Pharmaceuticals

476 KiB

Open AccessArticle

Vasoinhibins Prevent Bradykinin-Stimulated Endothelial Cell Proliferation by Inactivating eNOS via Reduction of both Intracellular Ca²⁺ Levels and eNOS Phosphorylation at Ser¹¹⁷⁹

by Stéphanie Thebault, Carmen González, Celina García, David Arredondo Zamarripa, Gabriel Nava, Luis Vaca, Fernando López-Casillas, Gonzalo Martínez De la Escalera and Carmen Clapp

Pharmaceuticals 2011, 4(7), 1052-1069; https://doi.org/10.3390/ph4071052 - 20 Jul 2011

Cited by 11 | Viewed by 8734

Abstract

Vasoinhibins, a family of antiangiogenic peptides derived from prolactin proteolysis, inhibit the vascular effects of several proangiogenic factors, including bradykinin (BK). Here, we report that vasoinhibins block the BK-induced proliferation of bovine umbilical vein endothelial cells. This effect is mediated by the inactivation [...] Read more.

Vasoinhibins, a family of antiangiogenic peptides derived from prolactin proteolysis, inhibit the vascular effects of several proangiogenic factors, including bradykinin (BK). Here, we report that vasoinhibins block the BK-induced proliferation of bovine umbilical vein endothelial cells. This effect is mediated by the inactivation of endothelial nitric oxide synthase (eNOS), as the NO donor DETA-NONOate reverted vasoinhibin action. It is an experimentally proven fact that the elevation of intracellular Ca²⁺ levels ([Ca²⁺]_i) upon BK stimulation activates eNOS, and vasoinhibins blocked the BK-mediated activation of phospholipase C and the formation of inositol 1,4,5-triphosphate leading to a reduced release of Ca²⁺ from intracellular stores. The [Ca²⁺]_i rise evoked by BK also involves the influx of extracellular Ca²⁺ via canonical transient receptor potential (TRPC) channels. Vasoinhibins likely interfere with TRPC-mediated Ca²⁺ entry since La³⁺, which is an enhancer of TRPC4 and TRPC5 channel activity, prevented vasoinhibins from blocking the stimulation by BK of endothelial cell NO production and proliferation, and vasoinhibins reduced the BK-induced increase of TRPC5 mRNA expression. Finally, vasoinhibins prevented the BK-induced phosphorylation of eNOS at Ser¹¹⁷⁹, a post-translational modification that facilitates Ca²⁺-calmodulin activation of eNOS. Together, our data show that vasoinhibins, by lowering NO production through the inhibition of both [Ca²⁺]_i mobilization and eNOS phosphorylation, prevent the BK-induced stimulation of endothelial cell proliferation. Thus, vasoinhibins help to regulate BK effects on angiogenesis and vascular homeostasis. Full article

(This article belongs to the Special Issue Angiogenesis Inhibitors)

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654 KiB

Open AccessArticle

The Uses of 2-Ethoxy-(4H)-3,1-benzoxazin-4-one in the Synthesis of Some Quinazolinone Derivatives of Antimicrobial Activity

by Maher A. El-Hashash, Khalid M. Darwish, Sameh A. Rizk and Fakhry A. El-Bassiouny

Pharmaceuticals 2011, 4(7), 1032-1051; https://doi.org/10.3390/ph4071032 - 14 Jul 2011

Cited by 23 | Viewed by 6955

Abstract

The behavior of 2-ethoxy-(4H)-3,1-benzoxazin-4-one (1) towards nitrogen nucleo-philes, e.g. ethanolamine, aromatic amines (namely: p-toluidine, p-anisidine, p-hydroxyaniline, o-hydroxyaniline, o-bromoaniline, o-phenylenediamine, p-phenylene- diamine, o-tolidinediamine) p-aminobenzoic acid, glucosamine hydrochloride, 2-amino- nicotinic acid, 1-naphthalenesulfonic [...] Read more.

The behavior of 2-ethoxy-(4H)-3,1-benzoxazin-4-one (1) towards nitrogen nucleo-philes, e.g. ethanolamine, aromatic amines (namely: p-toluidine, p-anisidine, p-hydroxyaniline, o-hydroxyaniline, o-bromoaniline, o-phenylenediamine, p-phenylene- diamine, o-tolidinediamine) p-aminobenzoic acid, glucosamine hydrochloride, 2-amino- nicotinic acid, 1-naphthalenesulfonic acid hydrazide, n-decanoic acid hydrazide, benzoic acid hydrazide, semicarbazide, aminoacids (e.g. D,L-alanine, L-asparagine, L-arginine) and derivatives of 2-aminothiodiazole has been investigated. The behavior of the benzoxazinone towards a selected sulfur nucleophile, L-cysteine, has also been discussed. Formation of an amidine salt as a reaction intermediate has been assumed. The effect of solvent in some reactions has been elucidated. The structures of all the novel quinazoline and quinazolinone derivatives, obtained by heterocyclic ring opening and ring closure were inferred by the IR, MS as well as ¹H-NMR spectral analysis. Moreover, the antimicrobial potential of some of the new synthesized derivatives has been evaluated. Full article

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67 KiB

Open AccessReview

Echinacea—A Source of Potent Antivirals for Respiratory Virus Infections

by James Hudson and Selvarani Vimalanathan

Pharmaceuticals 2011, 4(7), 1019-1031; https://doi.org/10.3390/ph4071019 - 13 Jul 2011

Cited by 48 | Viewed by 15004

Abstract

Extracts of Echinacea species have been used traditionally in North America for the control of symptoms of colds, influenza, and other diseases, and some of them have become very popular as “herbal medicines”. Recent studies have revealed that preparations derived from certain species [...] Read more.

Extracts of Echinacea species have been used traditionally in North America for the control of symptoms of colds, influenza, and other diseases, and some of them have become very popular as “herbal medicines”. Recent studies have revealed that preparations derived from certain species and plant parts, but not all of them, possess potent antiviral activities, at non-cytotoxic concentrations, particularly against membrane-containing viruses. Thus all strains of human and avian influenza viruses tested (including a Tamiflu-resistant strain), as well as herpes simplex virus, respiratory syncytial virus, and rhinoviruses, were very sensitive to a standardized Echinacea purpurea preparation. In mechanistic studies the influenza virus-specific hemagglutinin and neuraminidase were inhibited. In addition some extracts displayed anti-inflammatory activity in virus-infected cells, and numerous other effects on the expression of cellular genes. Multiple components, either discrete compounds or mixtures, appeared to be responsible for the various antiviral activities. Full article

(This article belongs to the Special Issue Antivirals)

401 KiB

Open AccessReview

Methylenedioxymethamphetamine (MDMA, 'Ecstasy'): Neurodegeneration versus Neuromodulation

by Elena Puerta and Norberto Aguirre

Pharmaceuticals 2011, 4(7), 992-1018; https://doi.org/10.3390/ph4070992 - 5 Jul 2011

Cited by 5 | Viewed by 17976

Abstract

The amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is widely abused as a recreational drug due to its unique psychological effects. Of interest, MDMA causes long-lasting deficits in neurochemical and histological markers of the serotonergic neurons in the brain of different animal species. Such deficits [...] Read more.

The amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is widely abused as a recreational drug due to its unique psychological effects. Of interest, MDMA causes long-lasting deficits in neurochemical and histological markers of the serotonergic neurons in the brain of different animal species. Such deficits include the decline in the activity of tryptophan hydroxylase in parallel with the loss of 5-HT and its main metabolite 5-hydoxyindoleacetic acid (5-HIAA) along with a lower binding of specific ligands to the 5-HT transporters (SERT). Of concern, reduced 5-HIAA levels in the CSF and SERT density have also been reported in human ecstasy users, what has been interpreted to reflect the loss of serotonergic fibers and terminals. The neurotoxic potential of MDMA has been questioned in recent years based on studies that failed to show the loss of the SERT protein by western blot or the lack of reactive astrogliosis after MDMA exposure. In addition, MDMA produces a long-lasting down-regulation of SERT gene expression; which, on the whole, has been used to invoke neuromodulatory mechanisms as an explanation to MDMA-induced 5-HT deficits. While decreased protein levels do not necessarily reflect neurodegeneration, the opposite is also true, that is, neuroregulatory mechanisms do not preclude the existence of 5-HT terminal degeneration. Full article

(This article belongs to the Special Issue Drug Abuse Targets)

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156 KiB

Open AccessReview

Psychostimulant Drugs and Neuroplasticity

by Emilio Fernandez-Espejo and Nieves Rodriguez-Espinosa

Pharmaceuticals 2011, 4(7), 976-991; https://doi.org/10.3390/ph4070976 - 30 Jun 2011

Cited by 11 | Viewed by 9742

Abstract

Drugs of abuse induce plastic changes in the brain that seem to underlie addictive phenomena. These plastic changes can be structural (morphological) or synaptic (biochemical), and most of them take place in the mesolimbic and mesostriatal circuits. Several addiction-related changes in brain circuits [...] Read more.

Drugs of abuse induce plastic changes in the brain that seem to underlie addictive phenomena. These plastic changes can be structural (morphological) or synaptic (biochemical), and most of them take place in the mesolimbic and mesostriatal circuits. Several addiction-related changes in brain circuits (hypofrontality, sensitization, tolerance) as well as the outcome of treatment have been visualized in addicts to psychostimulants using neuroimaging techniques. Repeated exposure to psychostimulants induces morphological changes such as increase in the number of dendritic spines, changes in the morphology of dendritic spines, and altered cellular coupling through new gap junctions. Repeated exposure to psychostimulants also induces various synaptic adaptations, many of them related to sensitization and neuroplastic processes, that include up- or down-regulation of D1, D2 and D3 dopamine receptors, changes in subunits of G proteins, increased adenylyl cyclase activity, cyclic AMP and protein kinase A in the nucleus accumbens, increased tyrosine hydroxylase enzyme activity, increased calmodulin and activated CaMKII in the ventral tegmental area, and increased deltaFosB, c-Fos and AP-1 binding proteins. Most of these changes are transient, suggesting that more lasting plastic brain adaptations should take place. In this context, protein synthesis inhibitors block the development of sensitization to cocaine, indicating that rearrangement of neural networks must develop for the long-lasting plasticity required for addiction to occur. Self-administration studies indicate the importance of glutamate neurotransmission in neuroplastic changes underlying transition from use to abuse. Finally, plastic changes in the addicted brain are enhanced and aggravated by neuroinflammation and neurotrophic disbalance after repeated psychostimulants. Full article

(This article belongs to the Special Issue Drug Abuse Targets)

262 KiB

Open AccessArticle

Spectrophotometric Determination of Metoprolol Tartrate in Pharmaceutical Dosage Forms on Complex Formation with Cu(II)

by Mustafa Cesme, Derya Tarinc and Aysegul Golcu

Pharmaceuticals 2011, 4(7), 964-975; https://doi.org/10.3390/ph4070964 - 28 Jun 2011

Cited by 19 | Viewed by 10761

Abstract

A new, simple, sensitive and accurate spectrophotometric method has been developed for the assay of metoprolol tartrate (MPT), which is based on the complexation of drug with copper(II) [Cu(II)] at pH 6.0, using Britton-Robinson buffer solution, to produce a blue adduct. The latter [...] Read more.

A new, simple, sensitive and accurate spectrophotometric method has been developed for the assay of metoprolol tartrate (MPT), which is based on the complexation of drug with copper(II) [Cu(II)] at pH 6.0, using Britton-Robinson buffer solution, to produce a blue adduct. The latter has a maximum absorbance at 675 nm and obeys Beer’s law within the concentration range 8.5-70 mg/mL. Regression analysis of the calibration data showed a good correlation coefficient (r = 0.998) with a limit of detection of 5.56 mg/mL. The proposed procedure has been successfully applied to the determination of this drug in its tablets. In addition, the spectral data and stability constant for the binuclear copper(II) complex of MPT (Cu₂MPT₂Cl₂) have been reported. Full article

(This article belongs to the Special Issue Betablockers)

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269 KiB

Open AccessArticle

Monoclonal Antibodies against Small Molecule Natural Products and Their Applications, Eastern Blotting and Knockout Extract

by Yukihiro Shoyama

Pharmaceuticals 2011, 4(7), 950-963; https://doi.org/10.3390/ph4070950 - 28 Jun 2011

Cited by 4 | Viewed by 8192

Abstract

To determine the hapten number in hapten-carrier protein conjugate matrix-assisted laser desorption/ionization (MALDI) tof mass spectrometry was applied. Highly specific anti-ginsenoside Rb₁ and Rg₁ monoclonal antibodies (MAbs) were prepared. Ginsenosides were developed on thin layer chromatography (TLC) plates which were covered [...] Read more.

To determine the hapten number in hapten-carrier protein conjugate matrix-assisted laser desorption/ionization (MALDI) tof mass spectrometry was applied. Highly specific anti-ginsenoside Rb₁ and Rg₁ monoclonal antibodies (MAbs) were prepared. Ginsenosides were developed on thin layer chromatography (TLC) plates which were covered by a polyvinylidene difluoride (PVDF) membrane resulting in blotting. The membrane was treated with NaIO₄ solution to release the aldehyde group on the sugar moiety of the ginsenosides. By treatment of the membrane with a protein solution the ginsenoside-protein conjugation as a Schiff-base occurred, which can function to fix it to the PVDF membrane. A part of the ginsenoside aglycone was reacted with anti-ginsenoside Rb₁ MAb, secondary MAb conjugated with enzyme and finally a substrate was added, resulting in a specific and highly sensitive staining that we named Eastern blotting. Furthermore, it makes one-step isolation of ginsenoside Rb₁ possible using an immuno-affinity column conjugated with anti-ginsenoside Rb₁ MAb. Furthermore, immunoaffinity concentration was carried out allowing high sensitivity analysis of lower concentrations of ginsenoside Rb₁ so that several unknown bands could be structurally determined. Full article

(This article belongs to the Special Issue Monoclonal Antibody)

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Pharmaceuticals, Volume 4, Issue 7 (July 2011) – 7 articles , Pages 950-1069

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