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Pharmaceuticals, Volume 4, Issue 11 (November 2011), Pages 1400-1517

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Research

Jump to: Review

Open AccessArticle Effects of the Ethyl Acetate Fraction of Alchornea triplinervia on Healing Gastric Ulcer in Rats
Pharmaceuticals 2011, 4(11), 1423-1433; doi:10.3390/ph4111423
Received: 14 October 2011 / Accepted: 17 October 2011 / Published: 25 October 2011
Cited by 3 | PDF Full-text (3202 KB) | HTML Full-text | XML Full-text
Abstract
Alchornea triplinervia (Spreng.) Muell. Arg (Euphorbiaceae) is a medicinal plant commonly used by people living in the Cerrado region of Brazil to treat gastrointestinal ulcers. We previously described the gastroprotective action of methanolic extract (ME) of Alchornea triplinervia and the ethyl acetate [...] Read more.
Alchornea triplinervia (Spreng.) Muell. Arg (Euphorbiaceae) is a medicinal plant commonly used by people living in the Cerrado region of Brazil to treat gastrointestinal ulcers. We previously described the gastroprotective action of methanolic extract (ME) of Alchornea triplinervia and the ethyl acetate fraction (EAF) in increasing of prostaglandin E2 (PGE2) gastric levels in the mucosa. In this work we evaluated the effect of EAF in promoting the healing process in rats with acetic acid-induced gastric ulcers. In addition, toxicity was investigated during treatment with EAF. After 14 days of treatment with EAF, the potent stimulator of gastric cell proliferation contributed to the acceleration of gastric ulcer healing. Upon immunohistochemical analysis, we observed a pronounced expression of COX-2, mainly in the submucosal layer. The 14-day EAF treatment also significantly increased the number of neutrophils in the gastric mucosa regeneration area. The EAF induced angiogenesis on gastric mucosa, observed as an increase of the number of blood vessels supplying the stomach in rats treated with EAF. Oral administration for 14 days of the ethyl acetate fraction from Alchornea triplinervia accelerated the healing of gastric ulcers in rats by promoting epithelial cell proliferation, increasing the number of neutrophils and stimulation of mucus production. This fraction, which contained mainly phenolic compounds, contributed to gastric mucosa healing. Full article
Open AccessArticle Photodynamic Therapy with Hypericin Improved by Targeting HSP90 Associated Proteins
Pharmaceuticals 2011, 4(11), 1488-1502; doi:10.3390/ph4111488
Received: 1 September 2011 / Revised: 1 November 2011 / Accepted: 7 November 2011 / Published: 10 November 2011
Cited by 2 | PDF Full-text (322 KB) | HTML Full-text | XML Full-text
Abstract
In this study we have focused on the response of SKBR-3 cells to both single 17-DMAG treatment as well as its combination with photodynamic therapy with hypericin. Low concentrations of 17-DMAG without any effect on survival of SKBR-3 cells significantly reduced metabolic [...] Read more.
In this study we have focused on the response of SKBR-3 cells to both single 17-DMAG treatment as well as its combination with photodynamic therapy with hypericin. Low concentrations of 17-DMAG without any effect on survival of SKBR-3 cells significantly reduced metabolic activity, viability and cell number when combined with photodynamic therapy with hypericin. Moreover, IC10 concentation of 17-DMAG resulted in significant increase of SKBR-3 cells in G1 phase of the cell cycle, followed by an increase of cells in G2 phase when combined with photodynamic therapy. Furthermore, 17-DMAG already decreased HER2, Akt, P-Erk1/2 and survivin protein levels in SKBR-3 cells a short time after its application. In this regard, 17-DMAG protected also SKBR-3 cells against both P-Erk1/2 as well as survivin upregulations induced by photodynamic therapy with hypericin. Interestingly, IC10 concentration of 17-DMAG led to total depletion of Akt, P-Erk1/2 proteins and to decrease of survivin level at 48 h. On the other hand, 17-DMAG did not change HER2 relative expression in SKBR-3 cells, but caused a significant decrease of HER2 mRNA in MCF-7 cells characterized by low HER2 expression. These results show that targeting HSP90 client proteins increases the efficiency of antineoplastic effect of photodynamic therapy in vitro. Full article
(This article belongs to the Special Issue Hsp90 Inhibitors)
Open AccessArticle Real-Time Translocation and Function of PKCβII Isoform in Response to Nociceptive Signaling via the TRPV1 Pain Receptor
Pharmaceuticals 2011, 4(11), 1503-1517; doi:10.3390/ph4111503
Received: 12 October 2011 / Revised: 26 October 2011 / Accepted: 7 November 2011 / Published: 11 November 2011
Cited by 1 | PDF Full-text (1086 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Serine/threonine protein kinase C βII isoform (PKCβII) or the pain receptor transient receptor potential vanilloid 1 (TRPV1) have been separately implicated in mediating heat hyperalgesia during inflammation or diabetic neuropathy. However, detailed information on the role of PKC βII in nociceptive signaling [...] Read more.
Serine/threonine protein kinase C βII isoform (PKCβII) or the pain receptor transient receptor potential vanilloid 1 (TRPV1) have been separately implicated in mediating heat hyperalgesia during inflammation or diabetic neuropathy. However, detailed information on the role of PKC βII in nociceptive signaling mediated by TRPV1 is lacking. This study presents evidence for activation and translocation of the PKC βII isoform as a signaling event in nociception mediated by activation of TRPV1 by capsaicin. We show that capsaicin induces translocation of cytosolic PKCβII isoform fused with enhanced green fluorescence protein (PKCβII-EGFP) in dorsal root ganglion (DRG) neurons. We also show capsaicin-induced translocation in Chinese Hamster Ovarian (CHO) cells co-transfected with TRPV1 and PKCβII-EGFP, but not in CHO cells expressing PKCβII-EGFP alone. By contrast, the PKC activator phorbol-12-myristate-13-acetate (PMA) induced translocation of PKCβII-EGFP which was sustained and independent of calcium or TRPV1. In addition PMA-induced sensitization of TRPV1 to capsaicin response in DRG neurons was attenuated by PKCβII blocker CGP 53353. Capsaicin response via TRPV1 in the DRG neurons was confirmed by TRPV1 antagonist AMG 9810. These results suggested a novel and potential signaling link between PKCβII and TRPV1. These cell culture models provide a platform for investigating mechanisms of painful neuropathies mediated by nociceptors expressing the pain sensing gene TRPV1, and its regulation by the PKC isoform PKCβII. Full article
(This article belongs to the Special Issue Emerging Pain Targets and Therapy)

Review

Jump to: Research

Open AccessReview Mechanisms of Resistance to Hsp90 Inhibitor Drugs: A Complex Mosaic Emerges
Pharmaceuticals 2011, 4(11), 1400-1422; doi:10.3390/ph4111400
Received: 31 August 2011 / Revised: 4 October 2011 / Accepted: 17 October 2011 / Published: 25 October 2011
Cited by 15 | PDF Full-text (384 KB) | HTML Full-text | XML Full-text
Abstract
The molecular chaperone Hsp90 holds great promise as a cancer drug target, despite some of the initial clinical trials of Hsp90 inhibitor drugs having not lived up to expectation. Effective use of these drugs will benefit greatly from a much more detailed [...] Read more.
The molecular chaperone Hsp90 holds great promise as a cancer drug target, despite some of the initial clinical trials of Hsp90 inhibitor drugs having not lived up to expectation. Effective use of these drugs will benefit greatly from a much more detailed understanding of the factors that contribute to resistance, whether intrinsic or acquired. We review how cell culture studies have revealed a number of different mechanisms whereby cells can be rendered less susceptible to the effects of Hsp90 inhibitor treatment. A major influence is Hsp90 inhibition causing strong induction of the heat shock response, a stress response that increases cellular levels of prosurvival chaperones such as Hsp27 and Hsp70. Another problem seems to be that these inhibitors do not always access the Hsp90 proteins of the mitochondrion, forms of Hsp90 that—in cancer cells—are operating to suppress apoptosis. It should be possible to overcome these drawbacks through the appropriate drug redesign or with the combinatorial use of an Hsp90 inhibitor with a drug that targets either heat shock factor or the chaperone Hsp70. Still though, cells will often differ in the key antiapoptotic versus proapoptotic activities that are dependent on Hsp90, in the key steps in their apoptotic pathways responsive to Hsp90 inhibition or Hsp70 level, as well as the extents to which their survival is dependent on oncogenic tyrosine kinases that are clients of Hsp90. A systems approach will therefore often be required in order to establish the most prominent effects of Hsp90 inhibition in each type of cancer cell. Full article
(This article belongs to the Special Issue Hsp90 Inhibitors)
Open AccessReview Coupling Aptamers to Short Interfering RNAs as Therapeutics
Pharmaceuticals 2011, 4(11), 1434-1449; doi:10.3390/ph4111434
Received: 22 September 2011 / Revised: 13 October 2011 / Accepted: 24 October 2011 / Published: 27 October 2011
Cited by 4 | PDF Full-text (254 KB) | HTML Full-text | XML Full-text
Abstract
RNA-based approaches are among the most promising strategies aimed at developing safer and more effective therapeutics. RNA therapeutics include small non-coding miRNAs, small interfering RNA, RNA aptamers and more recently, small activating RNAs. However, major barriers exist to the use of RNAs [...] Read more.
RNA-based approaches are among the most promising strategies aimed at developing safer and more effective therapeutics. RNA therapeutics include small non-coding miRNAs, small interfering RNA, RNA aptamers and more recently, small activating RNAs. However, major barriers exist to the use of RNAs as therapeutics such as resistance to nucleases present in biological fluids, poor chemical stability, need of specific cell targeted delivery and easy entry into the cell. Such issues have been addressed by several recent reports that show the possibility of introducing chemical modifications in small RNAs to stabilize the molecular conformation and increase by several fold their integrity, while still preserving the functional activity. Further, several aptamers have been developed as excellent candidates for the specific recognition of cell surface targets. In the last few years, by taking advantage of recent advances in the small RNA field, molecular bioconjugates have been designed that permit specific targeting and may act as cargoes for cell internalization of small RNAs acting on gene expression that will be discussed in this review. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
Open AccessReview Anti-Inflammatory Drug Design Using a Molecular Hybridization Approach
Pharmaceuticals 2011, 4(11), 1450-1474; doi:10.3390/ph4111450
Received: 8 August 2011 / Revised: 20 October 2011 / Accepted: 20 October 2011 / Published: 27 October 2011
Cited by 16 | PDF Full-text (787 KB) | HTML Full-text | XML Full-text
Abstract
The design of new drugs with better physiochemical properties, adequate absorption, distribution, metabolism, and excretion, effective pharmacologic potency and lacking toxicity remains is a challenge. Inflammation is the initial trigger of several different diseases, such as Alzheimer’s disease, asthma, atherosclerosis, colitis, rheumatoid [...] Read more.
The design of new drugs with better physiochemical properties, adequate absorption, distribution, metabolism, and excretion, effective pharmacologic potency and lacking toxicity remains is a challenge. Inflammation is the initial trigger of several different diseases, such as Alzheimer’s disease, asthma, atherosclerosis, colitis, rheumatoid arthritis, depression, cancer; and disorders such as obesity and sexual dysfunction. Although inflammation is not the direct cause of these disorders, inflammatory processes often increase related pain and suffering. New anti-inflammatory drugs developed using molecular hybridization techniques to obtain multiple-ligand drugs can act at one or multiple targets, allowing for synergic action and minimizing toxicity. This work is a review of new anti-inflammatory drugs developed using the molecular modification approach. Full article
(This article belongs to the Special Issue Advances in Drug Design)
Figures

Open AccessReview Therapeutic Interchange of Parenteral Anticoagulants: Challenges for Pharmacy and Therapeutics Committees
Pharmaceuticals 2011, 4(11), 1475-1487; doi:10.3390/ph4111475
Received: 13 September 2011 / Revised: 22 October 2011 / Accepted: 24 October 2011 / Published: 7 November 2011
PDF Full-text (205 KB) | HTML Full-text | XML Full-text
Abstract
This is a review of key factors for pharmacy and therapeutics committees to consider when developing a therapeutic interchange (TI) program for venous thromboembolism (VTE) prophylaxis. Recent patient safety initiatives aimed at reducing the incidence of hospital-acquired VTE may increase the prescribing [...] Read more.
This is a review of key factors for pharmacy and therapeutics committees to consider when developing a therapeutic interchange (TI) program for venous thromboembolism (VTE) prophylaxis. Recent patient safety initiatives aimed at reducing the incidence of hospital-acquired VTE may increase the prescribing of thromboprophylactic agents recommended in VTE management guidelines. As a result, more pharmacy and therapeutics committees may consider TI programs for parenteral anticoagulants. However, the TI of anticoagulants appears challenging at this time. Firstly, the therapeutic equivalence of the commonly prescribed parenteral anticoagulants, enoxaparin, dalteparin and fondaparinux, has not been established. Secondly, because of the wide range of clinical indications for these anticoagulants, a blanket agent-specific TI program could lead to off-label use. Use of an indication-specific TI program could be difficult to manage administratively, and may cause prescribing confusion and errors. Thirdly, careful dosing and contraindications of certain parenteral anticoagulants in special patient populations, such as those with renal impairment, further impact the suitability of these agents for inclusion in TI programs. Finally, although TI may appear to offer lower drug-acquisition costs, it is important to determine its effect on all cost parameters and ultimately ensure that the care of patients requiring VTE prophylaxis is not compromised. Full article
(This article belongs to the Special Issue Anticoagulants)

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