chen, Chaomin

    2013-06-01

    This article presents the development and design of a new type intelligent high potential therapeutic apparatus, by using Atmega1280 as its controller. The circuit transforms voltage from 220 V ac to 110 V ac and constitutes different circuits with relays. In order to get different treatment waveforms, inductance of various values is used in different circuits. The circuit generates appropriate treatment voltage with the transformer booster. Simultaneously, the corresponding control software was composed. Finally the hardware and software designs of the high potential therapeutic apparatus were completed. Result of the experiment showed that the high potential therapeutic apparatus worked steadily and the effect of treatment was satisfactory.

  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. The Therapeutic Potential of Medicinal Foods

    PubMed Central

    Ramalingum, Nelvana; Mahomoodally, M. Fawzi

    2014-01-01

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

  12. Therapeutic potential of active stent coating.

    PubMed

    Wieneke, Heinrich; Schmermund, Axel; von Birgelen, Clemens; Haude, Michael; Erbel, Raimund

    2003-05-01

    Various clinical studies have shown the superiority of stent implantation as compared to conventional balloon angioplasty for the treatment of significant coronary stenosis. However, restenosis remains a major drawback of this interventional technique. Against the background of this serious problem, the concept of stent coating has been developed. In general, coatings can be classified into two types: passive coatings, which only serve as a barrier between the stainless steel, and the tissue and active coatings, which directly interfere with the process of intima proliferation. At this moment, primarily immunosuppressive and cytostatic substances are used as active coatings. Large randomised studies have shown that this novel concept can be successfully implemented into clinical practice. Beside these promising results, studies also revealed potential risks of this new approach. Not only the dosage of the drug but also an optimised kinetic of drug release seem to be essential in preventing restenosis. As with most drugs, the inhibition of neointima proliferation is not restricted to vascular smooth muscle cells but also affects the process of re-endothelialisation, thus we may face a new pitfall of late-stent thrombosis. Although this technique may harbour potential risks, the introduction of stent coating has the potential to dramatically reduce the incidence of restenosis and an exciting chapter in the field of cardiology has been opened.

  13. Exploring the therapeutic potential of jellyfish venom.

    PubMed

    Daly, Norelle L; Seymour, Jamie; Wilson, David

    2014-10-01

    The venom of certain jellyfish has long been known to be potentially fatal to humans, but it is only recently that details of the proteomes of these fascinating creatures are emerging. The molecular contents of the nematocysts from several jellyfish species have now been analyzed using proteomic MS approaches and include the analysis of Chironex fleckeri, one of the most venomous jellyfish known. These studies suggest that some species contain toxins related to peptides and proteins found in other venomous creatures. The detailed characterization of jellyfish venom is likely to provide insight into the diversification of toxins and might be a valuable resource in drug design.

  14. Targeted Smart pH and Thermoresponsive N,O-Carboxymethyl Chitosan Conjugated Nanogels for Enhanced Therapeutic Efficacy of Doxorubicin in MCF-7 Breast Cancer Cells.

    PubMed

    Verma, Neeraj K; Purohit, Mahaveer P; Equbal, Danish; Dhiman, Nitesh; Singh, Amrita; Kar, Aditya K; Shankar, Jai; Tehlan, Sarita; Patnaik, Satyakam

    2016-11-16

    In cancer treatment, developing ideal anticancer drug delivery systems to target tumor microenvironment by circumventing various physiological barriers still remains a daunting challenge. Here, in our work, a series of pH- and temperature-responsive nanogels based on poly(N-isopropylacrylamide-co-1-propene-2-3-dicarboxylate-co-2-acrylamido-2-methyl-1-propanesulfonate [poly(NIPAAm-IA-AMPS)] cross-linked by ethylene glycol dimethacrylate (EGDMA) were synthesized by random copolymerization. The molar ratio between monomer-comonomers-cross-linker was varied to fine-tune the optimum responsiveness of the nanogels. These optimized nanogels were further coupled to N,O-carboxymethyl chitosan (NOCC) stoichiometrically using EDC-NHS coupling chemistry to enhance the swelling behavior at lower pH. Interestingly, these NOCC-g-nanogels, when dispersed in aqueous media under sonication, attain nanosize and retain their high water-retention capacity with conspicuous pH and temperature responsiveness (viz. nanogel shrinkage in size beyond 35 °C and swelled at acidic pH) in vitro, as reflected by dynamic light scattering data. Doxorubicin (DOX), a potent anticancer drug, was loaded into these nanogels using the physical entrapment method. These drug-loaded nanogels exhibited a slow and sustained DOX release profile at physiological temperature and cytosolic pH. Furthermore, confocal and TEM results demonstrate that these nanogels were swiftly internalized by MCF-7 cells, and cell viability data showed preferential heightened cytotoxicity toward cancer cells (MCF-7 and MDA-MB231) compared to the MCF10A cells (human breast epithelial cell). Furthermore, intracellular DNA damage and cell cycle arrest assays suggest a mitochondrial mediated apoptosis in MCF-7 cells. This study substantiates our NOCC-g-nanogel platform as an excellent modality for passive diffusive loading and targeted release of entrapped drug(s) at physiological conditions in a controlled way for the improved

  15. 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

  16. 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.

  17. 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.

  18. Therapeutic potential of amniotic fluid stem cells.

    PubMed

    Abdulrazzak, Hassan; De Coppi, Paolo; Guillot, Pascale V

    2013-03-01

    Human amniotic fluid cells have been used traditionally as a diagnostic tool for genetic anomalies. More recently it has been recognized that amniotic fluid contains populations of stem cells. Mesenchymal stem cells (AFMSC) were first to be described. These cells are able to differentiate towards mesodermal lineages. More recently cells with broader potential, defined as amniotic fluid stem cells (AFSC), were also isolated. They have intermediate characteristics between embryonic and adult stem cells and are able to differentiate into lineages representative of all three germ layers but unlike ES cells they do not form tumours in vivo. Furthermore, AFSC have been reverted to functional pluripotency in a transgene-free approach using an epigenetics modifier. These characteristics, together with absence of ethical issues concerning their employment, have made stem cells from amniotic fluid a promising candidate for cell therapy and tissue engineering.

  19. Doxorubicin loaded pH-responsive micelles capable of rapid intracellular drug release for potential tumor therapy.

    PubMed

    Li, Shuai; Wu, Wei; Xiu, Kemao; Xu, Fujian; Li, Zhongming; Li, Jianshu

    2014-08-01

    Amphiphilic copolymers have been paid much attention for controlled drug release for many years due to their obvious advantages. In this study, an acid-triggered drug carrier system capable of rapid intracellular drug release is investigated for potential tumor therapy. The amphiphilic diblock copolymer poly(2-diisopropylaminoethyl methacrylate)-b-poly(2-aminoethyl methacrylate hydrochloride) (PDPA-b-PAMA) is prepared by atom transfer radical polymerization (ATRP). The molecular structure of the copolymer is confirmed by 1H NMR and gel permeation chromatography (GPC). The critical micelle concentration (CMC) value of the PDPA-b-PAMA is 0.005 mg/mL, which can ensure the thermodynamical stability of micelles even after significant dilution. The drug loading and encapsulation efficiencies of doxorubicin (DOX)-loaded micelles are 9.96% and 55.31%, respectively. Dynamic light scattering (DLS) and transmission electron microscope (TEM) show that the amphiphilic block copolymers self-assemble into spherical micelles with narrow polydispersity indexes (PDLs) at pH 7.4 and 6.8, but disassemble into random chain aggregations at pH 5.0. The DOX-loaded PDPA-b-PAMA shows obvious pH-responsive drug release profile when the pH value changes from 7.4 to 5.0, since it transforms from amphiphilicity to double hydrophilicity through the protonation of PDPA block (pK(a) - 6.2) in a relatively low pH condition, thus the loaded DOX can be rapidly released from the disassembling micelles. In addition, the micellar system also exhibits relatively low cytotoxicity and rapid drug release behaviour in tumor cells, which make it promising for tumor therapy.

  20. Therapeutic Potential of Dietary Phenolic Acids

    PubMed Central

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

    2015-01-01

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

  1. 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

  2. Resveratrol: therapeutic potential for improving cardiometabolic health.

    PubMed

    Pollack, Rena M; Crandall, Jill P

    2013-11-01

    Resveratrol, a natural polyphenol, has gained attention in recent years because of its connection with the health benefits of red wine and its anticancer activity in vitro. Studies in animal models have demonstrated beneficial effects on glucose metabolism, vascular function and anti-inflammatory and antioxidant properties. Human studies designed to understand the role of resveratrol in the prevention and treatment of age-related conditions such as diabetes, heart disease, and cancer have recently been undertaken. We searched PubMed for original articles that reported studies of resveratrol in humans, using search terms, including resveratrol, human studies, glucose metabolism, vascular function, and inflammation. We also searched the reference lists of identified articles for additional papers and sought expert opinion on relevant studies. Resveratrol treatment has shown beneficial effects on glucose and lipid metabolism in some, but not all studies. Study population, resveratrol source, and dose have varied widely, potentially explaining inconsistent findings. Improvements were noted in endothelial function, systolic blood pressure, and markers of oxidative stress and inflammation in several studies. Despite the strong preclinical evidence of positive cardiometabolic effects, studies to date have not confirmed resveratrol's benefit in humans. Study variability and methodological issues limit interpretation of available results. Additional research, focusing on subjects with defined metabolic defects and using a range of doses, is needed to advance the field. © American Journal of Hypertension, Ltd 2013. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. 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.

  4. Phytochemicals as potential therapeutics for thrombocytopenia.

    PubMed

    Manasa, K; Soumya, R; Vani, R

    2016-04-01

    Medical knowledge has always relied on plants as the main sources of important beneficial compounds. Many species have been recognized to have medicinal properties and beneficial impact on health, e.g. antioxidant activity, digestive stimulation action, anti-inflammatory, antimicrobial, hypolipidemic, antimutagenic and anticarcinogenic potential. This review focuses on the promising role of plants and their products in attenuating thrombocytopenia, a common and complex bleeding disorder. When the platelet count decreases below 150,000/µl, it causes thrombocytopenia. This bleeding disorder is observed in 2.5 % of the normal population. The risk of spontaneous muco-cutaneous bleeding and life threatening intracranial haemorrhage or gastrointestinal bleeding increases rapidly when the platelet count decreases below 10,000/µl. The inability to provide supportive treatment to increase the platelet counts often proves fatal to patients. Currently, treatment for thrombocytopenia includes use of drugs or splenectomy or platelet transfusions, in severe cases. Recently, studies have shown platelet augmenting activity of various plant extracts. The effectiveness, toxicity and side effects of the phytochemicals have to be critically evaluated in clinical trials. An in depth understanding of the role and mechanism of these phytochemicals would lead to their successful implementation in treatment and management of thrombocytopenia and other related bleeding disorders.

  5. Spices: Therapeutic Potential in Cardiovascular Health.

    PubMed

    Rastogi, Subha; Pandey, Madan Mohan; Rawat, Ajay Kumar Singh

    2017-01-01

    Dietary factors play a key role in the development as well as prevention of certain human diseases, including cardiovascular diseases. Currently there has been an increase in global interest to identify medicinal plants that are pharmacologically effective and have low or no side effects for use in preventive medicine. Culinary herbs and spices are an important part of human nutrition in all the cultures of the world. There is a growing amount of literature concerning the potential benefits of these herbs and spices from a health perspective especially in conferring protection against cardiovascular diseases. The objective of this review is to provide information on the recent scientific findings on some common spices that have a distinct place in folk medicine in several of the Asian countries as well as on their traditional uses for the role they can play in the management of heart diseases and which may be useful in defining cost effective and inexpensive interventions for the prevention and control of CVDs. Systematic literature searches were carried out and the available information on various medicinal plants traditionally used for cardiovascular disorders was collected via electronic search (using Pubmed, SciFinder, Scirus, GoogleScholar, JCCC@INSTIRC and Web of Science) and a library search for articles published in peerreviewed journals. No restrictions regarding the language of publication were imposed. This article highlights the recent scientific findings on four common spices viz. Greater cardamom (Amomum subulatum Roxb.), Coriander (Coriandrum sativum L.), Turmeric (Curcuma longa L.) and Ginger (Zingiber officinale Roscoe), for the role they can play in the management of heart diseases. Although they have been used by many cultures since ancient times and have been known to exhibit several medicinal properties, current research shows that they can also be effectively used for the prevention and control of CVDs. Although scientific evidences supporting

  6. Artemether Regulates Chemosensitivity to Doxorubicin via Regulation of B7-H3 in Human Neuroblastoma Cells.

    PubMed

    Tan, Wei-Qiang; Chen, Gang; Ye, Ming; Jia, Bing

    2017-09-03

    BACKGROUND Artemether, originally used for malaria, exhibits potential therapeutic efficacy against several types of cancer, including gastric cancer, hepatocellular carcinoma, and gliomas. In this study, we investigated the role and mechanism of artemether on drug resistance of neuroblastoma cells. MATERIAL AND METHODS Cell viability and proliferation were determined by CCK-8 and EdU incorporation assay, respectively. Gene expression was measured by real-time PCR and Western blot analysis. RESULTS Our results revealed that artemether treatment remarkably inhibited the proliferation of neuroblastoma cell lines SH-SY5Y, SK-N-SH, and SK-N-BE2. In addition, co-treatment of tumor cells with artemether and doxorubicin significantly reduced cell viability and DNA synthesis compared with doxorubicin-treated cells. On the molecular level, we found that combined treatment with artemether and doxorubicin suppressed the expression of B7-H3 both at the mRNA and protein levels. In addition, artemether failed to sensitize tumor cells to doxorubicin in SH-SY5Y cells overexpressing B7-H3. CONCLUSIONS Artemether-mediated inhibition of B7-H3 may contribute to doxorubicin sensitivity in neuroblastoma cells, suggesting that artemether could serve as a potential therapeutic option for neuroblastoma.

  7. Localised delivery of doxorubicin to prostate cancer cells through a PSMA-targeted hyperbranched polymer theranostic.

    PubMed

    Pearce, Amanda K; Simpson, Joshua D; Fletcher, Nicholas L; Houston, Zachary H; Fuchs, Adrian V; Russell, Pamela J; Whittaker, Andrew K; Thurecht, Kristofer J

    2017-10-01

    The therapeutic potential of hyperbranched polymers targeted to prostate cancer and loaded with doxorubicin was investigated. Polyethylene glycol hyperbranched polymers were synthesised via RAFT polymerisation to feature glutamate urea targeting ligands for PSMA on the periphery. The chemotherapeutic, doxorubicin, was attached to the hyperbranched polymers through hydrazone formation, which allowed controlled release of the drug from the polymers in vitro endosomal conditions, with 90% release of the drug over 36 h. The polymers were able to target to PSMA-expressing prostate cancer cells in vitro, and demonstrated comparable cytotoxicity to free doxorubicin. The ability of the hyperbranched polymers to specifically facilitate transport of loaded doxorubicin into the cells was confirmed using live cell confocal imaging, which demonstrated that the drug was able to travel with the polymer into cells by receptor mediated internalisation, and subsequently be released into the nucleus following hydrazone degradation. Finally, the ability of the complex to induce a therapeutic effect on prostate cancer cells was investigated through a long term tumour regression study, which confirmed that the DOX-loaded polymers were able to significantly reduce the volume of subcutaneous prostate tumours in vivo in comparison to free doxorubicin and a polymer control, with no adverse toxicity to the animals. This work therefore demonstrates the potential of a hyperbranched polymer system to be utilised for prostate cancer theranostics. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. HER2-targeted liposomal doxorubicin displays enhanced anti-tumorigenic effects without associated cardiotoxicity

    SciTech Connect

    Reynolds, Joseph G.; Geretti, Elena; Hendriks, Bart S.; Lee, Helen; Leonard, Shannon C.; Klinz, Stephan G.; Noble, Charles O.; Lücker, Petra B.; Zandstra, Peter W.; Drummond, Daryl C.; Olivier, Kenneth J.; Nielsen, Ulrik B.; Niyikiza, Clet; Agresta, Samuel V.; Wickham, Thomas J.

    2012-07-01

    Anthracycline-based regimens are a mainstay of early breast cancer therapy, however their use is limited by cardiac toxicity. The potential for cardiotoxicity is a major consideration in the design and development of combinatorial therapies incorporating anthracyclines and agents that target the HER2-mediated signaling pathway, such as trastuzumab. In this regard, HER2-targeted liposomal doxorubicin was developed to provide clinical benefit by both reducing the cardiotoxicity observed with anthracyclines and enhancing the therapeutic potential of HER2-based therapies that are currently available for HER2-overexpressing cancers. While documenting the enhanced therapeutic potential of HER2-targeted liposomal doxorubicin can be done with existing models, there has been no validated human cardiac cell-based assay system to rigorously assess the cardiotoxicity of anthracyclines. To understand if HER2-targeting of liposomal doxorubicin is possible with a favorable cardiac safety profile, we applied a human stem cell-derived cardiomyocyte platform to evaluate the doxorubicin exposure of human cardiac cells to HER2-targeted liposomal doxorubicin. To the best of our knowledge, this is the first known application of a stem cell-derived system for evaluating preclinical cardiotoxicity of an investigational agent. We demonstrate that HER2-targeted liposomal doxorubicin has little or no uptake into human cardiomyocytes, does not inhibit HER2-mediated signaling, results in little or no evidence of cardiomyocyte cell death or dysfunction, and retains the low penetration into heart tissue of liposomal doxorubicin. Taken together, this data ultimately led to the clinical decision to advance this drug to Phase I clinical testing, which is now ongoing as a single agent in HER2-expressing cancers. -- Highlights: ► Novel approach using stem cell-derived cardiomyocytes to assess preclinical safety. ► HER2-targeted liposomal doxorubicin has improved safety profile vs free doxorubicin

  9. Hydroxytyrosol ameliorates oxidative stress and mitochondrial dysfunction in doxorubicin-induced cardiotoxicity in rats with breast cancer.

    PubMed

    Granados-Principal, Sergio; El-Azem, Nuri; Pamplona, Reinald; Ramirez-Tortosa, Cesar; Pulido-Moran, Mario; Vera-Ramirez, Laura; Quiles, Jose L; Sanchez-Rovira, Pedro; Naudí, Alba; Portero-Otin, Manuel; Perez-Lopez, Patricia; Ramirez-Tortosa, Mcarmen

    2014-07-01

    Oxidative stress is involved in several processes including cancer, aging and cardiovascular disease, and has been shown to potentiate the therapeutic effect of drugs such as doxorubicin. Doxorubicin causes significant cardiotoxicity characterized by marked increases in oxidative stress and mitochondrial dysfunction. Herein, we investigate whether doxorubicin-associated chronic cardiac toxicity can be ameliorated with the antioxidant hydroxytyrosol in rats with breast cancer. Thirty-six rats bearing breast tumors induced chemically were divided into 4 groups: control, hydroxytyrosol (0.5mg/kg, 5days/week), doxorubicin (1mg/kg/week), and doxorubicin plus hydroxytyrosol. Cardiac disturbances at the cellular and mitochondrial level, mitochondrial electron transport chain complexes I-IV and apoptosis-inducing factor, and oxidative stress markers have been analyzed. Hydroxytyrosol improved the cardiac disturbances enhanced by doxorubicin by significantly reducing the percentage of altered mitochondria and oxidative damage. These results suggest that hydroxytyrosol improve the mitochondrial electron transport chain. This study demonstrates that hydroxytyrosol protect rat heart damage provoked by doxorubicin decreasing oxidative damage and mitochondrial alterations.

  10. Calcium modulation of doxorubicin cytotoxicity in yeast and human cells.

    PubMed

    Nguyen, Thi Thuy Trang; Lim, Ying Jun; Fan, Melanie Hui Min; Jackson, Rebecca A; Lim, Kim Kiat; Ang, Wee Han; Ban, Kenneth Hon Kim; Chen, Ee Sin

    2016-03-01

    Doxorubicin is a widely used chemotherapeutic agent, but its utility is limited by cellular resistance and off-target effects. To understand the molecular mechanisms regulating chemotherapeutic responses to doxorubicin, we previously carried out a genomewide search of doxorubicin-resistance genes in Schizosaccharomyces pombe fission yeast and showed that these genes are organized into networks that counteract doxorubicin cytotoxicity. Here, we describe the identification of a subgroup of doxorubicin-resistance genes that, when disrupted, leads to reduced tolerance to exogenous calcium. Unexpectedly, we observed a suppressive effect of calcium on doxorubicin cytotoxicity, where concurrent calcium and doxorubicin treatment resulted in significantly higher cell survival compared with cells treated with doxorubicin alone. Conversely, inhibitors of voltage-gated calcium channels enhanced doxorubicin cytotoxicity in the mutants. Consistent with these observations in fission yeast, calcium also suppressed doxorubicin cytotoxicity in human breast cancer cells. Further epistasis analyses in yeast showed that this suppression of doxorubicin toxicity by calcium was synergistically dependent on Rav1 and Vph2, two regulators of vacuolar-ATPase assembly; this suggests potential modulation of the calcium-doxorubicin interaction by fluctuating proton concentrations within the cellular environment. Thus, the modulatory effects of drugs or diet on calcium concentrations should be considered in doxorubicin treatment regimes.

  11. TRAIL and taurolidine enhance the anticancer activity of doxorubicin, trabectedin and mafosfamide in HT1080 human fibrosarcoma cells.

    PubMed

    Harati, K; Chromik, A M; Bulut, D; Goertz, O; Hahn, S; Hirsch, T; Klein-Hitpass, L; Lehnhardt, M; Uhl, W; Daigeler, A

    2012-07-01

    Disseminated fibrosarcoma still represents a therapeutic dilemma because of lack of effective cytostatics. Therefore we tested tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and taurolidine, in combination with established and new chemotherapeutic agents on human fibrosarcoma (HT1080). Human fibrosarcoma cells (HT1080) were incubated with doxorubicin, mafosfamide and trabectedin both alone and in combination with taurolidine and TRAIL. Vital, apoptotic and necrotic cells were quantified using flow cytometric analysis. Cell proliferation was analysed using a bromodeoxyuridine (BrdU) ELISA assay. Single application of doxorubicin and trabectedin induced apoptotic cell death and significantly reduced the proliferation of HT1080 cells. In combination treatment, the addition of taurolidine and TRAIL resulted in a stronger reduction in the degree of cell viability when compared to single treatment. Trabectedin and taurolidine displayed a greater potential for inhibiting proliferation than did doxorubicin alone. When combined with TRAIL and taurolidine, treatment with doxorubicin and trabectedin demonstrated stronger apoptosis-inducing and antiproliferative effects.

  12. Oncogenic histone methyltransferase EZH2: A novel prognostic marker with therapeutic potential in endometrial cancer

    PubMed Central

    Oki, Shinya; Sone, Kenbun; Oda, Katsutoshi; Hamamoto, Ryuji; Ikemura, Masako; Maeda, Daichi; Takeuchi, Makoto; Tanikawa, Michihiro; Mori-Uchino, Mayuyo; Nagasaka, Kazunori; Miyasaka, Aki; Kashiyama, Tomoko; Ikeda, Yuji; Arimoto, Takahide; Kuramoto, Hiroyuki; Wada-Hiraike, Osamu; Kawana, Kei; Fukayama, Masashi; Osuga, Yutaka; Fujii, Tomoyuki

    2017-01-01

    The histone methyltransferase EZH2, a key epigenetic modifier, is known to be associated with human tumorigenesis. However, the physiological importance of EZH2 and its clinical relevance in endometrial cancer remain unclear. Hence, in the present study, we investigated the expression and function of EZH2 in endometrial cancer. In a quantitative real-time PCR analysis of 11 endometrial cancer cell lines and 52 clinical endometrial cancer specimens, EZH2 was significantly overexpressed in cancer cells and tissues compared to that in corresponding normal control cells and tissues. Kaplan-Meier survival analysis using data of the TCGA RNA-seq database and tissue microarrays (TMAs) indicated that EZH2 overexpression is associated with endometrial cancer prognosis. In addition, knockdown of EZH2 using specific siRNAs resulted in growth suppression and apoptosis induction of endometrial cancer cells, accompanied by attenuation of H3K27 trimethylation. Consistent with these results, treatment with GSK126, a specific EZH2 inhibitor, suppressed endometrial cancer cell growth and decreased the number of cancer cell colonies. Furthermore, GSK126 showed additive effects with doxorubicin or cisplatin, which are conventional drugs for treatment of endometrial cancer. Further studies should explore the therapeutic potential of inhibiting EZH2 in patients with endometrial cancer. PMID:28418882

  13. Therapeutic potential of HO-1 in autoimmune diseases.

    PubMed

    Li, Bao-Zhu; Guo, Biao; Zhang, Hai-Yan; Liu, Juan; Tao, Sha-Sha; Pan, Hai-Feng; Ye, Dong-Qing

    2014-10-01

    Heme oxygenase-1 (HO-1), the inducible isoform of heme oxygenase (HO), has raised a lot of concerns in recent years due to its multiple functions. HO-1 was found to be a pivotal cytoprotective, antioxidant, anti-apoptotic, immunosuppressive, as well as anti-inflammatory molecule. Recent studies have clarified its significant functions in many diseases with substantial findings. In autoimmune diseases, HO-1 may have promising therapeutic potential. Here, we briefly reviewed recent advances in this field, aiming at hopefully exploring the potential therapeutic roles of HO-1, and design HO-1-based strategies for the treatment of autoimmune diseases.

  14. Hydrogen-containing saline attenuates doxorubicin-induced heart failure in rats.

    PubMed

    Wu, Shujing; Zhu, Liqun; Yang, Jing; Fan, Zhixin; Dong, Yanli; Luan, Rui; Cai, Jingjing; Fu, Lu

    2014-08-01

    Interactions between doxorubicin (DOX) and iron generate reactive oxygen species and contribute to DOX-induced heart failure. Hydrogen, as a selective antioxidant, is a promising potential therapeutic option for the treatment of a variety of diseases. Therefore, we investigated the preventive effects of hydrogen treatment on DOX-induced heart failure in rats. We found that cardiac function was significantly improved and that the plasma levels of oxidative-stress markers and myocardial autophagic activity were decreased in animals treated with hydrogen-containing saline. Therefore, we conclude that hydrogen-containing saline may have beneficial effects for doxorubicin-induced heart failure.

  15. 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

  16. Distinct phenotype and therapeutic potential of gingival fibroblasts.

    PubMed

    Häkkinen, Lari; Larjava, Hannu; Fournier, Benjamin P J

    2014-09-01

    Gingiva of the oral mucosa provides a practical source to isolate fibroblasts for therapeutic purposes because the tissue is easily accessible, tissue discards are common during routine clinical procedures and wound healing after biopsy is fast and results in complete wound regeneration with very little morbidity or scarring. In addition, gingival fibroblasts have unique traits, including neural crest origin, distinct gene expression and synthetic properties and potent immunomodulatory functions. These characteristics may provide advantages for certain therapeutic approaches over other more commonly used cells, including skin fibroblasts, both in intraoral and extra-oral sites. However, identity and phenotype of gingival fibroblasts, like other fibroblasts, are still not completely understood. Gingival fibroblasts are phenotypically heterogeneous, and these…fibroblast subpopulations may play different roles in tissue maintenance, regeneration and pathologies. The purpose of this review is to summarize what is currently known about gingival fibroblasts, their distinct potential for tissue regeneration and their potential therapeutic uses in the future.

  17. Repurposing antipsychotics as glioblastoma therapeutics: Potentials and challenges

    PubMed Central

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

    2016-01-01

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

  18. Decreased Soluble Guanylate Cyclase Contributes to Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice.

    PubMed

    Vandenwijngaert, Sara; Swinnen, Melissa; Walravens, Ann-Sophie; Beerens, Manu; Gillijns, Hilde; Caluwé, Ellen; Tainsh, Robert E; Nathan, Daniel I; Allen, Kaitlin; Brouckaert, Peter; Bartunek, Jozef; Scherrer-Crosbie, Marielle; Bloch, Kenneth D; Bloch, Donald B; Janssens, Stefan P; Buys, Emmanuel S

    2017-02-01

    The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity. Doxorubicin administration (20 mg/kg, intraperitoneally [IP]) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC α1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGCα1 allele [sGCα1(-/-CM)]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGCα1(-/-CM) than WT mice. To further assess whether reduced sGC activity plays a pathogenic role in doxorubicin-induced cardiotoxicity, we studied a mouse model in which decreased cardiac sGC activity was induced by cardiomyocyte-specific expression of a dominant negative sGCα1 mutant (DNsGCα1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGCα1(tg/+), but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGCα1(tg/+) and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGCα1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGCα1-deficient than WT hearts. Innovation and Conclusion: These data demonstrate that a reduction in cardiac sGC activity worsens doxorubicin-induced cardiotoxicity in mice and identify sGC as a potential therapeutic target. Various pharmacological sGC agonists are in clinical development or use and may represent a promising approach to limit doxorubicin

  19. Decreased Soluble Guanylate Cyclase Contributes to Cardiac Dysfunction Induced by Chronic Doxorubicin Treatment in Mice

    PubMed Central

    Vandenwijngaert, Sara; Swinnen, Melissa; Walravens, Ann-Sophie; Beerens, Manu; Gillijns, Hilde; Caluwé, Ellen; Tainsh, Robert E.; Nathan, Daniel I.; Allen, Kaitlin; Brouckaert, Peter; Bartunek, Jozef; Scherrer-Crosbie, Marielle; Bloch, Kenneth D.; Bloch, Donald B.; Janssens, Stefan P.

    2017-01-01

    Abstract Aims: The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity. Results: Doxorubicin administration (20 mg/kg, intraperitoneally [IP]) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC α1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGCα1 allele [sGCα1−/−CM]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGCα1−/−CM than WT mice. To further assess whether reduced sGC activity plays a pathogenic role in doxorubicin-induced cardiotoxicity, we studied a mouse model in which decreased cardiac sGC activity was induced by cardiomyocyte-specific expression of a dominant negative sGCα1 mutant (DNsGCα1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGCα1tg/+, but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGCα1tg/+ and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGCα1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGCα1-deficient than WT hearts. Innovation and Conclusion: These data demonstrate that a reduction in cardiac sGC activity worsens doxorubicin-induced cardiotoxicity in mice and identify sGC as a potential therapeutic target. Various pharmacological sGC agonists are in clinical development or use and may represent a promising approach to limit doxorubicin

  20. Therapeutic Potential of Stem Cells Strategy for Cardiovascular Diseases

    PubMed Central

    Lee, Chang Youn; Lee, Jihyun; Oh, Sekyung; Lee, Hojin; Lee, Minyoung; Kim, Jongmin

    2016-01-01

    Despite development of medicine, cardiovascular diseases (CVDs) are still the leading cause of mortality and morbidity worldwide. Over the past 10 years, various stem cells have been utilized in therapeutic strategies for the treatment of CVDs. CVDs are characterized by a broad range of pathological reactions including inflammation, necrosis, hyperplasia, and hypertrophy. However, the causes of CVDs are still unclear. While there is a limit to the currently available target-dependent treatments, the therapeutic potential of stem cells is very attractive for the treatment of CVDs because of their paracrine effects, anti-inflammatory activity, and immunomodulatory capacity. Various studies have recently reported increased therapeutic potential of transplantation of microRNA- (miRNA-) overexpressing stem cells or small-molecule-treated cells. In addition to treatment with drugs or overexpressed miRNA in stem cells, stem cell-derived extracellular vesicles also have therapeutic potential because they can deliver the stem cell-specific RNA and protein into the host cell, thereby improving cell viability. Here, we reported the state of stem cell-based therapy for the treatment of CVDs and the potential for cell-free based therapy. PMID:27829839

  1. Therapeutic Potential of Intravenous Immunoglobulin in Acute Brain Injury

    PubMed Central

    Thom, Vivien; Arumugam, Thiruma V.; Magnus, Tim; Gelderblom, Mathias

    2017-01-01

    Acute ischemic and traumatic injury of the central nervous system (CNS) is known to induce a cascade of inflammatory events that lead to secondary tissue damage. In particular, the sterile inflammatory response in stroke has been intensively investigated in the last decade, and numerous experimental studies demonstrated the neuroprotective potential of a targeted modulation of the immune system. Among the investigated immunomodulatory agents, intravenous immunoglobulin (IVIg) stand out due to their beneficial therapeutic potential in experimental stroke as well as several other experimental models of acute brain injuries, which are characterized by a rapidly evolving sterile inflammatory response, e.g., trauma, subarachnoid hemorrhage. IVIg are therapeutic preparations of polyclonal immunoglobulin G, extracted from the plasma of thousands of donors. In clinical practice, IVIg are the treatment of choice for diverse autoimmune diseases and various mechanisms of action have been proposed. Only recently, several experimental studies implicated a therapeutic potential of IVIg even in models of acute CNS injury, and suggested that the immune system as well as neuronal cells can directly be targeted by IVIg. This review gives further insight into the role of secondary inflammation in acute brain injury with an emphasis on stroke and investigates the therapeutic potential of IVIg. PMID:28824617

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

    PubMed

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

    2016-07-01

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

  3. Therapeutic potential of cone snail venom peptides (conopeptides).

    PubMed

    Vetter, Irina; Lewis, Richard J

    2012-01-01

    Cone snails have evolved many 1000s of small, structurally stable venom peptides (conopeptides) for prey capture and defense. Whilst < 0.1% have been pharmacologically characterised, those with known function typically target membrane proteins of therapeutic importance, including ion channels, transporters and GPCRs. Several conopeptides reduce pain in animals models, with one in clinical development (χ-conopeptide analogue Xen2174) and one marketed (ω- conotoxin MVIIA or Prialt) for the treatment of severe pain. In addition to their therapeutic potential, conopeptides have been valuable probes for studying the role of a number of key membrane proteins in normal and disease physiology.

  4. Aptamer Oligonucleotides: Novel Potential Therapeutic Agents in Autoimmune Disease.

    PubMed

    Li, Weibin; Lan, Xiaopeng

    2015-08-01

    Aptamers are single-stranded deoxyribonucleic acid or ribonucleic acid oligonucleotides generated in vitro based on affinity for certain target molecules by a process known as Systematic Evolution of Ligands by Exponential Enrichment. Aptamers can bind their target molecules with high specificity and selectivity by means of structure compatibility, stacking of aromatic rings, electrostatic and van der Waals interactions, and hydrogen bonding. With several advantages over monoclonal antibodies and other conventional small-molecule therapeutics, such as high specificity and affinity, negligible batch to batch variation, flexible modification and stability, lack of toxicity and low immunogenicity, aptamers are becoming promising novel diagnostic and therapeutic agents. This review focuses on the development of aptamers as potential therapeutics for autoimmune diseases, including diabetes mellitus, multiple sclerosis, rheumatoid arthritis, myasthenia gravis, and systemic lupus erythematosus.

  5. A rapid screening system evaluates novel inhibitors of DNA methylation and suggests F-box proteins as potential therapeutic targets for high-risk neuroblastoma.

    PubMed

    Penter, Livius; Maier, Bert; Frede, Ute; Hackner, Benjamin; Carell, Thomas; Hagemeier, Christian; Truss, Matthias

    2015-12-01

    After extensive research on radiochemotherapy, 5-year survival rates of children with high risk neuroblastoma still do not exceed 50%, owing to adverse side-effects exemplified by doxorubicin-induced cardiomyopathy. A promising new approach is the combination of conventional therapies with specific modulation of cell signaling pathways promoting therapeutic resistance, such as inhibition of aberrant kinase activity or re-expression of silenced tumor suppressor genes by means of chromatin remodeling. In this regard, we established a system that allows to identify potential drug targets as well as to validate respective candidate inhibitors in high-risk neuroblastoma model cell lines. Cell culture, drug exposure, shRNA-mediated knockdown and phenotype analysis are integrated into an efficient and versatile single well-based protocol. By utilizing this system, we assessed RG108, SGI-1027 and nanaomycin A, three novel DNA methyltransferase inhibitors that have not been tested in neuroblastoma cell lines so far, for their potential of synergistic anti-tumor activity in combination with doxorubicin. We found that, similarly to azacytidine, SGI-1027 and nanaomycin A mediate synergistic growth inhibition with doxorubicin independently of N-Myc status. However, they display high cytotoxicity but lack global DNA demethylation activity. Secondly, we conducted a lentiviral shRNA screen of F-box proteins, key regulators of protein stability, and identified Fbxw11/β-TrCP2 as well as Fbxo5/Emi1 as potential therapeutic targets in neuroblastoma. These results complement existing studies and underline the reliability and versatility of our single well-based protocol.

  6. Inhibition of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin

    SciTech Connect

    Wang, Feng; Yang, Yong

    2014-11-21

    Highlights: • Suppression of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin. • Repression of PKM2 affects the glycolysis and decreases ATP production. • Downregulation of PKM2 increases the intracellular accumulation of doxorubicin. • Inhibition of PKM2 enhances the antitumor efficacy of doxorubicin in vivo. - Abstract: Cancer cells alter regular metabolic pathways in order to sustain rapid proliferation. One example of metabolic remodeling in cancerous tissue is the upregulation of pyruvate kinase isoenzyme M2 (PKM2), which is involved in aerobic glycolysis. Indeed, PKM2 has previously been identified as a tumor biomarker and as a potential target for cancer therapy. Here, we examined the effects of combined treatment with doxorubicin and anti-PKM2 small interfering RNA (siRNA) on triple-negative breast cancer (TNBC). The suppression of PKM2 resulted in changes in glucose metabolism, leading to decreased synthesis of adenosine triphosphate (ATP). Reduced levels of ATP resulted in the intracellular accumulation of doxorubicin, consequently enhancing the therapeutic efficacy of this drug in several triple-negative breast cancer cell lines. Furthermore, the combined effect of PKM2 siRNA and doxorubicin was evaluated in an in vivo MDA-MB-231 orthotopic breast cancer model. The siRNA was systemically administered through a polyethylenimine (PEI)-based delivery system that has been extensively used. We demonstrate that the combination treatment showed superior anticancer efficacy as compared to doxorubicin alone. These findings suggest that targeting PKM2 can increase the efficacy of chemotherapy, potentially providing a new approach for improving the outcome of chemotherapy in patients with TNBC.

  7. Doxorubicin, DNA torsion, and chromatin dynamics

    PubMed Central

    Yang, Fan; Teves, Sheila S.; Kemp, Christopher J.; Henikoff, Steven

    2014-01-01

    Doxorubicin is one of the most important anti-cancer chemotherapeutic drugs, being widely used for the treatment of solid tumors and acute leukemias. The action of doxorubicin and other anthracycline drugs has been intensively investigated during the last several decades, but the mechanisms that have been proposed for cell killing remain disparate and controversial. In this review, we examine the proposed models for doxorubicin action from the perspective of the chromatin landscape, which is altered in many types of cancer due to recurrent mutations in chromatin modifiers. We highlight recent evidence for effects of anthracyclines on DNA torsion and chromatin dynamics that may underlie basic mechanisms of doxorubicin-mediated cell death and suggest new therapeutic strategies for cancer treatment. PMID:24361676

  8. Potential Therapeutic Uses of Mecamylamine and its Stereoisomers

    PubMed Central

    Nickell, Justin R.; Grinevich, Vladimir P.; Siripurapu, Kiran B.; Smith, Andrew M.; Dwoskin, Linda P.

    2013-01-01

    Mecamylamine (3-methylaminoisocamphane hydrochloride) is a nicotinic parasympathetic ganglionic blocker, originally utilized as a therapeutic agent to treat hypertension. Mecamylamine administration produces several deleterious side-effects at therapeutically relevant doses. As such, mecamylamine’s use as an antihypertensive agent was phased out, except in severe hypertension. Mecamylamine easily traverses the blood-brain barrier to reach the central nervous system (CNS), where it acts as a nicotinic acetylcholine receptor (nAChR) antagonist, inhibiting all known nAChR subtypes. Since nAChRs play a major role in numerous physiological and pathological processes, it is not surprising that mecamylamine has been evaluated for its potential therapeutic effects in a wide variety of CNS disorders, including addiction. Importantly, mecamylamine produces its therapeutic effects on the CNS at doses 3-fold lower than those used to treat hypertension, which diminishes the probability of peripheral side-effects. This review focuses on the pharmacological properties of mecamylamine, the differential effects of its stereoisomers, S(+)- and R(−)-mecamylamine, and the potential for effectiveness in treating CNS disorders, including nicotine and alcohol addiction, mood disorders, cognitive impairment and attention deficit hyperactivity disorder. PMID:23603417

  9. The therapeutic potential of cannabinoids for movement disorders.

    PubMed

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

    2015-03-01

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

  10. The Therapeutic Potential of Cannabinoids for Movement Disorders

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2016-09-01

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

  12. Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha-Targeting Antibody-Drug Conjugate, Potentiates the Activity of Standard of Care Therapeutics in Ovarian Cancer Models.

    PubMed

    Ponte, Jose F; Ab, Olga; Lanieri, Leanne; Lee, Jenny; Coccia, Jennifer; Bartle, Laura M; Themeles, Marian; Zhou, Yinghui; Pinkas, Jan; Ruiz-Soto, Rodrigo

    2016-12-01

    Elevated folate receptor alpha (FRα) expression is characteristic of epithelial ovarian cancer (EOC), thus establishing this receptor as a candidate target for the development of novel therapeutics to treat this disease. Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate (ADC) that targets FRα for tumor-directed delivery of the maytansinoid DM4, a potent agent that induces mitotic arrest by suppressing microtubule dynamics. Here, combinations of IMGN853 with approved therapeutics were evaluated in preclinical models of EOC. Combinations of IMGN853 with carboplatin or doxorubicin resulted in synergistic antiproliferative effects in the IGROV-1 ovarian cancer cell line in vitro. IMGN853 potentiated the cytotoxic activity of carboplatin via growth arrest and augmented DNA damage; cell cycle perturbations were also observed in cells treated with the IMGN853/doxorubicin combination. These benefits translated into improved antitumor activity in patient-derived xenograft models in vivo in both the platinum-sensitive (IMGN853/carboplatin) and platinum-resistant (IMGN853/pegylated liposomal doxorubicin) settings. IMGN853 co-treatment also improved the in vivo efficacy of bevacizumab in platinum-resistant EOC models, with combination regimens causing significant regressions and complete responses in the majority of tumor-bearing mice. Histological analysis of OV-90 ovarian xenograft tumors revealed that concurrent administration of IMGN853 and bevacizumab caused rapid disruption of tumor microvasculature and extensive necrosis, underscoring the superior bioactivity profile of the combination regimen. Overall, these demonstrations of combinatorial benefit conferred by the addition of the first FRα-targeting ADC to established therapies provide a compelling framework for the potential application of IMGN853 in the treatment of patients with advanced ovarian cancer.

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

    PubMed Central

    Tun, Maung Kyaw Moe; Herzon, Seth B

    2012-01-01

    (−)-Huperzine A (1) is an alkaloid isolated from a Chinese club moss. Due to its potent neuroprotective activities, it has been investigated as a candidate for the treatment of neurodegenerative diseases, including Alzheimer’s disease. In this review, we will discuss the pharmacology and therapeutic potential of (−)-huperzine A (1). Synthetic studies of (−)-huperzine A (1) aimed at enabling its development as a pharmaceutical will be described. PMID:27186124

  14. Therapeutic potential of selenium and tellurium compounds: opportunities yet unrealised.

    PubMed

    Tiekink, Edward R T

    2012-06-07

    Despite being disparaged for their malodorous and toxic demeanour, compounds of selenium, a bio-essential element, and tellurium, offer possibilities as therapeutic agents. Herein, their potential use as drugs, for example, as anti-viral, anti-microbial, anti-inflammatory agents, etc., will be surveyed along with a summary of the established biological functions of selenium. The natural biological functions of tellurium remain to be discovered.

  15. 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

  16. (-)-Epicatechin-3-gallate (a polyphenol from green tea) potentiates doxorubicin-induced apoptosis in H9C2 cardiomyocytes.

    PubMed

    Cai, Yi; Hong, Hui-Qi; Zhao, Li; Cai, Yue-Peng; Qin, Yuan

    2015-10-01

    The effect of epicatechin-3-gallate (ECG), a polyphenol that is present in green tea, on doxorubicin (DOX) cytotoxicity in H9C2 cardiomyocytes and its underlying mechanisms were investigated. Pretreatment with ECG (20 and 30 μM) significantly increased DOX-induced apoptosis to 16-18% in H9C2 cardiomyocytes. The Bax/Bcl-2 ratio increased significantly after 1 h pretreatment with ECG. ECG also enhanced the phosphorylation of AMP-activated protein kinase (AMPK) which was induced by DOX in a dose-dependent manner. Pretreatment with ECG sensitized H9C2 cells to DOX-mediated apoptosis through modulation of proteins involved in apoptosis and AMPK.

  17. Curcumin as potential therapeutic natural product: a nanobiotechnological perspective.

    PubMed

    Shome, Soumitra; Talukdar, Anupam Das; Choudhury, Manabendra Dutta; Bhattacharya, Mrinal Kanti; Upadhyaya, Hrishikesh

    2016-12-01

    Nanotechnology-based drug delivery systems can resolve the poor bioavailability issue allied with curcumin. The therapeutic potential of curcumin can be enhanced by making nanocomposite preparation of curcumin with metal oxide nanoparticles, poly lactic-co-glycolic acid (PLGA) nanoparticles and solid lipid nanoparticles that increases its bioavailability in the tissue. Curcumin has manifold therapeutic effects which include antidiabetic, antihypertensive, anticancer, anti-inflammatory and antimicrobial properties. Curcumin can inhibit diabetes, heavy metal and stress-induced hypertension with its antioxidant, chelating and inhibitory effects on the pathways that lead to hypertension. Curcumin is an anticancer agent that can prevent abnormal cell proliferation. Nanocurcumin is an improved form of curcumin with enhanced therapeutic properties due to improved delivery to the diseased tissue, better internalization and reduced systemic elimination. Curcumin has multiple pharmacologic effects, but its poor bioavailability reduces its therapeutic effects. By conjugating curcumin to metal oxide nanoparticles or encapsulation in lipid nanoparticles, dendrimers, nanogels and polymeric nanoparticles, the water solubility and bioavailability of curcumin can be improved and thus increase its pharmacological effectiveness. © 2016 Royal Pharmaceutical Society.

  18. Injectable small molecule hydrogel as a potential nanocarrier for localized and sustained in vivo delivery of doxorubicin

    NASA Astrophysics Data System (ADS)

    Singh, Manish; Kundu, Somanath; Reddy M, Amarendar; Sreekanth, Vedagopuram; Motiani, Rajender K.; Sengupta, Sagar; Srivastava, Aasheesh; Bajaj, Avinash

    2014-10-01

    The majority of the localized drug delivery systems are based on polymeric or polypeptide scaffolds, as weak intermolecular interactions of low molecular weight hydrogelators (LMHGs, Mw <500 Da) are significantly perturbed in the presence of anticancer drugs. Here, we present l-alanine derived low molecular weight hydrogelators (LMHGs) that remain injectable even after entrapping the anticancer drug doxorubicin (DOX). These DOX containing nanoassemblies (DOX-Gel) showed promising anticancer activity in mice models. Subcutaneous injection of DOX-Gel near the tumor achieved a greater decrease in tumour load than by intravenous injection of DOX (DOX-IV), and local injection of DOX alone (DOX-Local) at the tumor site. We noticed that DOX-Gel nanocarriers are especially effective when injected during the early stage of tumor progression, and achieve a substantial decrease in tumor load in the long term.The majority of the localized drug delivery systems are based on polymeric or polypeptide scaffolds, as weak intermolecular interactions of low molecular weight hydrogelators (LMHGs, Mw <500 Da) are significantly perturbed in the presence of anticancer drugs. Here, we present l-alanine derived low molecular weight hydrogelators (LMHGs) that remain injectable even after entrapping the anticancer drug doxorubicin (DOX). These DOX containing nanoassemblies (DOX-Gel) showed promising anticancer activity in mice models. Subcutaneous injection of DOX-Gel near the tumor achieved a greater decrease in tumour load than by intravenous injection of DOX (DOX-IV), and local injection of DOX alone (DOX-Local) at the tumor site. We noticed that DOX-Gel nanocarriers are especially effective when injected during the early stage of tumor progression, and achieve a substantial decrease in tumor load in the long term. Electronic supplementary information (ESI) available: Scheme 1, Fig. S1-S6, synthesis of hydrogels; experimental section for gelation, rheology, MALDI, microscopy and

  19. Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin.

    PubMed

    Xu, Xiao Dong; Zhao, Yan; Zhang, Min; He, Rui Zhi; Shi, Xiu Hui; Guo, Xing Jun; Shi, Cheng Jian; Peng, Feng; Wang, Min; Shen, Min; Wang, Xin; Li, Xu; Qin, Ren Yi

    2017-02-10

    Pancreatic cancer is the fourth most common cause of cancer mortality worldwide. Furthermore, patients with pancreatic cancer experience limited benefit from current chemotherapeutic approaches because of drug resistance. Therefore, an effective therapeutic strategy for patients with pancreatic cancer is urgently required. Deguelin is a natural chemopreventive drug that exerts potent antiproliferative activity in solid tumors by inducing cell death. However, the molecular mechanisms underlying this activity have not been fully elucidated. Here we show that deguelin blocks autophagy and induces apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells, and suppressing autophagy by chloroquine or silencing autophagy protein 5 enhanced doxorubicin-induced cell death. Similarly, inhibition of autophagy by deguelin also chemosensitized pancreatic cancer cell lines to doxorubicin. These findings suggest that deguelin has potent anticancer effects against pancreatic cancer and potentiates the anti-cancer effects of doxorubicin. These findings provide evidence that combined treatment with deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer.

  20. Inhibition of Autophagy by Deguelin Sensitizes Pancreatic Cancer Cells to Doxorubicin

    PubMed Central

    Xu, Xiao Dong; Zhao, Yan; Zhang, Min; He, Rui Zhi; Shi, Xiu Hui; Guo, Xing Jun; Shi, Cheng Jian; Peng, Feng; Wang, Min; Shen, Min; Wang, Xin; Li, Xu; Qin, Ren Yi

    2017-01-01

    Pancreatic cancer is the fourth most common cause of cancer mortality worldwide. Furthermore, patients with pancreatic cancer experience limited benefit from current chemotherapeutic approaches because of drug resistance. Therefore, an effective therapeutic strategy for patients with pancreatic cancer is urgently required. Deguelin is a natural chemopreventive drug that exerts potent antiproliferative activity in solid tumors by inducing cell death. However, the molecular mechanisms underlying this activity have not been fully elucidated. Here we show that deguelin blocks autophagy and induces apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells, and suppressing autophagy by chloroquine or silencing autophagy protein 5 enhanced doxorubicin-induced cell death. Similarly, inhibition of autophagy by deguelin also chemosensitized pancreatic cancer cell lines to doxorubicin. These findings suggest that deguelin has potent anticancer effects against pancreatic cancer and potentiates the anti-cancer effects of doxorubicin. These findings provide evidence that combined treatment with deguelin and doxorubicin represents an effective strategy for treating pancreatic cancer. PMID:28208617

  1. Cannabinoids in medicine: A review of their therapeutic potential.

    PubMed

    Ben Amar, Mohamed

    2006-04-21

    In order to assess the current knowledge on the therapeutic potential of cannabinoids, a meta-analysis was performed through Medline and PubMed up to July 1, 2005. The key words used were cannabis, marijuana, marihuana, hashish, hashich, haschich, cannabinoids, tetrahydrocannabinol, THC, dronabinol, nabilone, levonantradol, randomised, randomized, double-blind, simple blind, placebo-controlled, and human. The research also included the reports and reviews published in English, French and Spanish. For the final selection, only properly controlled clinical trials were retained, thus open-label studies were excluded. Seventy-two controlled studies evaluating the therapeutic effects of cannabinoids were identified. For each clinical trial, the country where the project was held, the number of patients assessed, the type of study and comparisons done, the products and the dosages used, their efficacy and their adverse effects are described. Cannabinoids present an interesting therapeutic potential as antiemetics, appetite stimulants in debilitating diseases (cancer and AIDS), analgesics, and in the treatment of multiple sclerosis, spinal cord injuries, Tourette's syndrome, epilepsy and glaucoma.

  2. Berberine: a potential phytochemical with multispectrum therapeutic activities.

    PubMed

    Vuddanda, Parameswara Rao; Chakraborty, Subhashis; Singh, Sanjay

    2010-10-01

    The use of traditional medicines of natural origin is being encouraged for the treatment of chronic disorders, as synthetic drugs in such cases may cause unpredictable adverse effects. Berberine, a traditional plant alkaloid, is used in Ayurvedic and Chinese medicine for its antimicrobial and antiprotozoal properties. Interestingly, current clinical research on berberine has revealed its various pharmacological properties and multi-spectrum therapeutic applications. An extensive search in three electronic databases (Unbound Medline, PubMed and ScienceDirect) and internet search engines (Scirus and Google Scholar) were used to identify the clinical studies on berberine, without any time constraints. This review elaborates the recent studies which reveal that with time, the drug has evolved with superior therapeutic activities. In addition, this review will also attract the attention of formulation scientists towards the issues and challenges associated in its drug delivery and the probable approaches that may be explored to help patients reap the maximum benefit of this potentially useful drug. A relatively large number of studies discussed here have revealed the possible areas where this phytochemical constituent can exhibit its therapeutic activities in the treatment of chronic ailments or diseases including diabetes, cancer, depression, hypertension and hypercholesterolemia. The potential of the drug remains to be harvested by designing a suitable formulation that could overcome its inherent low bioavailability.

  3. miRNA therapeutics: a new class of drugs with potential therapeutic applications in the heart.

    PubMed

    Bernardo, Bianca C; Ooi, Jenny Y Y; Lin, Ruby C Y; McMullen, Julie R

    2015-01-01

    miRNAs are small non-coding RNAs (ncRNAs), which regulate gene expression. Here, the authors describe the contribution of miRNAs to cardiac biology and disease. They discuss various strategies for manipulating miRNA activity including antisense oligonucleotides (antimiRs, blockmiRs), mimics, miRNA sponges, Tough Decoys and miRNA mowers. They review developments in chemistries (e.g., locked nucleic acid) and modifications (sugar, 'ZEN', peptide nucleic acids) and miRNA delivery tools (viral vectors, liposomes, nanoparticles, pHLIP). They summarize potential miRNA therapeutic targets for heart disease based on preclinical studies. Finally, the authors review current progress of miRNA therapeutics in clinical development for HCV and cancer, and discuss challenges that will need to be overcome for similar therapies to enter the clinic for patients with cardiac disease.

  4. Potential therapeutic applications of hyaluronan in the lung

    PubMed Central

    Cantor, Jerome O

    2007-01-01

    Hyaluronan (HA), a long-chain polysaccharide, is currently being evaluated as a potential therapeutic agent for a number of inflammatory disorders. The effect of HA on inflammation appears to be related to its molecular size, with larger polysaccharide chains having anti-inflammatory activity and smaller ones having proinflammatory properties. This dichotomous behavior is particularly relevant to the work of our laboratory on an aerosolized preparation of HA to treat pulmonary emphysema. The breakdown of inhaled HA into smaller fragments could possibly induce an inflammatory reaction in the lung that counteracts any beneficial effect. Consequently, the proposed therapeutic use of HA will require development of treatment strategies aimed at minimizing its proinflammatory activity. PMID:18229566

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

    PubMed

    Cruden, Nicholas L M; Newby, David E

    2008-09-01

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

  6. 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

  7. Therapeutic potential of carbohydrates as regulators of macrophage activation.

    PubMed

    Lundahl, Mimmi L E; Scanlan, Eoin M; Lavelle, Ed C

    2017-09-08

    It is well established for a broad range of disease states, including cancer and Mycobacterium tuberculosis infection, that pathogenesis is bolstered by polarisation of macrophages towards an anti-inflammatory phenotype, known as M2. As these innate immune cells are relatively long-lived, their re-polarisation to pro-inflammatory, phagocytic and bactericidal "classically activated" M1 macrophages is an attractive therapeutic approach. On the other hand, there are scenarios where the resolving inflammation, wound healing and tissue remodelling properties of M2 macrophages are beneficial - for example the successful introduction of biomedical implants. Although there are numerous endogenous and exogenous factors that have an impact on the macrophage polarisation spectrum, this review will focus specifically on prominent macrophage-modulating carbohydrate motifs with a view towards highlighting structure-function relationships and therapeutic potential. Copyright © 2017. Published by Elsevier Inc.

  8. Potential therapeutic benefits of strategies directed to mitochondria.

    PubMed

    Camara, Amadou K S; Lesnefsky, Edward J; Stowe, David F

    2010-08-01

    The mitochondrion is the most important organelle in determining continued cell survival and cell death. Mitochondrial dysfunction leads to many human maladies, including cardiovascular diseases, neurodegenerative disease, and cancer. These mitochondria-related pathologies range from early infancy to senescence. The central premise of this review is that if mitochondrial abnormalities contribute to the pathological state, alleviating the mitochondrial dysfunction would contribute to attenuating the severity or progression of the disease. Therefore, this review will examine the role of mitochondria in the etiology and progression of several diseases and explore potential therapeutic benefits of targeting mitochondria in mitigating the disease processes. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate and manipulate mitochondrial function and genomics for therapeutic benefit. These approaches to treat mitochondrial dysfunction rationally could lead to selective protection of cells in different tissues and various disease states. However, most of these approaches are in their infancy.

  9. Coleus aromaticus: a therapeutic herb with multiple potentials.

    PubMed

    Wadikar, Dadasaheb D; Patki, Prakash E

    2016-07-01

    The herb Coleus aromaticus belonging to Lamiaceae family and Coleus genus is known by numerous names in different parts of the world and several language specific vernacular names. The herb has been extensively studied as well as reported in several fields of science. The multiple potential of the herb includes allelopathic potential, antibacterial property, antimicrobial activity, insecticidal property; free radical scavenging and radio-protective components from herb extracts and most recently the appetizing potential of the herb have been reported. The herb has carvacrol and thymol as the major components responsible for the flavour; while chlorogenic acid, rosmarinic acid etc. as the phenolic components. The herb has been used in therapeutic and medicinal applications as well as in culinary preparations.

  10. Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease

    PubMed Central

    Horowitz, Alana M.; Villeda, Saul A.

    2017-01-01

    Neurodegenerative diseases are a devastating group of conditions that cause progressive loss of neuronal integrity, affecting cognitive and motor functioning in an ever-increasing number of older individuals. Attempts to slow neurodegenerative disease advancement have met with little success in the clinic; however, a new therapeutic approach may stem from classic interventions, such as caloric restriction, exercise, and parabiosis. For decades, researchers have reported that these systemic-level manipulations can promote major functional changes that extend organismal lifespan and healthspan. Only recently, however, have the functional effects of these interventions on the brain begun to be appreciated at a molecular and cellular level. The potential to counteract the effects of aging in the brain, in effect rejuvenating the aged brain, could offer broad therapeutic potential to combat dementia-related neurodegenerative disease in the elderly. In particular, results from heterochronic parabiosis and young plasma administration studies indicate that pro-aging and rejuvenating factors exist in the circulation that can independently promote or reverse age-related phenotypes. The recent demonstration that human umbilical cord blood similarly functions to rejuvenate the aged brain further advances this work to clinical translation. In this review, we focus on these blood-based rejuvenation strategies and their capacity to delay age-related molecular and functional decline in the aging brain. We discuss new findings that extend the beneficial effects of young blood to neurodegenerative disease models. Lastly, we explore the translational potential of blood-based interventions, highlighting current clinical trials aimed at addressing therapeutic applications for the treatment of dementia-related neurodegenerative disease in humans. PMID:28815019

  11. Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease.

    PubMed

    Horowitz, Alana M; Villeda, Saul A

    2017-01-01

    Neurodegenerative diseases are a devastating group of conditions that cause progressive loss of neuronal integrity, affecting cognitive and motor functioning in an ever-increasing number of older individuals. Attempts to slow neurodegenerative disease advancement have met with little success in the clinic; however, a new therapeutic approach may stem from classic interventions, such as caloric restriction, exercise, and parabiosis. For decades, researchers have reported that these systemic-level manipulations can promote major functional changes that extend organismal lifespan and healthspan. Only recently, however, have the functional effects of these interventions on the brain begun to be appreciated at a molecular and cellular level. The potential to counteract the effects of aging in the brain, in effect rejuvenating the aged brain, could offer broad therapeutic potential to combat dementia-related neurodegenerative disease in the elderly. In particular, results from heterochronic parabiosis and young plasma administration studies indicate that pro-aging and rejuvenating factors exist in the circulation that can independently promote or reverse age-related phenotypes. The recent demonstration that human umbilical cord blood similarly functions to rejuvenate the aged brain further advances this work to clinical translation. In this review, we focus on these blood-based rejuvenation strategies and their capacity to delay age-related molecular and functional decline in the aging brain. We discuss new findings that extend the beneficial effects of young blood to neurodegenerative disease models. Lastly, we explore the translational potential of blood-based interventions, highlighting current clinical trials aimed at addressing therapeutic applications for the treatment of dementia-related neurodegenerative disease in humans.

  12. 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

  13. Leveraging biodiversity knowledge for potential phyto-therapeutic applications

    PubMed Central

    Sharma, Vivekanand; Sarkar, Indra Neil

    2013-01-01

    Objective To identify and highlight the feasibility, challenges, and advantages of providing a cross-domain pipeline that can link relevant biodiversity information for phyto-therapeutic assessment. Materials and methods A public repository of clinical trials information (ClinicalTrials.gov) was explored to determine the state of plant-based interventions under investigation. Results The results showed that ∼15% of drug interventions in ClinicalTrials.gov were potentially plant related, with about 60% of them clustered within 10 taxonomic families. Further analysis of these plant-based interventions identified ∼3.7% of associated plant species as endangered as determined from the International Union for the Conservation of Nature Red List. Discussion The diversity of the plant kingdom has provided human civilization with life-sustaining food and medicine for centuries. There has been renewed interest in the investigation of botanicals as sources of new drugs, building on traditional knowledge about plant-based medicines. However, data about the plant-based biodiversity potential for therapeutics (eg, based on genetic or chemical information) are generally scattered across a range of sources and isolated from contemporary pharmacological resources. This study explored the potential to bridge biodiversity and biomedical knowledge sources. Conclusions The findings from this feasibility study suggest that there is an opportunity for developing plant-based drugs and further highlight taxonomic relationships between plants that may be rich sources for bioprospecting. PMID:23518859

  14. Leveraging biodiversity knowledge for potential phyto-therapeutic applications.

    PubMed

    Sharma, Vivekanand; Sarkar, Indra Neil

    2013-01-01

    To identify and highlight the feasibility, challenges, and advantages of providing a cross-domain pipeline that can link relevant biodiversity information for phyto-therapeutic assessment. A public repository of clinical trials information (ClinicalTrials.gov) was explored to determine the state of plant-based interventions under investigation. The results showed that ≈ 15% of drug interventions in ClinicalTrials.gov were potentially plant related, with about 60% of them clustered within 10 taxonomic families. Further analysis of these plant-based interventions identified ≈ 3.7% of associated plant species as endangered as determined from the International Union for the Conservation of Nature Red List. The diversity of the plant kingdom has provided human civilization with life-sustaining food and medicine for centuries. There has been renewed interest in the investigation of botanicals as sources of new drugs, building on traditional knowledge about plant-based medicines. However, data about the plant-based biodiversity potential for therapeutics (eg, based on genetic or chemical information) are generally scattered across a range of sources and isolated from contemporary pharmacological resources. This study explored the potential to bridge biodiversity and biomedical knowledge sources. The findings from this feasibility study suggest that there is an opportunity for developing plant-based drugs and further highlight taxonomic relationships between plants that may be rich sources for bioprospecting.

  15. Therapeutic Potential of Secreted Amyloid Precursor Protein APPsα

    PubMed Central

    Mockett, Bruce G.; Richter, Max; Abraham, Wickliffe C.; Müller, Ulrike C.

    2017-01-01

    Cleavage of the amyloid precursor protein (APP) by α-secretase generates an extracellularly released fragment termed secreted APP-alpha (APPsα). Not only is this process of interest due to the cleavage of APP within the amyloid-beta sequence, but APPsα itself has many physiological properties that suggest its great potential as a therapeutic target. For example, APPsα is neurotrophic, neuroprotective, neurogenic, a stimulator of protein synthesis and gene expression, and enhances long-term potentiation (LTP) and memory. While most early studies have been conducted in vitro, effectiveness in animal models is now being confirmed. These studies have revealed that either upregulating α-secretase activity, acutely administering APPsα or chronic delivery of APPsα via a gene therapy approach can effectively treat mouse models of Alzheimer’s disease (AD) and other disorders such as traumatic head injury. Together these findings suggest the need for intensifying research efforts to harness the therapeutic potential of this multifunctional protein. PMID:28223920

  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. Therapeutic Potential of Transcranial Focused Ultrasound for Rett Syndrome

    PubMed Central

    Tsai, Shih-Jen

    2016-01-01

    Rett syndrome (RTT) is a severe neurodevelopmental disorder occurring almost exclusively in females and is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) in the majority of cases. MeCP2 is essential for the normal function of nerve cells, including neuronal development, maturation, and synaptic activity. RTT is characterized by normal early development followed by autistic-like features, slowed brain and head growth, gait abnormalities, seizures, breathing irregularities, and cognitive disabilities. Medical management in RTT remains supportive and symptomatic. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of RTT. Recent studies have shown a phenotypic reversal by increasing BDNF expression in a RTT mouse model. Thus, manipulation of BDNF expression/signaling in the brain could be therapeutic for this disease. Transcranial focused ultrasound for (tFUS) can noninvasively focally modulate human cortical function, stimulate neurogenesis, and increase BDNF in animal studies. Consequently, tFUS may be of therapeutic potential for Rett syndrome. Further evaluation of the therapeutic effects of tFUS in Mecp2 deficient animal models is needed before clinical trials can begin. PMID:27786169

  18. 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

  19. Therapeutic Potential of Transcranial Focused Ultrasound for Rett Syndrome.

    PubMed

    Tsai, Shih-Jen

    2016-10-27

    Rett syndrome (RTT) is a severe neurodevelopmental disorder occurring almost exclusively in females and is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2) in the majority of cases. MeCP2 is essential for the normal function of nerve cells, including neuronal development, maturation, and synaptic activity. RTT is characterized by normal early development followed by autistic-like features, slowed brain and head growth, gait abnormalities, seizures, breathing irregularities, and cognitive disabilities. Medical management in RTT remains supportive and symptomatic. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of RTT. Recent studies have shown a phenotypic reversal by increasing BDNF expression in a RTT mouse model. Thus, manipulation of BDNF expression/signaling in the brain could be therapeutic for this disease. Transcranial focused ultrasound for (tFUS) can noninvasively focally modulate human cortical function, stimulate neurogenesis, and increase BDNF in animal studies. Consequently, tFUS may be of therapeutic potential for Rett syndrome. Further evaluation of the therapeutic effects of tFUS in Mecp2 deficient animal models is needed before clinical trials can begin.

  20. 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.

  1. 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.

  2. Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease.

    PubMed

    Ayton, Scott; Lei, Peng; Duce, James A; Wong, Bruce X W; Sedjahtera, Amelia; Adlard, Paul A; Bush, Ashley I; Finkelstein, David I

    2013-04-01

    Ceruloplasmin is an iron-export ferroxidase that is abundant in plasma and also expressed in glia. We found a ∼80% loss of ceruloplasmin ferroxidase activity in the substantia nigra of idiopathic Parkinson disease (PD) cases, which could contribute to the pro-oxidant iron accumulation that characterizes the pathology. Consistent with a role for ceruloplasmin in PD etiopathogenesis, ceruloplasmin knockout mice developed parkinsonism that was rescued by iron chelation. Additionally, peripheral infusion of ceruloplasmin attenuated neurodegeneration and nigral iron elevation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model for PD. These findings show, in principle, that intravenous ceruloplasmin may have therapeutic potential in PD.

  3. 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.

  4. Aptamer oligonucleotides as potential therapeutics in hematologic diseases.

    PubMed

    Li, Weibin; Zhao, Meng; Wang, Kaiyu; Yan, Huihui; Lan, XIaopeng

    2017-10-02

    Aptamers are single-stranded DNA or RNA oligonucleotides generated by a novel in vitro selection technique termed Systematic Evolution of Ligands by Exponential Enrichment (SELEX). During the past two decades, various aptamer drugs have been developed and many of them have entered into clinical trials. In the present review, we focus on aptamers as potential therapeutics for hematological diseases, including anemia of chronic inflammation (ACI) and anemia of chronic disease (ACD), hemophilia, thrombotic thrombocytopenic purpura (TTP) or VWD type-2B, and sickle cell disease (SCD), in particular, those that have entered into clinical trials. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Potential therapeutic strategy to treat substance abuse related disorders

    PubMed Central

    Chang, Sulie L.

    2014-01-01

    The “Potential Therapeutic Strategy to Treat Substance Abuse Related Disorders” session was chaired by Dr. Sulie Chang, director of NeuroImmune Phamacology at Seton University. The four presenters (and their topics) were: Dr. Wen-zhe Ho (Miniway to stop HIV/HCV), Dr. Ru-Band Lu (Low dose of memantine in the treatment of opioid dependence in human), Dr. Ping Zhang (Treatment of alcohol-related disorders-Learning from stem/progenitor cell), and Chia-Hsiang Chen (Treatment of methamphetamine abuse: an antibody-based immunotherapy approach). PMID:25267886

  6. Potential therapeutic strategy to treat substance abuse related disorders.

    PubMed

    Chang, Sulie L

    2013-12-01

    The "Potential Therapeutic Strategy to Treat Substance Abuse Related Disorders" session was chaired by Dr. Sulie Chang, director of NeuroImmune Phamacology at Seton University. The four presenters (and their topics) were: Dr. Wen-zhe Ho (Miniway to stop HIV/HCV), Dr. Ru-Band Lu (Low dose of memantine in the treatment of opioid dependence in human), Dr. Ping Zhang (Treatment of alcohol-related disorders-Learning from stem/progenitor cell), and Chia-Hsiang Chen (Treatment of methamphetamine abuse: an antibody-based immunotherapy approach).

  7. Targeting PEPT1: a novel strategy to improve the antitumor efficacy of doxorubicin in human hepatocellular carcinoma therapy

    PubMed Central

    Gong, Yanxia; Wu, Xiang; Wang, Tao; Zhao, Jia; Liu, Xi; Yao, Zhi; Zhang, Qingyu; Jian, Xu

    2017-01-01

    Proton coupled oligopeptide transporter 1 (PEPT1) is a member of the peptide transporter superfamily and plays important role in the absorption of oligopeptide and peptidomimetic drugs. Our previous research verified that PEPT1 expressed specifically in human Hepatocellular carcinoma (HCC) tissue and cell lines and showed potential transport activity to be a new candidate of the tumor therapeutic target. In this study, we aim to explore the feasibility of a novel tumor target therapeutic strategy: Targeting PEPT1 to improve the antitumor efficacy of Doxorubicin in human HCC therapy. First, Doxorubicin was conjugated with Glycylglycylglycine (Gly-Gly-Gly) − a tripeptide which was known as the substrate of PEPT1 and characterized by HPLC and MS successfully. Doxorubicin-tripeptide conjugate was then observed to clarify the target delivery by PEPT1 and the antitumor effect on human hepatocarcinoma in vivo and in vitro. Furthermore, the improvement of the toxic and side effect of Doxorubicin after conjugation was also evaluated by some biochemical tests. Our results reveal that targeting PEPT1 may contribute to the efficient delivery of Doxorubicin to hepatocarcinoma cells and the reduction of drug toxicity. PEPT1 has the prospect to be a novel target of HCC therapy. PMID:28465466

  8. CXCR4-Specific Nanobodies as Potential Therapeutics for WHIM syndrome.

    PubMed

    de Wit, Raymond H; Heukers, Raimond; Brink, Hendrik J; Arsova, Angela; Maussang, David; Cutolo, Pasquale; Strubbe, Beatrijs; Vischer, Henry F; Bachelerie, Françoise; Smit, Martine J

    2017-10-01

    WHIM syndrome is a rare congenital immunodeficiency disease, named after its main clinical manifestations: warts, hypogammaglobulinemia, infections, and myelokathexis, which refers to abnormal accumulation of mature neutrophils in the bone marrow. The disease is primarily caused by C-terminal truncation mutations of the chemokine receptor CXCR4, giving these CXCR4-WHIM mutants a gain of function in response to their ligand CXCL12. Considering the broad functions of CXCR4 in maintaining leukocyte homeostasis, patients are panleukopenic and display altered immune responses, likely as a consequence of impairment in the differentiation and trafficking of leukocytes. Treatment of WHIM patients currently consists of symptom relief, leading to unsatisfactory clinical responses. As an alternative and potentially more effective approach, we tested the potency and efficacy of CXCR4-specific nanobodies on inhibiting CXCR4-WHIM mutants. Nanobodies are therapeutic proteins based on the smallest functional fragments of heavy chain antibodies. They combine the advantages of small-molecule drugs and antibody-based therapeutics due to their relative small size, high stability, and high affinity. We compared the potential of monovalent and bivalent CXCR4-specific nanobodies to inhibit CXCL12-induced CXCR4-WHIM-mediated signaling with the small-molecule clinical candidate AMD3100. The CXCR4-targeting nanobodies displace CXCL12 binding and bind CXCR4-wild type and CXCR4-WHIM (R334X/S338X) mutants and with (sub-) nanomolar affinities. The nanobodies' epitope was mapped to extracellular loop 2 of CXCR4, overlapping with the binding site of CXCL12. Monovalent, and in particular bivalent, nanobodies were more potent than AMD3100 in reducing CXCL12-mediated G protein activation. In addition, CXCR4-WHIM-dependent calcium flux and wound healing of human papillomavirus-immortalized cell lines in response to CXCL12 was effectively inhibited by the nanobodies. Based on these in vitro results

  9. Gadolinium oxide nanoparticles as potential multimodal imaging and therapeutic agents.

    PubMed

    Kim, Tae Jeong; Chae, Kwon Seok; Chang, Yongmin; Lee, Gang Ho

    2013-01-01

    Potentials of hydrophilic and biocompatible ligand coated gadolinium oxide nanoparticles as multimodal imaging agents, drug carriers, and therapeutic agents are reviewed. First of all, they can be used as advanced T1 magnetic resonance imaging (MRI) contrast agents because they have r1 larger than those of Gd(III)-chelates due to a high density of Gd(III) per nanoparticle. They can be further functionalized by conjugating other imaging agents such as fluorescent imaging (FI), X-ray computed tomography (CT), positron emission tomography (PET), and single photon emission tomography (SPECT) agents. They can be also useful for drug carriers through morphology modifications. They themselves are also potential CT and ultrasound imaging (USI) contrast and thermal neutron capture therapeutic (NCT) agents, which are superior to commercial iodine compounds, air-filled albumin microspheres, and boron ((10)B) compounds, respectively. They, when conjugated with targeting agents such as antibodies and peptides, will provide enhanced images and be also very useful for diagnosis and therapy of diseases (so called theragnosis).

  10. Naturally Occurring Anthraquinones: Chemistry and Therapeutic Potential in Autoimmune Diabetes

    PubMed Central

    Wu, Yueh-Chen

    2015-01-01

    Anthraquinones are a class of aromatic compounds with a 9,10-dioxoanthracene core. So far, 79 naturally occurring anthraquinones have been identified which include emodin, physcion, cascarin, catenarin, and rhein. A large body of literature has demonstrated that the naturally occurring anthraquinones possess a broad spectrum of bioactivities, such as cathartic, anticancer, anti-inflammatory, antimicrobial, diuretic, vasorelaxing, and phytoestrogen activities, suggesting their possible clinical application in many diseases. Despite the advances that have been made in understanding the chemistry and biology of the anthraquinones in recent years, research into their mechanisms of action and therapeutic potential in autoimmune disorders is still at an early stage. In this paper, we briefly introduce the etiology of autoimmune diabetes, an autoimmune disorder that affects as many as 10 million worldwide, and the role of chemotaxis in autoimmune diabetes. We then outline the chemical structure and biological properties of the naturally occurring anthraquinones and their derivatives with an emphasis on recent findings about their immune regulation. We discuss the structure and activity relationship, mode of action, and therapeutic potential of the anthraquinones in autoimmune diabetes, including a new strategy for the use of the anthraquinones in autoimmune diabetes. PMID:25866536

  11. Preventive and therapeutic potential of placental extract in contact hypersensitivity

    PubMed Central

    Kim, Youn Son; Park, Jang-June; Sakoda, Yukimi; Zhao, Yuming; Hisamichi, Katsuya; Kaku, Tai-ichi; Tamada, Koji

    2010-01-01

    Immunoregulatory effects of placental extract and placenta-derived factors have been demonstrated in various conditions. Accordingly, placental extract has been used as certain types of medical intervention in Asian countries, whereas experimental evidence supporting its therapeutic effects and mechanisms has yet to be fully demonstrated. In this study, we investigate preventive and therapeutic effects of placental extract in contact hypersensitivity (CHS), a mouse model of allergic contact dermatitis. Administration of placental extract prior to the sensitization of allergic antigen (Ag) significantly inhibited the severity of CHS induced by Ag challenge. This effect was associated with reduced numbers of CD4+ T cells in peripheral blood, decrease of tissue-infiltrating lymphocytes, and preferential production of Th2-type cytokines in Ag-challenged sites. In addition, CHS caused by repetitive challenges of allergic Ag was also prevented and treated by administration of placental extract. Finally, administration of cyclo-trans-4-Lhydroxyprolyl-L-serine, a dipeptide derived from placental extract, also alleviated CHS, suggesting its potential role in the effects of placental extract in CHS. Taken together, our findings demonstrated experimental evidence supporting immunoregulatory effects of placental extract in allergic skin diseases and elucidated its potential mechanisms. PMID:20619383

  12. Vitamin D in Autoimmunity: Molecular Mechanisms and Therapeutic Potential

    PubMed Central

    Dankers, Wendy; Colin, Edgar M.; van Hamburg, Jan Piet; Lubberts, Erik

    2017-01-01

    Over the last three decades, it has become clear that the role of vitamin D goes beyond the regulation of calcium homeostasis and bone health. An important extraskeletal effect of vitamin D is the modulation of the immune system. In the context of autoimmune diseases, this is illustrated by correlations of vitamin D status and genetic polymorphisms in the vitamin D receptor with the incidence and severity of the disease. These correlations warrant investigation into the potential use of vitamin D in the treatment of patients with autoimmune diseases. In recent years, several clinical trials have been performed to investigate the therapeutic value of vitamin D in multiple sclerosis, rheumatoid arthritis, Crohn’s disease, type I diabetes, and systemic lupus erythematosus. Additionally, a second angle of investigation has focused on unraveling the molecular pathways used by vitamin D in order to find new potential therapeutic targets. This review will not only provide an overview of the clinical trials that have been performed but also discuss the current knowledge about the molecular mechanisms underlying the immunomodulatory effects of vitamin D and how these advances can be used in the treatment of autoimmune diseases. PMID:28163705

  13. Dock GEFs and their therapeutic potential: neuroprotection and axon regeneration.

    PubMed

    Namekata, Kazuhiko; Kimura, Atsuko; Kawamura, Kazuto; Harada, Chikako; Harada, Takayuki

    2014-11-01

    The dedicator of cytokinesis (Dock) family is composed of atypical guanine exchange factors (GEFs) that activate the Rho GTPases Rac1 and Cdc42. Rho GTPases are best documented for their roles in actin polymerization and they regulate important cellular functions, including morphogenesis, migration, neuronal development, and cell division and adhesion. To date, 11 Dock family members have been identified and their roles have been reported in diverse contexts. There has been increasing interest in elucidating the roles of Dock proteins in recent years and studies have revealed that they are potential therapeutic targets for various diseases, including glaucoma, Alzheimer's disease, cancer, attention deficit hyperactivity disorder and combined immunodeficiency. Among the Dock proteins, Dock3 is predominantly expressed in the central nervous system and recent studies have revealed that Dock3 plays a role in protecting retinal ganglion cells from neurotoxicity and oxidative stress as well as in promoting optic nerve regeneration. In this review, we discuss the current understanding of the 11 Dock GEFs and their therapeutic potential, with a particular focus on Dock3 as a novel target for the treatment of glaucoma and other neurodegenerative diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Exosomes: Origins and Therapeutic Potential for Neurodegenerative Disease

    PubMed Central

    Sarko, Diana K.; McKinney, Cindy E.

    2017-01-01

    Exosomes, small lipid bilayer vesicles, are part of the transportable cell secretome that can be taken up by nearby recipient cells or can travel through the bloodstream to cells in distant organs. Selected cellular cytoplasm containing proteins, RNAs, and other macromolecules is packaged into secreted exosomes. This cargo has the potential to affect cellular function in either healthy or pathological ways. Exosomal content has been increasingly shown to assist in promoting pathways of neurodegeneration such as β-amyloid peptide (Aβ) accumulation forming amyloid plaques in the brains of patients with Alzheimer's disease, and pathological aggregates of proteins containing α-synuclein in Parkinson's disease transferred to the central nervous system via exosomes. In attempting to address such debilitating neuropathologies, one promising utility of exosomes lies in the development of methodology to use exosomes as natural delivery vehicles for therapeutics. Because exosomes are capable of penetrating the blood-brain barrier, they can be strategically engineered to carry drugs or other treatments, and possess a suitable half-life and stability for this purpose. Overall, analyses of the roles that exosomes play between diverse cellular sites will refine our understanding of how cells communicate. This mini-review introduces the origin and biogenesis of exosomes, their roles in neurodegenerative processes in the central nervous system, and their potential utility to deliver therapeutic drugs to cellular sites. PMID:28289371

  15. Therapeutic Potential of Steroidal Alkaloids in Cancer and Other Diseases.

    PubMed

    Jiang, Qi-Wei; Chen, Mei-Wan; Cheng, Ke-Jun; Yu, Pei-Zhong; Wei, Xing; Shi, Zhi

    2016-01-01

    Steroidal alkaloids are a class of secondary metabolites isolated from plants, amphibians, and marine invertebrates. Evidence accumulated in the recent two decades demonstrates that steroidal alkaloids have a wide range of bioactivities including anticancer, antimicrobial, anti-inflammatory, antinociceptive, etc., suggesting their great potential for application. It is therefore necessary to comprehensively summarize the bioactivities, especially anticancer activities and mechanisms of steroidal alkaloids. Here we systematically highlight the anticancer profiles both in vitro and in vivo of steroidal alkaloids such as dendrogenin, solanidine, solasodine, tomatidine, cyclopamine, and their derivatives. Furthermore, other bioactivities of steroidal alkaloids are also discussed. The integrated molecular mechanisms in this review can increase our understanding on the utilization of steroidal alkaloids and contribute to the development of new drug candidates. Although the therapeutic potentials of steroidal alkaloids look promising in the preclinical and clinical studies, further pharmacokinetic and clinical studies are mandated to define their efficacy and safety in cancer and other diseases.

  16. 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

  17. Therapeutic Potential of Curcumin for the Treatment of Brain Tumors

    PubMed Central

    Klinger, Neil V.

    2016-01-01

    Brain malignancies currently carry a poor prognosis despite the current multimodal standard of care that includes surgical resection and adjuvant chemotherapy and radiation. As new therapies are desperately needed, naturally occurring chemical compounds have been studied for their potential chemotherapeutic benefits and low toxicity profile. Curcumin, found in the rhizome of turmeric, has extensive therapeutic promise via its antioxidant, anti-inflammatory, and antiproliferative properties. Preclinical in vitro and in vivo data have shown it to be an effective treatment for brain tumors including glioblastoma multiforme. These effects are potentiated by curcumin's ability to induce G2/M cell cycle arrest, activation of apoptotic pathways, induction of autophagy, disruption of molecular signaling, inhibition of invasion, and metastasis and by increasing the efficacy of existing chemotherapeutics. Further, clinical data suggest that it has low toxicity in humans even at large doses. Curcumin is a promising nutraceutical compound that should be evaluated in clinical trials for the treatment of human brain tumors. PMID:27807473

  18. Griffithsin: An Antiviral Lectin with Outstanding Therapeutic Potential

    PubMed Central

    Lusvarghi, Sabrina; Bewley, Carole A.

    2016-01-01

    Griffithsin (GRFT), an algae-derived lectin, is one of the most potent viral entry inhibitors discovered to date. It is currently being developed as a microbicide with broad-spectrum activity against several enveloped viruses. GRFT can inhibit human immunodeficiency virus (HIV) infection at picomolar concentrations, surpassing the ability of most anti-HIV agents. The potential to inhibit other viruses as well as parasites has also been demonstrated. Griffithsin’s antiviral activity stems from its ability to bind terminal mannoses present in high-mannose oligosaccharides and crosslink these glycans on the surface of the viral envelope glycoproteins. Here, we review structural and biochemical studies that established mode of action and facilitated construction of GRFT analogs, mechanisms that may lead to resistance, and in vitro and pre-clinical results that support the therapeutic potential of this lectin. PMID:27783038

  19. Aptamer nanomedicine for cancer therapeutics: barriers and potential for translation.

    PubMed

    Lao, Yeh-Hsing; Phua, Kyle K L; Leong, Kam W

    2015-03-24

    Aptamer nanomedicine, including therapeutic aptamers and aptamer nanocomplexes, is beginning to fulfill its potential in both clinical trials and preclinical studies. Especially in oncology, aptamer nanomedicine may perform better than conventional or antibody-based chemotherapeutics due to specificity compared to the former and stability compared to the latter. Many proof-of-concept studies on applying aptamers to drug delivery, gene therapy, and cancer imaging have shown promising efficacy and impressive safety in vivo toward translation. Yet, there remains ample room for improvement and critical barriers to be addressed. In this review, we will first introduce the recent progress in clinical trials of aptamer nanomedicine, followed by a discussion of the barriers at the design and in vivo application stages. We will then highlight recent advances and engineering strategies proposed to tackle these barriers. Aptamer cancer nanomedicine has the potential to address one of the most important healthcare issues of the society.

  20. Therapeutic potential and health benefits of Sargassum species

    PubMed Central

    Yende, Subhash R.; Harle, Uday N.; Chaugule, Bhupal B.

    2014-01-01

    Sargassum species are tropical and sub-tropical brown macroalgae (seaweed) of shallow marine meadow. These are nutritious and rich source of bioactive compounds such as vitamins, carotenoids, dietary fibers, proteins, and minerals. Also, many biologically active compounds like terpenoids, flavonoids, sterols, sulfated polysaccharides, polyphenols, sargaquinoic acids, sargachromenol, pheophytine were isolated from different Sargassum species. These isolated compounds exhibit diverse biological activities like analgesic, anti-inflammatory, antioxidant, neuroprotective, anti-microbial, anti-tumor, fibrinolytic, immune-modulatory, anti-coagulant, hepatoprotective, anti-viral activity etc., Hence, Sargassum species have great potential to be used in pharmaceutical and neutralceutical areas. This review paper explores the current knowledge of phytochemical, therapeutic potential, and health benefits of different species of genus Sargassum. PMID:24600190

  1. 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.

  2. Gingerol Synergizes the Cytotoxic Effects of Doxorubicin against Liver Cancer Cells and Protects from Its Vascular Toxicity.

    PubMed

    Al-Abbasi, Fahad A; Alghamdi, Eman A; Baghdadi, Mohammed A; Alamoudi, Abdulmohsin J; El-Halawany, Ali M; El-Bassossy, Hany M; Aseeri, Ali H; Al-Abd, Ahmed M

    2016-07-08

    Hydroxyphenylalkanes and diarylheptanoids possess potential therapeutic value in different pathophysiological conditions, such as malignancy. In the current study, naturally isolated hydroxyphenylalkane and diarylheptanoid compounds were investigated for potential chemo-modulatory effects in addition to potential vascular protective roles with doxorubicin. Diarylheptanoids showed stronger antioxidant effects, in comparison to hydroxyphenylalkanes, as demonstrated by DPPH assay and amelioration of CCl₄-induced disturbed intracellular GSH/GSSG balance. Shogaol and 4'-methoxygingerol showed considerable cytotoxic effects against HCT116, HeLa, HepG2 and MCF7 cells, with IC50 values ranging from 3.1 to 19.4 µM. Gingerol significantly enhanced the cytotoxic profile of doxorubicin against HepG₂ and Huh7, cells decreasing its IC50s by 10- and 4-fold, respectively. Cell cycle distribution was studied using DNA cytometry. Doxorubicin alone induced cell accumulation at S-phase and G₂/M-phase, while in combination with gingerol it significantly induced cell cycle arrest at the G₂/M-phase. Additionally, the vascular protective effect of gingerol against doxorubicin (10 µM) was examined on isolated aortic rings. Co-incubation with 6-gingerol (30 µM) completely blocked the exaggerated vasoconstriction and impaired vascular relaxation induced by doxorubicin. In conclusion, despite its relatively weak antioxidant properties, gingerol protected from DOX-induced vascular damage, apparently not through a ROS scavenging mechanism. Besides, gingerol synergized the cytotoxic effects of DOX against liver cancer cells without influencing the cellular pharmacokinetics.

  3. 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

  4. Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice.

    PubMed

    Guenancia, Charles; Li, Na; Hachet, Olivier; Rigal, Eve; Cottin, Yves; Dutartre, Patrick; Rochette, Luc; Vergely, Catherine

    2015-04-15

    Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran-iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran-iron (15mg/kg) for 3weeks (D0-D20) and then (D21) a single sub-lethal intra-peritoneal injection of 6mg/kg of DOX. While DOX significantly decreased cell viability in EMT-6 and H9c2, pretreatment with dextran-iron (125-1000μg/mL) in combination with DOX, paradoxically limited cytotoxicity in H9c2 and increased it in EMT-6. In mice, IO alone resulted in cardiac hypertrophy (+22%) and up-regulation of brain natriuretic peptide and β-myosin heavy-chain (β-MHC) expression, as well as an increase in cardiac nitro-oxidative stress revealed by electron spin resonance spectroscopy. In DOX-treated mice, there was a significant decrease in left-ventricular ejection fraction (LVEF) and an up-regulation of cardiac β-MHC and atrial natriuretic peptide (ANP) expression. However, prior IO did not exacerbate the DOX-induced fall in LVEF and there was no increase in ANP expression. IO did not impair the capacity of DOX to decrease cancer cell viability and could even prevent some aspects of DOX cardiotoxicity in cardiomyocytes and in mice.

  5. Antioxidants as a Potential Preventive and Therapeutic Strategy for Cadmium.

    PubMed

    Brzóska, Malgorzata M; Borowska, Sylwia; Tomczyk, Michal

    2016-01-01

    Epidemiological studies provide a growing number of evidences that chronic exposure to relatively low levels of cadmium (Cd), nowadays taking place in industrialized countries, may cause health hazard. Thus, growing interest has been focused on effective ways of protection from adverse effects of exposure to this heavy metal. Because numerous effects to Cd's toxic action result from its prooxidative properties, it seems reasonable that special attention should be directed to agents that can prevent or reduce this metal-induced oxidative stress and its consequences in tissues, organs and systems at risk of toxicity, including liver, kidneys, testes, ears, eyes, cardiovascular system and nervous system as well as bone tissue. This review discusses a wide range of natural (plant and animal origin) and synthetic antioxidants together with many plant extracts (e.g. black and green tea, Aronia melanocarpa, Allium sativum, Allium cepa, Ocimum sanctum, Phoenix dactylifera, Physalis peruviana, Zingiber officinale) that have been shown to prevent from Cd toxicity. Moreover, some attention has been focused on the fact that substances not possessing antioxidative potential may also prevent Cd-induced oxidative stress and its consequences. So far, most of the data on the protective effects of the natural and synthetic antioxidants and plant extracts come from studies in animals' models; however, numerous of them seem to be promising preventive/therapeutic strategies for Cd toxicity in humans. Further investigation of prophylactic and therapeutic use of antioxidants in populations exposed to Cd environmentally and occupationally is warranted, given that therapeutically effective chelation therapy for this toxic metal is currently lacking.

  6. The Ghrelin Axis in Disease; Potential Therapeutic Indications

    PubMed Central

    Nass, Ralf; Gaylinn, Bruce D.; Thorner, Michael O.

    2011-01-01

    Ghrelin, the natural ligand for the growth hormone (GH)-secretagogue receptor (GHS-R), is produced predominantly in the stomach. It is present in the circulation in two major forms, an acylated and an unacylated form, both of which have reported activities. Some of the best understood main effects of acylated ghrelin administration include anorexic effects, increased appetite and the stimulation of GH secretion. Ghrelin also seems to plays a role in glucose homeostasis, lipid metabolism and immune function. Based on its orexigenic and metabolic effects, ghrelin and ghrelin mimetics have potential benefit in antagonizing protein breakdown and weight loss in catabolic conditions such as cancer cachexia, renal, cardiac and pulmonary disease, and age-related frailty. Ghrelin also has potentially useful positive effects on cardiac function and gastric motility. Ghrelin antagonists may be of benefit to increase insulin sensitivity and potentiate weight loss. The following chapter presents some background on ghrelin and ghrelin assays and discusses some of the potential therapeutic approaches for the use of ghrelin, ghrelin mimetic compounds and ghrelin antagonists in clinical disease. PMID:21356273

  7. Maximizing the Therapeutic Potential of Hsp90 Inhibitors

    PubMed Central

    Butler, Lisa M.; Ferraldeschi, Roberta; Armstrong, Heather K.; Centenera, Margaret M.; Workman, Paul

    2015-01-01

    Hsp90 is required for maintaining the stability and activity of a diverse group of client proteins, including protein kinases, transcription factors and steroid hormone receptors involved in cell signaling, proliferation, survival, oncogenesis and cancer progression. Inhibition of Hsp90 alters the Hsp90-client protein complex, leading to reduced activity, misfolding, ubiquitination and, ultimately, proteasomal degradation of client proteins. Hsp90 inhibitors have demonstrated significant antitumor activity in a wide variety of preclinical models with evidence of selectivity for cancer versus normal cells. In the clinic however, the efficacy of this class of therapeutic agents has been relatively limited to date, with promising responses mainly observed in breast and lung cancer, but no major activity seen in other tumor types. In addition, adverse events and some significant toxicities have been documented. Key to improving these clinical outcomes is a better understanding of the cellular consequences of inhibiting Hsp90 that may underlie treatment response or resistance. This review considers the recent progress that has been made in the study of Hsp90 and its inhibitors, and highlights new opportunities to maximize their therapeutic potential. PMID:26219697

  8. Dedifferentiation-reprogrammed mesenchymal stem cells with improved therapeutic potential.

    PubMed

    Liu, Yang; Jiang, Xiaohua; Zhang, Xiaohu; Chen, Rui; Sun, Tingting; Fok, Kin Lam; Dong, Jianda; Tsang, Lai Ling; Yi, Shaoqiong; Ruan, Yechun; Guo, Jinghui; Yu, Mei Kuen; Tian, Yuemin; Chung, Yiu Wa; Yang, Mo; Xu, Wenming; Chung, Chin Man; Li, Tingyu; Chan, Hsiao Chang

    2011-12-01

    Stem cell transplantation has been shown to improve functional outcome in degenerative and ischemic disorders. However, low in vivo survival and differentiation potential of the transplanted cells limits their overall effectiveness and thus clinical usage. Here we show that, after in vitro induction of neuronal differentiation and dedifferentiation, on withdrawal of extrinsic factors, mesenchymal stem cells (MSCs) derived from bone marrow, which have already committed to neuronal lineage, revert to a primitive cell population (dedifferentiated MSCs) retaining stem cell characteristics but exhibiting a reprogrammed phenotype distinct from their original counterparts. Of therapeutic interest, the dedifferentiated MSCs exhibited enhanced cell survival and higher efficacy in neuronal differentiation compared to unmanipulated MSCs both in vitro and in vivo, with significantly improved cognition function in a neonatal hypoxic-ischemic brain damage rat model. Increased expression of bcl-2 family proteins and microRNA-34a appears to be the important mechanism giving rise to this previously undefined stem cell population that may provide a novel treatment strategy with improved therapeutic efficacy.

  9. Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

    PubMed Central

    Rebouças, Júlio S.; Spasojević, Ivan

    2010-01-01

    Abstract Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia–reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO3·−, peroxyl radical, and less efficiently H2O2. By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and/or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds. Antioxid. Redox Signal. 13, 877–918. PMID:20095865

  10. Gingiva as a source of stem cells with therapeutic potential.

    PubMed

    Fournier, Benjamin P J; Larjava, Hannu; Häkkinen, Lari

    2013-12-15

    Postnatal connective tissues contain phenotypically heterogeneous cells populations that include distinct fibroblast subpopulations, pericytes, myofibroblasts, fibrocytes, and tissue-specific mesenchymal stem cells (MSCs). These cells play key roles in tissue development, maintenance, and repair and contribute to various pathologies. Depending on the origin of tissue, connective tissue cells, including MSCs, have different phenotypes. Understanding the identity and specific functions of these distinct tissue-specific cell populations may allow researchers to develop better treatment modalities for tissue regeneration and find novel approaches to prevent pathological conditions. Interestingly, MSCs from adult oral mucosal gingiva possess distinct characteristics, including neural crest origin, multipotent differentiation capacity, fetal-like phenotype, and potent immunomodulatory properties. These characteristics and an easy, relatively noninvasive access to gingival tissue, and fast tissue regeneration after tissue biopsy make gingiva an attractive target for cell isolation for therapeutic purposes aiming to promote tissue regeneration and fast, scar-free wound healing. The purpose of this review is to discuss the identity, phenotypical heterogeneity, and function of gingival MSCs and summarize what is currently known about their properties, role in scar-free healing, and their future therapeutic potential.

  11. Therapeutic potential and outlook of alternative medicine for osteoporosis.

    PubMed

    Wang, Tao; Liu, Qian; Tjhioe, William; Zhao, Jinmin; Lu, Aiping; Zhang, Ge; Tan, Renxiang; Zhou, Mengyu; Xu, Jiake; Feng, Haotian

    2017-03-21

    Osteoporosis, a bone disease resulting in loss of bone density and microstructure quality, is often associated with fragility fractures, and the latter imposes a great burden on the patient and society. Although there are several different treatments available for osteoporosis such as hormone replacement therapy, bisphosphonates, Denosumab, and parathyroid hormone some concern has been raised regarding the inherent side effects of their long term use. It would be of great relevance to search for alternative natural compounds, which could complementarily overcome the limitations of the currently available therapy. Herein, we review current literature on natural compounds that might have therapeutic values for osteoporosis. Search terms included bone resorption, bone density, osteoporosis, postmenopausal, osteoporosis or bone density conservation agents, and any of the terms related to traditional, herbal, natural therapy, natural health, diet, or phytoestrogens. All the compounds and herbs included in the review are naturally bioactive or are used in folk herbal medicine and have been reported to be capable of attenuating osteopenia or osteoporosis in vivo or in vitro, through various mechanisms - estrogen-like activity, antioxidant and anti-inflammatory properties, or by modulating the key signaling pathways in the pathogenesis of osteoporosis. Through our assessment of the therapeutic potential and outlook of alternative medicine, we aim to provide an appealing perspective for the consideration of the application of a complementary anti-osteoporotic treatment option and prevention strategy for osteoporosis or osteolytic bone disorders.

  12. Biochemistry and therapeutic potential of hydrogen sulfide - reality or fantasy?

    PubMed

    Brodek, Paulina; Olas, Beata

    2016-08-11

    Hydrogen sulfide (H2S) is a signaling gasotransmitter, involved in different physiological and pathological processes. H2S regulates apoptosis, the cell cycle and oxidative stress. H2S exerts powerful effects on smooth muscle cells, endothelial cells, inflammatory cells, endoplasmic reticulum, mitochondria and nuclear transcription factors. H2S is known to be produced from L-cysteine, D-cysteine and L-homocysteine in the body. Four enzymes - cystathionine-b synthase (CBS), mercaptopyruvate sulfurtransferase (3-MST), cystathionine-γ lyase (CSE) and cysteine aminotransferase (CAT) - are involved in H2S synthesis. The biosynthetic pathway for the production of H2S from D-cysteine involves 3-MST and D-amino acid oxidase (DAO). The therapeutic potential of H2S is not clear. However, recently results have demonstrated that H2S has protective action for ischemic heart disease or hypertension, and protects against ischemia of the brain. This review summarizes the negative and the positive roles of H2S in various biological systems, for example the cardiovascular system and nervous system. We also discuss the function of classical, therapeutic and natural (for example garlic) donors of H2S in pre-clinical and clinical studies.

  13. 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.

  14. Potential Therapeutic Benefits of Strategies Directed to Mitochondria

    PubMed Central

    Lesnefsky, Edward J.; Stowe, David F.

    2010-01-01

    Abstract The mitochondrion is the most important organelle in determining continued cell survival and cell death. Mitochondrial dysfunction leads to many human maladies, including cardiovascular diseases, neurodegenerative disease, and cancer. These mitochondria-related pathologies range from early infancy to senescence. The central premise of this review is that if mitochondrial abnormalities contribute to the pathological state, alleviating the mitochondrial dysfunction would contribute to attenuating the severity or progression of the disease. Therefore, this review will examine the role of mitochondria in the etiology and progression of several diseases and explore potential therapeutic benefits of targeting mitochondria in mitigating the disease processes. Indeed, recent advances in mitochondrial biology have led to selective targeting of drugs designed to modulate and manipulate mitochondrial function and genomics for therapeutic benefit. These approaches to treat mitochondrial dysfunction rationally could lead to selective protection of cells in different tissues and various disease states. However, most of these approaches are in their infancy. Antioxid. Redox Signal. 13, 279–347. PMID:20001744

  15. MicroRNAs in Neurodegenerative Diseases and Their Therapeutic Potential

    PubMed Central

    Junn, Eunsung; Mouradian, M. Maral

    2011-01-01

    MicroRNAs (miRNAs) are abundant, endogenous, short, noncoding RNAs that act as important post-transcriptional regulators of gene expression by base-pairing with their target mRNA. During the last decade, substantial knowledge has accumulated regarding the biogenesis of miRNAs, their molecular mechanisms and functional roles in a variety of cellular contexts. Altered expression of certain miRNA molecules in the brains of patients with neurodegenerative diseases such as Alzheimer and Parkinson suggests that miRNAs could have a crucial regulatory role in these disorders. Polymorphisms in miRNA target sites may also constitute an important determinant of disease risk. Additionally, emerging evidence points to specific miRNAs targeting and regulating the expression of particular proteins that are key to disease pathogenesis. Considering that the amount of these proteins in susceptible neuronal populations appears to be critical to neurodegeneration, miRNA-mediated regulation represents a new target of significant therapeutic prospects. In this review, the implications of miRNAs in several neurodegenerative disorders and their potential as therapeutic interventions are discussed. PMID:22008259

  16. 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

  17. Therapeutic potential of the endocannabinoid system in the brain.

    PubMed

    Ramos, José Antonio; González, Sara; Sagredo, Onintza; Gómez-Ruiz, María; Fernández-Ruiz, Javier

    2005-07-01

    Cannabinoids have been predominantly considered as the substances responsible of the psychoactive properties of marijuana and other derivatives of Cannabis sativa. However, these compounds are now being also considered for their therapeutic potential, since the term "cannabinoid" includes much more compounds than those present in Cannabis sativa derivatives. Among them, there are numerous synthetic cannabinoids obtained by modifications from plant-derived cannabinoids, but also from the compounds that behave as endogenous ligands for the different cannabinoid receptor subtypes. Within the family of "cannabinoid-related compounds", one should also include some prototypes of selective antagonists for these receptors, and also the recently developed inhibitors of the mechanism of finalization of the biological action of endocannabinoids (transporter + FAAH). All this boom of the cannabinoid pharmacology has, therefore, an explanation in the recent discovery and characterization of the endocannabinoid signaling system, which plays a modulatory role mainly in the brain but also in the periphery. The objective of the present article will be to review, from pharmacological and biochemical points of view, the more recent advances in the study of the endocannabinoid system and their functions in the brain, as well as their alterations in a variety of pathologies and the proposed therapeutic benefits of novel cannabinoid-related compounds that improve the pharmacokinetic and pharmacodynamic properties of classic cannabinoids.

  18. Therapeutic Potentials of Triterpenes in Diabetes and its Associated Complications.

    PubMed

    Putta, Swathi; Yarla, Nagendra Sastry; Kilari, Eswar Kumar; Surekha, Challa; Aliev, Gjumrakch; Divakara, Madhihalli Basavaraju; Santosh, Mysore Sridhar; Ramu, Ramith; Zameer, Farhan; Mn, Nagendra Prasad; Chintala, Ramakrishna; Rao, Pidugu Vijaya; Shiralgi, Yallappa; Dhananjaya, Bhadrapura Lakkappa

    2016-01-01

    Diabetes is a major chronic metabolic disorder globally and around of 285 million people are affected by the disease and the number is expected to double in the next two decades. The major focus of anti-diabetic therapies is to enhance insulin production, sensitivity and/or reduce the blood glucose level. Although several synthetic drugs have been developed as antidiabetic agents but their utility has been hampered due to their side effects and poor efficacy. In this scenario, research on natural products has been gained importance due their safety profile in toxicity studies. Terpenoids belong to an important class of natural products and several terpenoids have been reported as antidiabetic agents. Some of them are under various stages of pre-clinical and clinical evaluation to develop them as antidiabetic agents. These agents can inhibit enzymes responsible for the development of insulin resistance, normalization of plasma glucose and insulin levels and glucose metabolism. Triterpenes can act as promising agents in the treatment of diabetic retinopathy, neuropathy and nephropathy or in impaired wound healing by inhibiting several pathways involved in the diabetes and associated complications. However, efforts in understanding the biological actions and clinical studies involving the applications of triterpenes in treating diabetes are very limited. Hence, special attention is imperative to explore the therapeutic potential of these compounds and provide new information to the scientific community. This review aims to provide the recent advances in triterpenes chemistry, its derivatives, biological interventions and its therapeutic applications with special emphasis on diabetes and its associated disorders.

  19. 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.

  20. Melanocyte Stem Cells as Potential Therapeutics in Skin Disorders

    PubMed Central

    Lee, Ju Hee; Fisher, David E.

    2015-01-01

    Introduction Melanocytes produce pigment granules that color both skin and hair. In the hair follicles melanocytes are derived from stem cells (MelSC) that are present in hair bulges or sub-bulge regions and function as melanocyte reservoirs. Quiescence, maintenance, activation, and proliferation of MelSC are controlled by specific activities in the microenvironment that can influence the differentiation and regeneration of melanocytes. Therefore, understanding MelSC and their niche may lead to use of MelSC in new treatments for various pigmentation disorders. Areas covered We describe here pathophysiological mechanisms by which melanocyte defects lead to skin pigmentation disorders such as vitiligo and hair graying. The development, migration, and proliferation of melanocytes and factors involved in the survival, maintenance, and regeneration of MelSC are reviewed with regard to the biological roles and potential therapeutic applications in skin pigmentation diseases. Expert Opinion MelSC biology and niche factors have been studied mainly in murine experimental models. Human MelSC markers or methods to isolate them are much less well understood. Identification, isolation and culturing of human MelSC would represent a major step toward new biological therapeutic options for patients with recalcitrant pigmentary disorders or hair graying. By modulating the niche factors for MelSC it may one day be possible to control skin pigmentary disorders and prevent or reverse hair graying. PMID:25104310

  1. Melanocyte stem cells as potential therapeutics in skin disorders.

    PubMed

    Lee, Ju Hee; Fisher, David E

    2014-11-01

    Melanocytes produce pigment granules that color both skin and hair. In the hair follicles melanocytes are derived from stem cells (MelSCs) that are present in hair bulges or sub-bulge regions and function as melanocyte reservoirs. Quiescence, maintenance, activation and proliferation of MelSCs are controlled by specific activities in the microenvironment that can influence the differentiation and regeneration of melanocytes. Therefore, understanding MelSCs and their niche may lead to use of MelSCs in new treatments for various pigmentation disorders. We describe here pathophysiological mechanisms by which melanocyte defects lead to skin pigmentation disorders such as vitiligo and hair graying. The development, migration and proliferation of melanocytes and factors involved in the survival, maintenance and regeneration of MelSCs are reviewed with regard to the biological roles and potential therapeutic applications in skin pigmentation diseases. MelSC biology and niche factors have been studied mainly in murine experimental models. Human MelSC markers or methods to isolate them are much less well understood. Identification, isolation and culturing of human MelSCs would represent a major step toward new biological therapeutic options for patients with recalcitrant pigmentary disorders or hair graying. By modulating the niche factors for MelSCs, it may one day be possible to control skin pigmentary disorders and prevent or reverse hair graying.

  2. Wasp Venom Toxins as a Potential Therapeutic Agent.

    PubMed

    Dongol, Yashad; Dhananjaya, Bhadrapara L; Shrestha, Rakesh K; Aryal, Gopi

    2016-01-01

    It is high time now to discover novel drugs due to the increasing rate of drug resistance by the pathogen organisms and target cells as well as the dependence or tolerance of the body towards the drug. As it is obvious that significant numbers of the modern day pharmaceuticals are derived from natural products, it is equally astonishing to accept that venoms of various origins have therapeutic potentials. Wasp venoms are also a rich source of therapeutically important toxins which includes short cationic peptides, kinins, polyamines and polyDNA viruses, to name a few indentified. Wasp venom cationic peptides, namely mastoparan and its analogs, show a very important potency as an antimicrobial and anticancer agents of the future. They have proven to be the better candidates due to their lesser toxic effects and higher selectivity upon chemical modification and charge optimization. They also have superiority over the conventional chemical drugs as the target cells very rarely develop resistance against them because these peptides primarily imparts its effect through biophysical interaction with the target cell membrane which is dependent upon the net charge of the peptide, its hydrophobicity and anionicity and fluidity of the target cell membranes. Besides, the other components of wasp venom such as kinins, polyamines and polyDNA viruses show various pharmacological promise in the treatment of pain, inflammatory disease, and neurodegenerative diseases such as epilepsy and aversion.

  3. The human gut microbiota and virome: Potential therapeutic implications.

    PubMed

    Scarpellini, Emidio; Ianiro, Gianluca; Attili, Fabia; Bassanelli, Chiara; De Santis, Adriano; Gasbarrini, Antonio

    2015-12-01

    Human gut microbiota is a complex ecosystem with several functions integrated in the host organism (metabolic, immune, nutrients absorption, etc.). Human microbiota is composed by bacteria, yeasts, fungi and, last but not least, viruses, whose composition has not been completely described. According to previous evidence on pathogenic viruses, the human gut harbours plant-derived viruses, giant viruses and, only recently, abundant bacteriophages. New metagenomic methods have allowed to reconstitute entire viral genomes from the genetic material spread in the human gut, opening new perspectives on the understanding of the gut virome composition, the importance of gut microbiome, and potential clinical applications. This review reports the latest evidence on human gut "virome" composition and its function, possible future therapeutic applications in human health in the context of the gut microbiota, and attempts to clarify the role of the gut "virome" in the larger microbial ecosystem.

  4. 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

  5. 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

  6. High therapeutic potential of Spilanthes acmella: A review

    PubMed Central

    Prachayasittikul, Veda; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong

    2013-01-01

    Spilanthes acmella, a well known antitoothache plant with high medicinal usages, has been recognized as an important medicinal plant and has an increasingly high demand worldwide. From its traditional uses in health care and food, extensive phytochemical studies have been reported. This review provides an overview and general description of the plant species, bioactive metabolites and important pharmacological activities including the preparation, purification and in vitro large-scale production. Structure-activity relationships of the bioactive compounds have been discussed. Considering data from the literature, it could be demonstrated that S. acmella possesses diverse bioactive properties and immense utilization in medicine, health care, cosmetics and as health supplements. As a health food, it is enriched with high therapeutic value with high potential for further development. PMID:27092032

  7. Vitamin D: Implications for ocular disease and therapeutic potential.

    PubMed

    Reins, Rose Y; McDermott, Alison M

    2015-05-01

    Vitamin D is a multifunctional hormone that is now known to play a significant role in a variety of biological functions in addition to its traditional role in regulating calcium homeostasis. There are a large number of studies demonstrating that adequate vitamin D levels are important in maintaining health and show that vitamin D is able to be utilized at local tissue sites. In the eye, we have increasing evidence of the association between disease and vitamin D. In this narrative review, we summarize recent findings on vitamin D and its relationship to various ocular pathologies and the therapeutic potential for some of these, as well as examine the basic science studies that demonstrate that vitamin D is biologically relevant in the eye.

  8. Therapeutic potential of endothelin receptor antagonism in kidney disease.

    PubMed

    Czopek, Alicja; Moorhouse, Rebecca; Webb, David J; Dhaun, Neeraj

    2016-03-01

    Our growing understanding of the role of the endothelin (ET) system in renal physiology and pathophysiology is from emerging studies of renal disease in animal models and humans. ET receptor antagonists reduce blood pressure and proteinuria in chronic kidney disease and cause regression of renal injury in animals. However, the therapeutic potential of ET receptor antagonism has not been fully explored and clinical studies have been largely limited to patients with diabetic nephropathy. There remains a need for more work in nondiabetic chronic kidney disease, end-stage renal disease (patients requiring maintenance dialysis and those with a functioning kidney transplant), ischemia reperfusion injury, and sickle cell disease. The current review summarizes the most recent advances in both preclinical and clinical studies of ET receptor antagonists in the field of kidney disease. Copyright © 2016 the American Physiological Society.

  9. Transcription factor-mediated reprogramming: epigenetics and therapeutic potential.

    PubMed

    Firas, Jaber; Liu, Xiaodong; Lim, Sue Mei; Polo, Jose M

    2015-03-01

    Cellular reprogramming refers to the conversion of one cell type into another by altering its epigenetic marks. This can be achieved by three different methods: somatic cell nuclear transfer, cell fusion and transcription factor (TF)-mediated reprogramming. TF-mediated reprogramming can occur through several means, either reverting backwards to a pluripotent state before redifferentiating to a new cell type (otherwise known as induced pluripotency), by transdifferentiating directly into a new cell type (bypassing the intermediate pluripotent stage), or, by using the induced pluripotency pathway without reaching the pluripotent state. The possibility of reprogramming any cell type of interest not only sheds new insights on cellular plasticity, but also provides a novel use of this technology across several platforms, most notably in cellular replacement therapies, disease modelling and drug screening. This review will focus on the different ways of implementing TF-mediated reprogramming, their associated epigenetic changes and its therapeutic potential.

  10. Vitamin D: Implications for Ocular Disease and Therapeutic Potential

    PubMed Central

    Reins, Rose Y.; McDermott, Alison M.

    2015-01-01

    Vitamin D is a multifunctional hormone that is now known to play a significant role in a variety of biological functions in addition to its traditional role in regulating calcium homeostasis. There are a large number of studies demonstrating that adequate vitamin D levels are important in maintaining health and show that vitamin D is able to be utilized at local tissue sites. In the eye, we have increasing evidence of the association between disease and vitamin D. In this narrative review, we summarize recent findings on vitamin D and its relationship to various ocular pathologies and the therapeutic potential for some of these, as well as examine the basic science studies that demonstrate that vitamin D is biologically relevant in the eye. PMID:25724179

  11. Mitochondrial Mechanisms of Neuronal Cell Death: Potential Therapeutics.

    PubMed

    Dawson, Ted M; Dawson, Valina L

    2017-01-06

    Mitochondria lie at the crossroads of neuronal survival and cell death. They play important roles in cellular bioenergetics, control intracellular Ca(2+) homeostasis, and participate in key metabolic pathways. Mutations in genes involved in mitochondrial quality control cause a myriad of neurodegenerative diseases. Mitochondria have evolved strategies to kill cells when they are not able to continue their vital functions. This review provides an overview of the role of mitochondria in neurologic disease and the cell death pathways that are mediated through mitochondria, including their role in accidental cell death, the regulated cell death pathways of apoptosis and parthanatos, and programmed cell death. It details the current state of parthanatic cell death and discusses potential therapeutic strategies targeting initiators and effectors of mitochondrial-mediated cell death in neurologic disorders.

  12. The preventive and therapeutic potential of natural polyphenols on influenza.

    PubMed

    Bahramsoltani, Roodabeh; Sodagari, Hamid Reza; Farzaei, Mohammad Hosein; Abdolghaffari, Amir Hossein; Gooshe, Maziar; Rezaei, Nima

    2016-01-01

    Influenza virus belongs to orthomyxoviridae family. This virus is a major public health problems, with high rates of morbidity and mortality. Despite a wide range of pharmacotherapeutic choices inhibiting specific sequences of pathological process of influenza, developing more effective therapeutic options is an immediate challenge. In this paper, a comprehensively review of natural polyphenolic products used worldwide for the management of influenza infection is presented. Cellular and molecular mechanisms of the natural polyphenols on influenza infection including suppressing virus replication cycle, viral hemagglutination, viral adhesion and penetration into the host cells, also intracellular transductional signaling pathways have been discussed in detail. Based on cellular, animal, and human evidence obtained from several studies, the current paper demonstrates that natural polyphenolic compounds possess potential effects on both prevention and treatment of influenza, which can be used as adjuvant therapy with conventional chemical drugs for the management of influenza and its complications.

  13. Cathelicidin a potential therapeutic peptide for gastrointestinal inflammation and cancer.

    PubMed

    Chow, Jimmy Yip Chuen; Li, Zhi Jie; Wu, William Ka Kei; Cho, Chi Hin

    2013-05-14

    Cathelicidins, are host defense peptides synthesized and stored in circulating leukocytes and numerous types of epithelial tissues in particular the gastrointestinal (GI) tract and skin. They have been known for their antimicrobial activities against a variety of microbes. Recently it was discovered that they have other significant biological functions and produce appealing pharmacological actions against inflammation and cancer in the GI tract through defined mechanisms. Experimental evidence shows that these actions could be tissue and disease specific and concentration dependent. This article reviews some of the physiological functions of cathelicidins and also their therapeutic potential in the treatment of inflammation and cancer and also the delivery system for this peptide as targeted therapy for various disorders in the GI tract both in animals and humans.

  14. 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

  15. Bryostatin-1: pharmacology and therapeutic potential as a CNS drug.

    PubMed

    Sun, Miao-Kun; Alkon, Daniel L

    2006-01-01

    Bryostatin-1 is a powerful protein kinase C (PKC) agonist, activating PKC isozymes at nanomolar concentrations. Pharmacological studies of bryostatin-1 have mainly been focused on its action in preventing tumor growth. Emerging evidence suggests, however, that bryostatin-1 exhibits additional important pharmacological activities. In preclinical studies bryostatin-1 has been shown at appropriate doses to have cognitive restorative and antidepressant effects. The underlying pharmacological mechanisms may involve an activation of PKC isozymes, induction of synthesis of proteins required for long-term memory, restoration of stress-evoked inhibition of PKC activity, and reduction of neurotoxic amyloid accumulation and tau protein hyperphosphorylation. The therapeutic potential of bryostatin-1 as a CNS drug should be further explored.

  16. Therapeutic potential of Aegle marmelos (L.)-An overview

    PubMed Central

    Rahman, Shahedur; Parvin, Rashida

    2014-01-01

    Medicinal plants are used in herbalism. They form the easily available source for healthcare purposes in rural and tribal areas. In the present review, an attempt has been made to congregate the phytochemical and pharmacological studies done on an important medicinal plant Aegle marmelos. Extensive experimental and clinical studies prove that Aegle marmelos possesses antidiarrhoeal, antimicrobial, antiviral, radioprotective, anticancer, chemopreventive, antipyretic, ulcer healing, antigenotoxic, diuretic, antifertility and anti-inflammatory properties, which help it to play role in prevention and treatment of many disease. Therefore, it is worthwhile to review its therapeutic properties to give an overview of its status to scientist both modern and ancient. This review also encompasses on the potential application of the above plant in the pharmaceutical field due to its wide pharmacological activities.

  17. Human-derived natural antibodies: biomarkers and potential therapeutics

    PubMed Central

    Xu, Xiaohua; Ng, Sher May; Hassouna, Eamonn; Warrington, Arthur; Oh, Sang-Hyun; Rodriguez, Moses

    2015-01-01

    The immune system generates antibodies and antigen-specific T-cells as basic elements of the immune networks that differentiate self from non-self in a finely tuned manner. The antigen-specific nature of immune responses ensures that normal immune activation contains non-self when tolerating self. Here we review the B-1 subset of lymphocytes which produce self-reactive antibodies. By analyzing the IgM class of natural antibodies that recognize antigens from the nervous system, we emphasize that natural antibodies are biomarkers of how the immune system monitors the host. The immune response activated against self can be detrimental when triggered in an autoimmune genetic background. In contrast, tuning immune activity with natural antibodies is a potential therapeutic strategy. PMID:25678860

  18. 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

  19. Therapeutic potential of SIGIRR in systemic lupus erythematosus.

    PubMed

    Wang, Chao; Feng, Chen-Chen; Pan, Hai-Feng; Wang, De-Guang; Ye, Dong-Qing

    2013-08-01

    Single immunoglobulin IL-1-related receptor (SIGIRR), which is also known as Toll/interleukin-1 receptor 8, is a member of the interleukin-1 receptor (IL-1R) family. Different from other typical IL-1R superfamily members, SIGIRR seems to exert negatively modulates in immune responses. Several previous studies demonstrated that SIGIRR influences chronic inflammatory or autoimmune diseases, such as intestinal inflammation, rheumatoid arthritis and psoriatic arthritis. Recent work has explored the role of SIGIRR in systemic lupus erythematosus (SLE), for example, the role of SIGIRR protects the mice from hydrocarbon oil-induced lupus has been reported. These results indicate that SIGIRR may represent a novel target for the treatment of SLE. In this review, we will discuss the SIGIRR and the therapeutic potential of modulating the pathway in SLE.

  20. Targeted Magnetic Liposomes Loaded with Doxorubicin.

    PubMed

    Pradhan, Pallab; Banerjee, Rinti; Bahadur, Dhirendra; Koch, Christian; Mykhaylyk, Olga; Plank, Christian

    2017-01-01

    Targeted delivery systems for anticancer drugs are urgently needed to achieve maximum therapeutic efficacy by site-specific accumulation and thereby minimizing adverse effects resulting from systemic distribution of many potent anticancer drugs. We have prepared folate receptor-targeted magnetic liposomes loaded with doxorubicin, which are designed for tumor targeting through a combination of magnetic and biological targeting. Furthermore, these liposomes are designed for hyperthermia-induced drug release to be mediated by an alternating magnetic field and to be traceable by magnetic resonance imaging (MRI). Here, detailed preparation and relevant characterization techniques of targeted magnetic liposomes encapsulating doxorubicin are described.

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

    PubMed

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

    2014-01-01

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

  2. Therapeutic potential of intermittent hypoxia: a matter of dose

    PubMed Central

    Navarrete-Opazo, Angela

    2014-01-01

    Intermittent hypoxia (IH) has been the subject of considerable research in recent years, and triggers a bewildering array of both detrimental and beneficial effects in multiple physiological systems. Here, we review the extensive literature concerning IH and its impact on the respiratory, cardiovascular, immune, metabolic, bone, and nervous systems. One major goal is to define relevant IH characteristics leading to safe, protective, and/or therapeutic effects vs. pathogenesis. To understand the impact of IH, it is essential to define critical characteristics of the IH protocol under investigation, including potentially the severity of hypoxia within episodes, the duration of hypoxic episodes, the number of hypoxic episodes per day, the pattern of presentation across time (e.g., within vs. consecutive vs. alternating days), and the cumulative time of exposure. Not surprisingly, severe/chronic IH protocols tend to be pathogenic, whereas any beneficial effects are more likely to arise from modest/acute IH exposures. Features of the IH protocol most highly associated with beneficial vs. pathogenic outcomes include the level of hypoxemia within episodes and the number of episodes per day. Modest hypoxia (9–16% inspired O2) and low cycle numbers (3–15 episodes per day) most often lead to beneficial effects without pathology, whereas severe hypoxia (2–8% inspired O2) and more episodes per day (48–2,400 episodes/day) elicit progressively greater pathology. Accumulating evidence suggests that “low dose” IH (modest hypoxia, few episodes) may be a simple, safe, and effective treatment with considerable therapeutic potential for multiple clinical disorders. PMID:25231353

  3. Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics.

    PubMed

    Saha, M; McDaniel, J K; Zheng, X L

    2017-06-29

    Thrombotic thrombocytopenic purpura (TTP), a potentially fatal clinical syndrome, is primarily caused by autoantibodies against the von Willebrand factor (VWF)-cleaving metalloprotease ADAMTS-13. In general, severe deficiency of plasma ADAMTS-13 activity (< 10 IU dL(-1) ) with or without detectable inhibitory autoantibodies against ADAMTS-13 supports the diagnosis of TTP. A patient usually presents with thrombocytopenia and microangiopathic hemolytic anemia (i.e. schistocytes, elevated serum lactate dehydrogenase, decreased hemoglobin and haptoglobin) without other known etiologies that cause thrombotic microangiopathy (TMA). Normal to moderately reduced plasma ADAMTS-13 activity (> 10 IU dL(-1) ) in a similar clinical context supports an alternative diagnosis such as atypical hemolytic uremic syndrome (aHUS) or other types of TMA. Prompt differentiation of TTP from other causes of TMA is crucial for the initiation of an appropriate therapy to reduce morbidity and mortality. Although plasma infusion is often sufficient for prophylaxis or treatment of hereditary TTP due to ADAMTS-13 mutations, daily therapeutic plasma exchange remains the initial treatment of choice for acquired TTP with demonstrable autoantibodies. Immunomodulatory therapies, including corticosteroids, rituximab, vincristine, cyclosporine, cyclophosphamide and splenectomy, etc., should be considered to eliminate autoantibodies for a sustained remission. Other emerging therapeutic modalities, including recombinant ADAMTS-13, adeno-associated virus (AAV) 8-mediated gene therapy, platelet-delivered ADAMTS-13, and antagonists targeting the interaction between platelet glycoprotein 1b and VWF are under investigation. This review highlights the recent progress in our understanding of the pathogenesis and diagnosis of, and current and potential novel therapies for, hereditary and acquired TTP. © 2017 International Society on Thrombosis and Haemostasis.

  4. Therapeutic potential of intermittent hypoxia: a matter of dose.

    PubMed

    Navarrete-Opazo, Angela; Mitchell, Gordon S

    2014-11-15

    Intermittent hypoxia (IH) has been the subject of considerable research in recent years, and triggers a bewildering array of both detrimental and beneficial effects in multiple physiological systems. Here, we review the extensive literature concerning IH and its impact on the respiratory, cardiovascular, immune, metabolic, bone, and nervous systems. One major goal is to define relevant IH characteristics leading to safe, protective, and/or therapeutic effects vs. pathogenesis. To understand the impact of IH, it is essential to define critical characteristics of the IH protocol under investigation, including potentially the severity of hypoxia within episodes, the duration of hypoxic episodes, the number of hypoxic episodes per day, the pattern of presentation across time (e.g., within vs. consecutive vs. alternating days), and the cumulative time of exposure. Not surprisingly, severe/chronic IH protocols tend to be pathogenic, whereas any beneficial effects are more likely to arise from modest/acute IH exposures. Features of the IH protocol most highly associated with beneficial vs. pathogenic outcomes include the level of hypoxemia within episodes and the number of episodes per day. Modest hypoxia (9-16% inspired O2) and low cycle numbers (3-15 episodes per day) most often lead to beneficial effects without pathology, whereas severe hypoxia (2-8% inspired O2) and more episodes per day (48-2,400 episodes/day) elicit progressively greater pathology. Accumulating evidence suggests that "low dose" IH (modest hypoxia, few episodes) may be a simple, safe, and effective treatment with considerable therapeutic potential for multiple clinical disorders.

  5. 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

  6. TRPV4: physiological role and therapeutic potential in respiratory diseases.

    PubMed

    Goldenberg, Neil M; Ravindran, Krishnan; Kuebler, Wolfgang M

    2015-04-01

    Members of the family of transient receptor potential (TRP) channels have been implicated in the pathophysiology of a host of lung diseases. The role of these multimodal cation channels in lung homeostasis is thought to stem from their ability to respond to changes in mechanical stimuli (i.e., shear and stretch), as well as to various protein and lipid mediators. The vanilloid subfamily member, TRPV4, which is highly expressed in the majority of lung cell types, is well positioned for critical involvement in several pulmonary conditions, including edema formation, control of pulmonary vascular tone, and the lung response to local or systemic inflammatory insults. In recent years, several pharmacological inhibitors of TRPV4 have been developed, and the current generation of compounds possess high affinity and specificity for TRPV4. As such, we have now entered a time where the therapeutic potential of TRPV4 inhibitors can be systematically examined in a variety of lung diseases. Due to this fact, this review seeks to describe the current state of the art with respect to the role of TRPV4 in pulmonary homeostasis and disease, and to highlight the current and future roles of TRPV4 inhibitors in disease treatment. We will first focus on genera aspects of TRPV4 structure and function, and then will discuss known roles for TRPV4 in pulmonary diseases, including pulmonary edema formation, pulmonary hypertension, and acute lung injury. Finally, both promising aspects and potential pitfalls of the clinical use of TRPV4 inhibitors will be examined.

  7. Aspects of pericytes and their potential therapeutic use.

    PubMed

    Różycka, Justyna; Brzóska, Edyta; Skirecki, Tomasz

    2017-03-13

    Pericytes, which are multi-potential stem cells, co-create the walls of the microvessels: capillaries, terminal arterioles and postcapillary venules. These cells are localized under the basement membrane, tightly encircling the endothelium. The most frequently mentioned molecular markers of pericytes include NG2 (neural-glial antigen 2), β-type platelet-derived growth factor receptor (PDGFRβ), smooth muscle α-actin (α-SMA), regulator of G protein signalling 5 (RGS5), the adhesion protein CD146 and nestin. Different functions in physiological processes are assigned to pericytes such as maintaining the integrity and senescence of endothelial cells, transregulation of vascular tone or the potential to differentiate into other cells. Probably they are also involved in pathological processes such as tissues fibrosis. In this review, we focus on the participation of pericytes in the process of blood vessel formation, the regeneration of skeletal muscle tissue and fibrosis. Strong evidence for pericytes' participation in endothelial homeostasis, as well as in pathological conditions such as fibrosis, reveals a broad potential for the therapeutic use of these cells. Targeted pharmacological modulation of pericytes, leading to blocking signalling pathways responsible for the differentiation of pericytes into myofibroblasts, seems to be a promising strategy for the treatment of fibrosis in the early stages.

  8. The therapeutic potential of genome editing for β-thalassemia

    PubMed Central

    Glaser, Astrid; McColl, Bradley; Vadolas, Jim

    2015-01-01

    The rapid advances in the field of genome editing using targeted endonucleases have called considerable attention to the potential of this technology for human gene therapy. Targeted correction of disease-causing mutations could ensure lifelong, tissue-specific expression of the relevant gene, thereby alleviating or resolving a specific disease phenotype. In this review, we aim to explore the potential of this technology for the therapy of β-thalassemia. This blood disorder is caused by mutations in the gene encoding the β-globin chain of hemoglobin, leading to severe anemia in affected patients. Curative allogeneic bone marrow transplantation is available only to a small subset of patients, leaving the majority of patients dependent on regular blood transfusions and iron chelation therapy. The transfer of gene-corrected autologous hematopoietic stem cells could provide a therapeutic alternative, as recent results from gene therapy trials using a lentiviral gene addition approach have demonstrated. Genome editing has the potential to further advance this approach as it eliminates the need for semi-randomly integrating viral vectors and their associated risk of insertional mutagenesis. In the following pages we will highlight the advantages and risks of genome editing compared to standard therapy for β-thalassemia and elaborate on lessons learned from recent gene therapy trials. PMID:26918126

  9. Quercetin-induced cardioprotection against doxorubicin cytotoxicity

    PubMed Central

    2013-01-01

    Background Cancer has continually been the leading cause of death worldwide for decades. Thus, scientists have actively devoted themselves to studying cancer therapeutics. Doxorubicin is an efficient drug used in cancer therapy, but also produces reactive oxygen species (ROS) that induce severe cytotoxicity against heart cells. Quercetin, a plant-derived flavonoid, has been proven to contain potent antioxidant and anti-inflammatory properties. Thus, this in vitro study investigated whether quercetin can decrease doxorubicin-induced cytotoxicity and promote cell repair systems in cardiomyocyte H9C2 cells. Results Proteomic analysis and a cell biology assay were performed to investigate the quercetin-induced responses. Our data demonstrated that quercetin treatment protects the cardiomyocytes in a doxorubicin-induced heart damage model. Quercetin significantly facilitated cell survival by inhibiting cell apoptosis and maintaining cell morphology by rearranging the cytoskeleton. Additionally, 2D-DIGE combined with MALDI-TOF MS analysis indicated that quercetin might stimulate cardiomyocytes to repair damage after treating doxorubicin by modulating metabolic activation, protein folding and cytoskeleton rearrangement. Conclusion Based on a review of the literature, this study is the first to report detailed protective mechanisms for the action of quercetin against doxorubicin-induced cardiomyocyte toxicity based on in-depth cell biology and proteomic analysis. PMID:24359494

  10. Therapeutic Potential of Temperate Forage Legumes: A Review.

    PubMed

    Cornara, Laura; Xiao, Jianbo; Burlando, Bruno

    2016-07-29

    The discovery of bioactive molecules from botanical sources is an expanding field, preferentially oriented to plants having a tradition of use in medicine and providing high yields and availability. Temperate forage legumes are Fabaceae species that include worldwide-important crops. These plants possess therapeutic virtues that have not only been used in veterinary and folk medicine, but have also attracted the interest of official medicine. We have examined here Medicago sativa (alfalfa), Trifolium pratense and T. repens (clovers), Melilotus albus and M. officinalis (sweet clovers), Lotus corniculatus (birdsfoot trefoil), Onobrychis viciifolia (sainfoin), Lespedeza capitata (roundhead lespedeza), and Galega officinalis (goat's rue). The phytochemical complexes of these species contain secondary metabolites whose pharmacological potentials deserve investigation. Major classes of compounds include alkaloids and amines, cyanogenic glycosides, flavonoids, coumarins, condensed tannins, and saponins. Some of these phytochemicals have been related to antihypercholesterolemia, antidiabetic, antimenopause, anti-inflammatory, antiedema, anthelmintic, and kidney protective effects. Two widely prescribed drugs have been developed starting from temperate forage legumes, namely, the antithrombotic warfarin, inspired from sweet clover's coumarin, and the antidiabetic metformin, a derivative of sainfoin's guanidine. Available evidence suggests that temperate forage legumes are a potentially important resource for the extraction of active principles to be used as nutraceuticals and pharmaceuticals.

  11. Harnessing the Therapeutic Potential of Th17 Cells.

    PubMed

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

    2015-01-01

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

  12. Overview of the therapeutic potential of piplartine (piperlongumine).

    PubMed

    Bezerra, Daniel P; Pessoa, Claudia; de Moraes, Manoel O; Saker-Neto, Nicolau; Silveira, Edilberto R; Costa-Lotufo, Leticia V

    2013-02-14

    Piplartine (piperlongumine, 5,6-dihydro-1-[(2E)-1-oxo-3-(3,4,5-trimethoxyphenyl)-2-propenyl]-2(1H)-pyridinone) is a biologically active alkaloid/amide from peppers, as from long pepper (Piper longum L. - Piperaceae). Long pepper is one of the most widely used in Ayurvedic medicine, which is used to treat many diseases, including tumors. The purpose of the current paper is to address to the chemical structure establishment and to systematically survey the published articles and highlight recent advances in the knowledge of the therapeutic potential of piplartine, establishing new goals for future research. The reported pharmacological activities of piplartine include cytotoxic, genotoxic, antitumor, antiangiogenic, antimetastatic, antiplatelet aggregation, antinociceptive, anxiolytic, antidepressant, anti-atherosclerotic, antidiabetic, antibacterial, antifungal, leishmanicidal, trypanocidal, and schistosomicidal activities. Among the multiple pharmacological effects of piplartine, its anticancer property is the most promising. Therefore, the preclinical anticancer potential of piplartine has been extensively investigated, which recently resulted in one patent. This compound is selectively cytotoxic against cancer cells by induction of oxidative stress, induces genotoxicity, as an alternative strategy to killing tumor cells, has excellent oral bioavailability in mice, inhibits tumor growth in mice, and presents only weak systemic toxicity. In summary, we conclude that piplartine is effective for use in cancer therapy and its safety using chronic toxicological studies should be addressed to support the viability of clinical trials.

  13. Evaluating the Cancer Therapeutic Potential of Cardiac Glycosides

    PubMed Central

    Calderón-Montaño, José Manuel; Burgos-Morón, Estefanía; Orta, Manuel Luis; Maldonado-Navas, Dolores; García-Domínguez, Irene; López-Lázaro, Miguel

    2014-01-01

    Cardiac glycosides, also known as cardiotonic steroids, are a group of natural products that share a steroid-like structure with an unsaturated lactone ring and the ability to induce cardiotonic effects mediated by a selective inhibition of the Na+/K+-ATPase. Cardiac glycosides have been used for many years in the treatment of cardiac congestion and some types of cardiac arrhythmias. Recent data suggest that cardiac glycosides may also be useful in the treatment of cancer. These compounds typically inhibit cancer cell proliferation at nanomolar concentrations, and recent high-throughput screenings of drug libraries have therefore identified cardiac glycosides as potent inhibitors of cancer cell growth. Cardiac glycosides can also block tumor growth in rodent models, which further supports the idea that they have potential for cancer therapy. Evidence also suggests, however, that cardiac glycosides may not inhibit cancer cell proliferation selectively and the potent inhibition of tumor growth induced by cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact caused by their ability to selectively kill human cells versus rodent cells. This paper reviews such evidence and discusses experimental approaches that could be used to reveal the cancer therapeutic potential of cardiac glycosides in preclinical studies. PMID:24895612

  14. Oligo/polynucleotide-based gene modification: strategies and therapeutic potential.

    PubMed

    Sargent, R Geoffrey; Kim, Soya; Gruenert, Dieter C

    2011-01-01

    Oligonucleotide- and polynucleotide-based gene modification strategies were developed as an alternative to transgene-based and classical gene targeting-based gene therapy approaches for treatment of genetic disorders. Unlike the transgene-based strategies, oligo/polynucleotide gene targeting approaches maintain gene integrity and the relationship between the protein coding and gene-specific regulatory sequences. Oligo/polynucleotide-based gene modification also has several advantages over classical vector-based homologous recombination approaches. These include essentially complete homology to the target sequence and the potential to rapidly engineer patient-specific oligo/polynucleotide gene modification reagents. Several oligo/polynucleotide-based approaches have been shown to successfully mediate sequence-specific modification of genomic DNA in mammalian cells. The strategies involve the use of polynucleotide small DNA fragments, triplex-forming oligonucleotides, and single-stranded oligodeoxynucleotides to mediate homologous exchange. The primary focus of this review will be on the mechanistic aspects of the small fragment homologous replacement, triplex-forming oligonucleotide-mediated, and single-stranded oligodeoxynucleotide-mediated gene modification strategies as it relates to their therapeutic potential.

  15. Oligo/Polynucleotide-Based Gene Modification: Strategies and Therapeutic Potential

    PubMed Central

    Sargent, R. Geoffrey; Kim, Soya

    2011-01-01

    Oligonucleotide- and polynucleotide-based gene modification strategies were developed as an alternative to transgene-based and classical gene targeting-based gene therapy approaches for treatment of genetic disorders. Unlike the transgene-based strategies, oligo/polynucleotide gene targeting approaches maintain gene integrity and the relationship between the protein coding and gene-specific regulatory sequences. Oligo/polynucleotide-based gene modification also has several advantages over classical vector-based homologous recombination approaches. These include essentially complete homology to the target sequence and the potential to rapidly engineer patient-specific oligo/polynucleotide gene modification reagents. Several oligo/polynucleotide-based approaches have been shown to successfully mediate sequence-specific modification of genomic DNA in mammalian cells. The strategies involve the use of polynucleotide small DNA fragments, triplex-forming oligonucleotides, and single-stranded oligodeoxynucleotides to mediate homologous exchange. The primary focus of this review will be on the mechanistic aspects of the small fragment homologous replacement, triplex-forming oligonucleotide-mediated, and single-stranded oligodeoxynucleotide-mediated gene modification strategies as it relates to their therapeutic potential. PMID:21417933

  16. Inhibiting subthalamic nucleus decreases cocaine demand and relapse: therapeutic potential.

    PubMed

    Bentzley, Brandon S; Aston-Jones, Gary

    2017-07-01

    Preclinical evidence indicates that inactivation of subthalamic nucleus (STN) may be effective for treating cocaine addiction, and therapies that target STN, e.g. deep brain stimulation, are available indicating that this may have clinical promise. Here, we assessed the therapeutic potential of STN inactivation using a translationally relevant economic approach that quantitatively describes drug-taking behavior, and tested these results with drug-seeking tasks. Economic demand for cocaine was assessed in rats (n = 11) using a within-session threshold procedure in which cocaine price (responses/mg cocaine) was sequentially increased throughout the session. Cocaine demand was assessed in this manner immediately after bilateral microinfusions into STN of either vehicle (artificial cerebrospinal fluid) or the GABAA receptor agonist muscimol. A separate group of animals (n = 8) was tested for changes in cocaine seeking either during extinction or in response to cocaine-associated cues. Muscimol-induced inhibition of STN significantly attenuated cocaine consumption at high prices, drug seeking during extinction and cued reinstatement of cocaine seeking. In contrast, STN inhibition did not reduce cocaine consumption at low prices or locomotor activity. Thus, STN inactivation reduced economic demand for cocaine and multiple measures of drug seeking during extinction. In view of the association between economic demand and addiction severity in both rat and human, these results indicate that STN inactivation has substantial clinical potential for treatment of cocaine addiction. © 2016 Society for the Study of Addiction.

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

    PubMed

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

    2008-12-01

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

  18. 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.

  19. Characterization of an IL-2 mimetic with therapeutic potential.

    PubMed

    Eckenberg, R; Rose, T; Moreau, J L; Weil, R; Gesbert, F; Dubois, S; Tello, D; Bossus, M; Gras, H; Tartar, A; Bertoglio, J; Chouaïb, S; Jacques, Y; Alzari, P M; Thèze, J

    2001-06-01

    Human interleukin-2 (IL-2) interacts with two types of functional receptors (IL-2R alpha betagamma and IL-2R betagamma) and acts on a broad range of target cells involved in inflammatory reactions and immune responses. IL-2 is also used in different clinical trials aimed at improving the treatment of some cancers and the recovery of CD4 lymphocytes by HIV patients. The therapeutic index of IL-2 is limited by various side effects dominated by the vascular leak syndrome. We have shown that a chemically synthesised fragment of the IL-2 sequence can fold into a helical tetramer likely mimicking the quatemary structure of an hemopoietin. Indeed, peptide p1-30 (containing amino acids 1 to 30, including the sequence corresponding to the entire alpha helix A of IL-2) spontaneously folds into an alpha-helical homotetramer and stimulates the growth of T-cell lines expressing human IL-2R beta, whereas shorter versions of the peptide lack helical structure and are inactive. At the cellular level, p1-30 induces lymphokine-activated killer (LAK) cells and preferentially activates CD8 low lymphocytes and natural killer cells, which constitutively express IL-2R beta. A significant IFN-gamma production is also detected following p1-30 stimulation. A mutant form of p1-30 (Asp20-->Lys) which is likely unable to induce vascular leak syndrome remains capable to generate LAK cells like the original p1-30 peptide. Altogether our data suggest that p1-30 has therapeutic potential.

  20. 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

  1. Long noncoding RNA GAS5 inhibits malignant proliferation and chemotherapy resistance to doxorubicin in bladder transitional cell carcinoma.

    PubMed

    Zhang, Hui; Guo, Yan; Song, Yongsheng; Shang, Chao

    2017-01-01

    Bladder cancer is the most general malignant cancer in genitourinary system, more than 90% of BCs are bladder transitional cell carcinomas (BTCC). This study aimed to investigate the clinical significance of growth arrest-specific 5 (GAS5) gene and its regulatory effects of malignant proliferation and chemotherapy resistance to doxorubicin in BTCC cells. The expression of GAS5 was detected by quantitative real-time PCR. Statistical analysis was used to determine the relationship between GAS5 expression and clinical features and the prognostic value of GAS5 for disease free survival. MTT assay was used to detect cell proliferation ability and chemosensitivity. Dual-color flow cytometric method was used to detect cell apoptosis. The expression of Bcl-2 protein was examined by western blot. In this study, we found that GAS5 low-expressed in BTCC tissues and cells, and its low expression level had positive correlation with higher pathological grades of BTCC. Moreover, GAS5 was a prognostic biomarker of disease free survival for BTCC patients. GAS5 over-expression could inhibit cell proliferation of BTCC J82 and T24 cells significantly. The IC50 to doxorubicin in T24/DOX cells (resistance to doxorubicin) presented a conspicuous depression, GAS5 enhancement reduced the chemotherapy resistance to doxorubicin. GAS5 over-expression promoted apoptosis induced by doxorubicin in T24/DOX cells, and depressed the expression of anti-apoptosis protein Bcl-2. The results indicated that GAS5 regulated the chemotherapy resistance to doxorubicin via Bcl2 partly. In summary, lncRNA GAS5 was a prognostic biomarker of disease free survival in BTCC patients, and acted as a tumor-suppressing gene to inhibit malignant proliferation and resistance to doxorubicin in BTCC cells. LncRNA GAS5 might be a novel potential therapeutic target for BTCC.

  2. Protective effects of agmatine on doxorubicin-induced chronic cardiotoxicity in rat.

    PubMed

    Yarmohmmadi, Fatemeh; Rahimi, Nastaran; Faghir-Ghanesefat, Hedyeh; Javadian, Nina; Abdollahi, Alireza; Pasalar, Parvin; Jazayeri, Farahnaz; Ejtemaeemehr, Shahram; Dehpour, Ahmad Reza

    2017-02-05

    The detrimental cardio-toxic effect of doxorubicin, an effective chemotherapeutic agent, limited its clinical use. It has been claimed that doxorubicin cardio-toxicity occurs through calcium ions (Ca(2+)) overload and reactive oxygen species production. Agmatine, an endogenous imidazoline receptor agonist, induce uptake of cytosolic Ca(2+) and cause an increase in activity of calcium pumps, including Ca(2+)-ATPase. Also it shows self-scavenging effect against reactive oxygen species production. Therefore, present study was designed to investigate the effects of agmatine against chronic cardio-toxicity of doxorubicin in rats. Male wistar rats were intraperitoneally injected with doxorubicin and agmatine four times a week for a month. Agmatine significantly alleviate the adverse effect of doxorubicin on left ventricular papillary muscle stimulation threshold and contractibility. Chronic co-administration of agmatine with doxorubicin blocked electrocardiographic changes induced by doxorubicin. In addition, agmatine improved body weight and decreased the mortality rate of animals by doxorubicin. Moreover, reversing the doxorubicin induced myocardial lesions was observed in animals treated by agmatine. A significant rise in the total antioxidant capacity of rat plasma was achieved in agmatine-treated animals in comparison to doxorubicin. To conclude, agmatine may improve therapeutic outcomes of doxorubicin since it exerts protective effects against doxorubicin-induced chronic cardiotoxicity in rats. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Covalent attachment of Mn-porphyrin onto doxorubicin-loaded poly(lactic acid) nanoparticles for potential magnetic resonance imaging and pH-sensitive drug delivery.

    PubMed

    Jing, Lijia; Liang, Xiaolong; Li, Xiaoda; Yang, Yongbo; Dai, Zhifei

    2013-12-01

    In this paper, theranostic nanoparticles (MnP-DOX NPs) were fabricated by conjugating Mn-porphyrin onto the surface of doxorubicin (DOX)-loaded poly(lactic acid) (PLA) nanoparticles (DOX NPs) for potential T1 magnetic resonance imaging and pH-sensitive drug delivery. An in vitro drug release study showed that the release rate of DOX from MnP-DOX NPs was slow at neutral pH but accelerated significantly in acidic conditions. It was found that MnP-DOX NPs could be easily internalized by HeLa cells and effectively suppressed the growth of HeLa cells and HT-29 cells due to the accelerated drug release in acidic lysosomal compartments. Magnetic resonance imaging (MRI) scanning analysis demonstrated that MnP-DOX NPs had much higher longitudinal relaxivity in water (r1 value of 27.8 mM(-1) s(-1) of Mn(3+)) than Mn-porphyrin (Mn(III)TPPS3NH2; r1 value of 6.70 mM(-1) s(-1) of Mn(3+)), behaving as an excellent contrast agent for T1-weighted MRI both in vitro and in vivo. In summary, such a smart and promising nanoplatform integrates multiple capabilities for effective cancer diagnosis and therapy. Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  4. Identification of anti-proliferative kinase inhibitors as potential therapeutic agents to treat canine osteosarcoma.

    PubMed

    Mauchle, Ulrike; Selvarajah, Gayathri T; Mol, Jan A; Kirpensteijn, Jolle; Verheije, Monique H

    2015-08-01

    Osteosarcoma is the most common primary bone tumour in dogs but various forms of therapy have not significantly improved clinical outcomes. As dysregulation of kinase activity is often present in tumours, kinases represent attractive molecular targets for cancer therapy. The purpose of this study was to identify novel compounds targeting kinases with the potential to induce cell death in a panel of canine osteosarcoma cell lines. The ability of 80 well-characterized kinase inhibitor compounds to inhibit the proliferation of four canine osteosarcoma cell lines was investigated in vitro. For those compounds with activity, the mechanism of action and capability to potentiate the activity of doxorubicin was further evaluated. The screening showed 22 different kinase inhibitors that induced significant anti-proliferative effects across the four canine osteosarcoma cell lines investigated. Four of these compounds (RO 31-8220, 5-iodotubercidin, BAY 11-7082 and an erbstatin analog) showed significant cell growth inhibitory effects across all cell lines in association with variable induction of apoptosis. RO 31-8220 and 5-iodotubercidin showed the highest ability to potentiate the effects of doxorubicin on cell viability. In conclusion, the present study identified several potent kinase inhibitors targeting the PKC, CK1, PKA, ErbB2, mTOR and NF-κB pathways, which may warrant further investigations for the treatment of osteosarcoma in dogs. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Knockdown of heme oxygenase-1 promotes apoptosis and autophagy and enhances the cytotoxicity of doxorubicin in breast cancer cells

    PubMed Central

    ZHU, XIAO-FENG; LI, WEN; MA, JIE-YI; SHAO, NAN; ZHANG, YUN-JIAN; LIU, RUI-MING; WU, WEI-BIN; LIN, YING; WANG, SHEN-MING

    2015-01-01

    Heme oxygenase-1 (HMOX-1) is a microsomal enzyme that exerts anti-apoptotic and cytoprotective effects. In the present study, HMOX-1 was demonstrated to be overexpressed and able to be induced by doxorubicin in breast cancer cell lines. Knockdown of HMOX-1 using short interfering (si)RNA enhanced the cytotoxicity of doxorubicin in MDA-MB-231 and BT549 cells. Knockdown of HMOX-1 downregulated B cell lymphoma (Bcl)-2 and Bcl-extra large expression, and significantly enhanced doxorubicin-induced apoptosis in MDA-MB-231 and BT549 cells. Additionally, knockdown of HMOX-1 upregulated light chain 3B expression and markedly increased the accumulation of autophagic vacuoles in MDA-MB-231 and BT549 cells treated with doxorubicin. These results indicated that HMOX-1 may be involved in conferring the chemoresistance of breast cancer cells, by preventing apoptosis and autophagy. Therefore, HMOX-1 may represent a potential therapeutic target for enhancing the cytotoxicity and efficacy of doxorubicin during the treatment of breast cancer. PMID:26722274

  6. Inhibition of the JAK-STAT3 pathway by andrographolide enhances chemosensitivity of cancer cells to doxorubicin.

    PubMed

    Zhou, Jing; Ong, Choon-Nam; Hur, Gang-Min; Shen, Han-Ming

    2010-05-01

    Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess potent anti-inflammatory and anticancer properties. In this study, we sought to examine the effect of Andro on signal transducer and activator of transcription 3 (STAT3) pathway and evaluate whether suppression of STAT3 activity by Andro could sensitize cancer cells to a chemotherapeutic drug doxorubicin. First, we demonstrated that Andro is able to significantly suppress both constitutively activated and IL-6-induced STAT3 phosphorylation and subsequent nuclear translocation in cancer cells. Such inhibition is found to be achieved through suppression of Janus-activated kinase (JAK)1/2 and interaction between STAT3 and gp130. For understanding the biological significance of the inhibitory effect of Andro on STAT3, we next investigated the effect of Andro on doxorubicin-induced apoptosis in human cancer cells. In our study the constitutive activation level of STAT3 was found to be correlated to the resistance of cancer cells to doxorubicin-induced apoptosis. Both the short-term MTT assay and the long-term colony formation assay showed that Andro dramatically promoted doxorubicin-induced cell death in cancer cells, indicating that Andro enhances the sensitivity of cancer cells to doxorubicin mainly via STAT3 suppression. These observations thus reveal a novel anticancer function of Andro and suggest a potential therapeutic strategy of using Andro in combination with chemotherapeutic agents for treatment of cancer.

  7. A Small Molecule Inhibitor of Human RAD51 Potentiates Breast Cancer Cell Killing by Therapeutic Agents in Mouse Xenografts

    PubMed Central

    Huang, Fei; Mazin, Alexander V.

    2014-01-01

    The homologous recombination pathway is responsible for the repair of DNA double strand breaks. RAD51, a key homologous recombination protein, promotes the search for homology and DNA strand exchange between homologous DNA molecules. RAD51 is overexpressed in a variety of cancer cells. Downregulation of RAD51 by siRNA increases radio- or chemo-sensitivity of cancer cells. We recently developed a specific RAD51 small molecule inhibitor, B02, which inhibits DNA strand exchange activity of RAD51 in vitro. In this study, we used human breast cancer cells MDA-MB-231 to investigate the ability of B02 to inhibit RAD51 and to potentiate an anti-cancer effect of chemotherapeutic agents including doxorubicin, etoposide, topotecan, and cisplatin. We found that the combination of B02 with cisplatin has the strongest killing effect on the cancer cells. We then tested the effect of B02 and cisplatin on the MDA-MB-231 cell proliferation in mouse xenografts. Our results showed that B02 significantly enhances the therapeutic effect of cisplatin on tumor cells in vivo. Our current data demonstrate that use of RAD51-specific small molecule inhibitor represents a feasible strategy of a combination anti-cancer therapy. PMID:24971740

  8. 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

  9. Notch signaling: its roles and therapeutic potential in hematological malignancies.

    PubMed

    Gu, Yisu; Masiero, Massimo; Banham, Alison H

    2016-05-17

    Notch is a highly conserved signaling system that allows neighboring cells to communicate, thereby controlling their differentiation, proliferation and apoptosis, with the outcome of its activation being highly dependent on signal strength and cell type. As such, there is growing evidence that disturbances in physiological Notch signaling contribute to cancer development and growth through various mechanisms. Notch was first reported to contribute to tumorigenesis in the early 90s, through identification of the involvement of the Notch1 gene in the chromosomal translocation t(7;9)(q34;q34.3), found in a small subset of T-cell acute lymphoblastic leukemia. Since then, Notch mutations and aberrant Notch signaling have been reported in numerous other precursor and mature hematological malignancies, of both myeloid and lymphoid origin, as well as many epithelial tumor types. Of note, Notch has been reported to have both oncogenic and tumor suppressor roles, dependent on the cancer cell type. In this review, we will first give a general description of the Notch signaling pathway, and its physiologic role in hematopoiesis. Next, we will review the role of aberrant Notch signaling in several hematological malignancies. Finally, we will discuss current and potential future therapeutic approaches targeting this pathway.

  10. 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.

  11. Chitosan oligosaccharide: Biological activities and potential therapeutic applications.

    PubMed

    Muanprasat, Chatchai; Chatsudthipong, Varanuj

    2017-02-01

    Chitosan oligosaccharide (COS) is an oligomer of β-(1➔4)-linked d-glucosamine. COS can be prepared from the deacetylation and hydrolysis of chitin, which is commonly found in the exoskeletons of arthropods and insects and the cell walls of fungi. COS is water soluble, non-cytotoxic, readily absorbed through the intestine and mainly excreted in the urine. Of particular importance, COS and its derivatives have been demonstrated to possess several biological activities including anti-inflammation, immunostimulation, anti-tumor, anti-obesity, anti-hypertension, anti-Alzheimer's disease, tissue regeneration promotion, drug and DNA delivery enhancement, anti-microbial, anti-oxidation and calcium-absorption enhancement. The mechanisms of actions of COS have been found to involve the modulation of several important pathways including the suppression of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) and the activation of AMP-activated protein kinase (AMPK). This review summarizes the current knowledge of the preparation methods, pharmacokinetic profiles, biological activities, potential therapeutic applications and safety profiles of COS and its derivatives. In addition, future research directions are discussed.

  12. Therapeutic potential of growth factors and their antagonists.

    PubMed Central

    Garner, A.

    1992-01-01

    This article describes studies with four peptides, epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), gastrin-releasing peptide/bombesin (GRP), and gastrin. The mitogenic and anti-secretory activities of EGF/TGF alpha appear to be mediated by a single class of high-affinity membrane receptors but may involve different signal transducing mechanisms. Biological activity of EGF resides in the N-terminal 42 amino acid fragment with the C-terminal undecapeptide determining binding affinity. A parenteral depot formulation of an EGF-related peptide or a small molecule agonist of the EGF receptor could have utility in treating various ulcerative disorders of the gut. Although antagonism of EGF (and thus TGF alpha) receptors and/or transducing mechanisms is frequently cited as a potential therapeutic approach to hyperproliferative diseases, blocking the action of TGF alpha, GRP, or gastrin with neutralizing antibodies or receptor antagonists did not influence the growth of a wide range of solid tumors in nude mice. These findings suggest that, unless tumor growth displays absolute dependency on one particular mitogen, antagonism of a specific growth factor is unlikely to have great effect in cancer therapy. PMID:1341074

  13. MSC and Tumors: Homing, Differentiation, and Secretion Influence Therapeutic Potential.

    PubMed

    D'souza, Naomi; Burns, Jorge Sans; Grisendi, Giulia; Candini, Olivia; Veronesi, Elena; Piccinno, Serena; Horwitz, Edwin M; Paolucci, Paolo; Conte, Pierfranco; Dominici, Massimo

    2013-01-01

    : Mesenchymal stromal/stem cells (MSC) are adult multipotent progenitors with fibroblast-like morphology able to differentiate into adipocytic, osteogenic, chondrogenic, and myogenic lineages. Due to these properties, MSC have been studied and introduced as therapeutics in regenerative medicine. Preliminary studies have also shown a possible involvement of MSC as precursors of cellular elements within tumor microenvironments, in particular tumor-associated fibroblasts (TAF). Among a number of different possible origins, TAF may originate from a pool of circulating progenitors from bone marrow or adipose tissue-derived MSC. There is growing evidence to corroborate that cells immunophenotypically defined as MSC are able to reside as TAF influencing the tumor microenvironment in a potentially bi-phasic and obscure manner: either promoting or inhibiting growth depending on tumor context and MSC sources. Here we focus on relationships between the tumor microenvironment, cancer cells, and MSC, analyzing their diverse ability to influence neoplastic development. Associated activities include MSC homing driven by the secretion of various mediators, differentiation towards TAF phenotypes, and reciprocal interactions with the tumor cells. These are reviewed here with the aim of understanding the biological functions of MSC that can be exploited for innovative cancer therapy.

  14. Reactive astrocytes and therapeutic potential in focal ischemic stroke

    PubMed Central

    Choudhury, Gourav Roy; Ding, Shinghua

    2015-01-01

    Astrocytes are specialized and the most abundant cell type in the central nervous system (CNS). They play important roles in the physiology of the brain. Astrocytes are also critically involved in many CNS disorders including focal ischemic stroke, the leading cause of brain injury and death in patients. One of the prominent pathological features of a focal ischemic stroke is reactive astrogliosis and glial scar formation. Reactive astrogliosis is accompanied with changes in morphology, proliferation and gene expression in the reactive astrocytes. This study provides an overview of the most recent advances in astrocytic Ca2+ signaling, spatial and temporal dynamics of the morphology and proliferation of reactive astrocytes as well as signaling pathways involved in the reactive astrogliosis after ischemic stroke based on results from experimental studies performed in various animal models. This review also discusses the therapeutic potential of reactive astrocytes in a focal ischemic stroke. As reactive astrocytes exhibit high plasticity, we suggest that modulation of local reactive astrocytes is a promising strategy for cell-based stroke therapy. PMID:25982835

  15. 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.

  16. Notch signaling: its roles and therapeutic potential in hematological malignancies

    PubMed Central

    Gu, Yisu

    2016-01-01

    Notch is a highly conserved signaling system that allows neighboring cells to communicate, thereby controlling their differentiation, proliferation and apoptosis, with the outcome of its activation being highly dependent on signal strength and cell type. As such, there is growing evidence that disturbances in physiological Notch signaling contribute to cancer development and growth through various mechanisms. Notch was first reported to contribute to tumorigenesis in the early 90s, through identification of the involvement of the Notch1 gene in the chromosomal translocation t(7;9)(q34;q34.3), found in a small subset of T-cell acute lymphoblastic leukemia. Since then, Notch mutations and aberrant Notch signaling have been reported in numerous other precursor and mature hematological malignancies, of both myeloid and lymphoid origin, as well as many epithelial tumor types. Of note, Notch has been reported to have both oncogenic and tumor suppressor roles, dependent on the cancer cell type. In this review, we will first give a general description of the Notch signaling pathway, and its physiologic role in hematopoiesis. Next, we will review the role of aberrant Notch signaling in several hematological malignancies. Finally, we will discuss current and potential future therapeutic approaches targeting this pathway. PMID:26934331

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

    PubMed Central

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

    2014-01-01

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

  18. Investigation of Stilbenoids as Potential Therapeutic Agents for Rotavirus Gastroenteritis.

    PubMed

    Ball, Judith M; Medina-Bolivar, Fabricio; Defrates, Katelyn; Hambleton, Emily; Hurlburt, Megan E; Fang, Lingling; Yang, Tianhong; Nopo-Olazabal, Luis; Atwill, Richard L; Ghai, Pooja; Parr, Rebecca D

    2015-01-01

    Rotavirus (RV) infections cause severe diarrhea in infants and young children worldwide. Vaccines are available but cost prohibitive for many countries and only reduce severe symptoms. Vaccinated infants continue to shed infectious particles, and studies show decreased efficacy of the RV vaccines in tropical and subtropical countries where they are needed most. Continuing surveillance for new RV strains, assessment of vaccine efficacy, and development of cost effective antiviral drugs remain an important aspect of RV studies. This study was to determine the efficacy of antioxidant and anti-inflammatory stilbenoids to inhibit RV replication. Peanut (A. hypogaea) hairy root cultures were induced to produce stilbenoids, which were purified by high performance countercurrent chromatography (HPCCC) and analyzed by HPLC. HT29.f8 cells were infected with RV in the presence stilbenoids. Cell viability counts showed no cytotoxic effects on HT29.f8 cells. Viral infectivity titers were calculated and comparatively assessed to determine the effects of stilbenoid treatments. Two stilbenoids, trans-arachidin-1 and trans-arachidin-3, show a significant decrease in RV infectivity titers. Western blot analyses performed on the infected cell lysates complemented the infectivity titrations and indicated a significant decrease in viral replication. These studies show the therapeutic potential of the stilbenoids against RV replication.

  19. Therapeutic potential of siRNA and DNAzymes in cancer.

    PubMed

    Karnati, Hanuma Kumar; Yalagala, Ravi Shekar; Undi, Rambabu; Pasupuleti, Satya Ratan; Gutti, Ravi Kumar

    2014-10-01

    Cancer is characterized by uncontrolled cell growth, invasion, and metastasis and possess threat to humans worldwide. The scientific community is facing numerous challenges despite several efforts to cure cancer. Though a number of studies were done earlier, the molecular mechanism of cancer progression is not completely understood. Currently available treatments like surgery resection, adjuvant chemotherapy, and radiotherapy are not completely effective in curing all the cancers. Recent advances in the antisense technology provide a powerful tool to investigate various cancer pathways and target them. Small interfering RNAs (siRNAs) could be effective in downregulating the cancer-associated genes, but their in vivo delivery is the main obstacle. DNA enzymes (DNAzymes) have great potential in the treatment of cancer due to high selectivity and significant catalytic efficiency. In this review, we are focusing on antisense molecules such as siRNA and DNAzymes in cancer therapeutics development. This review also describes the challenges and approaches to overcome obstacles involved in using siRNA and DNAzymes in the treatment of cancers.

  20. 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

  1. Astaxanthin: A Potential Therapeutic Agent in Cardiovascular Disease

    PubMed Central

    Fassett, Robert G.; Coombes, Jeff S.

    2011-01-01

    Astaxanthin is a xanthophyll carotenoid present in microalgae, fungi, complex plants, seafood, flamingos and quail. It is an antioxidant with anti-inflammatory properties and as such has potential as a therapeutic agent in atherosclerotic cardiovascular disease. Synthetic forms of astaxanthin have been manufactured. The safety, bioavailability and effects of astaxanthin on oxidative stress and inflammation that have relevance to the pathophysiology of atherosclerotic cardiovascular disease, have been assessed in a small number of clinical studies. No adverse events have been reported and there is evidence of a reduction in biomarkers of oxidative stress and inflammation with astaxanthin administration. Experimental studies in several species using an ischaemia-reperfusion myocardial model demonstrated that astaxanthin protects the myocardium when administered both orally or intravenously prior to the induction of the ischaemic event. At this stage we do not know whether astaxanthin is of benefit when administered after a cardiovascular event and no clinical cardiovascular studies in humans have been completed and/or reported. Cardiovascular clinical trials are warranted based on the physicochemical and antioxidant properties, the safety profile and preliminary experimental cardiovascular studies of astaxanthin. PMID:21556169

  2. 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.

  3. 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.

  4. Chelating polymeric beads as potential therapeutics for Wilson's disease.

    PubMed

    Mattová, Jana; Poučková, Pavla; Kučka, Jan; Skodová, Michaela; Vetrík, Miroslav; Stěpánek, Petr; Urbánek, Petr; Petřík, Miloš; Nový, Zbyněk; Hrubý, Martin

    2014-10-01

    Wilson's disease is a genetic disorder caused by a malfunction of ATPase 7B that leads to high accumulation of copper in the organism and consequent toxic effects. We propose a gentle therapy to eliminate the excessive copper content with oral administration of insoluble non-resorbable polymer sorbents containing selective chelating groups for copper(II). Polymeric beads with the chelating agents triethylenetetramine, N,N-di(2-pyridylmethyl)amine, and 8-hydroxyquinoline (8HQB) were investigated. In a preliminary copper uptake experiment, we found that 8HQB significantly reduced copper uptake (using copper-64 as a radiotracer) after oral administration in Wistar rats. Furthermore, we measured organ radioactivity in rats to demonstrate that 8HQB radiolabelled with iodine-125 is not absorbed from the gastrointestinal tract after oral administration. Non-resorbability and the blockade of copper uptake were also confirmed with small animal imaging (PET/CT) in mice. In a long-term experiment with Wistar rats fed a diet containing the polymers, we have found that there were no signs of polymer toxicity and the addition of polymers to the diet led to a significant reduction in the copper contents in the kidneys, brains, and livers of the rats. We have shown that polymers containing specific ligands could potentially be novel therapeutics for Wilson's disease. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. The Therapeutic Potential of Milk Thistle in Diabetes

    PubMed Central

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

    2014-01-01

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

  6. GLP-1: physiological effects and potential therapeutic applications.

    PubMed

    Aaboe, Kasper; Krarup, Thure; Madsbad, Sten; Holst, Jens Juul

    2008-11-01

    Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone with the potential to change diabetes. The physiological effects of GLP-1 are multiple, and many seem to ameliorate the different conditions defining the diverse physiopathology seen in type 2 diabetes. In animal studies, GLP-1 stimulates beta-cell proliferation and neogenesis and inhibits beta-cell apoptosis. In humans, GLP-1 stimulates insulin secretion and inhibits glucagon and gastrointestinal secretions and motility. It enhances satiety and reduces food intake and has beneficial effects on cardiovascular function and endothelial dysfunction. Enhancing incretin action for therapeutic use includes GLP-1 receptor agonists resistant to degradation (incretin mimetics) and dipeptidyl peptidase (DPP)-4 inhibitors. In clinical trials with type 2 diabetic patients on various oral antidiabetic regimes, both treatment modalities efficaciously improve glycaemic control and beta-cell function. Whereas the incretin mimetics induce weight loss, the DPP-4 inhibitors are considered weight neutral. In type 1 diabetes, treatment with GLP-1 shows promising effects. However, several areas need clinical confirmation: the durability of the weight loss, the ability to preserve functional beta-cell mass and the applicability in other than type 2 diabetes. As such, long-term studies and studies with cardiovascular end-points are needed to confirm the true benefits of these new classes of antidiabetic drugs in the treatment of diabetes mellitus.

  7. 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?

  8. Pueraria tuberosa: a review on its phytochemical and therapeutic potential.

    PubMed

    Maji, Amal K; Pandit, Subrata; Banerji, Pratim; Banerjee, Debdulal

    2014-01-01

    Pueraria tuberosa (Willd.) DC is a perennial herb commonly known as 'vidarikanda', distributed throughout south east Asia. The plant's tuber is widely used in ethanomedicine as well as in traditional systems of medicine, particularly in ayurveda. It has been used in various ayurvedic formulations as restorative tonic, antiaging, spermatogenic and immune booster and has been recommended for the treatment of cardiovascular diseases, hepatosplenomegaly, fertility disorders, menopausal syndrome, sexual debility and spermatorrhoea. Numerous bioactive phytochemicals, mostly isoflavonoids such as puerarin, genistein, daidzein, tuberosin and so on have been identified in the tuber. In vivo and in vitro studies have provided the support against traditional demands of the tuber as spermatogenic, immune booster, aphrodisiac, anti-inflammatory, cardiotonic and brain tonic. However, further studies are required to define the active phytochemical compositions and to validate its clinical utilisation in the herbal formulations for human uses. This review provides an overview of traditional applications, current knowledge on the phytochemistry, pharmacology and toxicology of P. tuberosa. This review also provides plausible hypotheses about how various isoflavones particularly puerarin, genistein and daidzein, individually or collectively, may be responsible for the therapeutic potential against a wide range of ailments.

  9. Therapeutic Potential of Induced Neural Stem Cells for Parkinson's Disease.

    PubMed

    Choi, Dong-Hee; Kim, Ji-Hye; Kim, Sung Min; Kang, Kyuree; Han, Dong Wook; Lee, Jongmin

    2017-01-22

    Parkinson's disease (PD) is a chronic, neurodegenerative disorder that results from the loss of cells in the substantia nigra (SN) which is located in the midbrain. However, no cure is available for PD. Recently, fibroblasts have been directly converted into induced neural stem cells (iNSCs) via the forced expression of specific transcription factors. Therapeutic potential of iNSC in PD has not been investigated yet. Here, we show that iNSCs directly converted from mouse fibroblasts enhanced functional recovery in an animal model of PD. The rotational behavior test was performed to assess recovery. Our results indicate that iNSC transplantation into the striatum of 6-hydroxydopamine (6-OHDA)-injected mice can significantly reduce apomorphine-induced rotational asymmetry. The engrafted iNSCs were able to survive in the striatum and migrated around the medial forebrain bundle and the SN pars compacta. Moreover, iNSCs differentiated into all neuronal lineages. In particular, the transplanted iNSCs that committed to the glial lineage were significantly increased in the striatum of 6-OHDA-injected mice. Engrafted iNSCs differentiated to dopaminergic (DA) neurons and migrated into the SN in the 6-OHDA lesion mice. Therefore, iNSC transplantation serves as a valuable tool to enhance the functional recovery in PD.

  10. Astaxanthin: a potential therapeutic agent in cardiovascular disease.

    PubMed

    Fassett, Robert G; Coombes, Jeff S

    2011-03-21

    Astaxanthin is a xanthophyll carotenoid present in microalgae, fungi, complex plants, seafood, flamingos and quail. It is an antioxidant with anti-inflammatory properties and as such has potential as a therapeutic agent in atherosclerotic cardiovascular disease. Synthetic forms of astaxanthin have been manufactured. The safety, bioavailability and effects of astaxanthin on oxidative stress and inflammation that have relevance to the pathophysiology of atherosclerotic cardiovascular disease, have been assessed in a small number of clinical studies. No adverse events have been reported and there is evidence of a reduction in biomarkers of oxidative stress and inflammation with astaxanthin administration. Experimental studies in several species using an ischaemia-reperfusion myocardial model demonstrated that astaxanthin protects the myocardium when administered both orally or intravenously prior to the induction of the ischaemic event. At this stage we do not know whether astaxanthin is of benefit when administered after a cardiovascular event and no clinical cardiovascular studies in humans have been completed and/or reported. Cardiovascular clinical trials are warranted based on the physicochemical and antioxidant properties, the safety profile and preliminary experimental cardiovascular studies of astaxanthin.

  11. Sesamol: an efficient antioxidant with potential therapeutic benefits.

    PubMed

    Geetha, Thiraviam; Rohit, Bhandari; Pal, Kaur Indu

    2009-07-01

    Sesamol has been shown earlier to exhibit antimutagenic (reactive oxygen mediated) and antiageing activity in our lab and it has also been found to exert chemopreventive effect. Here we report the in vitro antioxidant activity of sesamol. As most of the antioxidants act due to their property to auto-oxidise and the pro- or antioxidant activity would depend on the concentration of the agent used and the free radical source, at least 6 dilutions in concentration range of 5-1000 nmoles of sesamol were selected for each test system. Further the antioxidant activity was compared with a water soluble antioxidant (ascorbic acid). Eventhough some preliminary studies on the antioxidant activity of sesamol have been reported in DPPH assay & inhibition of lipid peroxidation, it is not complete. We, here in report comprehensively (both in terms of the no. of doses and also a variety of test systems being employed) on the antioxidant activity of sesamol. Furthermore, since all the data has been generated by the same workers and under same laboratory conditions, hence is scientifically significant. Also the process of dose selection as discussed earlier is more scientific; and the data treatment, i.e. calculation of IC(50) values and comparisons with ascorbic acid has been statistically validated. In conclusion, sesamol was found to be an efficient scavenger of the entire range of ROS in several test systems pointing towards the potential of sesamol to be developed as a possible therapeutic.

  12. Assessment of therapeutic potential of amantadine in methamphetamine induced neurotoxicity.

    PubMed

    Thrash-Williams, Bessy; Ahuja, Manuj; Karuppagounder, Senthilkumar S; Uthayathas, Subramaniam; Suppiramaniam, Vishnu; Dhanasekaran, Muralikrishnan

    2013-10-01

    Methamphetamine epidemic has a broad impact on world's health care system. Its abusive potential and neurotoxic effects remain a challenge for the anti-addiction therapies. In addition to oxidative stress, mitochondrial dysfunction and apoptosis, excitotoxicity is also involved in methamphetamine induced neurotoxicity. The N-methyl-D-aspartate (NMDA) type of glutamate receptor is thought to be one of the predominant mediators of excitotoxicity. There is growing evidence that NMDA receptor antagonists could be one of the therapeutic options to manage excitotoxicity. Amantadine, a well-tolerated and modestly effective antiparkinsonian agent, was found to possess NMDA antagonistic properties and has shown to release dopamine from the nerve terminals. The current study aimed to evaluate the effect of amantadine pre-treatment against methamphetamine induced neurotoxicity. Results showed that methamphetamine treatment had depleted striatal dopamine, generated of reactive oxygen species and decreased activity of complex I in the mitochondria. Interestingly, amantadine, at high dose (10 mg/kg), did not prevent dopamine depletion moreover it exacerbated the behavioral manifestations of methamphetamine toxicity such as akinesia and catalepsy. Only lower dose of amantadine (1 mg/kg) produced significant scavenging of the reactive oxygen species induced by methamphetamine. Overall results from the present study suggest that amantadine should not be used concomitantly with methamphetamine as it may results in excessive neurotoxicity.

  13. 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

  14. Potential therapeutic misadministration due to inappropriate electron beam field shaping.

    PubMed

    Olch, A J; Fallen, R; Conrad, J; Lavey, R S

    2000-01-01

    Lead or cerrobend blocking strips are used to shape electron treatment fields when an appropriate custom insert is not available. For the Varian 2100C accelerator, the structural supports of the electron applicators impede the free placement of these field-shaping strips on the open custom insert frame while placement at the top of the applicator is unimpeded. We have investigated the dosimetric ramifications of placing field shaping strips at the top level of the 15x15 applicator for 6, 9, and 16 MeV electrons. Our results demonstrate as much as a 30% dose decrease and 2 cm penumbral increase when this is done compared to field shaping at the insert level. The magnitude of this dosimetric error qualifies as a therapeutic misadministration in many states depending on how many treatments are delivered in this manner. Based on this finding, we recommend that routine use of lead strip blocking be discouraged in favor of custom inserts due to the potential for inappropriate placement on some linear accelerators.

  15. 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

  16. Parasitic infection as a potential therapeutic tool against rheumatoid arthritis

    PubMed Central

    Apaer, Shadike; Tuxun, Tuerhongjiang; Ma, Hai-Zhang; Zhang, Heng; Aierken, Amina; Aini, Abudusalamu; Li, Yu-Peng; Lin, Ren-Yong; Wen, Hao

    2016-01-01

    Parasites, which are a recently discovered yet ancient dweller in human hosts, remain a great public health burden in underdeveloped countries, despite preventative efforts. Rheumatoid arthritis is a predominantly cosmopolitan health problem with drastic morbidity rates, although encouraging progress has been achieved regarding treatment. However, although various types of methods and agents have been applied clinically, their broad usage has been limited by their adverse effects and/or high costs. Sustained efforts have been exerted on the ‘hygiene hypothesis’ since the 1870s. The immunosuppressive nature of parasitic infections may offer potential insight into therapeutic strategies for rheumatoid arthritis, in which the immune system is overactivated. An increasing number of published papers are focusing on the preventive and/or curative effect of various parasitic infection on rheumatoid arthritis from experimental studies to large-scale epidemiological studies and clinical trials. Therefore, the present review aimed to provide a general literature review on the possible beneficial role of parasitic infection on rheumatoid arthritis. PMID:27698735

  17. Ghrelin and its therapeutic potential for cachectic patients.

    PubMed

    Ashitani, Jun-ichi; Matsumoto, Nobuhiro; Nakazato, Masamitsu

    2009-10-01

    The discovery of ghrelin has resulted in the development of approaches to appetite, enabling a better understanding of the mechanisms regulating appetite through molecular analyses. Ghrelin is a 28-amino acid peptide that was isolated from the stomach only a decade ago, and has recently been investigated as a potential therapeutic endogenous agent. This peptide increases appetite, adjusts energy balance, suppresses inflammation, and enhances the release of growth hormone from the pituitary gland. Although many bioactive substances such as peptide YY, leptin, adiponectin and obestatin are involved in appetite control, ghrelin is the only known peptide to signal starvation information from a peripheral organ to the central nervous system, contributing to an increase in appetite. Clinical trials have revealed the effectiveness of ghrelin in increasing lean body mass and activity in cachectic patients. As shown in clinical research on humans and basic research using animal models, cachexia often occurs in response to excess release of proinflammatory cytokines and induces further appetite loss, which aggravates the physiological status of underlying diseases. Ghrelin functions as a protector against the vicious cycle of the cachectic paradigm through orexigenic, anabolic and anti-inflammatory effects, so administration of ghrelin may be able to improve quality of life in cachectic patients. We show here a significant role of ghrelin in the pathophysiology of cachectic diseases and the possibility of clinical applications.

  18. Doxorubicin Lipid Complex Injection

    MedlinePlus

    ... in combination with another chemotherapy drug to treat multiple myeloma (a type of cancer of the bone marrow) ... When doxorubicin lipid complex is used to treat multiple myeloma, it is given on certain days every 3 ...

  19. MicroRNAs in neuroblastoma: Biomarkers with Therapeutic potential.

    PubMed

    Galardi, Angela; Colletti, Marta; Businaro, Pietro; Quintarelli, Concetta; Locatelli, Franco; Di Giannatale, Angela

    2017-10-03

    Neuroblastoma is the most common extracranial solid tumor in infancy. The majority of children have a disseminated disease at diagnosis with bone marrow as the most common site of metastasis. Although several prognostic factors have been defined (i.e. age, stage, histology, recurrent genetic anomalies), the identification of non-invasive biomarkers for disease follow-up and therapy monitoring is indeed still a clinical need. Aberrant regulation of microRNAs (miRNAs) expression has been implicated in several malignancies. In this mini-review, we describe the recent findings about miRNAs in neuroblastoma, both in the tumor and circulation, with particular focus on those involved in tumor progression and drug resistance. Furthermore, we will discuss the use of specific miRNAs as potential therapeutic tools in this tumor. Several miRNAs have been identified to be down- or up-regulated in primary tumors and have been associated with MYCN amplification, differentiation, dissemination and chemoresistance. Little evidence is available in the literature about circulating miRNAs which are of particular interest due to them being potential biomarkers for liquid biopsy. Identification of body-fluid markers for non-invasive diagnosis, risk stratification, treatment monitoring and tumor follow-up, is gaining growing interest, especially in the pediatric field. miRNAs are suitable candidates as biomarkers in neuroblastoma but further investigations are needed to expand knowledge regarding their role in this malignancy to design specific approaches of miRNAs-mediated therapies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. Therapeutic Potential of Chinese Herbal Medicines in Alcoholic Liver Disease

    PubMed Central

    Lu, Kuan-Hung; Liu, Chun-Ting; Raghu, Rajasekaran; Sheen, Lee-Yan

    2012-01-01

    Alcoholic liver disease (ALD) is a complex chronic disease and is associated with a spectrum of liver injury ranging from steatosis and steatohepatitis to fibrosis and cirrhosis. Since effective therapies for ALD are still limited, Chinese herbal medicine is thought to be an important and alternative approach. This review focuses on the current scientific evidence of ALD by ten Chinese Materia Medica (中藥 zhōng yào), including Salviae Miltiorrhizae Radix (丹參 dān shēn), Notoginseng Radix (三七 sān qī), Lycii Fructus (枸杞子 gǒu qǐ zǐ), Cnidii Fructus (蛇床子 shé chuáng zǐ), Gentianae Radix (龍膽 lóng dǎn), Puerariae Radix (葛根 gé gēn), Puerariae Flos (葛花 gé huā), Magnoliae Officinalis Cortex (厚朴 hòu pò), Platycodonis Radix (桔梗 jié gěng), and Trigonellae Semen (胡蘆巴 hú lú bā). Potential mechanisms of these herbal medicines in ALD are involved in amelioration of enhanced inflammation, reduction of hepatic oxidative stress and lipogenesis, and enhancement of intestinal permeability in alcohol-induced liver injury models in vitro and in vivo. Accordingly, the evidenced therapeutic potential suggests that these herbs are promising candidates for prevention and development of new drugs for ALD in the future. PMID:24716123

  1. Transferrin targeted core-shell nanomedicine for combinatorial delivery of doxorubicin and sorafenib against hepatocellular carcinoma.

    PubMed

    Malarvizhi, Giridharan Loghanathan; Retnakumari, Archana Payickattu; Nair, Shantikumar; Koyakutty, Manzoor

    2014-11-01

    Combinatorial drug delivery is an attractive, but challenging requirement of next generation cancer nanomedicines. Here, we report a transferrin-targeted core-shell nanomedicine formed by encapsulating two clinically used single-agent drugs, doxorubicin and sorafenib against liver cancer. Doxorubicin was loaded in poly(vinyl alcohol) nano-core and sorafenib in albumin nano-shell, both formed by a sequential freeze-thaw/coacervation method. While sorafenib from the nano-shell inhibited aberrant oncogenic signaling involved in cell proliferation, doxorubicin from the nano-core evoked DNA intercalation thereby killing >75% of cancer cells. Upon targeting using transferrin ligands, the nanoparticles showed enhanced cellular uptake and synergistic cytotoxicity in ~92% of cells, particularly in iron-deficient microenvironment. Studies using 3D spheroids of liver tumor indicated efficient penetration of targeted core-shell nanoparticles throughout the tissue causing uniform cell killing. Thus, we show that rationally designed core-shell nanoparticles can effectively combine clinically relevant single-agent drugs for exerting synergistic activity against liver cancer. Transferrin-targeted core-shell nanomedicine encapsulating doxorubicin and sorafenib was studied as a drug delivery system against hepatocellular carcinoma, resulting in enhanced and synergistic therapeutic effects, paving the way towards potential future clinical applications of similar techniques. Copyright © 2014 Elsevier Inc. All rights reserved.

  2. Polyaspartic acid functionalized gold nanoparticles for tumor targeted doxorubicin delivery.

    PubMed

    Khandekar, Sameera V; Kulkarni, M G; Devarajan, Padma V

    2014-01-01

    In this paper, we present polyaspartic acid, a biodegradable polymer as a reducing and functionalizing agent for the synthesis of doxorubicin loaded gold nanoparticles by a green process. Gold nanoparticles were stable to electrolytes and pH. Secondary amino groups of polyaspartic acid enabled reduction of gold chloride to form gold nanoparticles of size 55 +/-10 nm, with face centered cubic crystalline structure as confirmed by UV, TEM, SAED and XRD studies. Cationic doxorubicin was readily loaded onto anionic polyaspartic acid gold nanoparticles by ionic complexation. Fluorescence studies confirmed doxorubicin loading while FTIR spectra confirmed ionic complexation. Doxorubicin loading onto polyaspartic acid gold nanoparticles was studied at doxorubicin/polyaspartic acid molar ratios 1:10 to 1:1. As the molar ratio tended to unity, although loading up to 60% was achieved, colloidal instability resulted and is attributed to effective covering of negative charges of polyaspartic acid. Stable doxorubicin loaded polyaspartic acid gold nanoparticles of 105 +/- 15.1 nm with doxorubicin loading of 23.85% w/w and zeta potential value of -28 +/- 0.77 mV were obtained at doxorubicin/polyaspartic acid molar ratio 1:10. Higher doxorubicin release rate from the doxorubicin loaded polyaspartic acid gold nanoparticles in an acid medium (i.e., pH 5.5) as compared to that in pH 7.4 and deionized water is a desirable characteristic for tumor targeted delivery. Enhanced cytotoxicity and 3 fold higher uptake of doxorubicin loaded polyaspartic acid gold nanoparticles as compared to doxorubicin solution were seen in MCF-7 breast cancer cells while polyaspartic acid gold nanoparticles revealed no cytotoxicity confirming safety. Prominent regression in tumor size in-vivo in fibrosarcoma tumor induced mouse model was observed upto 59 days with doxorubicin loaded polyaspartic acid gold nanoparticles while doxorubicin solution treated mice showed regrowth beyond 23rd day. Moreover, a

  3. Liposomal Coencapsulation of Doxorubicin with Listeriolysin O Increases Potency via Subcellular Targeting.

    PubMed

    Walls, Zachary F; Gong, Henry; Wilson, Rebecca J

    2016-03-07

    Liposomal doxorubicin is a clinically important drug formulation indicated for the treatment of several different forms of cancer. For doxorubicin to exert a therapeutic effect, it must gain access to the nucleus. However, a large proportion of the liposomal doxorubicin dose fails to work because it is sequestered within endolysosomal organelles following endocytosis of the liposomes due to the phenomenon of ion trapping. Listeriolysin O (LLO) is a pore-forming protein that can provide a mechanism for endosomal escape. The present study demonstrates that liposomal coencapsulation of doxorubicin with LLO enables a significantly larger percentage of the dose to colocalize with the nucleus compared to liposomes containing doxorubicin alone. The change in intracellular distribution resulted in a significantly more potent formulation of liposomal doxorubicin as demonstrated in both the ovarian carcinoma cell line A2780 and its doxorubicin-resistant derivative A2780ADR.

  4. Dextran-doxorubicin/chitosan nanoparticles for solid tumor therapy.

    PubMed

    Bisht, Savita; Maitra, Amarnath

    2009-01-01

    Chemotherapy is a major therapeutic approach for the treatment of localized and metastasized cancers. Whereas potent chemotherapeutic agents seem promising in the test tube, clinical trials often fail due to unfavorable pharmacokinetics, poor delivery, low local concentrations, and limited accumulation in the target cell. The pathophysiology of the tumor vasculature and stromal compartment presents a major obstacle to effective delivery of agents to solid tumors. Poor perfusion of the tumor, arterio-venous shunting, necrotic and hypoxic areas, as well as a high interstitial fluid pressure work against favorable drug uptake. Thus, targeted drug delivery using long-circulating particulate drug carriers such as hydrogels of controlled size (<100 nm diameter) holds immense potential to improve the treatment of cancer by selectively providing therapeutically effective drug concentrations at the tumor site [through enhanced permeability and retention (EPR) effect] while reducing undesirable side effects. This review focuses on the progress of targeted delivery of nanoparticulated anticancer drug such as doxorubicin chemically conjugated with dextran and encapsulated in chitosan nanoparticles to solid tumor with reduced side effect of drug. Regulated particle size and long circulation of these hydrogel nanoparticles in blood help them accumulate in tumor tissue through EPR effect as evident from the significant regression of the tumor volume. The cardiotoxicity of doxorubicin can be minimized by coupling the drug with dextran and encapsulating it in chitosan nanoparticles. (c) 2009 John Wiley & Sons, Inc.

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

    PubMed Central

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

    2015-01-01

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

  6. Llama Nanoantibodies with Therapeutic Potential against Human Norovirus Diarrhea

    PubMed Central

    Garaicoechea, Lorena; Aguilar, Andrea; Parra, Gabriel I.; Bok, Marina; Sosnovtsev, Stanislav V.; Canziani, Gabriela; Green, Kim Y.; Bok, Karin; Parreño, Viviana

    2015-01-01

    Noroviruses are a major cause of acute gastroenteritis, but no vaccines or therapeutic drugs are available. Llama-derived single chain antibody fragments (also called VHH) are small, recombinant monoclonal antibodies of 15 kDa with several advantages over conventional antibodies. The aim of this study was to generate recombinant monoclonal VHH specific for the two major norovirus (NoV) genogroups (GI and GII) in order to investigate their potential as immunotherapy for the treatment of NoV diarrhea. To accomplish this objective, two llamas were immunized with either GI.1 (Norwalk-1968) or GII.4 (MD2004) VLPs. After immunization, peripheral blood lymphocytes were collected and used to generate two VHH libraries. Using phage display technology, 10 VHH clones specific for GI.1, and 8 specific for GII.4 were selected for further characterization. All VHH recognized conformational epitopes in the P domain of the immunizing VP1 capsid protein, with the exception of one GII.4 VHH that recognized a linear P domain epitope. The GI.1 VHHs were highly specific for the immunizing GI.1 genotype, with only one VHH cross-reacting with GI.3 genotype. The GII.4 VHHs reacted with the immunizing GII.4 strain and showed a varying reactivity profile among different GII genotypes. One VHH specific for GI.1 and three specific for GII.4 could block the binding of homologous VLPs to synthetic HBGA carbohydrates, saliva, and pig gastric mucin, and in addition, could inhibit the hemagglutination of red blood cells by homologous VLPs. The ability of Nov-specific VHHs to perform well in these surrogate neutralization assays supports their further development as immunotherapy for NoV treatment and immunoprophylaxis. PMID:26267898

  7. Pharmacology of rosemary (Rosmarinus officinalis Linn.) and its therapeutic potentials.

    PubMed

    al-Sereiti, M R; Abu-Amer, K M; Sen, P

    1999-02-01

    The use of plants is as old as the mankind. Natural products are cheap and claimed to be safe. They are also suitable raw material for production of new synthetic agents. Rosemary (Rosmarinus officinalis Linn.) is a common household plant grown in many parts of the world. It is used for flavouring food, a beverage drink, as well as in cosmetics; in folk.medicine it is used as an antispasmodic in renal colic and dysmenorrhoea, in relieving respiratory disorders and to stimulate growth of hair. Extract of rosemary relaxes smooth muscles of trachea and intestine, and has choleretic, hepatoprotective and antitumerogenic activity. The most important constituents of rosemary are caffeic acid and its derivatives such as rosmarinic acid. These compounds have antioxidant effect. The phenolic compound, rosmarinic acid, obtains one of its phenolic rings from phenylalanine via caffeic acid and the other from tyrosine via dihydroxyphenyl-lactic acid. Relatively large-scale production of rosmarinic acid can be obtained from the cell culture of Coleus blumei Benth when supplied exogenously with phenylalanine and tyrosine. Rosmarinic acid is well absorbed from gastrointestinal tract and from the skin. It increases the production of prostaglandin E2 and reduces the production of leukotriene B4 in human polymorphonuclear leucocytes, and inhibits the complement system. It is concluded that rosemary and its constituents especially caffeic acid derivatives such as rosmarinic acid have a therapeutic potential in treatment or prevention of bronchial asthma, spasmogenic disorders, peptic ulcer, inflammatory diseases, hepatotoxicity, atherosclerosis, ischaemic heart disease, cataract, cancer and poor sperm motility.

  8. Recent developments in the therapeutic potential of cannabinoids.

    PubMed

    Corey, Susan

    2005-03-01

    To examine the recent evidence that marijuana and other cannabinoids have therapeutic potential. Literature published since 1997 was searched using the following terms: cannabinoid, marijuana, THC, analgesia, cachexia, glaucoma, movement, multiple sclerosis, neurological, pain, Parkinson, trial, vomiting. Qualifying clinical studies were randomized, double-blind, and placebo-controlled. Selected open-label studies and surveys are also discussed. A total of 15 independent, qualifying clinical trials were identified, of which only three had more than 100 patients each. Two large trials found that cannabinoids were significantly better than placebo in managing spasticity in multiple sclerosis. Patients self-reported greater sense of motor improvement in multiple sclerosis than could be confirmed objectively. In smaller qualifying trials, cannabinoids produced significant objective improvement of tics in Tourette's disease, and neuropathic pain. A new, non-psychotropic cannabinoid also has analgesic activity in neuropathic pain. No significant improvement was found in levodopa-induced dyskinesia in Parkinson's Disease or post-operative pain. No difference from active placebo was found for management of cachexia in a large trial. Some immune system parameters changed in HIV-1 and multiple sclerosis patients treated with cannabinoids, but the clinical significance is unknown. Quality of life assessments were made in only three of 15 qualifying clinical trials. Cannabinoids may be useful for conditions that currently lack effective treatment, such as spasticity, tics and neuropathic pain. New delivery systems for cannabinoids and cannabis-based medicinal extracts, as well as new cannabinoid derivatives expand the options for cannabinoid therapy. More well-controlled, large clinical tests are needed, especially with active placebo.

  9. Therapeutic potential of ginseng in the management of cardiovascular disorders.

    PubMed

    Karmazyn, Morris; Moey, Melissa; Gan, Xiaohong Tracey

    2011-10-22

    Although employed in Asian societies for thousands of years, the use of ginseng as an herbal medication for a variety of disorders has increased tremendously worldwide in recent years. Ginseng belongs to the genus Panax, of which there exists a variety, generally reflecting their geographic origin. North American ginseng (Panax quinquefolius) and Asian ginseng (Panax ginseng) are two such varieties possessing a plethora of pharmacological properties, which are attributed primarily to the presence of different ginsenosides that bestow these ginsengs with distinct pharmacodynamic profiles. The many cardiovascular benefits attributed to ginseng include cardioprotection, antihypertensive effects, and attenuation of myocardial hypertrophy and heart failure. Experimental studies have revealed a number of beneficial properties of ginseng, particularly in the area of cardiac protection, where ginseng and ginsenosides have been shown to protect the ischaemic and reperfused heart in a variety of experimental models. Emerging evidence also suggests that ginseng attenuates myocardial hypertrophy, thus blunting the remodelling and heart failure processes. However, clinical evidence of efficacy is not convincing, likely owing primarily to the paucity of well designed, randomized, controlled clinical trials. Adding to the complexity in understanding the cardiovascular effects of ginseng is the fact that each of the different ginseng varieties possesses distinct cardiovascular properties, as a result of their respective ginsenoside composition, rendering it difficult to assign a general, common cardiovascular effect to ginseng. Additional challenges include the identification of mechanisms (likely multifaceted) that account for the effects of ginseng and determining which ginsenoside(s) mediate these cardiovascular properties. These concerns notwithstanding, the potential cardiovascular benefit of ginseng is worthy of further studies in view of its possible development as a

  10. Therapeutic potential of thalidomide for gemcitabine-resistant bladder cancer.

    PubMed

    Huang, Yen Ta; Cheng, Chuan Chu; Chiu, Ted H; Lai, Pei Chun

    2015-11-01

    Controversial effects of thalidomide for solid malignancies have been reported. In the present study, we evaluate the effects of thalidomide for transitional cell carcinoma (TCC), the most common type of bladder cancer. Thalidomide precipitates were observed when its DMSO solution was added to the culture medium. No precipitation was found when thalidomide was dissolved in 45% γ-cyclodextrin, and this concentration of γ-cyclodextrin elicited slight cytotoxicity on TCC BFTC905 and primary human urothelial cells. Thalidomide-γ-cyclodextrin complex exerted a concentration-dependent cytotoxicity in TCC cells, but was relatively less cytotoxic (with IC50 of 200 µM) in BFTC905 cells than the other 3 TCC cell lines, possibly due to upregulation of Bcl-xL and HIF-1α mediated carbonic anhydrase IX, and promotion of quiescence. Gemcitabine-resistant BFTC905 cells were chosen for additional experiments. Thalidomide induced apoptosis through downregulation of survivin and securin. The secretion of VEGF and TNF-α was ameliorated by thalidomide, but they did not affect cell proliferation. Immune-modulating lenalidomide and pomalidomide did not elicit cytotoxicity. In addition, cereblon did not play a role in the thalidomide effect. Oxidative DNA damage was triggered by thalidomide, and anti-oxidants reversed the effect. Thalidomide also inhibited TNF-α induced invasion through inhibition of NF-κB, and downregulation of effectors, ICAM-1 and MMP-9. Thalidomide inhibited the growth of BFTC905 xenograft tumors in SCID mice via induction of DNA damage and suppression of angiogenesis. Higher average body weight, indicating less chachexia, was observed in thalidomide treated group. Sedative effect was observed within one-week of treatment. These pre-clinical results suggest therapeutic potential of thalidomide for gemcitabine-resistant bladder cancer.

  11. Llama nanoantibodies with therapeutic potential against human norovirus diarrhea.

    PubMed

    Garaicoechea, Lorena; Aguilar, Andrea; Parra, Gabriel I; Bok, Marina; Sosnovtsev, Stanislav V; Canziani, Gabriela; Green, Kim Y; Bok, Karin; Parreño, Viviana

    2015-01-01

    Noroviruses are a major cause of acute gastroenteritis, but no vaccines or therapeutic drugs are available. Llama-derived single chain antibody fragments (also called VHH) are small, recombinant monoclonal antibodies of 15 kDa with several advantages over conventional antibodies. The aim of this study was to generate recombinant monoclonal VHH specific for the two major norovirus (NoV) genogroups (GI and GII) in order to investigate their potential as immunotherapy for the treatment of NoV diarrhea. To accomplish this objective, two llamas were immunized with either GI.1 (Norwalk-1968) or GII.4 (MD2004) VLPs. After immunization, peripheral blood lymphocytes were collected and used to generate two VHH libraries. Using phage display technology, 10 VHH clones specific for GI.1, and 8 specific for GII.4 were selected for further characterization. All VHH recognized conformational epitopes in the P domain of the immunizing VP1 capsid protein, with the exception of one GII.4 VHH that recognized a linear P domain epitope. The GI.1 VHHs were highly specific for the immunizing GI.1 genotype, with only one VHH cross-reacting with GI.3 genotype. The GII.4 VHHs reacted with the immunizing GII.4 strain and showed a varying reactivity profile among different GII genotypes. One VHH specific for GI.1 and three specific for GII.4 could block the binding of homologous VLPs to synthetic HBGA carbohydrates, saliva, and pig gastric mucin, and in addition, could inhibit the hemagglutination of red blood cells by homologous VLPs. The ability of Nov-specific VHHs to perform well in these surrogate neutralization assays supports their further development as immunotherapy for NoV treatment and immunoprophylaxis.

  12. Doxorubicin induces mitochondrial permeability transition and contractile dysfunction in the human myocardium.

    PubMed

    Montaigne, David; Marechal, Xavier; Preau, Sebastien; Baccouch, Riadh; Modine, Thomas; Fayad, George; Lancel, Steve; Neviere, Remi

    2011-01-01

    In human atrial trabeculae, we examined the effects of doxorubicin on the isometric force of contraction, mitochondrial respiration, membrane potential and calcium retention capacity. Compared with untreated controls, doxorubicin induced contractile dysfunction and depression of mitochondrial respiration. Mitochondria isolated from doxorubicin-treated human atrial trabeculae displayed reduced transmembrane potential and calcium retention capacity. Cyclosporine A, a mitochondrial membrane transition pore opening blocker, prevented mitochondrial dysfunction and impaired contractile performance induced by doxorubicin. The study suggests that a mitochondrial membrane transition pore opening is involved in the development of doxorubicin cardiotoxicity in human hearts. Copyright © 2010 Mitochondria Research Society. Published by Elsevier B.V. All rights reserved.

  13. Surface functionalization of doxorubicin-loaded liposomes with octa-arginine for enhanced anticancer activity

    PubMed Central

    Biswas, Swati; Dodwadkar, Namita S.; Deshpande, Pranali P.; Parab, Shruti; Torchilin, Vladimir P.

    2014-01-01

    Doxorubicin-loaded PEGylated liposomes (commercially available as DOXIL® or Lipodox®) were surface functionalized with a cell-penetrating peptide, octa-arginine (R8). For this purpose, R8-peptide was conjugated to the polyethylene glycol–dioleoyl phosphatidylethanolamine (PEG–DOPE) amphiphilic co-polymer. The resultant R8–PEG–PE conjugate was introduced into the lipid bilayer of liposomes at 2 mol% of total lipid amount via spontaneous micelle-transfer technique. The liposomal modification did not alter the particle size distribution, as measured by Particle Size Analyzer and transmission electron microscopy (TEM). However, surface-associated cationic peptide increased zeta potential of the modified liposomes. R8-functionalized liposomes (R8-Dox-L) markedly increased the intracellular and intratumoral delivery of doxorubicin as measured by flow cytometry and visualizing by confocal laser scanning microscopy (CLSM) compared to unmodified Doxorubicin-loaded PEGylated liposomes (Dox-L). R8-Dox-L delivered loaded Doxorubicin to the nucleus, being released from the endosomes at higher efficiency compared to unmodified liposomes, which had marked entrapment in the endosomes at tested time point of 1 h. The significantly higher accumulation of loaded drug to its site of action for R8-Dox-L resulted in improved cytotoxic activity in vitro (cell viability of 58.5 ± 7% for R8-Dox-L compared to 90.6 ± 2% for Dox-L at Dox dose of 50 μg/mL for 4 h followed by 24 h incubation) and enhanced suppression of tumor growth (348 ± 53 mm3 for R8-Dox-L, compared to 504 ± 54 mm3 for Dox-L treatment) in vivo compared to Dox-L. R8-modification has the potential for broadening the therapeutic window of pegylated liposomal doxorubicin treatment, which could lead to lower non-specific toxicity. PMID:23333899

  14. Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression

    PubMed Central

    Dong, Qinghua; Chen, Long; Lu, Qunwei; Sharma, Sherven; Li, Lei; Morimoto, Sachio; Wang, Guanyu

    2014-01-01

    Background and Purpose Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin-induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi-1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin-mediated protection against doxorubicin-induced cardiotoxicity. Experimental Approach Effects of quercetin on doxorubicin-induced cardiotoxicity was evaluated using H9c2 cardiomyocytes and C57BL/6 mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2 cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre-treatment. Key Results In H9c2 cells, quercetin reduced doxorubicin-induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double-strand breaks. The quercetin-mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53 and oxidase (p47 and Nox1) and by increased expression of Bcl-2 and Bmi-1. Bmi-1 siRNA abolished the protective effect of quercetin against doxorubicin-induced toxicity in H9c2 cells. Furthermore, quercetin protected mice from doxorubicin-induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi-1 and anti-oxidative superoxide dismutase. Conclusions and Implications Our results demonstrate that quercetin decreased doxorubicin-induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up-regulation of Bmi-1 expression. The findings presented in this study have potential applications in preventing doxorubicin-induced cardiomyopathy. PMID:24902966

  15. Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression.

    PubMed

    Dong, Qinghua; Chen, Long; Lu, Qunwei; Sharma, Sherven; Li, Lei; Morimoto, Sachio; Wang, Guanyu

    2014-10-01

    Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin-induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi-1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin-mediated protection against doxorubicin-induced cardiotoxicity. Effects of quercetin on doxorubicin-induced cardiotoxicity was evaluated using H9c2 cardiomyocytes and C57BL/6 mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2 cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre-treatment. In H9c2 cells, quercetin reduced doxorubicin-induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double-strand breaks. The quercetin-mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53 and oxidase (p47 and Nox1) and by increased expression of Bcl-2 and Bmi-1. Bmi-1 siRNA abolished the protective effect of quercetin against doxorubicin-induced toxicity in H9c2 cells. Furthermore, quercetin protected mice from doxorubicin-induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi-1 and anti-oxidative superoxide dismutase. Our results demonstrate that quercetin decreased doxorubicin-induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up-regulation of Bmi-1 expression. The findings presented in this study have potential applications in preventing doxorubicin-induced cardiomyopathy. © 2014 The British Pharmacological Society.

  16. 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.

  17. In vivo evaluation of the genetic toxicity of Rubus niveus Thunb. (Rosaceae) extract and initial screening of its potential chemoprevention against doxorubicin-induced DNA damage.

    PubMed

    Tolentino, Flora; Araújo, Priscila Alves de; Marques, Eduardo de Souza; Petreanu, Marcel; Andrade, Sérgio Faloni de; Niero, Rivaldo; Perazzo, Fábio F; Rosa, Paulo César Pires; Maistro, Edson Luis

    2015-04-22

    Rubus niveus Thunb. plant belongs to Rosaceae family and have been used traditionally to treat wounds, burns, inflammation, dysentery, diarrhea and for curing excessive bleeding during menstrual cycle. The present study was undertaken to investigate the in vivo genotoxicity of Rubus niveus aerial parts extract and its possible chemoprotection on doxorubicin (DXR)-induced DNA damage. In parallel, the main phytochemicals constituents in the extract were determined. The animals were exposed to the extract for 24 and 48 h, and the doses selected were 500, 1000 and 2000 mg/kg b.w. administered by gavage alone or prior to DXR (30 mg/kg b.w.) administered by intraperitoneal injection. The endpoints analyzed were DNA damage in bone marrow and peripheral blood cells assessed by the alkaline alkaline (pH>13) comet assay and bone marrow micronucleus test. The results of chemical analysis of the extract showed the presence of tormentic acid, stigmasterol, quercitinglucoronide (miquelianin) and niga-ichigoside F1 as main compounds. Both cytogenetic endpoints analyzed showed that there were no statistically significant differences (p>0.05) between the negative control and the treated groups with the two higher doses of Rubus niveus extract alone, demonstrating absence of genotoxic and mutagenic effects. Aneugenic/clastogenic effect was observed only at 2000 mg/kg dose. On the other hand, in the both assays and all tested doses were observed a significant reduction of DNA damage and chromosomal aberrations in all groups co-treated with DXR and extract compared to those which received only DXR. These results indicate that Rubus niveus aerial parts extract did not revealed any genotoxic effect, but presented some aneugenic/clastogenic effect at higher dose; and suggest that it could be a potential adjuvant against development of second malignant neoplasms caused by the cancer chemotherapic DXR. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  18. PI3K inhibitors as potential therapeutics for autoimmune disease.

    PubMed

    Ball, Jennifer; Archer, Sophie; Ward, Stephen

    2014-08-01

    Aberrant overactivation of the immune system can give rise to chronic and persistent self-attack, culminating in autoimmune disease. This is currently managed therapeutically using potent immunosuppressive and anti-inflammatory drugs. Class I phosphoinositide 3-kinases (PI3Ks) have been identified as ideal therapeutic targets for autoimmune diseases given their wide-ranging roles in immunological processes. Recent studies into the function of selective PI3K inhibitors in vitro and in vivo have yielded encouraging results, allowing progression into the clinic. Here, we review their recent progress across a range of autoimmune diseases.

  19. Asparagus racemosus: a review on its phytochemical and therapeutic potential.

    PubMed

    Singh, Ram

    2016-09-01

    Asparagus racemosus (Willd.) is a widely found medicinal plant in tropical and subtropical parts of India. The therapeutic applications of this plant have been reported in Indian and British Pharmacopoeias and in traditional system of medicine, such as Ayurveda, Unani and Siddha. The crude, semi-purified and purified extracts obtained from different parts of this plant have been useful in therapeutic applications. Numerous bioactive phytochemicals mostly saponins and flavonoids have been isolated and identified from this plant which are responsible alone or in combination for various pharmacological activities. This review aims to give a comprehensive overview of traditional applications, current knowledge on the phytochemistry, pharmacology and overuse of A. racemosus.

  20. Self-assembled nanoparticle drug delivery systems from galactosylated polysaccharide-doxorubicin conjugate loaded doxorubicin.

    PubMed

    Cao, Yu; Gu, Ying; Ma, Hong; Bai, Jing; Liu, Lina; Zhao, Peiguang; He, Hongxuan

    2010-03-01

    Xyloglucan was grafted with the doxorubicin (DOX) and galactosamine, a terminal moiety that can be used to target polymeric conjugates to liver hepatocytes. The content of the DOX was over 5% (wt) in the conjugate. The polymeric drug assisted to form nanoparticle drug delivery systems (nanoDDSs) with an average size of 142 nm in diameter when combined with an excess amount of deprotonated doxorubicin in an aqueous phase. A loading content of doxorubicin is as high as 23.8% in the nanoDDS. In an in vitro cytotoxicity experiment, the novel nanoDDS has similar cytotoxicity as free DOX against HepG2 cells. In contrast, for the incubation with HeLa cells of the novel nanoDDS, there was no significant cytotoxicity change. In a human tumor xenograft nude mouse model, the novel nanoDDS generated higher therapeutic effect than non-targeted doxorubicin nanoparticles or free doxorubicin. Together, these results suggest that novel nanoDDS, which has improved transfection efficiency and hepatocyte specificity, may be useful for tumor therapy. 2009 Elsevier B.V. All rights reserved.

  1. Novel hepatocellular carcinoma molecules with prognostic and therapeutic potentials

    PubMed Central

    Scaggiante, Bruna; Kazemi, Maryam; Pozzato, Gabriele; Dapas, Barbara; Farra, Rosella; Grassi, Mario; Zanconati, Fabrizio; Grassi, Gabriele

    2014-01-01

    Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the sixth most common cancer worldwide and the third leading cause of cancer-related death. The difficulty to diagnose early cancer stages, the aggressive behaviors of HCC, and the poor effectiveness of therapeutic treatments, represent the reasons for the quite similar deaths per year and incidence number. Considering the fact that the diagnosis of HCC typically occurs in the advanced stages of the disease when the therapeutic options have only modest efficacy, the possibility to identify early diagnostic markers could be of significant benefit. So far, a large number of biomarkers have been associated to HCC progression and aggressiveness, but many of them turned out not to be of practical utility. This is the reason why active investigations are ongoing in this field. Given the huge amount of published works aimed at the identification of HCC biomarkers, in this review we mainly focused on the data published in the last year, with particular attention to the role of (1) molecular and biochemical cellular markers; (2) micro-interfering RNAs; (3) epigenetic variations; and (4) tumor stroma. It is worth mentioning that a significant number of the HCC markers described in the present review may be utilized also as targets for novel therapeutic approaches, indicating the tight relation between diagnosis and therapy. In conclusion, we believe that integrated researches among the different lines of investigation indicated above should represent the winning strategies to identify effective HCC markers and therapeutic targets. PMID:24574801

  2. A Novel Submicron Emulsion System Loaded with Doxorubicin Overcome Multi-Drug Resistance in MCF-7/ADR Cells

    PubMed Central

    Zhou, W. P.; Hua, H. Y.; Sun, P. C.; Zhao, Y. X.

    2015-01-01

    The purpose of the present study was to develop the Solutol HS15-based doxorubicin submicron emulsion with good stability and overcoming multi-drug resistance. In this study, we prepared doxorubicin submicron emulsion, and examined the stability after autoclaving, the in vitro cytotoxic activity, the intracellular accumulation and apoptpsis of doxorubicin submicron emulsion in MCF-7/ADR cells. The physicochemical properties of doxorubicin submicron emulsion were not significantly affected after autoclaving. The doxorubicin submicron emulsion significantly increased the intracellular accumulation of doxorubicin submicron emulsion and enhanced cytotoxic activity and apoptotic effects of doxorubicin. These results may be correlated to doxorubicin submicron emulsion inhibitory effects on efflux pumps through the progressive release of intracellular free Solutol HS15 from doxorubicin submicron emulsion. Furthermore, these in vitro results suggest that the Solutol HS15-based submicron emulsion may be a potentially useful drug delivery system to circumvent multi-drug resistance of tumor cells. PMID:26664069

  3. UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity

    PubMed Central

    An, Lin; Hu, Xiao-wen; Zhang, Shasha; Hu, Xiaowen; Song, Zongpei; Naz, Amber; Zi, Zhenguo; Wu, Jian; Li, Can; Zou, Yunzeng; He, Lin; Zhu, Hongxin

    2017-01-01

    Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity. PMID:28225086

  4. UVRAG Deficiency Exacerbates Doxorubicin-Induced Cardiotoxicity.

    PubMed

    An, Lin; Hu, Xiao-Wen; Zhang, Shasha; Hu, Xiaowen; Song, Zongpei; Naz, Amber; Zi, Zhenguo; Wu, Jian; Li, Can; Zou, Yunzeng; He, Lin; Zhu, Hongxin

    2017-02-22

    Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity. Mouse models of acute or chronic DOX-induced cardiotoxicity were established. UVRAG deficiency exacerbated DOX-induced mortality and cardiotoxicity manifested by increased cytoplasmic vacuolization, enhanced collagen accumulation, elevated serum activities of lactate dehydrogenase and myocardial muscle creatine kinase, higher ROS levels, aggravated apoptosis and more depressed cardiac function. Autophagic flux was impaired in DOX-induced cardiotoxicity. UVRAG deficiency aggravated impaired autophagic flux in DOX-induced cardiotoxicity. Intermittent fasting restored autophagy and ameliorated pathological alterations of DOX-induced cardiotoxicity. Collectively, our data suggest that UVRAG deficiency exacerbates DOX-induced cardiotoxicity, at least in part, through aggravation of DOX-induced impaired autophagic flux. Intermittent fasting, which restores blunted autophagic flux and ameliorates pathology in the mouse models of DOX-induced cardiotoxicity, may be used as a potential preventive or therapeutic approach for DOX cardiotoxicity.

  5. Nuclear proteomics with XRCC3 knockdown to reveal the development of doxorubicin-resistant uterine cancer.

    PubMed

    Chang, Jo-Fan; Lin, Szu-Ting; Hung, Eric; Lu, Yi-Ling; Soon May, Eugenie Wong; Lo, Yi-Wen; Chou, Hsiu-Chuan; Chan, Hong-Lin

    2014-06-01

    The nucleus is a key organelle in mammary cells, which is responsible for several cellular functions including cell proliferation, gene expression, and cell survival. In addition, the nucleus is the primary targets of doxorubicin treatment. In the current study, low-abundance nuclear proteins were enriched for proteomic analysis by using a state-of-the-art two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) strategy to compare and identify the nuclear protein profiling changes responsible for the development of doxorubicin resistance in human uterine cancer cells. The results of the nuclear proteomic analysis indicated that more than 2100 protein features were resolved from an equal pooled amount of three purified nuclear proteins and 117 differentially expressed spots were identified. Of these 117 identified proteins, 48 belonged to nuclear proteins and a positive correlation was observed between the expression levels of 32 of these nuclear proteins and an increase in drug resistance. According to our review of relevant research, nuclear proteins such as DNA repair protein XRCC3 (XRCC3) have not been reported to play roles in the formation of doxorubicin resistance. Previous studies have used RNA interference and cell viability analysis to evidence the essential roles of XRCC3 on its potency in the formation of doxorubicin resistance. To sum up, our nuclear proteomic approaches enabled us to identify numerous proteins, including XRCC3, involved in various drug-resistance-forming mechanisms. Our results provide potential diagnostic markers and therapeutic candidates for treating doxorubicin-resistant uterine cancer.

  6. Stratification and therapeutic potential of PML in metastatic breast cancer

    PubMed Central

    Martín-Martín, Natalia; Piva, Marco; Urosevic, Jelena; Aldaz, Paula; Sutherland, James D.; Fernández-Ruiz, Sonia; Arreal, Leire; Torrano, Verónica; Cortazar, Ana R.; Planet, Evarist; Guiu, Marc; Radosevic-Robin, Nina; Garcia, Stephane; Macías, Iratxe; Salvador, Fernando; Domenici, Giacomo; Rueda, Oscar M.; Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Zúñiga-García, Patricia; Caro-Maldonado, Alfredo; Valcárcel-Jiménez, Lorea; Sánchez-Mosquera, Pilar; Varela-Rey, Marta; Martínez-Chantar, Maria Luz; Anguita, Juan; Ibrahim, Yasir H.; Scaltriti, Maurizio; Lawrie, Charles H.; Aransay, Ana M.; Iovanna, Juan L.; Baselga, Jose; Caldas, Carlos; Barrio, Rosa; Serra, Violeta; dM Vivanco, Maria; Matheu, Ander; Gomis, Roger R.; Carracedo, Arkaitz

    2016-01-01

    Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification. PMID:27553708

  7. Therapeutic potential of neuropeptide Y (NPY) receptor ligands

    PubMed Central

    Brothers, Shaun P; Wahlestedt, Claes

    2010-01-01

    Neuropeptide Y (NPY) is widely distributed in the human body and contributes to a vast number of physiological processes. Since its discovery, NPY has been implicated in metabolic regulation and, although interest in its role in central mechanisms related to food intake and obesity has somewhat diminished, the topic remains a strong focus of research concerning NPY signalling. In addition, a number of other uses for modulators of NPY receptors have been implied in a range of diseases, although the development of NPY receptor ligands has been slow, with no clinically approved receptor therapeutics currently available. Nevertheless, several interesting small molecule compounds, notably Y2 receptor antagonists, have been published recently, fueling optimism in the field. Herein we review the role of NPY in the pathophysiology of a number of diseases and highlight instances where NPY receptor signalling systems are attractive therapeutic targets. PMID:20972986

  8. Stratification and therapeutic potential of PML in metastatic breast cancer.

    PubMed

    Martín-Martín, Natalia; Piva, Marco; Urosevic, Jelena; Aldaz, Paula; Sutherland, James D; Fernández-Ruiz, Sonia; Arreal, Leire; Torrano, Verónica; Cortazar, Ana R; Planet, Evarist; Guiu, Marc; Radosevic-Robin, Nina; Garcia, Stephane; Macías, Iratxe; Salvador, Fernando; Domenici, Giacomo; Rueda, Oscar M; Zabala-Letona, Amaia; Arruabarrena-Aristorena, Amaia; Zúñiga-García, Patricia; Caro-Maldonado, Alfredo; Valcárcel-Jiménez, Lorea; Sánchez-Mosquera, Pilar; Varela-Rey, Marta; Martínez-Chantar, Maria Luz; Anguita, Juan; Ibrahim, Yasir H; Scaltriti, Maurizio; Lawrie, Charles H; Aransay, Ana M; Iovanna, Juan L; Baselga, Jose; Caldas, Carlos; Barrio, Rosa; Serra, Violeta; Vivanco, Maria dM; Matheu, Ander; Gomis, Roger R; Carracedo, Arkaitz

    2016-08-24

    Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification.

  9. The potential of prison-based democratic therapeutic communities.

    PubMed

    Bennett, Jamie; Shuker, Richard

    2017-03-13

    Purpose The purpose of this paper is to describe the work of HMP Grendon, the only prison in the UK to operate entirely as a series of democratic therapeutic communities and to summarise the research of its effectiveness. Design/methodology/approach The paper is both descriptive, providing an overview of the work of a prison-based therapeutic community, and offers a literature review regarding evidence of effectiveness. Findings The work of HMP Grendon has a wide range of positive benefits including reduced levels of disruption in prison, reduced self-harm, improved well-being, an environment that is experienced as more humane and reduced levels of reoffending. Originality/value The work of HMP Grendon offers a well established and evidenced approach to managing men who have committed serious violent and sexually violent offences. It also promotes and embodies a progressive approach to managing prisons rooted in the welfare tradition.

  10. Therapeutic potential of nuclear receptor agonists in Alzheimer's disease.

    PubMed

    Moutinho, Miguel; Landreth, Gary E

    2017-10-01

    Alzheimer's disease (AD) is characterized by an extensive accumulation of amyloid-β (Aβ) peptide, which triggers a set of deleterious processes, including synaptic dysfunction, inflammation, and neuronal injury, leading to neuronal loss and cognitive impairment. A large body of evidence supports that nuclear receptor (NR) activation could be a promising therapeutic approach for AD. NRs are ligand-activated transcription factors that regulate gene expression and have cell type-specific effects. In this review, we discuss the mechanisms that underlie the beneficial effects of NRs in AD. Moreover, we summarize studies reported in the last 10-15 years and their major outcomes arising from the pharmacological targeting of NRs in AD animal models. The dissection of the pathways regulated by NRs in the context of AD is of importance in identifying novel and effective therapeutic strategies. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  11. Rhinacanthin-C enhances doxorubicin cytotoxicity via inhibiting the functions of P-glycoprotein and MRP2 in breast cancer cells.

    PubMed

    Chaisit, Tassarut; Siripong, Pongpun; Jianmongkol, Suree

    2017-01-15

    Rhinacanthin-C is a major bioactive naphthoquinone ester found in Rhinacanthus nasutus Kurz (Acanthaceae). This compound has potential therapeutic value as an anticancer and antiviral agent. In this study, we investigated an enhancement effect of rhinacanthin-C on doxorubicin cytotoxicity in human breast cancer cell lines and the involvement of the ABC drug efflux transporters. The cytotoxicity was determined by an MTT assay. Combination between doxorubicin and rhinacanthin-C at their non-cytotoxic concentrations when giving each compound alone significantly reduced cell viability in MCF-7 and MCF-7/DOX resistant cells. At the non-cytotoxic concentration (0.1µM), rhinacanthin-C enhanced doxorubicin cytotoxicity by 38 fold in MCF-7 cells after 48-h treatment. Moreover, intracellular doxorubicin accumulation significantly increased in both MCF-7 cells and MCF-7/DOX resistance cells in the presence of rhinacanthin-C for 6-h treatment period. The interference of rhinacanthin-C on the ABC drug transporters (P-gp, MRP1 and MRP2) was evaluated by substrate accumulation assay, using fluorescence spectroscopy technique. Our results showed that rhinacanthin-C at 0.1µM for 6-h treatment period could increase intracellular accumulation of transporter substrates in MCF-7 cells [i.e., CDCF by 1.65 fold (MRP2)] as well as in MCF-7/DOX resistance cells [i.e., CDCF by 1.18 fold (MRP2) and calcein by 1.38 fold (P-gp)]. In conclusion, rhinacanthin-C could enhance doxorubicin cytotoxicity through interference on MRP2 and P-gp functions. Consequently, intracellular doxorubicin accumulation in the cells increased up to its cytotoxic level. Another potential mechanism of the synergy between rhinacanthin-C and doxorubicin would be investigated further. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. 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.

  13. Protein-Remodeling Factors As Potential Therapeutics for Neurodegenerative Disease

    PubMed Central

    Jackrel, Meredith E.; Shorter, James

    2017-01-01

    Protein misfolding is implicated in numerous neurodegenerative disorders including amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington's disease. A unifying feature of patients with these disorders is the accumulation of deposits comprised of misfolded protein. Aberrant protein folding can cause toxicity through a loss or gain of protein function, or both. An intriguing therapeutic approach to counter these disorders is the application of protein-remodeling factors to resolve these misfolded conformers and return the proteins to their native fold and function. Here, we describe the application of protein-remodeling factors to alleviate protein misfolding in neurodegenerative disease. We focus on Hsp104, Hsp110/Hsp70/Hsp40, NMNAT, and HtrA1, which can prevent and reverse protein aggregation. While many of these protein-remodeling systems are highly promising, their activity can be limited. Thus, engineering protein-remodeling factors to enhance their activity could be therapeutically valuable. Indeed, engineered Hsp104 variants suppress neurodegeneration in animal models, which opens the way to novel therapeutics and mechanistic probes to help understand neurodegenerative disease. PMID:28293166

  14. Potential Therapeutic Benefits of Maintaining Mitochondrial Health in Peripheral Neuropathies

    PubMed Central

    Areti, Aparna; Yerra, Veera Ganesh; Komirishetty, Prashanth; Kumar, Ashutosh

    2016-01-01

    Background: Peripheral neuropathies are a group of diseases characterized by malfunctioning of peripheral nervous system. Neuropathic pain, one of the core manifestations of peripheral neuropathy remains as the most severe disabling condition affecting the social and daily routine life of patients suffering from peripheral neuropathy. Method: The current review is aimed at unfolding the possible role of mitochondrial dysfunction in peripheral nerve damage and to discuss on the probable therapeutic strategies against neuronal mitotoxicity. The article also highlights the therapeutic significance of maintaining a healthy mitochondrial environment in neuronal cells via pharmacological management in context of peripheral neuropathies. Results: Aberrant cellular signaling coupled with changes in neurotransmission, peripheral and central sensitization are found to be responsible for the pathogenesis of variant toxic neuropathies. Current research reports have indicated the possible involvement of mitochondria mediated redox imbalance as one of the principal causes of neuropathy aetiologies. In addition to imbalance in redox homeostasis, mitochondrial dysfunction is also responsible for alterations in physiological bioenergetic metabolism, apoptosis and autophagy pathways. Conclusions: In spite of various etiological factors, mitochondrial dysfunction has been found to be a major pathomechanism underlying the neuronal dysfunction associated with peripheral neuropathies. Pharmacological modulation of mitochondria either directly or indirectly is expected to yield therapeutic relief from various primary and secondary mitochondrial diseases. PMID:26818748

  15. Potential Therapeutic Benefits of Maintaining Mitochondrial Health in Peripheral Neuropathies.

    PubMed

    Areti, Aparna; Yerra, Veera Ganesh; Komirishetty, Prashanth; Kumar, Ashutosh

    2016-01-01

    Peripheral neuropathies are a group of diseases characterized by malfunctioning of peripheral nervous system. Neuropathic pain, one of the core manifestations of peripheral neuropathy remains as the most severe disabling condition affecting the social and daily routine life of patients suffering from peripheral neuropathy. The current review is aimed at unfolding the possible role of mitochondrial dysfunction in peripheral nerve damage and to discuss on the probable therapeutic strategies against neuronal mitotoxicity. The article also highlights the therapeutic significance of maintaining a healthy mitochondrial environment in neuronal cells via pharmacological management in context of peripheral neuropathies. Aberrant cellular signaling coupled with changes in neurotransmission, peripheral and central sensitization are found to be responsible for the pathogenesis of variant toxic neuropathies. Current research reports have indicated the possible involvement of mitochondria mediated redox imbalance as one of the principal causes of neuropathy aetiologies. In addition to imbalance in redox homeostasis, mitochondrial dysfunction is also responsible for alterations in physiological bioenergetic metabolism, apoptosis and autophagy pathways. In spite of various etiological factors, mitochondrial dysfunction has been found to be a major pathomechanism underlying the neuronal dysfunction associated with peripheral neuropathies. Pharmacological modulation of mitochondria either directly or indirectly is expected to yield therapeutic relief from various primary and secondary mitochondrial diseases.

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

    PubMed

    Hayakawa, Kazuhide; Mishima, Kenichi; Fujiwara, Michihiro

    2010-07-08

    Cannabis contains the psychoactive component delta⁸-tetrahydrocannabinol (delta⁸-THC), and the non-psychoactive components cannabidiol (CBD), cannabinol, and cannabigerol. It is well-known that delta⁸-THC and other cannabinoid CB₁ receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta⁸-THC also mediates psychological effects through the activation of the CB₁ receptor in the central nervous system. In addition to the CB₁ receptor agonists, cannabis also contains therapeutically active components which are CB₁ receptor independent. Of the CB₁ receptor-independent cannabis, the most important is CBD. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD. In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson's disease, Alzheimer's disease, and rheumatoid arthritis. The cerebroprotective action of CBD is CB₁ receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke.

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

    PubMed Central

    Hayakawa, Kazuhide; Mishima, Kenichi; Fujiwara, Michihiro

    2010-01-01

    Cannabis contains the psychoactive component delta9-tetrahydrocannabinol (delta9-THC), and the non-psychoactive components cannabidiol (CBD), cannabinol, and cannabigerol. It is well-known that delta9-THC and other cannabinoid CB1 receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta9-THC also mediates psychological effects through the activation of the CB1 receptor in the central nervous system. In addition to the CB1 receptor agonists, cannabis also contains therapeutically active components which are CB1 receptor independent. Of the CB1 receptor-independent cannabis, the most important is CBD. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD. In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson’s disease, Alzheimer’s disease, and rheumatoid arthritis. The cerebroprotective action of CBD is CB1 receptor-independent, long-lasting, and has potent anti-oxidant activity. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke. PMID:27713349

  18. Metformin: A Potential Therapeutic Agent for Recurrent Colon Cancer

    PubMed Central

    Nangia-Makker, Pratima; Yu, Yingjie; Vasudevan, Anita; Farhana, Lulu; Rajendra, Sindhu G.; Levi, Edi; Majumdar, Adhip P. N.

    2014-01-01

    Accumulating evidence suggests that metformin, a biguanide class of anti-diabetic drugs, possesses anti-cancer properties. However, most of the studies to evaluate therapeutic efficacy of metformin have been on primary cancer. No information is available whether metformin could be effectively used for recurrent cancer, specifically colorectal cancer (CRC) that affects up to 50% of patients treated by conventional chemotherapies. Although the reasons for recurrence are not fully understood, it is thought to be due to re-emergence of chemotherapy-resistant cancer stem/stem-like cells (CSCs/CSLCs). Therefore, development of non-toxic treatment strategies targeting CSCs would be of significant therapeutic benefit. In the current investigation, we have examined the effectiveness of metformin, in combination with 5-fluorouracil and oxaliplatin (FuOx), the mainstay of colon cancer therapeutics, on survival of chemo-resistant colon cancer cells that are highly enriched in CSCs/CSLCs. Our data show that metformin acts synergistically with FuOx to (a) induce cell death in chemo resistant (CR) HT-29 and HCT-116 colon cancer cells, (b) inhibit colonospheres formation and (c) enhance colonospheres disintegration. In vitro cell culture studies have further demonstrated that the combinatorial treatment inhibits migration of CR colon cancer cells. These changes were associated with increased miRNA 145 and reduction in miRNA 21. Wnt/β-catenin signaling pathway was also down-regulated indicating its pivotal role in regulating the growth of CR colon cancer cells. Data from SCID mice xenograft model of CR HCT-116 and CR HT-29 cells show that the combination of metformin and FuOX is highly effective in inhibiting the growth of colon tumors as evidenced by ∼50% inhibition in growth following 5 weeks of combination treatment, when compared with the vehicle treated controls. Our current data suggest that metformin together with conventional chemotherapy could be an effective treatment

  19. Cardiovascular calcifications in chronic kidney disease: Potential therapeutic implications.

    PubMed

    Bover, Jordi; Ureña-Torres, Pablo; Górriz, José Luis; Lloret, María Jesús; da Silva, Iara; Ruiz-García, César; Chang, Pamela; Rodríguez, Mariano; Ballarín, José

    Cardiovascular (CV) calcification is a highly prevalent condition at all stages of chronic kidney disease (CKD) and is directly associated with increased CV and global morbidity and mortality. In the first part of this review, we have shown that CV calcifications represent an important part of the CKD-MBD complex and are a superior predictor of clinical outcomes in our patients. However, it is also necessary to demonstrate that CV calcification is a modifiable risk factor including the possibility of decreasing (or at least not aggravating) its progression with iatrogenic manoeuvres. Although, strictly speaking, only circumstantial evidence is available, it is known that certain drugs may modify the progression of CV calcifications, even though a direct causal link with improved survival has not been demonstrated. For example, non-calcium-based phosphate binders demonstrated the ability to attenuate the progression of CV calcification compared with the liberal use of calcium-based phosphate binders in several randomised clinical trials. Moreover, although only in experimental conditions, selective activators of the vitamin D receptor seem to have a wider therapeutic margin against CV calcification. Finally, calcimimetics seem to attenuate the progression of CV calcification in dialysis patients. While new therapeutic strategies are being developed (i.e. vitamin K, SNF472, etc.), we suggest that the evaluation of CV calcifications could be a diagnostic tool used by nephrologists to personalise their therapeutic decisions. Copyright © 2016 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.

  20. Therapeutic Potential of Adipose-Derived Therapeutic Factor Concentrate for Treating Critical Limb Ischemia.

    PubMed

    Procházka, Václav; Jurčíková, Jana; Laššák, Ondrej; Vítková, Kateřina; Pavliska, Lubomír; Porubová, Ludmila; Buszman, Piotr P; Krauze, Agata; Fernandez, Carlos; Jalůvka, František; Špačková, Iveta; Lochman, Ivo; Jana, Dvořáčková; Merfeld-Clauss, Stephanie; March, Keith L; Traktuev, Dmitry O; Johnstone, Brian H

    2016-01-01

    Transplantation of adipose-derived stem cells (ADSCs) is an emerging therapeutic option for addressing intractable diseases such as critical limb ischemia (CLI). Evidence suggests that therapeutic effects of ADSCs are primarily mediated through paracrine mechanisms rather than transdifferentiation. These secreted factors can be captured in conditioned medium (CM) and concentrated to prepare a therapeutic factor concentrate (TFC) composed of a cocktail of beneficial growth factors and cytokines that individually and in combination demonstrate disease-modifying effects. The ability of a TFC to promote reperfusion in a rabbit model of CLI was evaluated. A total of 27 adult female rabbits underwent surgery to induce ischemia in the left hindlimb. An additional five rabbits served as sham controls. One week after surgery, the ischemic limbs received intramuscular injections of either (1) placebo (control medium), (2) a low dose of TFC, or (3) a high dose of TFC. Limb perfusion was serially assessed with a Doppler probe. Blood samples were analyzed for growth factors and cytokines. Tissue was harvested postmortem on day 35 and assessed for capillary density by immunohistochemistry. At 1 month after treatment, tissue perfusion in ischemic limbs treated with a high dose of TFC was almost double (p < 0.05) that of the placebo group [58.8 ± 23 relative perfusion units (RPU) vs. 30.7 ± 13.6 RPU; mean ± SD]. This effect was correlated with greater capillary density in the affected tissues and with transiently higher serum levels of the angiogenic and prosurvival factors vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). The conclusions from this study are that a single bolus administration of TFC demonstrated robust effects for promoting tissue reperfusion in a rabbit model of CLI and that a possible mechanism of revascularization was promotion of angiogenesis by TFC. Results of this study demonstrate that TFC represents a potent

  1. Autophagy modulation as a potential therapeutic target for diverse diseases

    PubMed Central

    Rubinsztein, David C.; Codogno, Patrice; Levine, Beth

    2012-01-01

    Autophagy is an essential, conserved lysosomal degradation pathway that controls the quality of the cytoplasm by eliminating protein aggregates and damaged organelles. It begins when double-membraned autophagosomes engulf portions of the cytoplasm, which is followed by fusion of these vesicles with lysosomes and degradation of the autophagic contents. In addition to its vital homeostatic role, this degradation pathway is involved in various human disorders, including metabolic conditions, neurodegenerative diseases, cancers and infectious diseases. This article provides an overview of the mechanisms and regulation of autophagy, the role of this pathway in disease and strategies for therapeutic modulation. PMID:22935804

  2. The endocrine system and sarcopenia: potential therapeutic benefits.

    PubMed

    McIntire, Kevin L; Hoffman, Andrew R

    2011-12-01

    Age related muscle loss, known as sarcopenia, is a major factor in disability, loss of mobility and quality of life in the elderly. There are many proposed mechanisms of age-related muscle loss that include the endocrine system. A variety of hormones regulate growth, development and metabolism throughout the lifespan. Hormone activity may change with age as a result of reduced hormone secretion or decreased tissue responsiveness. This review will focus on the complex interplay between the endocrine system, aging and skeletal muscle and will present possible benefits of therapeutic interventions for sarcopenia.

  3. 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.

  4. 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

  5. Melatonin and Nitrones As Potential Therapeutic Agents for Stroke

    PubMed Central

    Romero, Alejandro; Ramos, Eva; Patiño, Paloma; Oset-Gasque, Maria J.; López-Muñoz, Francisco; Marco-Contelles, José

    2016-01-01

    Stroke is a disease of aging affecting millions of people worldwide, and recombinant tissue-type plasminogen activator (r-tPA) is the only treatment approved. However, r-tPA has a low therapeutic window and secondary effects which limit its beneficial outcome, urging thus the search for new more efficient therapies. Among them, neuroprotection based on melatonin or nitrones, as free radical traps, have arisen as drug candidates due to their strong antioxidant power. In this Perspective article, an update on the specific results of the melatonin and several new nitrones are presented. PMID:27932976

  6. Therapeutic potential of growth factors in pulmonary emphysematous condition.

    PubMed

    Muyal, Jai Prakash; Muyal, Vandana; Kotnala, Sudhir; Kumar, Dhananjay; Bhardwaj, Harsh

    2013-04-01

    Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease (COPD), which is characterized by progressive destruction of alveolar parenchyma with persistent inflammation of the small airways. Such destruction in the distal respiratory tract is irreversible and irreparable. All-trans-retinoic acid was suggested as a novel therapy for regeneration of lost alveoli in emphysema. However, profound discrepancies were evident between studies. At present, no effective therapeutic options are available that allow for the regeneration of lost alveoli in emphysematous human lungs. Recently, some reports on rodent's models have suggested the beneficial effects of various growth factors toward alveolar maintenance and repair processes.

  7. Agaricus blazei Murill enhances doxorubicin-induced apoptosis in human hepatocellular carcinoma cells by NFκB-mediated increase of intracellular doxorubicin accumulation.

    PubMed

    Lee, Jong Seok; Hong, Eock Kee

    2011-02-01

    It has been demonstrated that the Agaricus blazei Murill (ABM) mushroom, which primarily consists of polysaccharides, possesses anti-tumor activities. However, the mechanisms by which ABM inhibits human hepatocellular carcinoma growth remain unknown. Our study demonstrates that ABM acts as an enhancer to sensitize doxorubicin (Dox)-mediated apoptotic signaling, and this sensitization can be achieved by enhancing intracellular Dox accumulation via the inhibition of NFκB activity. These findings suggest that ABM, when combined with low doses of Dox, has the potential to provide more efficient therapeutic effects against drug-resistant human hepatocellular carcinoma.

  8. [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.

  9. Combinatorial effects of doxorubicin and retargeted tissue factor by intratumoral entrapment of doxorubicin and proapoptotic increase of tumor vascular infarction

    PubMed Central

    Brand, Caroline; Höltke, Carsten; Schliemann, Christoph; Kessler, Torsten; Schmidt, Lars Henning; Harrach, Saliha; Mantke, Verena; Hintelmann, Heike; Hartmann, Wolfgang; Wardelmann, Eva; Lenz, Georg; Wünsch, Bernhard; Müller-Tidow, Carsten; Mesters, Rolf M.; Schwöppe, Christian; Berdel, Wolfgang E.

    2016-01-01

    Truncated tissue factor (tTF), retargeted to tumor vasculature by GNGRAHA peptide (tTF-NGR), and doxorubicin have therapeutic activity against a variety of tumors. We report on combination experiments of both drugs using different schedules. We have tested fluorescence- and HPLC-based intratumoral pharmacokinetics of doxorubicin, flow cytometry for cellular phosphatidylserine (PS) expression, and tumor xenograft studies for showing in vivo apoptosis, proliferation decrease, and tumor shrinkage upon combination therapy with doxorubicin and induced tumor vascular infarction. tTF-NGR given before doxorubicin inhibits the uptake of the drug into human fibrosarcoma xenografts in vivo. Reverse sequence does not influence the uptake of doxorubicin into tumor, but significantly inhibits the late wash-out phase, thus entrapping doxorubicin in tumor tissue by vascular occlusion. Incubation of endothelial and tumor cells with doxorubicin in vitro increases PS concentrations in the outer layer of the cell membrane as a sign of early apoptosis. Cells expressing increased PS concentrations show comparatively higher procoagulatory efficacy on the basis of equimolar tTF-NGR present in the Factor X assay. Experiments using human M21 melanoma and HT1080 fibrosarcoma xenografts in athymic nude mice indeed show a combinatorial tumor growth inhibition applying doxorubicin and tTF-NGR in sequence over single drug treatment. Combination of cytotoxic drugs such as doxorubicin with tTF-NGR-induced tumor vessel infarction can improve pharmacodynamics of the drugs by new mechanisms, entrapping a cytotoxic molecule inside tumor tissue and reciprocally improving procoagulatory activity of tTF-NGR in the tumor vasculature via apoptosis induction in tumor endothelial and tumor cells. PMID:27738341

  10. Therapeutic potential of turmeric in Alzheimer's disease: curcumin or curcuminoids?

    PubMed

    Ahmed, Touqeer; Gilani, Anwarul-Hassan

    2014-04-01

    Alzheimer's disease (AD) is the most common form of dementia. There is limited choice in modern therapeutics, and drugs available have limited success with multiple side effects in addition to high cost. Hence, newer and alternate treatment options are being explored for effective and safer therapeutic targets to address AD. Turmeric possesses multiple medicinal uses including treatment for AD. Curcuminoids, a mixture of curcumin, demethoxycurcumin, and bisdemethoxycurcumin, are vital constituents of turmeric. It is generally believed that curcumin is the most important constituent of the curcuminoid mixture that contributes to the pharmacological profile of parent curcuminoid mixture or turmeric. A careful literature study reveals that the other two constituents of the curcuminoid mixture also contribute significantly to the effectiveness of curcuminoids in AD. Therefore, it is emphasized in this review that each component of the curcuminoid mixture plays a distinct role in making curcuminoid mixture useful in AD, and hence, the curcuminoid mixture represents turmeric in its medicinal value better than curcumin alone. The progress in understanding the disease etiology demands a multiple-site-targeted therapy, and the curcuminoid mixture of all components, each with different merits, makes this mixture more promising in combating the challenging disease. Copyright © 2013 John Wiley & Sons, Ltd.

  11. Improvement of a potential anthrax therapeutic by computational protein design.

    PubMed

    Wu, Sean J; Eiben, Christopher B; Carra, John H; Huang, Ivan; Zong, David; Liu, Peixian; Wu, Cindy T; Nivala, Jeff; Dunbar, Josef; Huber, Tomas; Senft, Jeffrey; Schokman, Rowena; Smith, Matthew D; Mills, Jeremy H; Friedlander, Arthur M; Baker, David; Siegel, Justin B

    2011-09-16

    Past anthrax attacks in the United States have highlighted the need for improved measures against bioweapons. The virulence of anthrax stems from the shielding properties of the Bacillus anthracis poly-γ-d-glutamic acid capsule. In the presence of excess CapD, a B. anthracis γ-glutamyl transpeptidase, the protective capsule is degraded, and the immune system can successfully combat infection. Although CapD shows promise as a next generation protein therapeutic against anthrax, improvements in production, stability, and therapeutic formulation are needed. In this study, we addressed several of these problems through computational protein engineering techniques. We show that circular permutation of CapD improved production properties and dramatically increased kinetic thermostability. At 45 °C, CapD was completely inactive after 5 min, but circularly permuted CapD remained almost entirely active after 30 min. In addition, we identify an amino acid substitution that dramatically decreased transpeptidation activity but not hydrolysis. Subsequently, we show that this mutant had a diminished capsule degradation activity, suggesting that CapD catalyzes capsule degradation through a transpeptidation reaction with endogenous amino acids and peptides in serum rather than hydrolysis.

  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. Cotinine: a potential new therapeutic agent against Alzheimer's disease.

    PubMed

    Echeverria, Valentina; Zeitlin, Ross

    2012-07-01

    Tobacco smoking has been correlated with a lower incidence of Alzheimer's disease (AD). This negative correlation has been attributed to nicotine's properties. However, the undesired side-effects of nicotine and the absence of clear evidence of positive effects of this drug on the cognitive abilities of AD patients have decreased the enthusiasm for its therapeutic use. In this review, we discuss evidence showing that cotinine, the main metabolite of nicotine, has many of the beneficial effects but none of the negative side-effects of its precursor. Cotinine has been shown to be neuroprotective, to improve memory in primates as well as to prevent memory loss, and to lower amyloid-beta (Aβ)) burden in AD mice. In AD, cotinine's positive effect on memory is associated with the inhibition of Aβ aggregation, the stimulation of pro-survival factors such as Akt, and the inhibition of pro-apoptotic factors such as glycogen synthase kinase 3 beta (GSK3β). Because stimulation of the α7 nicotinic acetylcholine receptors (α7nAChRs) positively modulates these factors and memory, the involvement of these receptors in cotinine's effects are discussed. Because of its beneficial effects on brain function, good safety profile, and nonaddictive properties, cotinine may represent a new therapeutic agent against AD.

  14. 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.

  15. The evidence for natural therapeutics as potential anti-scarring agents in burn-related scarring.

    PubMed

    Mehta, M; Branford, O A; Rolfe, K J

    2016-01-01

    Though survival rate following severe thermal injuries has improved, the incidence and treatment of scarring have not improved at the same speed. This review discusses the formation of scars and in particular the formation of hypertrophic scars. Further, though there is as yet no gold standard treatment for the prevention or treatment of scarring, a brief overview is included. A number of natural therapeutics have shown beneficial effects both in vivo and in vitro with the potential of becoming clinical therapeutics in the future. These natural therapeutics include both plant-based products such as resveratrol, quercetin and epigallocatechin gallate as examples and includes the non-plant-based therapeutic honey. The review also includes potential mechanism of action for the therapeutics, any recorded adverse events and current administration of the therapeutics used. This review discusses a number of potential 'treatments' that may reduce or even prevent scarring particularly hypertrophic scarring, which is associated with thermal injuries without compromising wound repair.

  16. C-phycocyanin ameliorates doxorubicin-induced oxidative stress and apoptosis in adult rat cardiomyocytes.

    PubMed

    Khan, Mahmood; Varadharaj, Saradhadevi; Shobha, Jagdish C; Naidu, Madireddi U; Parinandi, Narasimham L; Kutala, Vijay Kumar; Kuppusamy, Periannan

    2006-01-01

    Doxorubicin (DOX), a potent antineoplastic agent, poses limitations for its therapeutic use due to the associated risk of developing cardiomyopathy and congestive heart failure. The cardiotoxicity of doxorubicin is associated with oxidative stress and apoptosis. We have recently shown that Spirulina, a blue-green alga with potent antioxidant properties, offered significant protection against doxorubicin-induced cardiotoxicity in mice. The aim of the present study was to establish the possible protective role of C-phycocyanin, one of the active ingredients of Spirulina, against doxorubicin-induced oxidative stress and apoptosis. The study was carried out using cardiomyocytes isolated from adult rat hearts. Doxorubicin significantly enhanced the formation of reactive oxygen species (ROS) in cells as measured by the 2',7'-dichlorodihydrofluorescein diacetate and dihydroethidium fluorescence. The doxorubicin-induced reactive oxygen species formation was significantly attenuated in cells pretreated with C-phycocyanin. It was further observed that the doxorubicin-induced DNA fragmentation and apoptosis, as assayed by TUNEL assay and flow cytometry coupled with BrdU-FITC/propidium iodide staining, were markedly attenuated by C-phycocyanin. C-phycocyanin also significantly attenuated the doxorubicin-induced increase in the expression of Bax protein, release of cytochrome c, and increase in the activity of caspase-3 in cells. In summary, C-phycocyanin ameliorated doxorubicin-induced oxidative stress and apoptosis in cardiomyocytes. This study further supports the crucial role of the antioxidant nature of C-phycocyanin in its cardioprotection against doxorubicin-induced oxidative stress and apoptosis.

  17. Targeted drug delivery of near IR fluorescent doxorubicin-conjugated poly(ethylene glycol) bisphosphonate nanoparticles for diagnosis and therapy of primary and metastatic bone cancer in a mouse model.

    PubMed

    Rudnick-Glick, S; Corem-Salkmon, E; Grinberg, I; Margel, S

    2016-12-05

    Most primary and metastatic bone tumors demonstrate increased osteoclast activity and bone resorption. Current treatment is based on a combination of surgery, radiotherapy and chemotherapy. Severe side effects are associated with chemotherapy due to use of high dosage and nonspecific uptake. Bisphosphonates have a strong affinity to Ca(2+) ions and are widely used in the treatment of bone disorders. We have engineered a unique biodegradable bisphosphonate nanoparticle (NPs) bearing two functional surface groups: (1) primary amine groups for covalent attachment of a dye/drug (e.g. NIR dye Cy 7 or doxorubicin); (2) bisphosphonate groups for targeting and chelation to bone hydroxyapatite. In addition, these engineered NPs contain high polyethyleneglycol (PEG) concentration in order to increase their blood half life time. In vitro experiments on Saos-2 human osteosarcoma cell line, demonstrated that at a tenth of the concentration, doxorubicin-conjugated bisphosphonate NPs achieved a similar uptake to free doxorubicin. In vivo targeting experiments using the NIR fluorescence bisphosphonate NPs on both Soas-2 human osteosarcoma xenograft mouse model and orthotopic bone metastases mCherry-labeled 4T1 breast cancer mouse model confirmed specific targeting. In addition, therapeutic in vivo experiments using doxorubicin-conjugated bisphosphonate NPs demonstrated a 40% greater inhibition of tumor growth in Saos-2 human osteosarcoma xenograft mouse model when compared to free doxorubicin. In this research we have shown the potential use of doxorubicin-conjugated BP NPs for the targeting and treatment of primary and metastatic bone tumors. The targeted delivery of doxorubicin to the tumor significantly increased the efficacy of the anti-cancer drug, thus enabling the effective use of a lower concentration of doxorubicin. Furthermore, the targeting ability of the BP NPs in an orthotopic xenograft mouse model reinforced our findings that these BP NPs have the potential to be

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

    PubMed Central

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

    2016-01-01

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

  19. Molecular and Therapeutic Potential and Toxicity of Valproic Acid

    PubMed Central

    Chateauvieux, Sébastien; Morceau, Franck; Dicato, Mario; Diederich, Marc

    2010-01-01

    Valproic acid (VPA), a branched short-chain fatty acid, is widely used as an antiepileptic drug and a mood stabilizer. Antiepileptic properties have been attributed to inhibition of Gamma Amino Butyrate (GABA) transaminobutyrate and of ion channels. VPA was recently classified among the Histone Deacetylase Inhibitors, acting directly at the level of gene transcription by inhibiting histone deacetylation and making transcription sites more accessible. VPA is a widely used drug, particularly for children suffering from epilepsy. Due to the increasing number of clinical trials involving VPA, and interesting results obtained, this molecule will be implicated in an increasing number of therapies. However side effects of VPA are substantially described in the literature whereas they are poorly discussed in articles focusing on its therapeutic use. This paper aims to give an overview of the different clinical-trials involving VPA and its side effects encountered during treatment as well as its molecular properties. PMID:20798865

  20. The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future.

    PubMed

    Carhart-Harris, Robin L; Goodwin, Guy M

    2017-10-01

    Plant-based psychedelics, such as psilocybin, have an ancient history of medicinal use. After the first English language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aids to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programs. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and three separate clinical trials of psilocybin for depressive symptoms. In this circumspective piece, RLC-H and GMG share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.

  1. Apoptotic cell clearance: basic biology and therapeutic potential

    PubMed Central

    Poon, Ivan K. H.; Lucas, Christopher D.

    2014-01-01

    Prompt removal of apoptotic cells by phagocytes is important for maintaining tissue homeostasis. The molecular and cellular events that underpin apoptotic cell recognition and uptake, and the subsequent biological responses are increasingly better defined. The detection and disposal of apoptotic cells generally promote an anti-inflammatory response at the tissue level, as well as immunological tolerance. Consequently, defects in apoptotic cell clearance have been linked with a variety of inflammatory diseases and autoimmunity. Conversely, under certain conditions such as killing tumour cells by specific cell death inducers, the recognition of apoptotic tumour cells can promote an immunogenic response and anti-tumour immunity. Here, we review the current understanding of the complex process of apoptotic cell clearance in physiology and pathology, and discuss how this knowledge could be harnessed for new therapeutic strategies. PMID:24481336

  2. Yoga school of thought and psychiatry: Therapeutic potential

    PubMed Central

    Rao, Naren P.; Varambally, Shivarama; Gangadhar, Bangalore N.

    2013-01-01

    Yoga is a traditional life-style practice used for spiritual reasons. However, the physical components like the asanas and pranayaamas have demonstrated physiological and therapeutic effects. There is evidence for Yoga as being a potent antidepressant that matches with drugs. In depressive disorder, yoga ‘corrects’ an underlying cognitive physiology. In schizophrenia patients, yoga has benefits as an add-on intervention in pharmacologically stabilized subjects. The effects are particularly notable on negative symptoms. Yoga also helps to correct social cognition. Yoga can be introduced early in the treatment of psychosis with some benefits. Elevation of oxytocin may be a mechanism of yoga effects in schizophrenia. Certain components of yoga have demonstrated neurobiological effects similar to those of vagal stimulation, indicating this (indirect or autogenous vagal stimulation) as a possible mechanism of its action. It is time, psychiatrists exploited the benefits if yoga for a comprehensive care in their patients. PMID:23858245

  3. Potential role of bromelain in clinical and therapeutic applications.

    PubMed

    Rathnavelu, Vidhya; Alitheen, Noorjahan Banu; Sohila, Subramaniam; Kanagesan, Samikannu; Ramesh, Rajendran

    2016-09-01

    Pineapple has been used as part of traditional folk medicine since ancient times and it continues to be present in various herbal preparations. Bromelain is a complex mixture of protease extracted from the fruit or stem of the pineapple plant. Although the complete molecular mechanism of action of bromelain has not been completely identified, bromelain gained universal acceptability as a phytotherapeutic agent due to its history of safe use and lack of side effects. Bromelain is widely administered for its well-recognized properties, such as its anti-inflammatory, antithrombotic and fibrinolytic affects, anticancer activity and immunomodulatory effects, in addition to being a wound healing and circulatory improvement agent. The current review describes the promising clinical applications and therapeutic properties of bromelain.

  4. Potential role of bromelain in clinical and therapeutic applications

    PubMed Central

    Rathnavelu, Vidhya; Alitheen, Noorjahan Banu; Sohila, Subramaniam; Kanagesan, Samikannu; Ramesh, Rajendran

    2016-01-01

    Pineapple has been used as part of traditional folk medicine since ancient times and it continues to be present in various herbal preparations. Bromelain is a complex mixture of protease extracted from the fruit or stem of the pineapple plant. Although the complete molecular mechanism of action of bromelain has not been completely identified, bromelain gained universal acceptability as a phytotherapeutic agent due to its history of safe use and lack of side effects. Bromelain is widely administered for its well-recognized properties, such as its anti-inflammatory, antithrombotic and fibrinolytic affects, anticancer activity and immunomodulatory effects, in addition to being a wound healing and circulatory improvement agent. The current review describes the promising clinical applications and therapeutic properties of bromelain. PMID:27602208

  5. Potential Therapeutic Strategies of Regenerative Medicine for Renal Failure.

    PubMed

    Mata-Miranda, Monica Maribel; Delgado-Macuil, Raul Jacobo; Rojas-Lopez, Marlon; Martinez-Flores, Ricardo; Vazquez-Zapien, Gustavo Jesus

    2017-03-17

    Kidney diseases are a public health problem worldwide; the mortality rate is between 50 and 80%. Available therapies include replacement function by dialysis or transplant, associated with a high morbidity and mortality; kidney transplantation is limited by the shortage of donor organs, immune rejection and lifelong treatment with immunosuppressive. Likewise, none of these treatments compensates all kidney functions. There is a great concern in developing more effective therapies with the ability to replace the wide range of renal functions, so that, new researches on developing therapeutic strategies have focused on regenerative medicine, science that includes artificial creation of tissues and organs, in order to repair or replace a tissue or organ function. The aim of this paper is to review the new advances in regenerative medicine strategies for treatment of renal failure. Generally, regenerative medicine comprises two therapeutic strategies: cell therapy and tissue engineering. Cell therapy techniques depend on cell and tissue culture, with the aim to grow specific cells that will replace morphological structures, tissues and functions. In this area, some investigations that include the use of stem cells have been carried out. Tissue engineering complements cell therapy combining techniques of biological sciences and engineering to create structures and devices as scaffolds, matrices or biocompatible materials, which alone or in combination will give support and facilitate the repair of damaged tissue. Even though there is a great advance in regenerative medicine strategies, we are far from using any of its techniques on health institutions, due to it is necessary to evaluate side effects, biodistribution, dosage, type of administration, vehicle of cell therapy, as well as the evaluation of response time and long-term studies, among other studies.

  6. Potential immunological markers for diagnosis and therapeutic assessment of toxocariasis.

    PubMed

    Rubinsky-Elefant, Guita; Hoshino-Shimizu, Sumie; Jacob, Cristina Miuki Abe; Sanchez, Maria Carmen Arroyo; Ferreira, Antonio Walter

    2011-01-01

    In human toxocariasis, there are few approaches using immunological markers for diagnosis and therapeutic assessment. An immunoblot (IB) assay using excretory-secretory Toxocara canis antigen was standardized for monitoring IgG, IgE and IgA antibodies in 27 children with toxocariasis (23 visceral, three mixed visceral and ocular, and one ocular form) for 22-116 months after chemotherapy. IB sensitivity was 100% for IgG antibodies to bands of molecular weight 29-38, 48-54, 95-116, 121-162, >205 kDa, 80.8% for IgE to 29-38, 48-54, 95-121, > 205 kDa, and 65.4% for IgA to 29-38, 48-54, 81-93 kDa. Candidates for diagnostic markers should be IgG antibodies to bands of low molecular weight (29-38 and 48-54 kDa). One group of patients presented the same antibody reactivity to all bands throughout the follow-up study; in the other group, antibodies decayed partially or completely to some or all bands, but these changes were not correlated with time after chemotherapy. Candidates for monitoring patients after chemotherapy may be IgG antibodies to > 205 kDa fractions, IgA to 29-38, 48-54, 81-93 kDa and IgE to 95-121 kDa. Further identification of antigen epitopes related to these markers will allow the development of sensitive and specific immunoassays for the diagnosis and therapeutic assessment of toxocariasis.

  7. Perspectives of new potential therapeutic applications of somatostatin analogs.

    PubMed

    Pawlikowski, Marek; Melen-Mucha, Gabriela

    2003-01-01

    At the present time only two long-acting somatostatin (SS) analogs, octreotide and lanreotide, are commonly used in the routine therapy. Both analogs have a high affinity mainly to a somatostatin receptor subtype 2 (SSTR2). The established indications for SS analogs treatment include acromegaly, neuroendocrine tumors of the pancreas and gastrointestinal tract, and some gastro-enterologic diseases (pancreatitis, gastrointestinal bleedings, refractory diarrheas, pancreatic and intestinal fistulas). The recent investigations allow to predict the enlargement of therapeutic applications of SS analogs. It concerns pituitary tumors other than somatotropinoma, tumors of other endocrine glands like thyroid and adrenal gland, as well as some non-endocrine tumors. The progress depends on the introduction of new SS analogs with high affinity for SS receptor subtypes other than SSTR2, because some tumors present the high expression of SSTR1 (e.g. prostatic cancers) or SSTR5 (e.g. colonic cancers). Great hopes are connected with the coupling of SS analogs with the radioactive isotopes or non-radioactive cytotoxic agents to destruct the neoplastic cells highly expressing the specific subtypes of SS receptors. The pre- or postoperative in vivo imaging of SS receptors by means of the receptor scintigraphy, as well as the post-operative identification of SS receptor subtypes in the excised tumor tissues using immunohistochemistry, should play an important role in the prediction of the effects of SS analog treatment. Beside oncology, new therapeutic applications of SS analogs could be presumed among others in ophthalmology; it concerns the treatment of progressive Graves-Basedow ophtalmopathy, diabetic retinopathy, glaucoma and corneal diseases connected with corneal vascularization.

  8. Biological Relevance and Therapeutic Potential of the Hypusine Modification System*

    PubMed Central

    Pällmann, Nora; Braig, Melanie; Sievert, Henning; Preukschas, Michael; Hermans-Borgmeyer, Irm; Schweizer, Michaela; Nagel, Claus Henning; Neumann, Melanie; Wild, Peter; Haralambieva, Eugenia; Hagel, Christian; Bokemeyer, Carsten; Hauber, Joachim; Balabanov, Stefan

    2015-01-01

    Hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) is emerging as a crucial regulator in cancer, infections, and inflammation. Although its contribution in translational regulation of proline repeat-rich proteins has been sufficiently demonstrated, its biological role in higher eukaryotes remains poorly understood. To establish the hypusine modification system as a novel platform for therapeutic strategies, we aimed to investigate its functional relevance in mammals by generating and using a range of new knock-out mouse models for the hypusine-modifying enzymes deoxyhypusine synthase and deoxyhypusine hydroxylase as well as for the cancer-related isoform eIF-5A2. We discovered that homozygous depletion of deoxyhypusine synthase and/or deoxyhypusine hydroxylase causes lethality in adult mice with different penetrance compared with haploinsufficiency. Network-based bioinformatic analysis of proline repeat-rich proteins, which are putative eIF-5A targets, revealed that these proteins are organized in highly connected protein-protein interaction networks. Hypusine-dependent translational control of essential proteins (hubs) and protein complexes inside these networks might explain the lethal phenotype observed after deletion of hypusine-modifying enzymes. Remarkably, our results also demonstrate that the cancer-associated isoform eIF-5A2 is dispensable for normal development and viability. Together, our results provide the first genetic evidence that the hypusine modification in eIF-5A is crucial for homeostasis in mammals. Moreover, these findings highlight functional diversity of the hypusine system compared with lower eukaryotes and indicate eIF-5A2 as a valuable and safe target for therapeutic intervention in cancer. PMID:26037925

  9. Current and Potential Therapeutic Strategies for Hemodynamic Cardiorenal Syndrome

    PubMed Central

    Obi, Yoshitsugu; Kim, Taehee; Kovesdy, Csaba P.; Amin, Alpesh N.; Kalantar-Zadeh, Kamyar

    2016-01-01

    Background Cardiorenal syndrome (CRS) encompasses conditions in which cardiac and renal disorders co-exist and are pathophysiologically related. The newest classification of CRS into seven etiologically and clinically distinct types for direct patient management purposes includes hemodynamic, uremic, vascular, neurohumoral, anemia- and/or iron metabolism-related, mineral metabolism-related and protein-energy wasting-related CRS. This classification also emphasizes the pathophysiologic pathways. The leading CRS category remains hemodynamic CRS, which is the most commonly encountered type in patient care settings and in which acute or chronic heart failure leads to renal impairment. Summary This review focuses on selected therapeutic strategies for the clinical management of hemodynamic CRS. This is often characterized by an exceptionally high ratio of serum urea to creatinine concentrations. Loop diuretics, positive inotropic agents including dopamine and dobutamine, vasopressin antagonists including vasopressin receptor antagonists such as tolvaptan, nesiritide and angiotensin-neprilysin inhibitors are among the pharmacologic agents used. Additional therapies include ultrafiltration (UF) via hemofiltration or dialysis. The beneficial versus unfavorable effects of these therapies on cardiac decongestion versus renal blood flow may act in opposite directions. Some of the most interesting options for the outpatient setting that deserve revisiting include portable continuous dobutamine infusion, peritoneal dialysis and outpatient UF via hemodialysis or hemofiltration. Key Messages The new clinically oriented CRS classification system is helpful in identifying therapeutic targets and offers a systematic approach to an optimal management algorithm with better understanding of etiologies. Most interventions including UF have not shown a favorable impact on outcomes. Outpatient portable dobutamine infusion is underutilized and not well studied. Revisiting traditional and

  10. The therapeutic potential of interleukin-10 in neuroimmune diseases

    PubMed Central

    Kwilasz, A.J.; Grace, P.M.; Serbedzija, P.; Maier, S.F.; Watkins, L.R.

    2016-01-01

    Neuroimmune diseases have diverse symptoms and etiologies but all involve pathological inflammation that affects normal central nervous system signaling. Critically, many neuroimmune diseases also involve insufficient signaling/bioavailability of interleukin-10 (IL-10). IL-10 is a potent anti-inflammatory cytokine released by immune cells and glia, which drives the regulation of a variety of anti-inflammatory processes. This review will focus on the signaling pathways and function of IL-10, the current evidence for insufficiencies in IL-10 signaling/bioavailability in neuroimmune diseases, as well as the implications for IL-10-based therapies to treating such problems. We will review in detail four pathologies as examples of the common etiologies of such disease states, namely neuropathic pain (nerve trauma), osteoarthritis (peripheral inflammation), Parkinson’s disease (neurodegeneration), and multiple sclerosis (autoimmune). A number of methods to increase IL-10 have been developed (e.g. protein administration, viral vectors, naked plasmid DNA, plasmid DNA packaged in polymers to enhance their uptake into target cells, and adenosine 2A agonists), which will also be discussed. In general, IL-10-based therapies have been effective at treating both the symptoms and pathology associated with various neuroimmune diseases, with more sophisticated gene therapy-based methods producing sustained therapeutic effects lasting for several months following a single injection. These exciting results have resulted in IL-10-targeted therapeutics being positioned for upcoming clinical trials for treating neuroimmune diseases, including neuropathic pain. Although further research is necessary to determine the full range of effects associated with IL-10-based therapy, evidence suggests IL-10 may be an invaluable target for the treatment of neuroimmune disease. This article is part of a Special Issue entitled ‘Neuroimmunology and Synaptic Function’. PMID:25446571

  11. The therapeutic potential of interleukin-10 in neuroimmune diseases.

    PubMed

    Kwilasz, A J; Grace, P M; Serbedzija, P; Maier, S F; Watkins, L R

    2015-09-01

    Neuroimmune diseases have diverse symptoms and etiologies but all involve pathological inflammation that affects normal central nervous system signaling. Critically, many neuroimmune diseases also involve insufficient signaling/bioavailability of interleukin-10 (IL-10). IL-10 is a potent anti-inflammatory cytokine released by immune cells and glia, which drives the regulation of a variety of anti-inflammatory processes. This review will focus on the signaling pathways and function of IL-10, the current evidence for insufficiencies in IL-10 signaling/bioavailability in neuroimmune diseases, as well as the implications for IL-10-based therapies to treating such problems. We will review in detail four pathologies as examples of the common etiologies of such disease states, namely neuropathic pain (nerve trauma), osteoarthritis (peripheral inflammation), Parkinson's disease (neurodegeneration), and multiple sclerosis (autoimmune). A number of methods to increase IL-10 have been developed (e.g. protein administration, viral vectors, naked plasmid DNA, plasmid DNA packaged in polymers to enhance their uptake into target cells, and adenosine 2A agonists), which will also be discussed. In general, IL-10-based therapies have been effective at treating both the symptoms and pathology associated with various neuroimmune diseases, with more sophisticated gene therapy-based methods producing sustained therapeutic effects lasting for several months following a single injection. These exciting results have resulted in IL-10-targeted therapeutics being positioned for upcoming clinical trials for treating neuroimmune diseases, including neuropathic pain. Although further research is necessary to determine the full range of effects associated with IL-10-based therapy, evidence suggests IL-10 may be an invaluable target for the treatment of neuroimmune disease. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. Copyright © 2014 Elsevier Ltd

  12. Interleukin-4 receptor-targeted liposomal doxorubicin as a model for enhancing cellular uptake and antitumor efficacy in murine colorectal cancer

    PubMed Central

    Yang, Chih-Yung; Liu, Hong-Wen; Tsai, Ya-Ching; Tseng, Ju-Yu; Liang, Shu-Ching; Chen, Chin-Yau; Lian, Wei-Nan; Wei, Ming-Cheng; Lu, Maggie; Lu, Ruey-Hwa; Lin, Chi-Hung; Jiang, Jeng-Kai

    2015-01-01

    Our previous studies showed that colorectal tumor has high interleukin-4 receptor α (IL-4Rα) expression, whereas adjacent normal tissue has low or no IL-4Rα expression. We also observed that human atherosclerotic plaque-specific peptide-1 (AP1) can specifically target to IL-4Rα. In this study, we investigated the therapeutic efficacy and systemic toxicity of AP1-conjuagted liposomal doxorubicin. AP1 bound more strongly to and was more efficiently internalized into IL-4Rα-overexpressing CT26 cells than CT26 control cells. Selective cytotoxicity experiment revealed that AP1-conjugated liposomal doxorubicin preferentially killed IL-4Rα-overexpressing CT26 cells. AP1-conjugated liposomal doxorubicin administered intravenously into mice produced significant inhibition of tumor growth and showed decreased cardiotoxicity of doxorubicin. These results indicated that AP1-conjugated liposomal doxorubicin has a potent and selective anticancer potential against IL-4Rα-overexpressing colorectal cancer cells, thus providing a model for targeted anticancer therapy. PMID:26436767

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

    PubMed Central

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

    2013-01-01

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

  14. Organometallic Rhenium Complexes Divert Doxorubicin to the Mitochondria.

    PubMed

    Imstepf, Sebastian; Pierroz, Vanessa; Rubbiani, Riccardo; Felber, Michael; Fox, Thomas; Gasser, Gilles; Alberto, Roger

    2016-02-18

    Doxorubicin, a well-established chemotherapeutic agent, is known to accumulate in the cell nucleus. By using ICP-MS, we show that the conjugation of two small organometallic rhenium complexes to this structural motif results in a significant redirection of the conjugates from the nucleus to the mitochondria. Despite this relocation, the two bioconjugates display excellent toxicity toward HeLa cells. In addition, we carried out a preliminarily investigation of aspects of cytotoxicity and present evidence that the conjugates disrupt the mitochondrial membrane potential, are strong inhibitors of human Topoisomerase II, and induce apoptosis. Such derivatives may enhance the therapeutic index of the aggressive parent drug and overcome drug resistance by influencing nuclear and mitochondrial homeostasis. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. 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.

  16. Therapeutic potential of matrix metalloproteinases in Duchenne muscular dystrophy

    PubMed Central

    Ogura, Yuji; Tajrishi, Marjan M.; Sato, Shuichi; Hindi, Sajedah M.; Kumar, Ashok

    2014-01-01

    Matrix metalloproteinases (MMPs) are secreted proteinases that have physiologic roles in degradation and remodeling of extracellular matrix (ECM) in almost all tissues. However, their excessive production in disease conditions leads to many pathological features including tissue breakdown, inflammation, cell death, and fibrosis. Duchenne Muscular dystrophy (DMD) is a devastating genetic muscle disorder caused by partial or complete loss of cytoskeletal protein dystrophin. Progressive muscle wasting in DMD is accompanied by myofiber necrosis followed by cycles of regeneration and degeneration and inflammation that eventually result in replacement of myofiber by connective and adipose tissues. Emerging evidence suggests that gene expression and the activity of various MMPs are aberrantly regulated in muscle biopsies from DMD patients and in skeletal muscle of animal models of DMD. Moreover, a few studies employing genetic mouse models have revealed that different MMPs play distinct roles in disease progression in DMD. Modulation of the activity of MMPs improves myofiber regeneration and enhances the efficacy of transplantation and engraftment of muscle progenitor cells in dystrophic muscle in mouse models of DMD. Furthermore, recent reports also suggest that some MMPs especially MMP-9 can serve as a biomarker for diagnosis and prognosis of DMD. In this article, we provide a succinct overview of the regulation of various MMPs and their therapeutic importance in DMD. PMID:25364719

  17. Guanosine: a Neuromodulator with Therapeutic Potential in Brain Disorders

    PubMed Central

    Lanznaster, Débora; Dal-Cim, Tharine; Piermartiri, Tetsadê C. B.; Tasca, Carla I.

    2016-01-01

    Guanosine is a purine nucleoside with important functions in cell metabolism and a protective role in response to degenerative diseases or injury. The past decade has seen major advances in identifying the modulatory role of extracellular action of guanosine in the central nervous system (CNS). Evidence from rodent and cell models show a number of neurotrophic and neuroprotective effects of guanosine preventing deleterious consequences of seizures, spinal cord injury, pain, mood disorders and aging-related diseases, such as ischemia, Parkinson’s and Alzheimer’s diseases. The present review describes the findings of in vivo and in vitro studies and offers an update of guanosine effects in the CNS. We address the protein targets for guanosine action and its interaction with glutamatergic and adenosinergic systems and with calcium-activated potassium channels. We also discuss the intracellular mechanisms modulated by guanosine preventing oxidative damage, mitochondrial dysfunction, inflammatory burden and modulation of glutamate transport. New and exciting avenues for future investigation into the protective effects of guanosine include characterization of a selective guanosine receptor. A better understanding of the neuromodulatory action of guanosine will allow the development of therapeutic approach to brain diseases. PMID:27699087

  18. Therapeutic potential of matrix metalloproteinases in Duchenne muscular dystrophy.

    PubMed

    Ogura, Yuji; Tajrishi, Marjan M; Sato, Shuichi; Hindi, Sajedah M; Kumar, Ashok

    2014-01-01

    Matrix metalloproteinases (MMPs) are secreted proteinases that have physiologic roles in degradation and remodeling of extracellular matrix (ECM) in almost all tissues. However, their excessive production in disease conditions leads to many pathological features including tissue breakdown, inflammation, cell death, and fibrosis. Duchenne Muscular dystrophy (DMD) is a devastating genetic muscle disorder caused by partial or complete loss of cytoskeletal protein dystrophin. Progressive muscle wasting in DMD is accompanied by myofiber necrosis followed by cycles of regeneration and degeneration and inflammation that eventually result in replacement of myofiber by connective and adipose tissues. Emerging evidence suggests that gene expression and the activity of various MMPs are aberrantly regulated in muscle biopsies from DMD patients and in skeletal muscle of animal models of DMD. Moreover, a few studies employing genetic mouse models have revealed that different MMPs play distinct roles in disease progression in DMD. Modulation of the activity of MMPs improves myofiber regeneration and enhances the efficacy of transplantation and engraftment of muscle progenitor cells in dystrophic muscle in mouse models of DMD. Furthermore, recent reports also suggest that some MMPs especially MMP-9 can serve as a biomarker for diagnosis and prognosis of DMD. In this article, we provide a succinct overview of the regulation of various MMPs and their therapeutic importance in DMD.

  19. Centipede venoms and their components: resources for potential therapeutic applications.

    PubMed

    Hakim, Md Abdul; Yang, Shilong; Lai, Ren

    2015-11-17

    Venomous animals have evolved with sophisticated bio-chemical strategies to arrest prey and defend themselves from natural predators. In recent years, peptide toxins from venomous animals have drawn considerable attention from researchers due to their surprising chemical, biochemical, and pharmacological diversity. Similar to other venomous animals, centipedes are one of the crucial venomous arthropods that have been used in traditional medicine for hundreds of years in China. Despite signifying pharmacological importance, very little is known about the active components of centipede venoms. More than 500 peptide sequences have been reported in centipede venomous glands by transcriptome analysis, but only a small number of peptide toxins from centipede has been functionally described. Like other venomous animals such as snakes, scorpions, and spiders, the venom of centipedes could be an excellent source of peptides for developing drugs for treatments as well as bio-insecticides for agrochemical applications. Although centipede venoms are yet to be adequately studied, the venom of centipedes as well as their components described to date, should be compiled to help further research. Therefore, based on previous reports, this review focusses on findings and possible therapeutic applications of centipede venoms as well as their components.

  20. [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.

  1. CD74 expression and its therapeutic potential in thyroid carcinoma.

    PubMed

    Cheng, Shih-Ping; Liu, Chien-Liang; Chen, Ming-Jen; Chien, Ming-Nan; Leung, Ching-Hsiang; Lin, Chi-Hsin; Hsu, Yi-Chiung; Lee, Jie-Jen

    2015-04-01

    CD74, the invariant chain of major histocompatibility complex class II, is also a receptor for macrophage migration inhibitory factor (MIF). CD74 and MIF have been associated with tumor progression and metastasis in hematologic and solid tumors. In this study, we found that 60 and 65% of papillary thyroid cancers were positive for CD74 and MIF immunohistochemical staining respectively. Anaplastic thyroid cancer was negative for MIF, but mostly positive for CD74 expression. Normal thyroid tissue and follicular adenomas were negative for CD74 expression. CD74 expression in papillary thyroid cancer was associated with larger tumor size (P=0.043), extrathyroidal invasion (P=0.021), advanced TNM stage (P=0.006), and higher MACIS score (P=0.026). No clinicopathological parameter was associated with MIF expression. Treatment with anti-CD74 antibody in thyroid cancer cells inhibited cell growth, colony formation, cell migration and invasion, and vascular endothelial growth factor secretion. In contrast, treatment with recombinant MIF induced an increase in cell invasion. Anti-CD74 treatment reduced AKT phosphorylation and stimulated AMPK activation. Our findings suggest that CD74 overexpression in thyroid cancer is associated with advanced tumor stage and may serve as a therapeutic target. © 2015 Society for Endocrinology.

  2. 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.

  3. 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

  4. Therapeutic potential of traditional chinese medicine on inflammatory diseases.

    PubMed

    Tsai, Wen-Hsin; Yang, Chih-Ching; Li, Ping-Chia; Chen, Wang-Chuan; Chien, Chiang-Ting

    2013-07-01

    Increased oxidative stress induces inflammation to several tissues/organs leading to cell death and long-term injury. Traditional Chinese Medicine (TCM) with antioxidant, anti-inflammatory, anti-apoptotic, and autophagic regulatory functions has been widely used as preventive or therapeutic strategy in modern medicine. Oxidative stress and inflammation have been widely reported to contribute to cigarette smoke-induced lung inflammation, hepatotoxicity, or sympathetic activation-induced liver inflammation, lipopolysaccharide-induced renal inflammation, and substance P-mediated neurogenic hyperactive bladder based on clinical findings. In this review, we introduce several evidences for TCM treatment including Monascus adlay (MA) produced by inoculating adlay (Cois lachrymal-jobi L. var. ma-yuen Stapf) with Monascus purpureus on lung injury, Amla (Emblica officinalis Gaertn. of Euphorbiaceae family) on hepatotoxin-induced liver inflammation, Virgate Wormwood Decoction (Yīn Chén Hāo tāng) and its active component genipin on sympathetic activation-induced liver inflammation, and green tea extract and its active components, catechins, or a modified TCM formula Five Stranguries Powder (Wǔ Lén Sǎn) plus Crataegi Fructus (Shān Zhā) on hyperactive bladder. The pathophysiologic and molecular mechanisms of TCM on ameliorating inflammatory diseases are discussed in the review.

  5. Synthetic and natural iron chelators: therapeutic potential and clinical use

    PubMed Central

    Hatcher, Heather C; Singh, Ravi N; Torti, Frank M; Torti, Suzy V

    2013-01-01

    Iron-chelation therapy has its origins in the treatment of iron-overload syndromes. For many years, the standard for this purpose has been deferoxamine. Recently, considerable progress has been made in identifying synthetic chelators with improved pharmacologic properties relative to deferoxamine. Most notable are deferasirox (Exjade®) and deferiprone (Ferriprox®), which are now available clinically. In addition to treatment of iron overload, there is an emerging role for iron chelators in the treatment of diseases characterized by oxidative stress, including cardiovascular disease, atherosclerosis, neurodegenerative diseases and cancer. While iron is not regarded as the underlying cause of these diseases, it does play an important role in disease progression, either through promotion of cellular growth and proliferation or through participation in redox reactions that catalyze the formation of reactive oxygen species and increase oxidative stress. Thus, iron chelators may be of therapeutic benefit in many of these conditions. Phytochemicals, many of which bind iron, may also owe some of their beneficial properties to iron chelation. This review will focus on the advances in iron-chelation therapy for the treatment of iron-overload disease and cancer, as well as neurodegenerative and chronic inflammatory diseases. Established and novel iron chelators will be discussed, as well as the emerging role of dietary plant polyphenols that effectively modulate iron biochemistry. PMID:21425984

  6. Immunological Defects in Neonatal Sepsis and Potential Therapeutic Approaches

    PubMed Central

    Raymond, Steven L.; Stortz, Julie A.; Mira, Juan C.; Larson, Shawn D.; Wynn, James L.; Moldawer, Lyle L.

    2017-01-01

    Despite advances in critical care medicine, neonatal sepsis remains a major cause of morbidity and mortality worldwide, with the greatest risk affecting very low birth weight, preterm neonates. The presentation of neonatal sepsis varies markedly from its presentation in adults, and there is no clear consensus definition of neonatal sepsis. Previous work has demonstrated that when neonates become septic, death can occur rapidly over a matter of hours or days and is generally associated with inflammation, organ injury, and respiratory failure. Studies of the transcriptomic response by neonates to infection and sepsis have led to unique insights into the early proinflammatory and host protective responses to sepsis. Paradoxically, this early inflammatory response in neonates, although lethal, is clearly less robust relative to children and adults. Similarly, the expression of genes involved in host protective immunity, particularly neutrophil function, is also markedly deficient. As a result, neonates have both a diminished inflammatory and protective immune response to infection which may explain their increased risk to infection, and their reduced ability to clear infections. Such studies imply that novel approaches unique to the neonate will be required for the development of both diagnostics and therapeutics in this high at-risk population. PMID:28224121

  7. Autophagy and mitophagy in the myocardium: therapeutic potential and concerns

    PubMed Central

    Jimenez, Rebecca E; Kubli, Dieter A; Gustafsson, Åsa B

    2014-01-01

    The autophagic-lysosomal degradation pathway is critical for cardiac homeostasis, and defects in this pathway are associated with development of cardiomyopathy. Autophagy is responsible for the normal turnover of organelles and long-lived proteins. Autophagy is also rapidly up-regulated in response to stress, where it rapidly clears dysfunctional organelles and cytotoxic protein aggregates in the cell. Autophagy is also important in clearing dysfunctional mitochondria before they can cause harm to the cell. This quality control mechanism is particularly important in cardiac myocytes, which contain a very high volume of mitochondria. The degradation of proteins and organelles also generates free fatty acids and amino acids, which help maintain energy levels in myocytes during stress conditions. Increases in autophagy have been observed in various cardiovascular diseases, but a major question that remains to be answered is whether enhanced autophagy is an adaptive or maladaptive response to stress. This review discusses the regulation and role of autophagy in the myocardium under baseline conditions and in various aetiologies of heart disease. It also discusses whether this pathway represents a new therapeutic target to treat or prevent cardiovascular disease and the concerns associated with modulating autophagy. 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:24148024

  8. Physiological mechanisms and therapeutic potential of bone mechanosensing

    PubMed Central

    Xiao, Zhousheng

    2016-01-01

    Skeletal loading is an important physiological regulator of bone mass. Theoretically, mechanical forces or administration of drugs that activate bone mechanosensors would be a novel treatment for osteoporotic disorders, particularly age-related osteoporosis and other bone loss caused by skeletal unloading. Uncertainty regarding the identity of the molecular targets that sense and transduce mechanical forces in bone, however, has limited the therapeutic exploitation of mechanosesning pathways to control bone mass. Recently, two evolutionally conserved mechanosensing pathways have been shown to function as “physical environment” sensors in cells of the osteoblasts lineage. Indeed, polycystin–1 (Pkd1, or PC1) and polycystin–2 (Pkd2, or PC2, or TRPP2), which form a flow sensing receptor channel complex, and TAZ (transcriptional coactivator with PDZ-binding motif, or WWTR1), which responds to the extracellular matrix microenvironment act in concert to reciprocally regulate osteoblastogenesis and adipogenesis through co-activating Runx2 and a co-repressing PPARγ activities. Interactions of polycystins and TAZ with other putative mechanosensing mechanism, such as primary cilia, integrins and hemichannels, may create multifaceted mechanosensing networks in bone. Moreover, modulation of polycystins and TAZ interactions identify novel molecular targets to develop small molecules that mimic the effects of mechanical loading on bone. PMID:26038304

  9. Pharmacology and therapeutic potential of pattern recognition receptors.

    PubMed

    Paul-Clark, M J; George, P M; Gatheral, T; Parzych, K; Wright, W R; Crawford, D; Bailey, L K; Reed, D M; Mitchell, J A

    2012-08-01

    Pharmacologists have used pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) for decades as a stimulus for studying mediators involved in inflammation and for the screening of anti-inflammatory compounds. However, in the view of immunologists, LPS was too non-specific for studying the mechanisms of immune signalling in infection and inflammation, as no receptors had been identified. This changed in the late 1990s with the discovery of the Toll-like receptors. These 'pattern recognition receptors' (PRRs) were able to recognise highly conserved sequences, the so called pathogen associated molecular patterns (PAMPs) present in or on pathogens. This specificity of particular PAMPs and their newly defined receptors provided a common ground between pharmacologists and immunologists for the study of inflammation. PRRs also recognise endogenous agonists, the so called danger-associated molecular patterns (DAMPs), which can result in sterile inflammation. The signalling pathways and ligands of many PRRs have now been characterised and there is no doubt that this rich vein of research will aid the discovery of new therapeutics for infectious conditions and chronic inflammatory disease.

  10. Melatonin receptors in diabetes: a potential new therapeutical target?

    PubMed

    She, Meihua; Laudon, Moshe; Yin, Weidong

    2014-12-05

    Melatonin is synthesized and secreted mainly by the pineal gland in a circadian fashion, and it thus mediates endogenous circadian rhythms and influences other physiological functions. Both the G-protein coupled receptors MT1 (encoded by MTNR1A) and MT2 (encoded by MTNR1B) in mammals mediate the actions of melatonin. Evidence from in vivo and in vitro studies proved a key role of melatonin in the regulation of glucose metabolism and the pathogenesis of diabetes, as further confirmed by the recent studies of human genetic variants of MTNR1B. Remarkably, it was also suggested that genetic variations within MTNR1B disordered β-cells function directly, i.e. insulin secretion. This indicated the functional link between MT2 and T2D risk at the protein level, and it may represent the prevailing pathomechanism for how impaired melatonin signaling causes metabolic disorders and increases the T2D risk. It is speculated that melatonin and its receptors may be a new therapeutic avenue in diabetes.

  11. Therapeutic Potential of Traditional Chinese Medicine on Inflammatory Diseases

    PubMed Central

    Tsai, Wen-Hsin; Yang, Chih-Ching; Li, Ping-Chia; Chen, Wang-Chuan; Chien, Chiang-Ting

    2013-01-01

    Increased oxidative stress induces inflammation to several tissues/organs leading to cell death and long-term injury. Traditional Chinese Medicine (TCM) with antioxidant, anti-inflammatory, anti-apoptotic, and autophagic regulatory functions has been widely used as preventive or therapeutic strategy in modern medicine. Oxidative stress and inflammation have been widely reported to contribute to cigarette smoke-induced lung inflammation, hepatotoxicity, or sympathetic activation-induced liver inflammation, lipopolysaccharide-induced renal inflammation, and substance P-mediated neurogenic hyperactive bladder based on clinical findings. In this review, we introduce several evidences for TCM treatment including Monascus adlay (MA) produced by inoculating adlay (Cois lachrymal-jobi L. var. ma-yuen Stapf) with Monascus purpureus on lung injury, Amla (Emblica officinalis Gaertn. of Euphorbiaceae family) on hepatotoxin-induced liver inflammation, Virgate Wormwood Decoction (Yīn Chén Hāo tāng) and its active component genipin on sympathetic activation–induced liver inflammation, and green tea extract and its active components, catechins, or a modified TCM formula Five Stranguries Powder (Wǔ Lén Sǎn) plus Crataegi Fructus (Shān Zhā) on hyperactive bladder. The pathophysiologic and molecular mechanisms of TCM on ameliorating inflammatory diseases are discussed in the review. PMID:24716170

  12. Nicotine: therapeutic potential for the treatment of ulcerative colitis.

    PubMed

    Green, J T; Thomas, G A; Rhodes, J

    1997-01-01

    Ulcerative colitis (UC) is predominantly a disease of non-smokers, and nicotine may be the agent responsible for this association. Transdermal nicotine has been shown to improve disease activity and sigmoidoscopic appearance in the active disease but in one study had no effect on maintenance of remission. Since side-effects with nicotine patches occur in up to two thirds of patients, attempts to reduce systemic levels and improve drug tolerance have been developed with colonic delivery systems of nicotine. Preliminary observations with nicotine enemas in UC have shown clinical benefit, but controlled trials are needed. Mechanisms responsible for the association of smoking with colitis and for the therapeutic effect of nicotine remain an enigma; possibilities include: modulation of the immune response, alterations of colonic mucus and eicosanoid production, changes in rectal blood flow, decreased intestinal permeability and the release of endogenous glucocorticoids. With current treatment for UC limited to corticosteroids and formulations of 5-aminosalicylic acid, alternative treatments are required and nicotine may fulfil this role.

  13. Therapeutic Potential of Immunoproteasome Inhibition in Duchenne Muscular Dystrophy.

    PubMed

    Farini, Andrea; Sitzia, Clementina; Cassani, Barbara; Cassinelli, Letizia; Rigoni, Rosita; Colleoni, Federica; Fusco, Nicola; Gatti, Stefano; Bella, Pamela; Villa, Chiara; Napolitano, Filomena; Maiavacca, Rita; Bosari, Silvano; Villa, Anna; Torrente, Yvan

    2016-11-01

    Duchenne muscular dystrophy is an inherited fatal genetic disease characterized by mutations in dystrophin gene, causing membrane fragility leading to myofiber necrosis and inflammatory cell recruitment in dystrophic muscles. The resulting environment enriched in proinflammatory cytokines, like IFN-γ and TNF-α, determines the transformation of myofiber constitutive proteasome into the immunoproteasome, a multisubunit complex involved in the activation of cell-mediate immunity. This event has a fundamental role in producing peptides for antigen presentation by MHC class I, for the immune response and also for cytokine production and T-cell differentiation. Here, we characterized for the first time the presence of T-lymphocytes activated against revertant dystrophin epitopes, in the animal model of Duchenne muscular dystrophy, the mdx mice. Moreover, we specifically blocked i-proteasome subunit LMP7, which was up-regulated in dystrophic skeletal muscles, and we demonstrated the rescue of the dystrophin expression and the amelioration of the dystrophic phenotype. The i-proteasome blocking lowered myofiber MHC class I expression and self-antigen presentation to T cells, thus reducing the specific antidystrophin T cell response, the muscular cell infiltrate, and proinflammatory cytokine production, together with muscle force recovery. We suggest that i-proteasome inhibition should be considered as new promising therapeutic approach for Duchenne muscular dystrophy pathology.

  14. Centipede Venoms and Their Components: Resources for Potential Therapeutic Applications

    PubMed Central

    Hakim, Md Abdul; Yang, Shilong; Lai, Ren

    2015-01-01

    Venomous animals have evolved with sophisticated bio-chemical strategies to arrest prey and defend themselves from natural predators. In recent years, peptide toxins from venomous animals have drawn considerable attention from researchers due to their surprising chemical, biochemical, and pharmacological diversity. Similar to other venomous animals, centipedes are one of the crucial venomous arthropods that have been used in traditional medicine for hundreds of years in China. Despite signifying pharmacological importance, very little is known about the active components of centipede venoms. More than 500 peptide sequences have been reported in centipede venomous glands by transcriptome analysis, but only a small number of peptide toxins from centipede has been functionally described. Like other venomous animals such as snakes, scorpions, and spiders, the venom of centipedes could be an excellent source of peptides for developing drugs for treatments as well as bio-insecticides for agrochemical applications. Although centipede venoms are yet to be adequately studied, the venom of centipedes as well as their components described to date, should be compiled to help further research. Therefore, based on previous reports, this review focusses on findings and possible therapeutic applications of centipede venoms as well as their components. PMID:26593947

  15. 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.

  16. The therapeutic potential of anti-interleukin-20 monoclonal antibody.

    PubMed

    Hsu, Yu-Hsiang; Chang, Ming-Shi

    2014-01-01

    Interleukin (IL)-20, a member of the IL-10 family of cytokines, was discovered in 2001. IL-20 acts on multiple cell types by activating on a heterodimer receptor complex of either IL-20R1-IL-20R2 or IL-22R1-IL-20R2. Recent evidence indicates that IL-20's interaction with its receptors might have proinflammatory effects on chronic inflammatory diseases, particularly rheumatoid arthritis (RA), osteoporosis, and breast cancer. Updated information about IL-20, such as its identification, expression, receptors, signaling, and biological activities, is illustrated in this review based on our research and the data available in the literature. IL-20 is a pleiotropic cytokine, which promotes inflammation, angiogenesis, and chemotaxis. IL-20 also regulates osteoclast differentiation by altering the receptor activator of NF-κB (RANK) and RANK ligand (RANKL) axis. Inflammation, angiogenesis, and osteoclastogenesis are critical for the pathogenesis of RA, osteoporosis, and breast cancer-induced osteolysis. Based on the in vitro and in vivo data and clinical samples, we demonstrated that IL-20 plays pivotal roles in these three diseases. In experimental models, anti-IL-20 monoclonal antibody ameliorates arthritis severity, protects against ovariectomized-induced bone loss, and inhibits breast tumor-induced osteolysis. This review presents the clinical implications of IL-20, which will lead to a better understanding of the biological functions of IL-20 in these diseases and provide new therapeutic options in the future.

  17. Marine Compounds with Therapeutic Potential in Gram-Negative Sepsis

    PubMed Central

    Solov’eva, Tamara; Davydova, Viktoria; Krasikova, Inna; Yermak, Irina

    2013-01-01

    This paper concerns the potential use of compounds, including lipid A, chitosan, and carrageenan, from marine sources as agents for treating endotoxemic complications from Gram-negative infections, such as sepsis and endotoxic shock. Lipid A, which can be isolated from various species of marine bacteria, is a potential antagonist of bacterial endotoxins (lipopolysaccharide (LPSs)). Chitosan is a widespread marine polysaccharide that is derived from chitin, the major component of crustacean shells. The potential of chitosan as an LPS-binding and endotoxin-neutralizing agent is also examined in this paper, including a discussion on the generation of hydrophobic chitosan derivatives to increase the binding affinity of chitosan to LPS. In addition, the ability of carrageenan, which is the polysaccharide of red alga, to decrease the toxicity of LPS is discussed. We also review data obtained using animal models that demonstrate the potency of carrageenan and chitosan as antiendotoxin agents. PMID:23783404

  18. Marine compounds with therapeutic potential in gram-negative sepsis.

    PubMed

    Solov'eva, Tamara; Davydova, Viktoria; Krasikova, Inna; Yermak, Irina

    2013-06-19

    This paper concerns the potential use of compounds, including lipid A, chitosan, and carrageenan, from marine sources as agents for treating endotoxemic complications from Gram-negative infections, such as sepsis and endotoxic shock. Lipid A, which can be isolated from various species of marine bacteria, is a potential antagonist of bacterial endotoxins (lipopolysaccharide (LPSs)). Chitosan is a widespread marine polysaccharide that is derived from chitin, the major component of crustacean shells. The potential of chitosan as an LPS-binding and endotoxin-neutralizing agent is also examined in this paper, including a discussion on the generation of hydrophobic chitosan derivatives to increase the binding affinity of chitosan to LPS. In addition, the ability of carrageenan, which is the polysaccharide of red alga, to decrease the toxicity of LPS is discussed. We also review data obtained using animal models that demonstrate the potency of carrageenan and chitosan as antiendotoxin agents.

  19. Therapeutic radiology: a potential unfolding through bioelectromagnetic sciences.

    PubMed

    Jacobson, J I

    1996-09-01

    Clinical and experimental research in the area of bioelectromagnetics is reviewed and considered from a physical standpoint. An equation relating the intrinsic or "rest" energy of a charged particle with its energy of interaction in an externally applied magnetic field is proposed. This equation is intended to represent an initial basic physical interaction that may be part of a more complex biological mechanism that may explain the potential effects of externally applied magnetic fields. Speculations are presented on the potential use of magnetic fields for the noninvasive treatment of such diverse conditions as cancer, AIDS, and neurological disorders.

  20. Therapeutic Potentials of Microalgae in the Treatment of Alzheimer's Disease.

    PubMed

    Olasehinde, Tosin A; Olaniran, Ademola O; Okoh, Anthony I

    2017-03-18

    Current research is geared towards the discovery of new compounds with strong neuroprotective potential and few or no side effects compared to synthetic drugs. This review focuses on the potentials of extracts and biologically active compounds derived from microalgal biomass for the treatment and management of Alzheimer's disease (AD). Microalgal research has gained much attention recently due to its contribution to the production of renewable fuels and the ability of alga cells to produce several secondary metabolites such as carotenoids, polyphenols, sterols, polyunsaturated fatty acids and polysaccharides. These compounds exhibit several pharmacological activities and possess neuroprotective potential. The pathogenesis of Alzheimer's disease (AD) involves complex mechanisms that are associated with oxidative stress, cholinergic dysfunction, neuronal damage, protein misfolding and aggregation. The antioxidant, anticholinesterase activities as well as the inhibitory effects of some bioactive compounds from microalgae extracts on β-amyloid aggregation and neuronal death are discussed extensively. Phytochemical compounds from microalgae are used as pharmaceuticals, nutraceuticals and food supplements, and may possess neuroprotective potentials that are relevant to the management and/or treatment of AD.

  1. The multifactorial nature of Alzheimer's disease for developing potential therapeutics.

    PubMed

    Carreiras, M Carmo; Mendes, Eduarda; Perry, M Jesus; Francisco, Ana Paula; Marco-Contelles, J

    2013-01-01

    Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder with several target proteins contributing to its aetiology. Pathological, genetic, biochemical, and modeling studies all point to a critical role of Aβ aggregation in AD. Though there are still many enigmatic aspects of the Aβ cascade, none of the gaps invalidate the hypothesis. The amyloid hypothesis determines that the production, aggregation and accumulation of Aβ in the brain gives rise to a cascade of neurotoxic events that proceed to neuronal degeneration. Different targets of the disease include APP pathogenic cleavage, cytoskeletal destabilization, neurotransmitter and ion dyshomeostasis, metal ion accumulation, protein misfolding, oxidative stress, neuronal death and gene mutations. Thus, disease-modifying treatments for AD must interfere with the pathogenic steps responsible for the clinical symptoms: the deposition of extracellular Aβ plaques, the intracellular neurofibrillary tangles, inflammation, oxidative stress, iron deregulation, among others. The observations supporting the development of multifunctional compounds in association with the perception that several dual binding site AChEIs were able to reach different targets guided the development of a new drug design strategy, the multi-target-directed-ligand (MTDL) approach. This may be regarded as the buildup of hybrid molecules composed of distinct pharmacophores of different drugs. Thus, each pharmacophore of the new hybrid drug would preserve the capacity of interacting with their specific sites on the targets and, therefore, generate multiple specific pharmacological responses which would enable the treatment of multi-factorial diseases. This review summarizes a few current therapeutic trends on MTDL strategy intended to halt or revert the progression of the disease.

  2. Thalidomide: chemistry, therapeutic potential and oxidative stress induced teratogenicity.

    PubMed

    Kumar, Neeraj; Sharma, Upendra; Singh, Chitra; Singh, Bikram

    2012-01-01

    lacking. In this review, we will concisely describe the therapeutic aspects, metabolism and synthesis of thalidomide.

  3. Prophylaxis and therapeutic potential of ozone in buiatrics: Current knowledge.

    PubMed

    Đuričić, Dražen; Valpotić, Hrvoje; Samardžija, Marko

    2015-08-01

    Ozone therapy has been in use since 1896 in the USA. As a highly reactive molecule, ozone may inactivate bacteria, viruses, fungi, yeasts and protozoans, stimulate the oxygen metabolism of tissue, treat diseases, activate the immune system, and exhibit strong analgesic activity. More recently, ozone has been used in veterinary medicine, particularly in buiatrics, but still insufficiently. Medical ozone therapy has shown effectiveness as an alternative to the use of antibiotics, which are restricted to clinical use and have been withdrawn from non-clinical use as in-feed growth promoters in animal production. This review is an overview of current knowledge regarding the preventive and therapeutic effects of ozone in ruminants for the treatment of puerperal diseases and improvement in their fertility. In particular, ozone preparations have been tested in the treatment of reproductive tract lesions, urovagina and pneumomovagina, metritis, endometritis, fetal membrane retention and mastitis, as well as in the functional restoration of endometrium in dairy cows and goats. In addition, the preventive use of the intrauterine application of ozone has been assessed in order to evaluate its effectiveness in improving reproductive efficiency in dairy cows. No adverse effects were observed in cows and goats treated with ozone preparations. Moreover, there is a lot of evidence indicating the advantages of ozone preparation therapy in comparison to the application of antibiotics. However, there are certain limitations on ozone use in veterinary medicine and buiatrics, such as inactivity against intracellular microbes and selective activity against the same bacterial species, as well as the induction of tissue inflammation through inappropriate application of the preparation.

  4. The therapeutic potential of the cerebellum in schizophrenia

    PubMed Central

    Parker, Krystal L.; Narayanan, Nandakumar S.; Andreasen, Nancy C.

    2014-01-01

    The cognitive role of the cerebellum is critically tied to its distributed connections throughout the brain. Accumulating evidence from anatomical, structural and functional imaging, and lesion studies advocate a cognitive network involving indirect connections between the cerebellum and non-motor areas in the prefrontal cortex. Cerebellar stimulation dynamically influences activity in several regions of the frontal cortex and effectively improves cognition in schizophrenia. In this manuscript, we summarize current literature on the cingulocerebellar circuit and we introduce a method to interrogate this circuit combining opotogenetics, neuropharmacology, and electrophysiology in awake-behaving animals while minimizing incidental stimulation of neighboring cerebellar nuclei. We propose the novel hypothesis that optogenetic cerebellar stimulation can restore aberrant frontal activity and rescue impaired cognition in schizophrenia. We focus on how a known cognitive region in the frontal cortex, the anterior cingulate, is influenced by the cerebellum. This circuit is of particular interest because it has been confirmed using tracing studies, neuroimaging reveals its role in cognitive tasks, it is conserved from rodents to humans, and diseases such as schizophrenia and autism appear in its aberrancy. Novel tract tracing results presented here provide support for how these two areas communicate. The primary pathway involves a disynaptic connection between the cerebellar dentate nuclei (DN) and the anterior cingulate cortex. Secondarily, the pathway from cerebellar fastigial nuclei (FN) to the ventral tegmental area, which supplies dopamine to the prefrontal cortex, may play a role as schizophrenia characteristically involves dopamine deficiencies. We hope that the hypothesis described here will inspire new therapeutic strategies targeting currently untreatable cognitive impairments in schizophrenia. PMID:25309350

  5. Anti-Transcription Factor RNA Aptamers as Potential Therapeutics

    PubMed Central

    Mondragón, Estefanía

    2016-01-01

    Transcription factors (TFs) are DNA-binding proteins that play critical roles in regulating gene expression. These proteins control all major cellular processes, including growth, development, and homeostasis. Because of their pivotal role, cells depend on proper TF function. It is, therefore, not surprising that TF deregulation is linked to disease. The therapeutic drug targeting of TFs has been proposed as a frontier in medicine. RNA aptamers make interesting candidates for TF modulation because of their unique characteristics. The products of in vitro selection, aptamers are short nucleic acids (DNA or RNA) that bind their targets with high affinity and specificity. Aptamers can be expressed on demand from transgenes and are intrinsically amenable to recognition by nucleic acid-binding proteins such as TFs. In this study, we review several natural prokaryotic and eukaryotic examples of RNAs that modulate the activity of TFs. These examples include 5S RNA, 6S RNA, 7SK, hepatitis delta virus-RNA (HDV-RNA), neuron restrictive silencer element (NRSE)-RNA, growth arrest-specific 5 (Gas5), steroid receptor RNA activator (SRA), trophoblast STAT utron (TSU), the 3′ untranslated region of caudal mRNA, and heat shock RNA-1 (HSR1). We then review examples of unnatural RNA aptamers selected to inhibit TFs nuclear factor-kappaB (NF-κB), TATA-binding protein (TBP), heat shock factor 1 (HSF1), and runt-related transcription factor 1 (RUNX1). The field of RNA aptamers for DNA-binding proteins continues to show promise. PMID:26509637

  6. Microtubule-Stabilizing Agents as Potential Therapeutics for Neurodegenerative Disease

    PubMed Central

    Brunden, Kurt R.; Trojanowski, John Q.; Smith, Amos B.; Lee, Virginia M.-Y.; Ballatore, Carlo

    2014-01-01

    Microtubules (MTs)1, cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer’s disease, frontotemporal lobar degeneration, and Parkinson’s disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington’s disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders. PMID:24433963

  7. Microtubule-stabilizing agents as potential therapeutics for neurodegenerative disease.

    PubMed

    Brunden, Kurt R; Trojanowski, John Q; Smith, Amos B; Lee, Virginia M-Y; Ballatore, Carlo

    2014-09-15

    Microtubules (MTs), cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington's disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Therapeutic potential of HDL in cardioprotection and tissue repair.

    PubMed

    Van Linthout, Sophie; Frias, Miguel; Singh, Neha; De Geest, Bart

    2015-01-01

    Epidemiological studies support a strong association between high-density lipoprotein (HDL) cholesterol levels and heart failure incidence. Experimental evidence from different angles supports the view that low HDL is unlikely an innocent bystander in the development of heart failure. HDL exerts direct cardioprotective effects, which are mediated via its interactions with the myocardium and more specifically with cardiomyocytes. HDL may improve cardiac function in several ways. Firstly, HDL may protect the heart against ischaemia/reperfusion injury resulting in a reduction of infarct size and thus in myocardial salvage. Secondly, HDL can improve cardiac function in the absence of ischaemic heart disease as illustrated by beneficial effects conferred by these lipoproteins in diabetic cardiomyopathy. Thirdly, HDL may improve cardiac function by reducing infarct expansion and by attenuating ventricular remodelling post-myocardial infarction. These different mechanisms are substantiated by in vitro, ex vivo, and in vivo intervention studies that applied treatment with native HDL, treatment with reconstituted HDL, or human apo A-I gene transfer. The effect of human apo A-I gene transfer on infarct expansion and ventricular remodelling post-myocardial infarction illustrates the beneficial effects of HDL on tissue repair. The role of HDL in tissue repair is further underpinned by the potent effects of these lipoproteins on endothelial progenitor cell number, function, and incorporation, which may in particular be relevant under conditions of high endothelial cell turnover. Furthermore, topical HDL therapy enhances cutaneous wound healing in different models. In conclusion, the development of HDL-targeted interventions in these strategically chosen therapeutic areas is supported by a strong clinical rationale and significant preclinical data.

  9. Drug delivery to the testis: current status and potential pathways for the development of novel therapeutics.

    PubMed

    Snow-Lisy, Devon C; Samplaski, Mary K; Labhasetwar, Vinod; Sabanegh, Edmund S

    2011-10-01

    Nanotechnology has been increasingly utilized for the targeting and delivery of novel therapeutic agents to different tissues and cell types. The current therapeutic options for testicular disorders fall short in many instances due to difficulty traversing the blood-testis barrier, systemic toxicities, and complicated dosing regiments. For testicular tissue, potential targeting can be obtained either via anatomic methods or specific ligands such as luteinizing hormone or follicle-stimulating hormone analogs. Potential novel therapeutic agents include DNA, RNA, cytokines, peptide receptor antagonists, peptide receptor agonists, hormones, and enzymes. Nanotherapeutic treatment of testicular cancer, infertility, testicular torsion, orchalgia, hypogonadism, testicular infections, and cryptorchidism within the framework of potential target cells are an emerging area of research. While there are many potential applications of nanotechnology in drug delivery to the testis, this remains a relatively unexplored field. This review highlights the current status as well as potential future of nanotechnology in the development of novel therapeutics for testicular disorders.

  10. Multipotency and therapeutic potential of NG2 cells.

    PubMed

    Valny, Martin; Honsa, Pavel; Kriska, Jan; Anderova, Miroslava

    2017-10-01

    NG2 cells represent one of the most proliferative glial cell populations in the intact mammalian central nervous system (CNS). They are well-known for their ability to renew themselves or to generate new oligodendrocytes during development as well as in adulthood, therefore also being termed oligodendrocyte progenitor cells. Following CNS injuries, such as demyelination, trauma or ischemia, the proliferative capacity of NG2 cells rapidly increases and moreover, their differentiation potential broadens, as documented by numerous reports also describing their differentiation into astrocytes or even neurons. Here, we summarize the current knowledge about NG2 cells proliferation, their fate plasticity during embryogenesis as well as in postnatal CNS under physiological and pathological conditions, with the main emphasis on the role of various signaling molecules, growth factors, hormones or even neurotransmitters on the fate potential of NG2 cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Therapeutic potential of snake venom in cancer therapy: current perspectives.

    PubMed

    Vyas, Vivek Kumar; Brahmbhatt, Keyur; Bhatt, Hardik; Parmar, Utsav

    2013-02-01

    Many active secretions produced by animals have been employed in the development of new drugs to treat diseases such as hypertension and cancer. Snake venom toxins contributed significantly to the treatment of many medical conditions. There are many published studies describing and elucidating the anti-cancer potential of snake venom. Cancer therapy is one of the main areas for the use of protein peptides and enzymes originating from animals of different species. Some of these proteins or peptides and enzymes from snake venom when isolated and evaluated may bind specifically to cancer cell membranes, affecting the migration and proliferation of these cells. Some of substances found in the snake venom present a great potential as anti-tumor agent. In this review, we presented the main results of recent years of research involving the active compounds of snake venom that have anticancer activity.

  12. [Classic psychedelic drugs and their potential therapeutic effect].

    PubMed

    Bayat, Michael

    2017-09-11

    Over the past decade we have witnessed a renewed scientific interest in the classic hallucinogens (psychedelic drugs). These are substances which exert their effects by an agonist action on the 5-HT2A receptors. The purpose of this paper is to provide a short review and discussion of the psychedelic drugs, their safety profile and their potential antidepressive, anxiolytic and antiaddictive effects. The article primarily focusses on the most recent clinical trials.

  13. Monoclonal Antibody Shows Promise as Potential Therapeutic for MERS | Poster

    Cancer.gov

    A monoclonal antibody has proven effective in preventing Middle Eastern Respiratory Syndrome (MERS) in lab animals, suggesting further development as a potential intervention for the deadly disease in humans, according to new research. MERS is a newly emerged coronavirus first detected in humans in 2012. Most cases have occurred in the Middle East, but the disease has appeared elsewhere. In all, MERS has infected more than 1,700 individuals and killed more than 600, according to the World Health Organization. No vaccines or antiviral therapies currently exist. Several candidate vaccines are being developed, and some have been tested in animal models, a prerequisite to human clinical trials.

  14. Potential therapeutic use of herbal extracts in trypanosomiasis

    PubMed Central

    Teixeira, Thaise L; Teixeira, Samuel Cota; da Silva, Claudio Vieira; de Souza, Maria A

    2014-01-01

    The aim of the present study was to evaluate the effects of crude extracts from Handroanthus impetiginosa, Ageratum conyzoides, and Ruta graveolens on Leishmania amazonensis and Trypanosoma cruzi infection in vitro. The results showed that the extracts caused significant toxicity in promastigotes and trypomastigotes. A significant decrease in the rate of cell invasion by pretreated trypomastigotes and promastigotes was also observed. The extracts caused a significant reduction of the multiplication of intracellular amastigotes of both parasites. Therefore, these herbal extracts may be potential candidates for the development of drugs for the treatment of leishmaniasis and Chagas disease. PMID:24548158

  15. Monoclonal Antibody Shows Promise as Potential Therapeutic for MERS | Poster

    Cancer.gov

    A monoclonal antibody has proven effective in preventing Middle Eastern Respiratory Syndrome (MERS) in lab animals, suggesting further development as a potential intervention for the deadly disease in humans, according to new research. MERS is a newly emerged coronavirus first detected in humans in 2012. Most cases have occurred in the Middle East, but the disease has appeared elsewhere. In all, MERS has infected more than 1,700 individuals and killed more than 600, according to the World Health Organization. No vaccines or antiviral therapies currently exist. Several candidate vaccines are being developed, and some have been tested in animal models, a prerequisite to human clinical trials.

  16. Potential therapeutic use of herbal extracts in trypanosomiasis.

    PubMed

    Teixeira, Thaise L; Teixeira, Samuel Cota; da Silva, Claudio Vieira; de Souza, Maria A

    2014-01-01

    The aim of the present study was to evaluate the effects of crude extracts from Handroanthus impetiginosa, Ageratum conyzoides, and Ruta graveolens on Leishmania amazonensis and Trypanosoma cruzi infection in vitro. The results showed that the extracts caused significant toxicity in promastigotes and trypomastigotes. A significant decrease in the rate of cell invasion by pretreated trypomastigotes and promastigotes was also observed. The extracts caused a significant reduction of the multiplication of intracellular amastigotes of both parasites. Therefore, these herbal extracts may be potential candidates for the development of drugs for the treatment of leishmaniasis and Chagas disease.

  17. HDL and glucose metabolism: current evidence and therapeutic potential

    PubMed Central

    Siebel, Andrew L.; Heywood, Sarah Elizabeth; Kingwell, Bronwyn A.

    2015-01-01

    High-density lipoprotein (HDL) and its principal apolipoprotein A-I (ApoA-I) have now been convincingly shown to influence glucose metabolism through multiple mechanisms. The key clinically relevant observations are that both acute HDL elevation via short-term reconstituted HDL (rHDL) infusion and chronically raising HDL via a cholesteryl ester transfer protein (CETP) inhibitor reduce blood glucose in individuals with type 2 diabetes mellitus (T2DM). HDL may mediate effects on glucose metabolism through actions in multiple organs (e.g., pancreas, skeletal muscle, heart, adipose, liver, brain) by three distinct mechanisms: (i) Insulin secretion from pancreatic beta cells, (ii) Insulin-independent glucose uptake, (iii) Insulin sensitivity. The molecular mechanisms appear to involve both direct HDL signaling actions as well as effects secondary to lipid removal from cells. The implications of glucoregulatory mechanisms linked to HDL extend from glycemic control to potential anti-ischemic actions via increased tissue glucose uptake and utilization. Such effects not only have implications for the prevention and management of diabetes, but also for ischemic vascular diseases including angina pectoris, intermittent claudication, cerebral ischemia and even some forms of dementia. This review will discuss the growing evidence for a role of HDL in glucose metabolism and outline related potential for HDL therapies. PMID:26582989

  18. HDL and glucose metabolism: current evidence and therapeutic potential.

    PubMed

    Siebel, Andrew L; Heywood, Sarah Elizabeth; Kingwell, Bronwyn A

    2015-01-01

    High-density lipoprotein (HDL) and its principal apolipoprotein A-I (ApoA-I) have now been convincingly shown to influence glucose metabolism through multiple mechanisms. The key clinically relevant observations are that both acute HDL elevation via short-term reconstituted HDL (rHDL) infusion and chronically raising HDL via a cholesteryl ester transfer protein (CETP) inhibitor reduce blood glucose in individuals with type 2 diabetes mellitus (T2DM). HDL may mediate effects on glucose metabolism through actions in multiple organs (e.g., pancreas, skeletal muscle, heart, adipose, liver, brain) by three distinct mechanisms: (i) Insulin secretion from pancreatic beta cells, (ii) Insulin-independent glucose uptake, (iii) Insulin sensitivity. The molecular mechanisms appear to involve both direct HDL signaling actions as well as effects secondary to lipid removal from cells. The implications of glucoregulatory mechanisms linked to HDL extend from glycemic control to potential anti-ischemic actions via increased tissue glucose uptake and utilization. Such effects not only have implications for the prevention and management of diabetes, but also for ischemic vascular diseases including angina pectoris, intermittent claudication, cerebral ischemia and even some forms of dementia. This review will discuss the growing evidence for a role of HDL in glucose metabolism and outline related potential for HDL therapies.

  19. Therapeutic Potential of Pterocarpus santalinus L.: An Update

    PubMed Central

    Bulle, Saradamma; Reddyvari, Hymavathi; Nallanchakravarthula, Varadacharyulu; Vaddi, Damodara Reddy

    2016-01-01

    Recently there has been increasing interest in plants and plant-derived compounds as raw food and medicinal agents. In Ayurveda, an Indian system of traditional medicine, a wide spectrum of medicinal properties of Pterocarpus santalinus is described. Many important bioactive phytocompounds have been extracted and identified from the heartwood of P. santalinus. Bioactive compounds typically occur in small amounts and have more subtle effects than nutrients. These bioactive compounds influence cellular activities that modify the risk of disease rather than prevent deficiency diseases. A wide array of biological activities and potential health benefits of P. santalinus have been reported, including antioxidative, antidiabetic, antimicrobial, anticancer, and anti-inflammatory properties, and protective effects on the liver, gastric mucosa, and nervous system. All these protective effects were attributed to bioactive compounds present in P. santalinus. The major bioactive compounds present in the heartwood of P. santalinus are santalin A and B, savinin, calocedrin, pterolinus K and L, and pterostilbenes. The bioactive compounds have potentially important health benefits: These compounds can act as antioxidants, enzyme inhibitors and inducers, inhibitors of receptor activities, and inducers and inhibitors of gene expression, among other actions. The present review aims to understand the pharmacological effects of P. santalinus on health and disease with “up-to-date” discussion. PMID:27041873

  20. Therapeutic Potential of Pterocarpus santalinus L.: An Update.

    PubMed

    Bulle, Saradamma; Reddyvari, Hymavathi; Nallanchakravarthula, Varadacharyulu; Vaddi, Damodara Reddy

    2016-01-01

    Recently there has been increasing interest in plants and plant-derived compounds as raw food and medicinal agents. In Ayurveda, an Indian system of traditional medicine, a wide spectrum of medicinal properties of Pterocarpus santalinus is described. Many important bioactive phytocompounds have been extracted and identified from the heartwood of P. santalinus. Bioactive compounds typically occur in small amounts and have more subtle effects than nutrients. These bioactive compounds influence cellular activities that modify the risk of disease rather than prevent deficiency diseases. A wide array of biological activities and potential health benefits of P. santalinus have been reported, including antioxidative, antidiabetic, antimicrobial, anticancer, and anti-inflammatory properties, and protective effects on the liver, gastric mucosa, and nervous system. All these protective effects were attributed to bioactive compounds present in P. santalinus. The major bioactive compounds present in the heartwood of P. santalinus are santalin A and B, savinin, calocedrin, pterolinus K and L, and pterostilbenes. The bioactive compounds have potentially important health benefits: These compounds can act as antioxidants, enzyme inhibitors and inducers, inhibitors of receptor activities, and inducers and inhibitors of gene expression, among other actions. The present review aims to understand the pharmacological effects of P. santalinus on health and disease with "up-to-date" discussion.

  1. G-quadruplexes in viruses: function and potential therapeutic applications

    PubMed Central

    Métifiot, Mathieu; Amrane, Samir; Litvak, Simon; Andreola, Marie-Line

    2014-01-01

    G-rich nucleic acids can form non-canonical G-quadruplex structures (G4s) in which four guanines fold in a planar arrangement through Hoogsteen hydrogen bonds. Although many biochemical and structural studies have focused on DNA sequences containing successive, adjacent guanines that spontaneously fold into G4s, evidence for their in vivo relevance has recently begun to accumulate. Complete sequencing of the human genome highlighted the presence of ∼300 000 sequences that can potentially form G4s. Likewise, the presence of putative G4-sequences has been reported in various viruses genomes [e.g., Human immunodeficiency virus (HIV-1), Epstein–Barr virus (EBV), papillomavirus (HPV)]. Many studies have focused on telomeric G4s and how their dynamics are regulated to enable telomere synthesis. Moreover, a role for G4s has been proposed in cellular and viral replication, recombination and gene expression control. In parallel, DNA aptamers that form G4s have been described as inhibitors and diagnostic tools to detect viruses [e.g., hepatitis A virus (HAV), EBV, cauliflower mosaic virus (CaMV), severe acute respiratory syndrome virus (SARS), simian virus 40 (SV40)]. Here, special emphasis will be given to the possible role of these structures in a virus life cycle as well as the use of G4-forming oligonucleotides as potential antiviral agents and innovative tools. PMID:25332402

  2. 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

  3. Trauma and Stem Cells: Biology and Potential Therapeutic Implications

    PubMed Central

    Thurairajah, Kabilan; Broadhead, Matthew L.; Balogh, Zsolt J.

    2017-01-01

    Trauma may cause irreversible tissue damage and loss of function despite current best practice. Healing is dependent both on the nature of the injury and the intrinsic biological capacity of those tissues for healing. Preclinical research has highlighted stem cell therapy as a potential avenue for improving outcomes for injuries with poor healing capacity. Additionally, trauma activates the immune system and alters stem cell behaviour. This paper reviews the current literature on stem cells and its relevance to trauma care. Emphasis is placed on understanding how stem cells respond to trauma and pertinent mechanisms that can be utilised to promote tissue healing. Research involving notable difficulties in trauma care such as fracture non-union, cartilage damage and trauma induced inflammation is discussed further. PMID:28272352

  4. Trauma and Stem Cells: Biology and Potential Therapeutic Implications.

    PubMed

    Thurairajah, Kabilan; Broadhead, Matthew L; Balogh, Zsolt J

    2017-03-07

    Trauma may cause irreversible tissue damage and loss of function despite current best practice. Healing is dependent both on the nature of the injury and the intrinsic biological capacity of those tissues for healing. Preclinical research has highlighted stem cell therapy as a potential avenue for improving outcomes for injuries with poor healing capacity. Additionally, trauma activates the immune system and alters stem cell behaviour. This paper reviews the current literature on stem cells and its relevance to trauma care. Emphasis is placed on understanding how stem cells respond to trauma and pertinent mechanisms that can be utilised to promote tissue healing. Research involving notable difficulties in trauma care such as fracture non-union, cartilage damage and trauma induced inflammation is discussed further.

  5. 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.

  6. Nutraceuticals as potential therapeutic agents for colon cancer: a review.

    PubMed

    Kuppusamy, Palaniselvam; Yusoff, Mashitah M; Maniam, Gaanty Pragas; Ichwan, Solachuddin Jauhari Arief; Soundharrajan, Ilavenil; Govindan, Natanamurugaraj

    2014-06-01

    Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer׳s disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis.

  7. Brown adipose tissue in humans: therapeutic potential to combat obesity.

    PubMed

    Carey, Andrew L; Kingwell, Bronwyn A

    2013-10-01

    Harnessing the considerable capacity of brown adipose tissue (BAT) to consume energy was first proposed as a potential target to control obesity nearly 40years ago. The plausibility of this approach was, however, questioned due to the prevailing view that BAT was either not present or not functional in adult humans. Recent definitive identification of functional BAT in adult humans as well as a number of important advances in the understanding of BAT biology has reignited interest in BAT as an anti-obesity target. Proof-of-concept evidence demonstrating drug-induced BAT activation provides an important foundation for development of targeted pharmacological approaches with clinical application. This review considers evidence from both human and relevant animal studies to determine whether harnessing BAT for the treatment of obesity via pharmacological intervention is a realistic goal. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Nutraceuticals as potential therapeutic agents for colon cancer: a review

    PubMed Central

    Kuppusamy, Palaniselvam; Yusoff, Mashitah M.; Maniam, Gaanty Pragas; Ichwan, Solachuddin Jauhari Arief; Soundharrajan, Ilavenil; Govindan, Natanamurugaraj

    2014-01-01

    Colon cancer is a world-wide health problem and the second-most dangerous type of cancer, affecting both men and women. The modern diet and lifestyles, with high meat consumption and excessive alcohol use, along with limited physical activity has led to an increasing mortality rate for colon cancer worldwide. As a result, there is a need to develop novel and environmentally benign drug therapies for colon cancer. Currently, nutraceuticals play an increasingly important role in the treatment of various chronic diseases such as colon cancer, diabetes and Alzheimer׳s disease. Nutraceuticals are derived from various natural sources such as medicinal plants, marine organisms, vegetables and fruits. Nutraceuticals have shown the potential to reduce the risk of colon cancer and slow its progression. These dietary substances target different molecular aspects of colon cancer development. Accordingly, this review briefly discusses the medicinal importance of nutraceuticals and their ability to reduce the risk of colorectal carcinogenesis. PMID:26579381

  9. Therapeutic potential of autologous stem cell transplantation for cerebral palsy.

    PubMed

    Purandare, Chaitanya; Shitole, D G; Belle, Vaijayantee; Kedari, Aarti; Bora, Neeta; Joshi, Meghnad

    2012-01-01

    Background. Cerebral palsy (CP) is a severe disabling disease with worldwide incidence being 2 to 3 per 1000 live births. CP was considered as a noncurable, nonreparative disorder, but stem cell therapy offers a potential treatment for CP. Objective. The present study evaluates the safety and efficacy of autologous bone-marrow-derived mononuclear cell (BMMNCs) transplantation in CP patient. Material and Methods. In the present study, five infusions of autologous stem cells were injected intrathecally. Changes in neurological deficits and improvements in function were assessed using Gross Motor Function Classification System (GMFCS-E&R) scale. Results. Significant motor, sensory, cognitive, and speech improvements were observed. Bowel and bladder control has been achieved. On the GMFCS-E&R level, the patient was promoted from grade III to I. Conclusion. In this study, we report that intrathecal infusion of autologous BMMNCs seems to be feasible, effective, and safe with encouraging functional outcome improvements in CP patient.

  10. The potential for emerging therapeutic options for Clostridium difficile infection.

    PubMed

    Mathur, Harsh; Rea, Mary C; Cotter, Paul D; Ross, R Paul; Hill, Colin

    2014-01-01

    Clostridium difficile is mainly a nosocomial pathogen and is a significant cause of antibiotic-associated diarrhea. It is also implicated in the majority of cases of pseudomembranous colitis. Recently, advancements in next generation sequencing technology (NGS) have highlighted the extent of damage to the gut microbiota caused by broad-spectrum antibiotics, often resulting in C. difficile infection (CDI). Currently the treatment of choice for CDI involves the use of metronidazole and vancomycin. However, recurrence and relapse of CDI, even after rounds of metronidazole/vancomycin administration is a problem that must be addressed. The efficacy of alternative antibiotics such as fidaxomicin, rifaximin, nitazoxanide, ramoplanin and tigecycline, as well as faecal microbiota transplantation has been assessed and some have yielded positive outcomes against C. difficile. Some bacteriocins have also shown promising effects against C. difficile in recent years. In light of this, the potential for emerging treatment options and efficacy of anti-C. difficile vaccines are discussed in this review.

  11. Possible therapeutic potential of berberine in diabetic osteopathy.

    PubMed

    Rahigude, A B; Kaulaskar, S V; Bhutada, P S

    2012-10-01

    Diabetic osteopathy is a complication that leads to decreased bone mineral density, bone formation and having high risk of fractures that heals slowly. Diabetic osteopathy is a result of increase in osteoclastogenesis and decrease in osteoblastogenesis. Various factors viz., oxidative stress, increased inflammatory markers, PPAR-γ activation in osteoblast, activation of apoptotic pathway, increased glucose levels and inhibitory effect on parathyroid hormone etc. are mainly responsible for decreased bone mineral density. Berberine is an isoquinoline alkaloid widely used in Asian countries as a traditional medicine. Berberine is extensively reported to be an antioxidant, anti-inflammatory, antidiabetic, and having potential to treat diabetic complications and glucocorticoid induced osteoporosis. The osteoclastogenesis decreasing property of berberine can be hypothesized for inhibiting diabetic osteopathy. In addition, chronic treatment of berberine will be helpful for increasing the osteoblastic activity and expression of the modulators that affect osteoblastic differentiation. The apoptotic pathways stimulated due to increased inflammatory markers and nucleic acid damages could be reduced due to berberine. Another important consideration that berberine is having stimulatory effect on glucagon like peptide release and insulin sensitization that will be helpful for decreasing glucose levels and therefore, may exerts osteogenesis. Thiazolidinediones show bone loss due to activation of PPAR-γ in osteoblasts, whereas berberine stimulates PPAR-γ only in adipocytes and not in osteoblasts, and therefore the decreased bone loss due to use of thiazolidinediones may not be observed in berberine treatment conditions. Berberine decreases the advanced glycation end-products (AGE) formation in diabetic condition which will be ultimately helpful to decrease the stiffness of collagen fibers due to AGE-induced cross linking. Lastly, it is also reported that berberine has

  12. Anticancer therapeutic potential of Mn porphyrin/ascorbate system.

    PubMed

    Tovmasyan, Artak; Sampaio, Romulo S; Boss, Mary-Keara; Bueno-Janice, Jacqueline C; Bader, Bader H; Thomas, Milini; Reboucas, Julio S; Orr, Michael; Chandler, Joshua D; Go, Young-Mi; Jones, Dean P; Venkatraman, Talaignair N; Haberle, Sinisa; Kyui, Natalia; Lascola, Christopher D; Dewhirst, Mark W; Spasojevic, Ivan; Benov, Ludmil; Batinic-Haberle, Ines

    2015-12-01

    Ascorbate (Asc) as a single agent suppressed growth of several tumor cell lines in a mouse model. It has been tested in a Phase I Clinical Trial on pancreatic cancer patients where it exhibited no toxicity to normal tissue yet was of only marginal efficacy. The mechanism of its anticancer effect was attributed to the production of tumoricidal hydrogen peroxide (H2O2) during ascorbate oxidation catalyzed by endogenous metalloproteins. The amount of H2O2 could be maximized with exogenous catalyst that has optimized properties for such function and is localized within tumor. Herein we studied 14 Mn porphyrins (MnPs) which differ vastly with regards to their redox properties, charge, size/bulkiness and lipophilicity. Such properties affect the in vitro and in vivo ability of MnPs (i) to catalyze ascorbate oxidation resulting in the production of H2O2; (ii) to subsequently employ H2O2 in the catalysis of signaling proteins oxidations affecting cellular survival pathways; and (iii) to accumulate at site(s) of interest. The metal-centered reduction potential of MnPs studied, E1/2 of Mn(III)P/Mn(II)P redox couple, ranged from -200 to +350 mV vs NHE. Anionic and cationic, hydrophilic and lipophilic as well as short- and long-chained and bulky compounds were explored. Their ability to catalyze ascorbate oxidation, and in turn cytotoxic H2O2 production, was explored via spectrophotometric and electrochemical means. Bell-shape structure-activity relationship (SAR) was found between the initial rate for the catalysis of ascorbate oxidation, vo(Asc)ox and E1/2, identifying cationic Mn(III) N-substituted pyridylporphyrins with E1/2>0 mV vs NHE as efficient catalysts for ascorbate oxidation. The anticancer potential of MnPs/Asc system was subsequently tested in cellular (human MCF-7, MDA-MB-231 and mouse 4T1) and animal models of breast cancer. At the concentrations where ascorbate (1mM) and MnPs (1 or 5 µM) alone did not trigger any alteration in cell viability, combined

  13. Silibinin as a potential therapeutic for sulfur mustard injuries.

    PubMed

    Balszuweit, Frank; John, Harald; Schmidt, Annette; Kehe, Kai; Thiermann, Horst; Steinritz, Dirk

    2013-12-05

    Sulfur mustard (SM) is a vesicating chemical warfare agent causing skin blistering, ulceration, impaired wound healing, prolonged hospitalization and permanent lesions. Silibinin, the lead compound from Silybum marianum, has also been discussed as a potential antidote to SM poisoning. However, its efficacy has been demonstrated only with regard to nitrogen mustards. Moreover, there are no data on the efficacy of the water-soluble prodrug silibinin-bis-succinat (silibinin-BS). We investigated the effect of SIL-BS treatment against SM toxicity in HaCaT cells with regard to potential reduction of necrosis, apoptosis and inflammation including dose-dependency of any protective effects. We also demonstrated the biotransformation of the prodrug into free silibinin. HaCaT cells were exposed to SM (30, 100, and 300μM) for 30min and treated thereafter with SIL-BS (10, 50, and 100μM) for 24h. Necrosis and apoptosis were quantified using the ToxiLight BioAssay and the nucleosome ELISA (CDDE). Pro-inflammatory interleukins-6 and -8 were determined by ELISA. HaCaT cells, incubated with silibinin-BS were lysed and investigated by LC-ESI MS/MS. LC-ESI MS/MS results suggest that SIL-BS is absorbed by HaCaT cells and biotransformed into free silibinin. SIL-BS dose-dependently reduced SM cytotoxicity, even after 300μM exposure. Doses of 50-100μM silibinin-BS were required for significant protection. Apoptosis and interleukin production remained largely unchanged by 10-50μM silibinin-BS but increased after 100μM treatment. Observed reductions of SM cytotoxicity by post-exposure treatment with SIL-BS suggest this as a promising approach for treatment of SM injuries. While 100μM SIL-BS is most effective to reduce necrosis, 50μM may be safer to avoid pro-inflammatory effects. Pro-apoptotic effects after high doses of SIL-BS are in agreement with findings in literature and might even be useful to eliminate cells irreversibly damaged by SM. Further investigations will focus on the

  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. Honey: A Potential Therapeutic Agent for Managing Diabetic Wounds

    PubMed Central

    Islam, Md. Asiful; Gan, Siew Hua; Khalil, Md. Ibrahim

    2014-01-01

    Diabetic wounds are unlike typical wounds in that they are slower to heal, making treatment with conventional topical medications an uphill process. Among several different alternative therapies, honey is an effective choice because it provides comparatively rapid wound healing. Although honey has been used as an alternative medicine for wound healing since ancient times, the application of honey to diabetic wounds has only recently been revived. Because honey has some unique natural features as a wound healer, it works even more effectively on diabetic wounds than on normal wounds. In addition, honey is known as an “all in one” remedy for diabetic wound healing because it can combat many microorganisms that are involved in the wound process and because it possesses antioxidant activity and controls inflammation. In this review, the potential role of honey's antibacterial activity on diabetic wound-related microorganisms and honey's clinical effectiveness in treating diabetic wounds based on the most recent studies is described. Additionally, ways in which honey can be used as a safer, faster, and effective healing agent for diabetic wounds in comparison with other synthetic medications in terms of microbial resistance and treatment costs are also described to support its traditional claims. PMID:25386217

  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. The potential for emerging therapeutic options for Clostridium difficile infection

    PubMed Central

    Mathur, Harsh; Rea, Mary C; Cotter, Paul D; Ross, R Paul; Hill, Colin

    2014-01-01

    Clostridium difficile is mainly a nosocomial pathogen and is a significant cause of antibiotic-associated diarrhea. It is also implicated in the majority of cases of pseudomembranous colitis. Recently, advancements in next generation sequencing technology (NGS) have highlighted the extent of damage to the gut microbiota caused by broad-spectrum antibiotics, often resulting in C. difficile infection (CDI). Currently the treatment of choice for CDI involves the use of metronidazole and vancomycin. However, recurrence and relapse of CDI, even after rounds of metronidazole/vancomycin administration is a problem that must be addressed. The efficacy of alternative antibiotics such as fidaxomicin, rifaximin, nitazoxanide, ramoplanin and tigecycline, as well as faecal microbiota transplantation has been assessed and some have yielded positive outcomes against C. difficile. Some bacteriocins have also shown promising effects against C. difficile in recent years. In light of this, the potential for emerging treatment options and efficacy of anti-C. difficile vaccines are discussed in this review. PMID:25564777

  18. 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

  19. Therapeutic Potential of Tea Tree Oil for Scabies

    PubMed Central

    Thomas, Jackson; Carson, Christine F.; Peterson, Greg M.; Walton, Shelley F.; Hammer, Kate A.; Naunton, Mark; Davey, Rachel C.; Spelman, Tim; Dettwiller, Pascale; Kyle, Greg; Cooper, Gabrielle M.; Baby, Kavya E.

    2016-01-01

    Globally, scabies affects more than 130 million people at any time. In the developed world, outbreaks in health institutions and vulnerable communities result in a significant economic burden. A review of the literature demonstrates the emergence of resistance toward classical scabicidal treatments and the lack of effectiveness of currently available scabicides in reducing the inflammatory skin reactions and pyodermal progression that occurs in predisposed patient cohorts. Tea tree oil (TTO) has demonstrated promising acaricidal effects against scabies mites in vitro and has also been successfully used as an adjuvant topical medication for the treatment of crusted scabies, including cases that did not respond to standard treatments. Emerging acaricide resistance threatens the future usefulness of currently used gold standard treatments (oral ivermectin and topical permethrin) for scabies. The imminent development of new chemical entities is doubtful. The cumulative acaricidal, antibacterial, antipruritic, anti-inflammatory, and wound healing effects of TTO may have the potential to successfully reduce the burden of scabies infection and the associated bacterial complications. This review summarizes current knowledge on the use of TTO for the treatment of scabies. On the strength of existing data for TTO, larger scale, randomized controlled clinical trials are warranted. PMID:26787146

  20. 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.

  1. Therapeutic Potential of Tea Tree Oil for Scabies.

    PubMed

    Thomas, Jackson; Carson, Christine F; Peterson, Greg M; Walton, Shelley F; Hammer, Kate A; Naunton, Mark; Davey, Rachel C; Spelman, Tim; Dettwiller, Pascale; Kyle, Greg; Cooper, Gabrielle M; Baby, Kavya E

    2016-02-01

    Globally, scabies affects more than 130 million people at any time. In the developed world, outbreaks in health institutions and vulnerable communities result in a significant economic burden. A review of the literature demonstrates the emergence of resistance toward classical scabicidal treatments and the lack of effectiveness of currently available scabicides in reducing the inflammatory skin reactions and pyodermal progression that occurs in predisposed patient cohorts. Tea tree oil (TTO) has demonstrated promising acaricidal effects against scabies mites in vitro and has also been successfully used as an adjuvant topical medication for the treatment of crusted scabies, including cases that did not respond to standard treatments. Emerging acaricide resistance threatens the future usefulness of currently used gold standard treatments (oral ivermectin and topical permethrin) for scabies. The imminent development of new chemical entities is doubtful. The cumulative acaricidal, antibacterial, antipruritic, anti-inflammatory, and wound healing effects of TTO may have the potential to successfully reduce the burden of scabies infection and the associated bacterial complications. This review summarizes current knowledge on the use of TTO for the treatment of scabies. On the strength of existing data for TTO, larger scale, randomized controlled clinical trials are warranted. © The American Society of Tropical Medicine and Hygiene.

  2. A small peptide with therapeutic potential for inflammatory acne vulgaris.

    PubMed

    Zhang, Zhiye; Mu, Lixian; Tang, Jing; Duan, Zilei; Wang, Fengyu; Wei, Lin; Rong, Mingqiang; Lai, Ren

    2013-01-01

    A designed peptide named LZ1 with 15 amino acid residues containing strong antimicrobial activity against bacteria pathogens of acne vulgaris including Propionibacterium acnes, Staphylococcus epidermidis and S. aureus. Especially, it exerted strong anti-P. acnes ability. The minimal inhibitory concentration against three strains of P. acnes was only 0.6 µg/ml, which is 4 times lower than that of clindamycin. In experimental mice skin colonization model, LZ1 significantly reduced the number of P. acnes colonized on the ear, P. acnes-induced ear swelling, and inflammatory cell infiltration. It ameliorated inflammation induced by P. acnes by inhibiting the secretion of inflammatory factors including tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β. LZ1 showed little cytotoxicity on human keratinocyte and hemolytic activity on human blood red cells. Furthermore, LZ1 was very stable in human plasma. Combined with its potential bactericidal and anti-inflammatory properties, simple structure and high stability, LZ1 might be an ideal candidate for the treatment of acne.

  3. 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

  4. Geographic atrophy: clinical features and potential therapeutic approaches.

    PubMed

    Holz, Frank G; Strauss, Erich C; Schmitz-Valckenberg, Steffen; van Lookeren Campagne, Menno

    2014-05-01

    In contrast to wet age-related macular degeneration (AMD), where loss of vision is typically acute and treatment leads to a relatively rapid reduction in retinal fluid and subsequent improvements in visual acuity (VA), disease progression and vision loss in geographic atrophy (GA) owing to AMD are gradual processes. Although GA can result in significant visual function deficits in reading, night vision, and dark adaptation, and produce dense, irreversible scotomas in the visual field, the initial decline in VA may be relatively minor if the fovea is spared. Because best-corrected VA does not correlate well with GA lesions or progression, alternative clinical endpoints are being sought. These include reduction in drusen burden, slowing the enlargement rate of GA lesion area, and slowing or eliminating the progression of intermediate to advanced AMD. Among these considerations, slowing the expansion of the GA lesion area seems to be a clinically suitable primary efficacy endpoint. Because GA lesion growth is characterized by loss of photoreceptors, it is considered a surrogate endpoint for vision loss. Detection of GA can be achieved with a number of different imaging techniques, i